WO2014190533A1 - Platinum ligand and complex thereof - Google Patents
Platinum ligand and complex thereof Download PDFInfo
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- WO2014190533A1 WO2014190533A1 PCT/CN2013/076528 CN2013076528W WO2014190533A1 WO 2014190533 A1 WO2014190533 A1 WO 2014190533A1 CN 2013076528 W CN2013076528 W CN 2013076528W WO 2014190533 A1 WO2014190533 A1 WO 2014190533A1
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 16
- 239000003446 ligand Substances 0.000 title claims abstract description 14
- 230000008685 targeting Effects 0.000 claims abstract description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 229960004316 cisplatin Drugs 0.000 claims description 38
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 26
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 18
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 18
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- 229940041181 antineoplastic drug Drugs 0.000 claims description 14
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- 239000003795 chemical substances by application Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229960004562 carboplatin Drugs 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 4
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 4
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
Definitions
- the present invention generally relates to a conjugate, and more particularly to a targeting conjugate.
- Tumors especially malignant tumors, directly affect human health and life, and bring enormous economic burden to society and patients.
- the incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%.
- China's cancer spectrum presents new characteristics. It has both the developed countries and the dual characteristics of developing countries, that is, the double burden of malignant tumors.
- the top five incidences of malignant tumors in China were lung cancer, stomach cancer, and colorectal. Cancer, liver cancer, breast cancer [ 1–3] .
- the incidence of lung cancer increased from 1.63% to 3% in 1988-2005.
- the number of new cases of lung cancer increased by 120,000 between 2000 and 2005 [4] , and its morbidity and mortality increased year by year.
- the prognosis of lung cancer is closely related to clinical stage.
- the overall 5-year survival rate of patients with stage I-IV is only about 15%.
- the main cause of lung cancer mortality is late detection, most patients are detected in the late stage of lung cancer or even after distant metastasis [5] .
- cytotoxic drugs such as cisplatin, carboplatin, oxaliplatin and other synthetic cisplatin compounds, such as vinblastine and paclitaxel.
- cytotoxic drugs also have serious side effects while killing cancer cells. This side effect includes, but is not limited to, severe adverse effects such as myelosuppression, gastrointestinal reactions, and neurotoxicity, which limits the clinical utility of such drugs.
- Cisplatin was first discovered by American physiologist Rosenberg B. It is a heavy metal complex with divalent platinum combined with two chlorine atoms and two ammonia molecules. It is similar to a bifunctional alkylating agent and acts on hypoxic cells. The human body diffuses through the charged cell membrane, first dissociates the contained chlorine, and then forms a cross-link between the 6 and 7 positions of the guanine in the DNA molecule, or forms two points within the DNA single strand with adenine and cytosine. The cross-linking may also form a cross-link between the double strands, thereby disrupting the structure and function of the DNA. The inhibition of RNA and protein synthesis is weak. It is a non-specific drug of the cycle.
- cisplatin Since its discovery, cisplatin has become one of the most effective drugs for the treatment of lung cancer. It has a wide anti-tumor spectrum, strong effect, synergy with a variety of anti-tumor drugs, and no cross-resistance. Although other platinum compounds such as carboplatin and oxaliplatin have a certain decrease in adverse reactions, the antitumor effect is still far from that of cisplatin. Therefore, cisplatin is still the most commonly used drug in the current combination chemotherapy. one.
- tumor-targeting polypeptides In recent years, some key enzymes of cell signal transduction pathways involved in the differentiation and proliferation of tumor cells have been used as drug screening targets, and new, highly effective, low-toxicity and specific anticancer drugs that selectively act on specific targets have been discovered. Molecular targeting drugs and antibody-targeted drugs have become an important direction for the development of anti-tumor drugs.
- the discovery of tumor-targeting polypeptides, tumor-targeting carrier polypeptides, polypeptides that inhibit tumor cell growth, and related polypeptide hormones or growth factors that inhibit lung cancer growth have laid the foundation for the treatment of targeted drugs.
- these peptides or receptors can be used as targeting carriers and play a pivotal role in tumor-targeted therapy, which can increase the solubility of drugs and change the distribution of anti-tumor drugs in various tissues and organs in the body [11] . It is also possible to target the chemotherapeutic drug to the tumor tissue, thereby improving the therapeutic effect of the tumor and reducing the side effects of the chemotherapy drug, thereby realizing targeted therapy of the tumor. These drugs are expected to achieve high affinity and high specificity of tumor tissues, and are expected to significantly reduce the side effects of chemotherapy drugs.
- Another object of the invention is to provide a targeted platinum ligand.
- Z is a saturated carbon chain of C2 ⁇ 4
- X and Y are independently NH 2 , NR' 2 , SR', C00H groups, respectively attached to different carbons of Z, R' is C1-4 alkyl.
- X and Y are independently NH 2 , SR′, and in particular, X and Y are independently NH 2 .
- Z is a saturated carbon chain of C2 ⁇ 4
- X and Y are independently NH 2 , NR' 2 , SR ', C00H groups, respectively attached to different carbons of Z
- R is a target To the recognition sequence
- R' is a C1-4 alkyl group.
- R is a targeted recognition polypeptide sequence.
- X and Y are independently NH 2 , SR′, and in particular, X and Y are independently NH 2 .
- a targeting agent is prepared by complexing a target polypeptide modified by the above terminal with a functional compound.
- the functional compound is selected from an antitumor drug, a detection reagent.
- the antitumor drug is selected from the group consisting of a platinum antitumor drug and an active antitumor polypeptide, wherein
- the general formula of the targeted platinum-containing antitumor drug obtained by the combination is as shown in formula III:
- Z is a saturated carbon chain of C2 ⁇ 4
- X and Y are independently NH 2 , NR' 2 , SR', COOH groups, respectively attached to different carbons of Z
- R' is C1-4 alkyl
- R is a targeting recognition sequence
- X and Y are independently NH 2 , SR′, in particular, X and Y are independently NH 2
- R 2 is an independent group, respectively, or R 2 Covalently connected into a ring.
- the antitumor drug is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin; and Ri, R 2 is independently C1 or H 2 0.
- the platinum ligand of the present invention can be well coupled to a plurality of reagents, and can be linked to a targeting sequence thereon, and can serve as a ligand for a plurality of reagents.
- the ligand itself has a simple structure, a low synthesis cost, and is easy to mass-produce.
- the targeting ligand of the invention has good targeting property, and is easily localized in the body after coordinating with the platinum reagent, thereby achieving better effects.
- the targeting agent of the invention has good targeting and can be well applied to targeted therapy and diagnosis of tumors.
- Figure 1 is a nuclear magnetic resonance diagram of a compound intermediate of the present invention
- Figure 4 is a nuclear magnetic resonance diagram of another compound intermediate of the present invention.
- Figures 5 to 10 are mass spectra of different compound intermediates of the present invention.
- Orn ornithine
- 5-AVA 5-aminovaleric acid
- TFA trifluoroacetic acid
- HOBt 1-hydroxybenzotriazole
- DMF dimethylformamide
- Ala 3-aminopropionic acid
- Dab 2,4-diaminobutyric acid
- RGD Arg-Gly-Asp
- RGN Arg-Gly-Asn
- HOSu N-hydroxysuccinimide
- the NMR data for Compound 4 are: 1H NMR (400 Hz, CDCl 3 ) ⁇ : 4.75 (m, 1H), 3.19-3.20 (m, 1H), 2.86 (s, 4H), 1.85-2.00 (m, 2H), 1.68 (m, 2H), 1.47 (s, 18H), 1.22-1.23 (m, 2H), and its magnetic resonance spectrum is shown in Fig. 1.
- the reaction mixture was concentrated by rotary evaporation to about 50 ml of the reaction mixture, and poured into 500 ml of ice-cold isopropyl ether. A white precipitate was precipitated, and after standing for a while, it was centrifuged and dried. Obtaining a white product;
- the reaction mixture was rotary evaporated to about 50 ml of the reaction mixture, poured into 500 ml of ice-cold isopropyl ether, and a white precipitate was precipitated. After standing for a while, it was centrifuged and dried. Obtaining a white product;
- Boc-Met-OH and HOSu were dissolved in EA, and the DCC/EA mixed solution was slowly added dropwise. After the completion of the dropwise addition, the ice bath was removed, and the reaction was continued for 2 hours; the reaction was completely filtered, and the filtrate was evaporated to a white solid; toluene was added and stirred in a water bath at 60 ° C until the solid was completely dissolved; It was filtered and washed with a small amount of toluene and diethyl ether and dried in a dry room for 2h to give a white solid.
- TFA.H-Met-5-AVA-OH is dissolved in water, the pH is adjusted to 8 ⁇ 9 with Na 2 CO 3 , K 2 PtC solution is added, pH is continuously monitored during the reaction, pH 8 ⁇ 9 is maintained, and the reaction is overnight; It was suction filtered and dried to give a yellow solid.
- the above actual examples are merely illustrative and are not to be considered as limiting the invention.
- the above-mentioned targeted recognition sequence may be other tripeptides well known to those skilled in the art, such as RGE, RGQ, HGD, HGE, HGN, HGQ KGD, KGE, KGN, KGQ DGR, in addition to the above RGD, RGN. , DGK, NGR, etc., may also be other polypeptides that have been reported to have tumor targeting properties.
- mice Healthy Balb-c nude mice, male and female, were inoculated for 3-4 weeks after inoculation of nude mice with a tumor diameter of about 0.3-0.5 cm.
- Drugs Peptide-cisplatin-conjugated complex RGD-5-AVA-Om-PtCl 2 (batch number: zp-2-pl9), cisplatin for injection (Shandong Qilu, Lot No. 203008CF).
- the peptide-cisplatin-conjugated complex was dissolved in physiological saline for injection, mixed, and sterilized by filtration through a 0.22 ⁇ filter in a clean bench.
- the cisplatin for injection was dissolved in physiological saline solution for injection in a clean bench, and mixed for use.
- Grouping Experimental setting negative control group, positive control group and RGD-cisplatin complex experimental group (high, medium and low dose groups, set at 6:3:1). Each group included 6 nude mice that had been successfully modeled.
- the dose of RGD-cisplatin complex is: high dose group 90 ⁇ .13 ⁇ 4- medium dose group 30 ⁇ .13 ⁇ 4- low dose group 10 ⁇ .13 ⁇ 4-cisplatin group 10 ⁇ .13 ⁇ 4- ⁇ administered by tail vein injection, The amount of administration was determined according to the body weight, once a day, for 5 days.
- mice Healthy Balb-c nude mice, male and female, about 3 weeks old, weighing 18-22g.
- Human lung squamous cell carcinoma cell line NCI-H1299 was cultured in large amounts, digested with 0.25% trypsin containing 0.01% EDTA, centrifuged at 1000 rpm for 1.5 min, de-cleared, resuspended in serum-free DMEM medium, and cell count adjusted for cell density.
- Nude mice were inoculated with 2 ⁇ 10 6 cells/nose in front of the right axilla, and the tumor formation rate was about 95%. After 3-4 weeks of inoculation, nude mice with a tumor diameter of about 0.3-0.5 cm were used for the nude mice. experiment.
- the polypeptide-cisplatin-conjugated complex was dissolved in physiological saline for injection, mixed, and sterilized by filtration through a 0.22 ⁇ filter in a clean bench.
- the cisplatin for injection was dissolved in physiological saline solution for injection in a clean bench, and mixed for use. Weigh before dosing, press
- the mode dose dose low dose cisplatin group high type 15 body weight determines the dose.
- the drug was administered by tail vein injection once a day for 5 days, and after the end of the administration, the observation was continued for 9 days, and on the 15th day, the animals were sacrificed, and organs and tumors were taken.
- mice Healthy Kunming mice, male and female, about 4 weeks old, weighing 18-22g, purchased from Guangdong Medical Laboratory Animal Center.
- zp-2-pl9 is dissolved in physiological saline for injection, mixed, and passed through a 0.22 ⁇ filter in a clean bench. Filter the bacteria.
- the cisplatin for injection was dissolved in physiological saline solution for injection in a clean bench, and mixed for use.
- Grouping A small number of animals were used to gradually explore the upper and lower limits, even the minimum dose (Dm) for all animals and the maximum dose (Dn) for an animal. The number of experimental groups and the dose were determined based on the results of the preliminary experiments, and the animals were divided into 7 dose groups.
- Methods Grouped by random method, sorted by weight from low to high, grouped according to random number table method.
- Quantity Meets statistical requirements, usually consisting of at least 10 animals per dose group.
- Dosage A formal test is performed on a pre-test basis.
- the Zp-2 dose was set to 152.82 mg.kg - 230 mg.kg 1 , 305.64 mg.kg” 1 382.05 mg.kg” 1 420.26 mg.kg” 1 458.46 mg.kg” 1 611.28 mg.kg - 1 7 groups .
- the cisplatin dose was set to 5.00 mg.kg” 1 8.75 mg.kg” 1 13.10 mg.kg” 1 17.50 mg.kg” 1 26.25 mg.kg” 1 35.00 mg.kg" 1 52.50 mg.kg - 1 seven groups.
- Method of administration Fasting for 6-12 hours before administration and fasting for 3-4 hours after administration.
- Test indicators Observe the changes in animal weight, diet, appearance, behavior, secretions, excretion and poisoning symptoms, record the death of the animal, the symptoms of poisoning and the start time, severity, duration of the poisoning reaction, etc. Animal body weight (D0), day 3 (D3), and day 5 (D5) were weighed. The results are shown in Table 5 and Table 6.
- Cisplatin y (Probit) :-2.102+6.0344Log(D) 50.08
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Abstract
Provided are a ligand having the structure of formula (I) and a complex formed by platinum and the ligand, wherein the ligand is simple in structure, capable of coupling with a variety of reagents, has a low synthesis cost and good targeting, and thus can be used for targeted therapy and diagnosis of tumours.
Description
说 明 书 一种铂配体及其配合物 Description A platinum ligand and its complex
技术领域 Technical field
本发明主要涉及一种偶联物， 特别涉及一种靶向偶联体。 The present invention generally relates to a conjugate, and more particularly to a targeting conjugate.
背景技术 Background technique
肿瘤， 特别是恶性肿瘤， 直接影响人类的健康和生命， 给社会和患者带来巨大的经济负 担。 我国恶性肿瘤发病率总体呈上升趋势， 发病率以年均 3%〜5%的速度递增。 我国癌谱呈 现新的特征， 既有发达国家又保留发展中国家的双重特征， 即出现恶性肿瘤发病的双重负担 局面， 2009年我国恶性肿瘤发病率居前 5位的是肺癌、 胃癌、 结直肠癌、 肝癌、 乳腺癌 [1— 3]。 肺癌 1988〜2005年发病率以每年 1.63%的速度增加， 2000〜2005年间肺癌的新发病例增加了 12万[4]， 并且其发病率及死亡率均呈逐年上升的趋势。肺癌的预后与临床分期密切相关， I-IV 期患者总的 5年生存率仅约 15%。 导致肺癌致死率高的主要原因是检测晚， 多数病人是在肺 癌晚期甚至是发生了远处转移后才检测出来 [5]。 Tumors, especially malignant tumors, directly affect human health and life, and bring enormous economic burden to society and patients. The incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%. China's cancer spectrum presents new characteristics. It has both the developed countries and the dual characteristics of developing countries, that is, the double burden of malignant tumors. In 2009, the top five incidences of malignant tumors in China were lung cancer, stomach cancer, and colorectal. Cancer, liver cancer, breast cancer [ 1–3] . The incidence of lung cancer increased from 1.63% to 3% in 1988-2005. The number of new cases of lung cancer increased by 120,000 between 2000 and 2005 [4] , and its morbidity and mortality increased year by year. The prognosis of lung cancer is closely related to clinical stage. The overall 5-year survival rate of patients with stage I-IV is only about 15%. The main cause of lung cancer mortality is late detection, most patients are detected in the late stage of lung cancer or even after distant metastasis [5] .
为了减少肿瘤给人们带来的危害， 需要尽可能早， 并尽可能准确的诊断 [6]。 近年来虽然 肿瘤的早期诊断如血清标志物诊断 [7]、 蛋白质组[8]、 正电子断层扫描技术 [9'1()]等新型诊断技术 取得了一定的进步， 但这些诊断技术受限于特异性和假阳性率的影响， 临床上对于肺癌诊断 的金标准仍然是以病理诊断为主， 肿瘤标志物的分子诊断和分子影像诊断等新技术仅作为肺 癌诊断的辅助手段。 但是现有的多肽， 及其与其他化合物， 特别是无机化合物的结合力差， 无法形成较为稳定的偶联物。 同样以顺铂为例， 其与氨基的结合力较弱， 且一般难以保证其 顺式铂结构， 这也是其难以制备成为靶向药物的一个重要原因。 In order to reduce the harm caused by tumors, it is necessary to diagnose as early as possible and as accurate as possible [6] . In recent years, although early diagnosis of tumors such as serum marker diagnosis [7] , proteome [8] , positron emission tomography [9 ' 1 ()] and other new diagnostic techniques have made some progress, but these diagnostic techniques are limited Due to the influence of specificity and false positive rate, the gold standard for the diagnosis of lung cancer is still based on pathological diagnosis. New techniques such as molecular diagnosis and molecular imaging diagnosis of tumor markers are only used as an auxiliary means for diagnosis of lung cancer. However, existing polypeptides, and their binding to other compounds, particularly inorganic compounds, are inferior to form a relatively stable conjugate. Similarly, in the case of cisplatin, its binding ability to amino groups is weak, and it is generally difficult to ensure its cis-platinum structure, which is also an important reason why it is difficult to prepare into a targeted drug.
现有的肿瘤临床治疗中， 仍然以手术治疗、 化疗和放疗为主。 目前肿瘤药物治疗中， 主 要依赖于细胞毒类药物， 如顺铂、 卡铂、 奥沙利铂等人工合成的具有顺式铂的化合物， 长春 碱、 紫杉醇等天然或半合成化合物。 但是细胞毒类药物在杀灭癌细胞的同时， 也存在严重的 副作用。 这个副作用包括但不限于骨髓抑制、 胃肠道反应、神经***毒性等严重的不良不应， 这限制了这类药物的临床应用。 In the existing clinical treatment of tumors, surgical treatment, chemotherapy and radiotherapy are still the main treatment. At present, the main treatment of tumor drugs depends on cytotoxic drugs, such as cisplatin, carboplatin, oxaliplatin and other synthetic cisplatin compounds, such as vinblastine and paclitaxel. However, cytotoxic drugs also have serious side effects while killing cancer cells. This side effect includes, but is not limited to, severe adverse effects such as myelosuppression, gastrointestinal reactions, and neurotoxicity, which limits the clinical utility of such drugs.
顺铂最早由美国生理学家 Rosenberg B等发现， 是中心以二价铂同两个氯原子和两个氨 分子结合的重金属络合物， 类似于双功能烷化剂， 对乏氧细胞作用， 进入人体后扩散通过带 电的细胞膜， 先将所含之氯解离， 然后在 DNA分子中鸟嘌呤的 6位和 7位之间形成交叉连 接、 或与腺嘌呤和胞嘧啶形成 DNA单链内两点的交叉联结， 也可能形成双链间的交叉联结， 从而破坏 DNA的结构和功能。对 RNA和蛋白质合成的抑制作用较弱。属周期非特异性药物。
顺铂自发现以来， 已成为治疗肺癌最有效的药物之一。 它具有抗瘤谱广、 作用强、 与多种抗 肿瘤药有协同作用、 且无交叉耐药等特点。 其他铂类化合物如卡铂、 奥沙利铂等虽然在不良 反应上有一定降低， 但抑瘤效果与顺铂相比仍有较大差距， 因此顺铂仍为当前联合化疗中最 常用的药物之一。 Cisplatin was first discovered by American physiologist Rosenberg B. It is a heavy metal complex with divalent platinum combined with two chlorine atoms and two ammonia molecules. It is similar to a bifunctional alkylating agent and acts on hypoxic cells. The human body diffuses through the charged cell membrane, first dissociates the contained chlorine, and then forms a cross-link between the 6 and 7 positions of the guanine in the DNA molecule, or forms two points within the DNA single strand with adenine and cytosine. The cross-linking may also form a cross-link between the double strands, thereby disrupting the structure and function of the DNA. The inhibition of RNA and protein synthesis is weak. It is a non-specific drug of the cycle. Since its discovery, cisplatin has become one of the most effective drugs for the treatment of lung cancer. It has a wide anti-tumor spectrum, strong effect, synergy with a variety of anti-tumor drugs, and no cross-resistance. Although other platinum compounds such as carboplatin and oxaliplatin have a certain decrease in adverse reactions, the antitumor effect is still far from that of cisplatin. Therefore, cisplatin is still the most commonly used drug in the current combination chemotherapy. one.
近年来， 以一些与肿瘤细胞分化增殖相关的细胞信号转导通路的关键酶作为药物筛选靶 点， 发现选择性作用于特定靶位的高效、 低毒、 特异性强的新型抗癌药， 即分子靶向药和抗 体靶向药， 已成为当今抗肿瘤药研发的重要方向。 而用于诊断肿瘤的多肽、 肿瘤靶向性的载 体多肽、 抑制肿瘤细胞生长的多肽、 抑制肺癌生长的相关多肽激素或生长因子等具有肿瘤靶 向性多肽的发现为靶向性药物的治疗奠定了基础， 这些多肽或受体可作为靶向载体， 在肿瘤 靶向治疗中起到举足轻重的作用， 其可增加药物的溶解性、 改变抗肿瘤药物在体内各组织器 官的分布[11]， 同时还可以将化疗药物靶向浓集于肿瘤组织， 起到提高肿瘤的治疗作用和降低 化疗药物毒副作用的目的， 从而实现肿瘤的靶向治疗。 该类药物可有望实现肿瘤组织的高亲 和力和高特异性， 同时有望显著降低化疗药物的毒副作用。 In recent years, some key enzymes of cell signal transduction pathways involved in the differentiation and proliferation of tumor cells have been used as drug screening targets, and new, highly effective, low-toxicity and specific anticancer drugs that selectively act on specific targets have been discovered. Molecular targeting drugs and antibody-targeted drugs have become an important direction for the development of anti-tumor drugs. The discovery of tumor-targeting polypeptides, tumor-targeting carrier polypeptides, polypeptides that inhibit tumor cell growth, and related polypeptide hormones or growth factors that inhibit lung cancer growth have laid the foundation for the treatment of targeted drugs. Fundamentally, these peptides or receptors can be used as targeting carriers and play a pivotal role in tumor-targeted therapy, which can increase the solubility of drugs and change the distribution of anti-tumor drugs in various tissues and organs in the body [11] . It is also possible to target the chemotherapeutic drug to the tumor tissue, thereby improving the therapeutic effect of the tumor and reducing the side effects of the chemotherapy drug, thereby realizing targeted therapy of the tumor. These drugs are expected to achieve high affinity and high specificity of tumor tissues, and are expected to significantly reduce the side effects of chemotherapy drugs.
但是现有的多肽， 及其与其他化合物， 特别是无机化合物的结合力差， 无法形成较为稳 定的偶联物。 同样以顺铂为例， 其与氨基的结合力较弱， 且一般难以保证其顺式铂结构， 这 也是其难以制备成为靶向药物的一个重要原因。 However, existing polypeptides, and their binding to other compounds, particularly inorganic compounds, are inferior to form a relatively stable conjugate. Similarly, in the case of cisplatin, its binding ability to amino groups is weak, and it is generally difficult to ensure its cis-platinum structure, which is also an important reason why it is difficult to prepare into a targeted drug.
参考文献 references
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本发明的一个目的在于提供一种铂配体。 It is an object of the present invention to provide a platinum ligand.
本发明的另一个目的在于提供一种靶向性铂配体。 Another object of the invention is to provide a targeted platinum ligand.
本发明的再一个目的在于提供一种靶向试剂。 It is still another object of the present invention to provide a targeting agent.
本发明所采取的技术方案是： The technical solution adopted by the present invention is:
一种铂配体， 其化学式如式 I所示： A platinum ligand having the chemical formula shown in Formula I:
式 （ I ) Formula ( I )
式中， m=2-5， Z为 C2〜4的饱和碳链， X和 Y独立为 NH2、 NR'2、 SR'， C00H基团， 分别连接在 Z的不同碳上， R'为 C1-4烷基。 进一步的， X和 Y独立为 NH2， SR'， 特别的， X和 Y独立为 NH2。 Where m = 2-5, Z is a saturated carbon chain of C2~4, X and Y are independently NH 2 , NR' 2 , SR', C00H groups, respectively attached to different carbons of Z, R' is C1-4 alkyl. Further, X and Y are independently NH 2 , SR′, and in particular, X and Y are independently NH 2 .
一种末端修饰的靶向多肽， 其通式如式 II所示： A terminally modified targeting polypeptide having the general formula shown in Formula II:
式 （Π ) Type (Π)
式中， m=2-5， Z为 C2〜4的饱和碳链， X和 Y独立为 NH2、 NR'2、 SR'、 C00H基团， 分别连接在 Z的不同碳上， R为靶向识别序列， R'为 C1-4烷基。 特别的， R为靶向识别多肽 序列。 进一步的， X和 Y独立为 NH2， SR'， 特别的， X和 Y独立为 NH2。 Where m = 2-5, Z is a saturated carbon chain of C2~4, X and Y are independently NH 2 , NR' 2 , SR ', C00H groups, respectively attached to different carbons of Z, and R is a target To the recognition sequence, R' is a C1-4 alkyl group. In particular, R is a targeted recognition polypeptide sequence. Further, X and Y are independently NH 2 , SR′, and in particular, X and Y are independently NH 2 .
一种靶向试剂， 由上述末端修饰的靶向多肽与功能化合物配合而成。 功能化合物选自抗 肿瘤药物、 检测试剂。 特别的， 抗肿瘤药物选自铂类抗肿瘤药物、 活性抗肿瘤多肽， 其中，
配合得到的靶向含铂抗肿瘤药物的通式如式 III所示: A targeting agent is prepared by complexing a target polypeptide modified by the above terminal with a functional compound. The functional compound is selected from an antitumor drug, a detection reagent. Particularly, the antitumor drug is selected from the group consisting of a platinum antitumor drug and an active antitumor polypeptide, wherein The general formula of the targeted platinum-containing antitumor drug obtained by the combination is as shown in formula III:
式 （III) Formula (III)
式中， m=2-5， Z为 C2〜4的饱和碳链， X和 Y独立为 NH2、 NR'2、 SR'， COOH基团， 分别连接在 Z的不同碳上， R'为 C1-4烷基， R为靶向识别序列， 进一步的， X和 Y独立为 NH2， SR'， 特别的， X和 Y独立为 NH2; R2分别为独立的基团， 或 、 R2共价连接成 环。 更进一步的， 抗肿瘤药物选自顺铂、 卡铂、 奥沙利铂； Ri、 R2独立为 C1或 H20。 Where m = 2-5, Z is a saturated carbon chain of C2~4, X and Y are independently NH 2 , NR' 2 , SR', COOH groups, respectively attached to different carbons of Z, R' is C1-4 alkyl, R is a targeting recognition sequence, further, X and Y are independently NH 2 , SR′, in particular, X and Y are independently NH 2; R 2 is an independent group, respectively, or R 2 Covalently connected into a ring. Further, the antitumor drug is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin; and Ri, R 2 is independently C1 or H 2 0.
本发明的有益效果是： The beneficial effects of the invention are:
本发明的铂配体， 可以很好偶联多种试剂， 并可以在其上连接靶向序列， 可以作为多种 试剂的配体。 配体本身结构简单， 合成成本较低， 易于批量生产。 The platinum ligand of the present invention can be well coupled to a plurality of reagents, and can be linked to a targeting sequence thereon, and can serve as a ligand for a plurality of reagents. The ligand itself has a simple structure, a low synthesis cost, and is easy to mass-produce.
本发明的靶向配体， 具有很好的靶向性， 与铂试剂配位后， 在体内易于局部集中， 起到 更好的效果。 The targeting ligand of the invention has good targeting property, and is easily localized in the body after coordinating with the platinum reagent, thereby achieving better effects.
本发明的靶向试剂， 靶向性好， 可以很好地应用于肿瘤的靶向治疗、 诊断。 The targeting agent of the invention has good targeting and can be well applied to targeted therapy and diagnosis of tumors.
附图说明 DRAWINGS
图 1是本发明一化合物中间体的核磁共振图； Figure 1 is a nuclear magnetic resonance diagram of a compound intermediate of the present invention;
图 2、 3是本发明不同化合物中间体的质谱图； 2 and 3 are mass spectra of different compound intermediates of the present invention;
图 4是本发明另一化合物中间体的核磁共振图； Figure 4 is a nuclear magnetic resonance diagram of another compound intermediate of the present invention;
图 5〜10是本发明不同化合物中间体的质谱图。 Figures 5 to 10 are mass spectra of different compound intermediates of the present invention.
具体实 式 Specific form
下面结合实施例， 进一步说明本发明。 The invention will now be further described with reference to the embodiments.
以下实施例中所使用的縮写如下： The abbreviations used in the following examples are as follows:
Orn: 鸟氨酸； Orn: ornithine;
5-AVA: 5-氨基戊酸； 5-AVA: 5-aminovaleric acid;
TFA: 三氟乙酸； TFA: trifluoroacetic acid;
HOBt: 1-羟基苯并***； HOBt: 1-hydroxybenzotriazole;
DIC: Ν, Ν-二异丙基碳二亚胺； DIC: Ν, Ν-diisopropylcarbodiimide;
DMF: 二甲基甲酰胺；
Ala: 3-氨基丙酸； DMF: dimethylformamide; Ala: 3-aminopropionic acid;
Met: 蛋氨酸； Met: methionine;
Dab: 2,4-二氨基丁酸； Dab: 2,4-diaminobutyric acid;
Dap: 2,3-二氨基丙酸； Dap: 2,3-diaminopropionic acid;
EA: 乙酸乙酯； EA: ethyl acetate;
RGD: Arg-Gly-Asp; RGD: Arg-Gly-Asp;
RGQ: Arg-Gly-Gln; RGQ: Arg-Gly-Gln;
RGN: Arg-Gly-Asn; RGN: Arg-Gly-Asn;
THF: 四氢呋喃； THF: tetrahydrofuran;
DCC: 二环己基碳二亚胺 DCC: Dicyclohexylcarbodiimide
HOSu: N-羟基琥珀酰亚胺。 HOSu: N-hydroxysuccinimide.
实施例 1 化合物 7 (Cl2 Pt- Orn-5-AVA- RGD) 的合成
Example 1 Synthesis of Compound 7 (Cl 2 Pt- Orn-5-AVA-RDD)
1) 化合物 2的合成： 1) Synthesis of Compound 2:
冰浴条件下， 化合物 1溶解在水中， 4N NaOH溶液缓慢滴加。 滴加完毕后移走冰浴， 与 Boc20溶解在 THF溶液混合， 继续反应 2h; 监测反应完全后， 用酸调节 pH=2-3; EA萃取两 次； 合并有机相旋干， 得到白色固体； Under ice bath conditions, Compound 1 was dissolved in water and 4N NaOH solution was slowly added dropwise. After the completion of the dropwise addition, the ice bath was removed, mixed with Boc 2 0 in a THF solution, and the reaction was continued for 2 hours; after the reaction was completed, the pH was adjusted with acid to 2-3; EA was extracted twice; and the combined organic phases were dried to give a white color. solid;
2) 化合物 3的合成 2) Synthesis of compound 3
冰浴条件下， 化合物 2和 HOSu溶解在 EA中， DCC/EA混合溶液缓慢滴加。 滴加完毕 后移走冰浴， 继续反应 2h; 监测反应完全后过滤； 滤液旋蒸白色固体； 加入甲苯， 60°C水浴 搅拌至固体完全溶解； 旋蒸至有固体析出， 冷却放置过夜。 过滤并用少量甲苯和***洗涤， 干燥箱干燥 2h， 得到白色固体。
3)化合物 4的合成 Under ice bath conditions, Compound 2 and HOSu were dissolved in EA, and the DCC/EA mixed solution was slowly added dropwise. After the completion of the dropwise addition, the ice bath was removed, and the reaction was continued for 2 hours; the reaction was monitored and filtered; the filtrate was evaporated to a white solid; toluene was added, and the mixture was stirred in a water bath at 60 ° C until the solid was completely dissolved; the mixture was evaporated to solids and allowed to stand overnight. It was filtered and washed with a small amount of toluene and diethyl ether and dried in a dry room for 2h to give a white solid. 3) Synthesis of Compound 4
冰浴条件下， 化合物 3溶解在 DMF中， 缓慢滴加到 5-AVA-OH的 DMF溶液中。 滴加 完毕后， 撤去冰浴， 反应过夜。 确认反应完成后， 加入过量的水中， 过滤得到化合物 4。 Under ice bath conditions, Compound 3 was dissolved in DMF and slowly added dropwise to a 5-AVA-OH DMF solution. After the addition was completed, the ice bath was removed and the reaction was allowed overnight. After confirming the completion of the reaction, it was added to excess water and filtered to give Compound 4.
化合物 4的核磁数据为: 1H NMR (400Hz,CDCl3) δ: 4.75(m， 1H)， 3.19-3.20 (m， 1H)， 2.86 ( s， 4H) ,1.85-2.00 (m， 2H)， 1.68(m， 2H)， 1.47 ( s， 18H)， 1.22-1.23(m, 2H)， 其 核磁共振图如图 1所示。 The NMR data for Compound 4 are: 1H NMR (400 Hz, CDCl 3 ) δ: 4.75 (m, 1H), 3.19-3.20 (m, 1H), 2.86 (s, 4H), 1.85-2.00 (m, 2H), 1.68 (m, 2H), 1.47 (s, 18H), 1.22-1.23 (m, 2H), and its magnetic resonance spectrum is shown in Fig. 1.
4)化合物 5的合成 4) Synthesis of compound 5
冰浴条件下， 化合物 4加入 TFA中， 反应 lh。 监测反应完毕后， 旋蒸并与甲苯共沸 2 次 ， 得到油状产物。 Under ice bath conditions, compound 4 was added to TFA and reacted for 1 h. After monitoring the completion of the reaction, it was rotary evaporated and azeotroped twice with toluene to give an oily product.
5)化合物 6的合成 5) Synthesis of Compound 6
化合物 5溶解在水中， 用 Na2C03调 pH至 8〜9， 加入 K2PtC 溶液， 反应进行期间连续 监测 pH值， 保持 PH=8〜9， 反应过夜； 抽滤并干燥， 得黄色固体。 Compound 5 was dissolved in water, adjusted to pH 8 to 9 with Na 2 CO 3 , K 2 PtC solution was added, pH was continuously monitored during the reaction, pH = 8 to 9 was maintained, and the reaction was allowed to stand overnight; filtered and dried to give a yellow solid. .
质谱分析 （relative intensity): 496 Anal. (C10H21Cl2N3O3Pt 497.15),其质谱图如图 2所示。 Respective intensity: 496 Anal. (C 10 H 21 Cl 2 N 3 O 3 Pt 497.15), the mass spectrum of which is shown in FIG.
6)化合物 7的合成 6) Synthesis of compound 7
a) 取已连接 RGD 多肽的树脂加入固相反应瓶中， DMF溶胀后， 依次加入化合物 6， HOBt, DIC, 反应过夜。 检测反应完全后， 抽干， DMF洗 3次， 二氯甲烷洗 3次， 甲醇收縮树脂； a) Add the resin to which the RGD peptide has been added to the solid phase reaction bottle. After the DMF is swollen, add the compound 6, HOBt, DIC, and react overnight. After the reaction was completed, it was drained, washed 3 times with DMF, washed 3 times with dichloromethane, and the methanol was shrunk;
b) 树脂加入裂解液 （TFA:TIS: H20=95:2.5:2.5), 搅拌 2h， 过滤并用 TFA洗涤树脂 2 次。 反应液旋蒸至到约 50ml反应液后， 倒入已冰浴过的异丙醚 500ml中， 有白色沉 淀析出， 稍静置片刻后， 离心并干燥。 得到白色产物； b) The resin was added to the lysate (TFA: TIS: H 2 0 = 95: 2.5: 2.5), stirred for 2 h, filtered and the resin was washed twice with TFA. The reaction mixture was evaporated to about 50 ml of the reaction mixture, poured into 500 ml of ice-cold isopropyl ether, and a white precipitate was precipitated. After standing for a while, it was centrifuged and dried. Obtaining a white product;
c) 用液相制备纯化， 收集纯度大于 95%的产品化合物 7。 c) Purification by liquid phase preparation to collect product compounds with a purity greater than 95%.
实施例 2 化合物 11 (Cl2Pt-Orn-p-Ala-RGD) 的合成
Example 2 Synthesis of Compound 11 (Cl 2 Pt-Orn-p-Ala-RGD)
1)化合物 8的合成 1) Synthesis of compound 8
冰浴条件下， 化合物 3溶解在 DMF中， 缓慢的滴加到 β-丙氨酸的 DMF溶液中。 滴加完 毕后， 撤去冰浴， 反应过夜。 确认反应完成后， 加入过量的水中， 过滤得到化合物 8。 Under ice bath conditions, Compound 3 was dissolved in DMF and slowly added dropwise to a solution of β-alanine in DMF. After the addition was completed, the ice bath was removed and the reaction was allowed overnight. After confirming the completion of the reaction, it was added to an excess of water and filtered to give Compound 8.
质谱分析 （relative intensity): 403 Anal. (C18H33N307 404.07)， 其质谱图如图 3所示。 Spectrum intensity (relative intensity): 403 Anal. (C 18 H 33 N 3 0 7 404.07), the mass spectrum is shown in Figure 3.
2)化合物 9的合成 2) Synthesis of compound 9
冰浴条件下， 化合物 8加入 TFA中， 反应 lh。 监测反应完毕后， 旋蒸并与甲苯共沸 2 次 ， 得到油状产物。 Under ice bath conditions, compound 8 was added to TFA and reacted for 1 h. After monitoring the completion of the reaction, it was rotary evaporated and azeotroped twice with toluene to give an oily product.
3)化合物 10的合成 3) Synthesis of Compound 10
化合物 9溶解在水中， 用 Na2C03调节 pH至 8〜9， 加入 K2PtC 溶液， 反应进行期间连 续监测 pH值， 保持 pH 8〜9， 反应过夜； 抽滤并干燥， 得黄色固体。 Compound 9 was dissolved in water, pH was adjusted to 8 to 9 with Na 2 CO 3 , K 2 PtC solution was added, pH was continuously monitored during the reaction, pH 8 to 9 was maintained, and the reaction was allowed to stand overnight; suction filtration and drying gave a yellow solid.
4)化合物 11的合成 4) Synthesis of compound 11
a) 取已连接 RGD多肽的树脂加入固相反应瓶中， DMF溶胀后， 加入化合物 10， HOBt, DIC, 反应过夜。 检测反应完全后， 抽干， DMF洗 3次， 二氯甲烷洗 3次， 甲醇收縮
树脂； a) The resin to which the RGD polypeptide has been attached is added to the solid phase reaction flask, and after the DMF is swollen, the compound 10, HOBt, DIC is added and reacted overnight. After the reaction was completed, it was drained, washed 3 times with DMF, washed 3 times with dichloromethane, and the methanol was shrunk. Resin
b) 树脂加入裂解液 （TFA:TIS: 水 =95:2.5:2.5)， 搅拌 2h， 过滤并用 TFA洗涤树脂 2次。 b) The resin was added to the lysate (TFA: TIS: water = 95:2.5:2.5), stirred for 2 h, filtered and the resin was washed twice with TFA.
反应液旋蒸浓縮至约 50ml反应液后， 倒入已冰浴过的异丙醚 500ml中， 有白色沉淀析 出， 稍静置片刻后， 离心并干燥。 得到白色产物； The reaction mixture was concentrated by rotary evaporation to about 50 ml of the reaction mixture, and poured into 500 ml of ice-cold isopropyl ether. A white precipitate was precipitated, and after standing for a while, it was centrifuged and dried. Obtaining a white product;
c) 用液相色谱纯化， 收集纯度大于 95%的产品 C12Pt-Orn-P-Ala-RGD。 c) Purification by liquid chromatography to collect the product C12Pt-Orn-P-Ala-RGD with a purity greater than 95%.
实施例 3 化合物 18 (PtCl2-Dab -5-AVA - RGD) 的合成 Example 3 Synthesis of Compound 18 (PtCl 2 -Dab -5-AVA - RGD)
16
16
17 17
18 18
1)化合物 14的合成 1) Synthesis of compound 14
a) 冰浴条件下， 化合物 13和 HOSu溶解在 EA中， DCC/EA混合溶液缓慢滴加。 滴 加完毕后移走冰浴， 继续反应 2h; 监测反应完全后过滤， 滤液旋蒸白色固体；
b) 加入甲苯， 60°C水浴搅拌至固体完全溶解； 旋蒸至有固体析出， 冷却放置过夜。 过 滤并用少量甲苯和***洗涤， 干燥箱干燥 2h， 得到白色固体。 a) Under the ice bath conditions, compound 13 and HOSu were dissolved in EA, and the DCC/EA mixed solution was slowly added dropwise. After the completion of the dropwise addition, the ice bath was removed, and the reaction was continued for 2 hours ; the reaction was completely filtered, and the filtrate was evaporated to a white solid; b) Add toluene, stir in a water bath at 60 ° C until the solid is completely dissolved; spin to a solid precipitate, and cool to stand overnight. It was filtered and washed with a small amount of toluene and diethyl ether and dried in a dry room for 2h to give a white solid.
取得到的白色固体进行核磁共振分析，其核磁共振图如图 4所示，具体数据为： 1H NMR (400Hz,CDCl3) δ: 5.48 ( s， 1H) ,5.23 ( s， 1H) ，4.80 (d， 1H)， 3.54 ( s， 1H)， 3.10 ( s， 1H)， 2.86 ( s， 4H)， 2.18 (m， 1H) ,2.05-2.08 (m， 1H) ,1.47 ( s， 9H) ,1.45 ( s， 9H)， 1.22-1.23 (m， 2H)。 The obtained white solid was subjected to nuclear magnetic resonance analysis, and its nuclear magnetic resonance image is shown in Fig. 4. The specific data are: 1H NMR (400 Hz, CDCl 3 ) δ: 5.48 (s, 1H), 5.23 (s, 1H), 4.80 ( d, 1H), 3.54 ( s, 1H), 3.10 ( s, 1H), 2.86 ( s, 4H), 2.18 (m, 1H) , 2.05-2.08 (m, 1H) , 1.47 ( s, 9H) , 1.45 (s, 9H), 1.22-1.23 (m, 2H).
2)化合物 15的合成 2) Synthesis of compound 15
冰浴条件下， 化合物 14溶解在 DMF中， 缓慢滴加到 5-氨基戊酸的 DMF溶液中。 滴加 完毕后， 撤去冰浴， 反应过夜。 确认反应完成后， 加入过量的水中， 过滤得到化合物 15。 质 谱分析 （relative intensity): 417 Anal. (C19H35N307 418.25)， 其质谱图如图 5所示。 Under ice bath conditions, Compound 14 was dissolved in DMF and slowly added dropwise to a solution of 5-aminopentanoic acid in DMF. After the addition was completed, the ice bath was removed and the reaction was allowed overnight. After confirming the completion of the reaction, it was added to excess water and filtered to give Compound 15. Spectral intensity: 417 Anal. (C 19 H 35 N 3 0 7 418.25), the mass spectrum of which is shown in Figure 5.
3)化合物 16的合成 3) Synthesis of Compound 16
冰浴条件下， 化合物 15加入 TFA中， 反应 lh。 监测反应完毕后， 旋蒸并与甲苯共沸 2 次 ， 得到油状产物。 Under ice bath conditions, compound 15 was added to TFA and reacted for 1 h. After monitoring the completion of the reaction, it was rotary evaporated and azeotroped twice with toluene to give an oily product.
质谱分析 （relative intensity): 217 Anal. (C9H19N303 218.27) ， 其质谱图如图 6所示。 Spectral intensity: 217 Anal. (C 9 H 19 N 3 0 3 218.27), the mass spectrum of which is shown in Figure 6.
4)化合物 17的合成 4) Synthesis of compound 17
化合物 16溶解在水中， 用 Na2C03调节 pH至 8〜9， 加入 K2PtC 溶液， 反应进行期间 连续监测 pH值， 保持 pH 8〜9， 反应过夜； 抽滤并干燥， 得黄色固体。 Compound 16 was dissolved in water, pH was adjusted to 8 to 9 with Na 2 CO 3 , K 2 PtC solution was added, pH was continuously monitored during the reaction, pH 8 to 9 was maintained, and the reaction was allowed to stand overnight; suction filtration and drying gave a yellow solid.
质谱分析 （relative intensity): 482 Anal. (C9H19C12N303Pt 484.18) ，其质谱图如图 7所示。 Respective intensity: 482 Anal. (C 9 H 19 C 12 N 3 0 3 Pt 484.18), the mass spectrum of which is shown in FIG.
5)化合物 18的合成 5) Synthesis of Compound 18
a) 取已连接 RGD 多肽的树脂加入固相反应瓶中， DMF 溶胀后， 依次加入 Cl2Pt -Dab-5-AVA-OH, HOBt, DIC， 反应过夜。 检测反应完全后， 抽干， DMF洗 3次， 二氯甲烷洗 3次， 甲醇收縮树脂； a) Add the resin to which the RGD peptide has been attached to the solid phase reaction flask. After the DMF is swollen, add Cl 2 Pt -Dab-5-AVA-OH, HOBt, DIC, and react overnight. After the reaction was completed, it was drained, DMF was washed 3 times, and dichloromethane was washed 3 times, and methanol was used to shrink the resin;
b) 树脂加入裂解液 （TFA:TIS: 水 =95:2.5:2.5)， 搅拌 2h， 过滤并用 TFA洗涤树脂 2次； 反应液旋蒸浓縮至约 50ml反应液后， 倒入已冰浴过的异丙醚 500ml中， 有白色沉淀 析出， 稍静置片刻后， 离心并干燥。 得到白色产物； b) Add the resin to the lysate (TFA: TIS: water = 95:2.5:2.5), stir for 2 h, filter and wash the resin twice with TFA; dilute the reaction solution to about 50 ml of the reaction solution, and pour into the ice bath. In 500 ml of isopropyl ether, a white precipitate precipitated, and after standing for a while, it was centrifuged and dried. Obtaining a white product;
c) 用液相制备纯化， 收集纯度大于 95%的产品化合物 18。 c) Purification by liquid phase preparation to collect product compounds 18 with a purity greater than 95%.
质谱分析 （relative intensity): 810 Anal. (C21H39C12N908Pt 810.44) ， 其质谱图如图 8 所示。 实施例 4 化合物 25 (PtCl2 -Dap-5-AVA-RGQ) 的合成
Relative intensity: 810 Anal. (C 21 H 39 C 12 N 9 0 8 Pt 810.44), the mass spectrum of which is shown in Figure 8. Example 4 Synthesis of Compound 25 (PtCl 2 -Dap-5-AVA-RGQ)
1) 化合物 20的合成 1) Synthesis of compound 20
冰浴条件下， 化合物 1溶解在水中， 4N NaOH溶液缓慢滴加。 滴加完毕后移走冰 浴，与 Boc20溶解在二氧六环溶液混合，继续反应 2h;监测反应完全后，用酸调节 pH=2-3; EA萃取两次； 合并有机相旋干， 得到白色固体； Under ice bath conditions, Compound 1 was dissolved in water and 4N NaOH solution was slowly added dropwise. After the completion of the dropwise addition, the ice bath was removed, and the mixture was dissolved in the dioxane solution with Boc 2 0 to continue the reaction for 2 hours; after the reaction was completed, the pH was adjusted to 2-3 with acid; the EA was extracted twice; , a white solid;
2) 化合物 21的合成 2) Synthesis of Compound 21
冰浴条件下， 化合物 20和 HOSu溶解在 EA中， DCC/EA混合溶液缓慢滴加。 滴加完 毕后移走冰浴， 继续反应 2h; 监测反应完全后过滤， 滤液旋蒸白色固体； 加入甲苯， 60°C 水浴搅拌至固体完全溶解； 旋蒸至有固体析出， 冷却放置过夜。 过滤并用少量甲苯和乙 醚洗涤， 干燥箱干燥 2h， 得到白色固体。 Under ice bath conditions, compound 20 and HOSu were dissolved in EA, and the DCC/EA mixed solution was slowly added dropwise. After the completion of the dropwise addition, the ice bath was removed, and the reaction was continued for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was evaporated to a white solid. Toluene was added, and the mixture was stirred in a water bath at 60 ° C until the solid was completely dissolved. The mixture was refluxed until solids were precipitated and allowed to stand overnight. It was filtered and washed with a small amount of toluene and diethyl ether, and dried in a dry oven for 2h to give a white solid.
取得到的白色固体进行核磁共振分析， 其核磁共振图如图 3所示， 具体数据为： iH NMR (400Hz,CDC13) δ: 5.42 ( s， 1H) ,4.76 ( s， 1H) ,3.81-3.82 (m, 1H)， 3.59-3.63 (m， 2H)， 2.88 (m， 4H)， 1.47(s, 18H)。 质谱分析 (relative intensity): 401 Anal. (C17H27N308+Na 425.22) ， 其质谱图如图 9所示。
3)化合物 22的合成 The obtained white solid was subjected to nuclear magnetic resonance analysis, and its nuclear magnetic resonance image is shown in Fig. 3. The specific data are: iH NMR (400 Hz, CDC13) δ: 5.42 (s, 1H), 4.76 (s, 1H), 3.81-3.82 (m, 1H), 3.59-3.63 (m, 2H), 2.88 (m, 4H), 1.47 (s, 18H). Spectral intensity: 401 Anal. (C 17 H 27 N 3 0 8 +Na 425.22), the mass spectrum of which is shown in FIG. 3) Synthesis of Compound 22
冰浴条件下， 化合物 21溶解在 DMF中， 缓慢滴加到 5-AVA-OH的 DMF溶液中。 滴加 完毕后， 撤去冰浴， 反应过夜。 确认反应完成后， 加入过量的水中， 过滤得到 Boc- Dap(Boc)-5-AVA-OH。 Under ice bath conditions, Compound 21 was dissolved in DMF and slowly added dropwise to a solution of 5-AVA-OH in DMF. After the addition was completed, the ice bath was removed and the reaction was allowed overnight. After confirming the completion of the reaction, it was added to excess water and filtered to obtain Boc-Dap(Boc)-5-AVA-OH.
4)化合物 23的合成 4) Synthesis of compound 23
冰浴条件下， 化合物 22加入 TFA中， 反应 lh。 监测反应完毕后， 旋蒸并与甲苯共 沸 2次 ， 得到油状产物。 Under ice bath conditions, compound 22 was added to TFA and reacted for 1 h. After monitoring the completion of the reaction, it was rotary evaporated and azeotroped twice with toluene to give an oily product.
质谱分析 （relative intensity): 203 Anal. (C8H17N303 204.10) ， 其质谱图如图 10所示。 Spectral intensity: 203 Anal. (C 8 H 17 N 3 0 3 204.10) , the mass spectrum of which is shown in FIG.
5)化合物 24的合成 5) Synthesis of compound 24
化合物 23溶解在水中， 用 Na2C03调节 pH至 8〜9， 加入 K2PtC 溶液， 反应进行期间 连续监测 pH值， 保持 pH8〜9， 反应过夜； 抽滤并干燥， 得黄色固体。 Compound 23 was dissolved in water, pH was adjusted to 8 to 9 with Na 2 CO 3 , K 2 PtC solution was added, pH was continuously monitored during the reaction, pH 8 to 9 was maintained, and the reaction was allowed to stand overnight; suction filtration and drying gave a yellow solid.
6)化合物 25的合成 6) Synthesis of compound 25
a) 取已连接 RGQ多肽的树脂加入固相反应瓶中， DMF溶胀后， 依次加入化合物 24， HOBt, DIC, 反应过夜。 检测反应完全后， 抽干， DMF洗 3次， 二氯甲烷洗 3次， 甲醇收縮树脂； a) The resin to which the RGQ polypeptide has been attached is added to the solid phase reaction flask. After the DMF is swollen, the compound 24, HOBt, DIC is added in sequence, and the reaction is continued overnight. After the reaction was completed, it was drained, washed 3 times with DMF, washed 3 times with dichloromethane, and the methanol was shrunk;
b) 树脂加入裂解液 （TFA:TIS: 水 =95:2.5:2.5)， 搅拌 2h， 过滤并用 TFA洗涤树脂 2次。 b) The resin was added to the lysate (TFA: TIS: water = 95:2.5:2.5), stirred for 2 h, filtered and the resin was washed twice with TFA.
反应液旋蒸至到约 50ml反应液后， 倒入已冰浴过的异丙醚 500ml中， 有白色沉淀析 出， 稍静置片刻后， 离心并干燥。 得到白色产物； The reaction mixture was rotary evaporated to about 50 ml of the reaction mixture, poured into 500 ml of ice-cold isopropyl ether, and a white precipitate was precipitated. After standing for a while, it was centrifuged and dried. Obtaining a white product;
c) 用液相色谱纯化， 收集纯度大于 95%的产品化合物 25。 c) Purification by liquid chromatography to collect product compound 25 with a purity greater than 95%.
实施例 5化合物 31 (PtCl2-Met-5-AVA- RGN) 的合成
Synthesis of Compound 31 (PtCl 2 -Met-5-AVA-RGN) of Example 5
31 31
1)化合物 27的合成 1) Synthesis of Compound 27
冰浴条件下， Boc- Met-OH和 HOSu溶解在 EA中， DCC/EA混合溶液缓慢滴加。 滴加 完毕后移走冰浴， 继续反应 2h; 监测反应完全后过滤， 滤液旋蒸白色固体； 加入甲苯， 60 °C水浴搅拌至固体完全溶解； 旋蒸至有固体析出， 冷却放置过夜。 过滤并用少量甲苯 和***洗涤， 干燥箱干燥 2h， 得到白色固体。 Under ice bath conditions, Boc-Met-OH and HOSu were dissolved in EA, and the DCC/EA mixed solution was slowly added dropwise. After the completion of the dropwise addition, the ice bath was removed, and the reaction was continued for 2 hours; the reaction was completely filtered, and the filtrate was evaporated to a white solid; toluene was added and stirred in a water bath at 60 ° C until the solid was completely dissolved; It was filtered and washed with a small amount of toluene and diethyl ether and dried in a dry room for 2h to give a white solid.
2)化合物 28的合成 2) Synthesis of Compound 28
冰浴条件下， 化合物 27溶解在 DMF中， 缓慢滴加到 5-AVA-OH的 DMF溶液中。滴加 完毕后， 撤去冰浴， 反应过夜。 确认反应完成后， 加入过量的水中， 过滤得到化合物 28。 Compound 27 was dissolved in DMF under ice bath and slowly added dropwise to a solution of 5-AVA-OH in DMF. After the addition was completed, the ice bath was removed and the reaction was allowed overnight. After confirming the completion of the reaction, it was added to an excess of water and filtered to give Compound 28.
3)化合物 29 的合成 3) Synthesis of compound 29
取化合物 28加入 TFA中， 反应 lh。 监测反应完毕后， 离心收集固体， 以异丙醚洗 涤， 得产物。 Compound 28 was added to TFA and reacted for 1 h. After the completion of the reaction, the solid was collected by centrifugation and washed with isopropyl ether to give the product.
4)化合物 30的合成 4) Synthesis of Compound 30
TFA.H-Met-5-AVA -OH溶解在水中， 用 Na2C03调节 pH至 8〜9， 加入 K2PtC 溶液， 反 应进行期间连续监测 pH值， 保持 pH 8〜9， 反应过夜； 抽滤并干燥， 得黄色固体。 TFA.H-Met-5-AVA-OH is dissolved in water, the pH is adjusted to 8~9 with Na 2 CO 3 , K 2 PtC solution is added, pH is continuously monitored during the reaction, pH 8~9 is maintained, and the reaction is overnight; It was suction filtered and dried to give a yellow solid.
5)化合物 31的合成 5) Synthesis of Compound 31
a) 取已连接 RGN多肽的树脂加入固相反应瓶中， DMF溶胀后，依次加入 Cl2Pt - Met
-5-AVA -OH, HOBt, DIC， 反应过夜， 检测反应完全后， 抽干， DMF洗 3次， 二氯甲烷洗 3次， 甲醇收縮树脂； a) Add the resin to which the RGN polypeptide has been attached to the solid phase reaction bottle. After the DMF is swollen, add the Cl 2 Pt - Met. -5-AVA -OH, HOBt, DIC, reaction overnight, after the reaction was completed, drained, DMF washed 3 times, washed with dichloromethane 3 times, methanol shrinkage resin;
b) 树脂加入裂解液 （TFA:TIS: 水 =95:2.5:2.5)， 搅拌 2h， 过滤并用 TFA洗涤树脂 2 次。 反应液旋蒸浓縮至约 50ml反应液后， 倒入已冰浴过的异丙醚 500ml中， 有 白色沉淀析出， 稍静置片刻后， 离心并干燥得到白色产物； b) The resin was added to the lysate (TFA: TIS: water = 95:2.5:2.5), stirred for 2 h, filtered and the resin was washed twice with TFA. The reaction solution was concentrated by rotary evaporation to about 50 ml of the reaction mixture, poured into 500 ml of ice-cold isopropyl ether, and precipitated as a white precipitate. After standing for a while, it was centrifuged and dried to obtain a white product;
c) 用液相色谱纯化， 收集纯度大于 95%的产品 Cl2Pt - Met -5-AVA -RGN。 c) Purification by liquid chromatography to collect the product Cl 2 Pt - Met -5-AVA -RGN with a purity greater than 95%.
上述实际例仅为示例性说明， 并不可被认为是对本发明的局限。 如上述的靶向识别序 列，除了上述的 RGD、 RGN，还可以是其他为本领域技术人员所熟知的三肽，如 RGE、 RGQ 、 HGD、 HGE、 HGN、 HGQ KGD、 KGE、 KGN、 KGQ DGR、 DGK、 NGR等， 也可以是 其他已经报导的具有肿瘤靶向性的多肽。 The above actual examples are merely illustrative and are not to be considered as limiting the invention. The above-mentioned targeted recognition sequence may be other tripeptides well known to those skilled in the art, such as RGE, RGQ, HGD, HGE, HGN, HGQ KGD, KGE, KGN, KGQ DGR, in addition to the above RGD, RGN. , DGK, NGR, etc., may also be other polypeptides that have been reported to have tumor targeting properties.
动物实验： Animal experiment:
多肽-顺铂偶联化合物 (PtCl2-Orn-5-AVA -RGD)对荷瘤裸鼠的抑瘤作用 Antitumor effect of peptide-cisplatin-conjugated compound (PtCl 2 -Orn-5-AVA -RGD) on tumor-bearing nude mice
细胞系： 人肺鳞癌细胞系 NCI-H1299 Cell line: Human lung squamous cell carcinoma cell line NCI-H1299
实验动物： 健康 Balb-c裸鼠， 雄雌各半， 接种 3-4周后取瘤体直径约 0.3-0.5cm的裸鼠用 于实验。 Experimental animals: Healthy Balb-c nude mice, male and female, were inoculated for 3-4 weeks after inoculation of nude mice with a tumor diameter of about 0.3-0.5 cm.
药品： 多肽-顺铂偶联配合物 RGD-5-AVA-Om-PtCl2 (批号： zp-2-pl9)、 注射用顺铂 （山 东齐鲁， 批号 203008CF)。 Drugs: Peptide-cisplatin-conjugated complex RGD-5-AVA-Om-PtCl 2 (batch number: zp-2-pl9), cisplatin for injection (Shandong Qilu, Lot No. 203008CF).
药品的配制： 多肽-顺铂偶联配合物以注射用生理盐水溶解， 混匀， 在超净工作台内以 0.22μηι滤头过滤除菌。 取注射用顺铂于超净工作台内以注射用生理盐水溶解， 混匀备用。 Preparation of the drug: The peptide-cisplatin-conjugated complex was dissolved in physiological saline for injection, mixed, and sterilized by filtration through a 0.22 μηι filter in a clean bench. The cisplatin for injection was dissolved in physiological saline solution for injection in a clean bench, and mixed for use.
分组： 实验设置阴性对照组、 阳性对照组和 RGD-顺铂配合物实验组 （高、 中、 低剂量 组， 按 6:3:1设置）。 每组包括已造模成功的裸鼠 6只。 Grouping: Experimental setting negative control group, positive control group and RGD-cisplatin complex experimental group (high, medium and low dose groups, set at 6:3:1). Each group included 6 nude mice that had been successfully modeled.
剂量： RGD-顺铂配合物的给药量为： 高剂量组 90μΜ.1¾- 中剂量组 30μΜ.1¾- 低剂量 组 10μΜ.1¾- 顺铂组 10μΜ.1¾- ^ 通过尾静脉注射给药， 根据体重确定给药量， 一天 1次、 连给 5天。 Dosage: The dose of RGD-cisplatin complex is: high dose group 90μΜ.13⁄4- medium dose group 30μΜ.13⁄4- low dose group 10μΜ.13⁄4-cisplatin group 10μΜ.13⁄4- ^ administered by tail vein injection, The amount of administration was determined according to the body weight, once a day, for 5 days.
实验方法： 健康 Balb-c裸鼠， 雄雌各半， 3 周龄左右， 体重 18-22g。 人肺鳞癌细胞株 NCI-H1299大量培养，用含有 0.01%EDTA的 0.25%胰酶消化， lOOOrpm离心 1.5min，去上清， 加入无血清的 DMEM 培养液重悬沉淀， 细胞计数调整细胞密度， 于裸鼠前右腋下皮下接种 2χ106个细胞 /只，三到四周左右观察，成瘤率达 95%左右，接种 3-4周后取瘤体直径约 0.3-0.5cm 的裸鼠用于实验。 Experimental methods: Healthy Balb-c nude mice, male and female, about 3 weeks old, weighing 18-22g. Human lung squamous cell carcinoma cell line NCI-H1299 was cultured in large amounts, digested with 0.25% trypsin containing 0.01% EDTA, centrifuged at 1000 rpm for 1.5 min, de-cleared, resuspended in serum-free DMEM medium, and cell count adjusted for cell density. Nude mice were inoculated with 2χ10 6 cells/nose in front of the right axilla, and the tumor formation rate was about 95%. After 3-4 weeks of inoculation, nude mice with a tumor diameter of about 0.3-0.5 cm were used for the nude mice. experiment.
多肽-顺铂偶联配合物以注射用生理盐水溶解， 混匀， 在超净工作台内以 0.22μηι滤头过 滤除菌。 取注射用顺铂于超净工作台内以注射用生理盐水溶解， 混匀备用。 给药前称重， 按
The polypeptide-cisplatin-conjugated complex was dissolved in physiological saline for injection, mixed, and sterilized by filtration through a 0.22 μηι filter in a clean bench. The cisplatin for injection was dissolved in physiological saline solution for injection in a clean bench, and mixed for use. Weigh before dosing, press
模剂量剂量低剂量顺铂组组高型中 15 体重确定给药量。 以尾静脉注射方式给药， 一天一次， 连续给药 5天， 给药结束后继续观察 9天， 于第 15天将动物处死， 取脏器和肿瘤。 The mode dose dose low dose cisplatin group high type 15 body weight determines the dose. The drug was administered by tail vein injection once a day for 5 days, and after the end of the administration, the observation was continued for 9 days, and on the 15th day, the animals were sacrificed, and organs and tumors were taken.
检测指标： 每 2日裸鼠称重并测量瘤体直径， 动态观察药物对受试裸鼠的抗肿瘤效应。 于第 15天将动物处死， 剥取瘤体、 肝脏和肾脏并称重， 计算脏器系数。 以瘤重为指标计算肿 瘤抑制率： 肿瘤抑制率 = ( 1- 给药组平均瘤重 /对照组平均瘤重） χΐοο%。 Detection index: The nude mice were weighed and measured the diameter of the tumor every 2 days, and the anti-tumor effect of the drug on the nude mice was observed dynamically. Animals were sacrificed on day 15 and the tumor, liver and kidneys were stripped and weighed to calculate the organ coefficient. Tumor inhibition rate was calculated using tumor weight as an indicator: Tumor inhibition rate = (1 - mean tumor weight of the administration group / mean tumor weight of the control group) χΐοο%.
结果见表 1、 表 2、 表 3、 表 4。 表 1 ζρ-2-ρ19对裸小鼠脏器重量、 脏器系数的影响 （ ± s， n = 6 ) ~~体重 肿瘤 肝脏 肾脏 脾脏 The results are shown in Table 1, Table 2, Table 3, and Table 4. Table 1 Effect of ζρ-2-ρ19 on organ weight and organ coefficient in nude mice (± s, n = 6 ) ~~ Body weight Tumor Liver Kidney Spleen
组 /g 重量 /g L 重量 /g L 重量 /g L 重量 /g L ~Group /g Weight /g L Weight /g L Weight /g L Weight /g L ~
18.7 18.7
0.522 0.0279 1.2633 0.0679 0.327 0.0175 0.0883 0.00473 士 0.97 0.522 0.0279 1.2633 0.0679 0.327 0.0175 0.0883 0.00473士 0.97
±0.180 ±0.0108 ±0.0840 士 0.00710 ±0.0528 士 0.00300 士 0.00750 ±0.00361 4 ±0.180 ±0.0108 ±0.0840 ± 0.00710 ±0.0528 ± 0.00300 ± 0.00750 ± 0.00361 4
20.5 0.418 0.0204 1.62 0.0664 0.342 0.0166 0.0917 0.0045 ±2.81 ±0.182 士 0.00970 ±0.870 ±0.0310 ±0.0717 ±0.0015 ±0.0279 ±0.0009 20.5 0.418 0.0204 1.62 0.0664 0.342 0.0166 0.0917 0.0045 ±2.81 ±0.182 ±0.0070 ±0.870 ±0.0310 ±0.0717 ±0.0015 ±0.0279 ±0.0009
19.3 0.932 0.0484 1.2367 0.0642 0.3050 0.0158 0.100 0.00520 ±1.04 ±0.438 士 0.0224 ±0.116 士 0.00481 士 0.0356 ±0.00110 士 0.0358 ±0.00181 19.3 0.932 0.0484 1.2367 0.0642 0.3050 0.0158 0.100 0.00520 ±1.04 ±0.438 ± 0.0224 ±0.116 ± 0.00481 ± 0.0356 ±0.00110 ± 0.0358 ±0.00181
0.00300 0.00300
14.1 0.398 0.0282 1.04 0.0724 0.262 0.0191 0.0417 14.1 0.398 0.0282 1.04 0.0724 0.262 0.0191 0.0417
±0.00176 ±2.72 ±0.192 ±0.0182 ±0.318 ±0.0142 士 0.0445 士 0.00438 士 0.0264 * ±0.00176 ±2.72 ±0.192 ±0.0182 ±0.318 ±0.0142 ± 0.0445 士 0.00438 士 0.0264 *
0.00491 0.00491
21.9 0.758 0.0346 1.42 0.0648 0.387 0.0176 0.107 21.9 0.758 0.0346 1.42 0.0648 0.387 0.0176 0.107
±0.00055 ±3.17 ±0.429 ±0.0272 ±0.283 ±0.00809 士 0.0841 ±0.00175 ±0.0137 ±0.00055 ±3.17 ±0.429 ±0.0272 ±0.283 ±0.00809 ± 0.0841 ±0.00175 ±0.0137
2 2
*— P<0.05 , 与空白组比较。 *—P<0.05, compared with the blank group.
表 2 zp-2-pl9对裸小鼠体重的影响 （x± s， n = 6 ) 给药前 2d 4d 6d 8d 10d 12d 14d Table 2 Effect of zp-2-pl9 on body weight of nude mice (x± s, n = 6) 2d 4d 6d 8d 8d 10d 12d 14d
1¾齐11量 19.2士 1.2 18.4士 1.2 18.2士 1.2 16.5士0.8 16.5士 0.7 17.2士 0.9 18.0士 1.0 18.3士0.9 中剂量 18.4士 1.4 17.5士 1.2 17.8士 1.2 17.9士 2.3 18.7士 2.5 19.6士 3.0 20.3士3.1 20.2士 2.8 低剂量 19.2士 0.8 18.4士 0.9 18.7士 0.8 18.4士 1.0 19.2士 1.0 19.5士 1.0 19.8士1.1 19.8士1.0 顺铂组 18.8士1.6 17.3士1.7 16.9士1.8 15.0士 1.9 13.7士1.8 13.5士2.5 14.0士 2.1 14.4士 1.9 模型组 21.1士0.8 22.4士 0.5 23.4士 1.1 22.4士 2.7 22.3士 2.4 22.4士 2.2 22.4士 2.8 22.7士 2.7 表 3、 zp-2-pl9对裸小鼠肿瘤体积的影响 （^± s， n = 6 ) 给药前 2d 4d 6d 8d lOd 12d 14d
71.3士 101.21士 138.8士 182.8士 9 277.7士 367.2士 453.7士 579.0士 507.7士13⁄4齐11量19.2士1.2 18.4士1.2 18.2士1.2 16.5士0.8 16.5士0.7 17.2士0.918.0士1.0 18.3士0.9中量18.4士1.417.5士1.2 17.8士1.2 17.9士2.3 18.7士2.5 19.6士3.0 20.3士3.1 20.2士2.8 Low dose 19.2士0.8 18.4士0.9 18.7士0.8 18.4士1.0 19.2士1.0 19.5士1.0 19.8士1.1 19.8士1.0 cisplatin group 18.8±1.6 17.3士1.7 16.9士1.8 15.0士1.9 13.7士1.8 13.5士2.5 14.0士2.1 14.14士1.9 Model group 21.1士0.8 22.4士0.5 23.4士1.1 22.4士2.7 22.3士2.4 22.4士2.2 22.4士2.8 22.7士2.7 Table 3, zp-2-pl9 effect on tumor volume of nude mice ( ^± s, n = 6 ) 2d before administration 4d 6d 8d lOd 12d 14d 71.3士101.21士138.8士182.8士9 277.7士367.2士453.7士579.0士507.7士
1¾齐11量 13⁄4 Qi 11 amount
38.9 58.8 103.2 9.2 172.3 157.3 180.3 127.5 128.6 38.9 58.8 103.2 9.2 172.3 157.3 180.3 127.5 128.6
63.6士 109.7士 129.4士 195.3士 251.3士 327.1士 446.8士 484.2士 420.7士 中剂量 63.6士 109.7士 129.4士 195.3士 251.3士 327.1士 446.8士 484.2士 420.7士中剂量
30.2 50.7 74.1 135.9 135.4 160.0 172.3 179.3 162.3 30.2 50.7 74.1 135.9 135.4 160.0 172.3 179.3 162.3
88.7士 252.5士 313.8士 465.7士 590.8士 680.0士 752.5士 810.6士 851.9士 低剂量 88.7士 252.5士 313.8士 465.7士 590.8士 680.0士 752.5士 810.6士 851.9士 Low dose
28.1 112.0 186.4 251.2 286.4 354.5 405.3 429.9 412.1 28.1 112.0 186.4 251.2 286.4 354.5 405.3 429.9 412.1
78.5士 268.0士 307.4 352.6 341.7 390.2 414.5 417.6 339.1士 顺铂组 78.5士 268.0士 307.4 352.6 341.7 390.2 414.5 417.6 339.1士 cisplatin group
20.1 165.3 士 169.5 ±178.1 ±173.0 士 221.9 士 204.4 ±189.3 177.7 20.1 165.3 ± 169.5 ± 178.1 ± 173.0 ± 221.9 ± 204.4 ± 189.3 177.7
62.3士 141.1 181.4 226.4 322.6 427.2 585.7 769.9 807.65士 模型组 62.3士 141.1 181.4 226.4 322.6 427.2 585.7 769.9 807.65 士模型组
19.5 ±40.0 ±97.8 士 221.6 ±273.4 ±344.3 ±387.0 ±487.3 495.5 19.5 ±40.0 ±97.8 ± 221.6 ±273.4 ±344.3 ±387.0 ±487.3 495.5
(单位： 立方毫米） (Unit: cubic mm)
表 4、 zp-2-pl9的抑瘤率 ( x± s, 组别 抑瘤率 （瘤重） （％) Table 4. Tumor inhibition rate of zp-2-pl9 (x± s, group inhibition rate (tumor weight) (%)
高齐 U量 41.21% High Qi U amount 41.21%
中剂量 31.91% Medium dose 31.91%
低剂量 12.86% Low dose 12.86%
顺铂组 52.95% Cisplatin group 52.95%
结果表明： 在表 1中， 对各剂量组裸小鼠脏器重量、 脏器系数进行统计学分析， 顺铂组 动物的肝脏、 肾脏显著肿大， 脾脏萎縮， 从脏器系数的相关数据， 显示顺铂对肝脏、 肾脏、 脾脏都具有明显的毒性， 而 zp-2-pl9各剂量组均无出现明显的肝脏、 肾脏、 脾脏毒副作用。 在表 2中， 从实验 14天的体重变化趋势， 与模型组对比， 顺铂组动物在给药第二天开始即出 现明显的下降趋势， 虽然给药结束后有一定程度回升， 但仍明显小于 zp-2 pl9实验组及模型 组， 而 zp-2-pl9各剂量组均无出现明显的体重改变。 在表 3中， 从实验前后肿瘤体积的变化 情况， 与模型组相比， zp-2-pl9 各剂量组和顺铂组均显示出较好的抑瘤效果， 从瘤体体积变 化趋势可见 zp-2的抑瘤作用具有一定的量效关系。在表 4中， 可见 zp-2-pl9与顺铂组均具有 较好的抑瘤效果， 且 zp-2-pl9的抑瘤作用与给药剂量有关。 多肽-顺铂偶联化合物 (zp-2-pl9)对昆明小鼠的急性毒性作用 The results showed that: In Table 1, the organ weight and organ coefficient of the nude mice in each dose group were statistically analyzed. The liver and kidney of the cisplatin group were significantly enlarged, the spleen was atrophied, and the data from the organ coefficient were It showed that cisplatin had obvious toxicity to liver, kidney and spleen, but no obvious side effects of liver, kidney and spleen appeared in zp-2-pl9 dose group. In Table 2, from the trend of body weight change in the experiment for 14 days, compared with the model group, the animals in the cisplatin group showed a significant downward trend from the second day after administration, although there was a certain degree of recovery after the end of the administration, it was still obvious. Less than the zp-2 pl9 experimental group and the model group, and no significant weight changes were observed in the zp-2-pl9 dose groups. In Table 3, compared with the model group, the zp-2-pl9 dose group and the cisplatin group showed better antitumor effect compared with the model group, and the zp was observed from the tumor volume change trend. The antitumor effect of -2 has a certain dose-effect relationship. In Table 4, it can be seen that both zp-2-pl9 and cisplatin have a good antitumor effect, and the antitumor effect of zp-2-pl9 is related to the dose administered. Acute Toxicity of Polypeptide-cisplatin-conjugated Compound (zp-2-pl9) to Kunming Mice
实验动物： 健康昆明小鼠， 雄雌各半， 4周龄左右， 体重 18-22g， 购自广东省医学实验 动物中心。 Experimental animals: Healthy Kunming mice, male and female, about 4 weeks old, weighing 18-22g, purchased from Guangdong Medical Laboratory Animal Center.
药品的配制： zp-2-pl9以注射用生理盐水溶解， 混匀， 在超净工作台内以 0.22μηι滤头过
滤除菌。 取注射用顺铂于超净工作台内以注射用生理盐水溶解， 混匀备用。 Preparation of the drug: zp-2-pl9 is dissolved in physiological saline for injection, mixed, and passed through a 0.22μηι filter in a clean bench. Filter the bacteria. The cisplatin for injection was dissolved in physiological saline solution for injection in a clean bench, and mixed for use.
分组： 预先采用少量动物逐步摸索出上下限量， 即使全部动物死亡的最小剂量（Dm)和 一个动物也不死亡的最大剂量 （Dn)。 根据预实验结果确定实验组数和剂量， 将动物分为 7 个剂量组。 Grouping: A small number of animals were used to gradually explore the upper and lower limits, even the minimum dose (Dm) for all animals and the maximum dose (Dn) for an animal. The number of experimental groups and the dose were determined based on the results of the preliminary experiments, and the animals were divided into 7 dose groups.
方法： 采用随机方法进行分组， 按体重自低到高排序编号， 依随机数字表法分组。 Methods: Grouped by random method, sorted by weight from low to high, grouped according to random number table method.
数量： 满足统计学要求， 通常每个剂量组至少包括 10只动物。 Quantity: Meets statistical requirements, usually consisting of at least 10 animals per dose group.
剂量： 在预试的基础上进行正式试验。 Zp-2剂量分别设为 152.82mg.kg- 230 mg.kg 1 , 305.64 mg.kg"1 382.05 mg.kg"1 420.26 mg.kg"1 458.46 mg.kg"1 611.28 mg.kg— 1七组。 顺铂剂 量设为 5.00 mg.kg"1 8.75 mg.kg"1 13.10 mg.kg"1 17.50 mg.kg"1 26.25 mg.kg"1 35.00 mg.kg"1 52.50 mg.kg—1七组。 Dosage: A formal test is performed on a pre-test basis. The Zp-2 dose was set to 152.82 mg.kg - 230 mg.kg 1 , 305.64 mg.kg" 1 382.05 mg.kg" 1 420.26 mg.kg" 1 458.46 mg.kg" 1 611.28 mg.kg - 1 7 groups . The cisplatin dose was set to 5.00 mg.kg" 1 8.75 mg.kg" 1 13.10 mg.kg" 1 17.50 mg.kg" 1 26.25 mg.kg" 1 35.00 mg.kg" 1 52.50 mg.kg - 1 seven groups.
给药方法： 给药前禁食 6-12小时， 给药后再禁食 3-4小时。 Method of administration: Fasting for 6-12 hours before administration and fasting for 3-4 hours after administration.
给药途径： 尾静脉注射。 Route of administration: Intravenous injection.
检测指标： 观察动物体重、 饮食、 外观、 行为、 分泌物、 ***物及中毒症状等变化， 记 录动物的死亡情况、 中毒症状及中毒反应的起始时间、 严重程度、 持续时间等并分别在给药 前 （D0)、 给药后第 3天 （D3)、 第 5天 （D5 ) 称量动物体重。 结果见表 5、 表 6。 Test indicators: Observe the changes in animal weight, diet, appearance, behavior, secretions, excretion and poisoning symptoms, record the death of the animal, the symptoms of poisoning and the start time, severity, duration of the poisoning reaction, etc. Animal body weight (D0), day 3 (D3), and day 5 (D5) were weighed. The results are shown in Table 5 and Table 6.
表 5 zp-2-p!9对 KM小鼠的急性毒性 Table 5 Acute toxicity of zp-2-p!9 in KM mice
(mg-kg 1 ) 动物数 （只） 死亡数 （只） 死亡百分率 （％) (mg-kg 1 ) Number of animals (only) Number of deaths (only) Percentage of death (%)
152.82 10 0 0.00 152.82 10 0 0.00
230.00 10 0 0.00 230.00 10 0 0.00
305.64 10 1 10.00 305.64 10 1 10.00
382.05 10 3 30.00 382.05 10 3 30.00
420.26 10 4 40.00 420.26 10 4 40.00
458.46 10 7 70.00 458.46 10 7 70.00
611.28 10 10 100.00 611.28 10 10 100.00
半数致死量 LD5Q=419.08mg.kg- 1 (相当于摩尔质量的 521.05μΜ.1¾- LD50(Feiller校正) 95%的可信限 =382.66-462.49mg.kg— 表 6 顺铂对 KM小鼠的急性毒性 The median lethal dose LD 5Q = 419.08 mg.kg - 1 (equivalent to the molar mass of 521.05 μΜ.13⁄4-LD 50 (Feiller correction) 95% confidence limit = 382.66-462.49 mg.kg - Table 6 cisplatin to KM small Acute toxicity of rats
齐 LI量 (mg.kg-1 ) 动物数 （只） 死亡数 （只） 死亡百分率 （％) Quantity of LI (mg.kg -1 ) Number of animals (only) Number of deaths (only) Percentage of death (%)
5.00 10 0 0.00 5.00 10 0 0.00
8.75 10 1 10.00
13.10 10 3 30.00 8.75 10 1 10.00 13.10 10 3 30.00
17.50 10 7 70.00 17.50 10 7 70.00
26.25 10 9 90.0026.25 10 9 90.00
35.00 10 10 100.0035.00 10 10 100.00
52.50 10 10 100.00 半数致死量 LD5 l5.029mg.kg-1 (相当于摩尔浓度的 50.08μΜ.1¾- ^ 52.50 10 10 100.00 LD5 l5.029mg.kg- 1 (equivalent to a molar concentration of 50.08μΜ.13⁄4-^
LD50(Feiller校正) 95%的可信限 =12.208-18.051mg.kg— LD 50 (Feiller correction) 95% confidence limit = 12.208-18.051mg.kg—
表 7 zp-2及顺铂对 KM小鼠的半数致死量 Table 7 The median lethal dose of zp-2 and cisplatin in KM mice
组别 回归方程 LD50 ( μΜ-kg-Group regression equation LD 50 ( μΜ-kg-
Zp-2 y(Probit)= -25.887+11.779Log(D) 521.05 Zp-2 y(Probit)= -25.887+11.779Log(D) 521.05
顺铂 y(Probit)= :-2.102+6.0344Log(D) 50.08 Cisplatin y (Probit) = :-2.102+6.0344Log(D) 50.08
结果表明： 在表 5中， zp-2-pl9对 KM小鼠的急性毒性结果表明， zp-2 pl9的安全范围 较大， LD5Q达到 419.08mg.kg- 表 6中， 顺铂对 KM小鼠的急性毒性结果表明， 顺铂的安全 范围较小， LD5o为 15.029mg.kg- 表 7中， zp-2 pl9及顺铂对 KM小鼠的半数致死量结果表 明， 由于 zp-2 pl9可选择性与整合素受体特异性结合， 对正常脏器组织的影响较小， 因此毒 性显著降低， 安全范围大。 而顺铂作为传统的细胞毒类抗肿瘤药物， 对肿瘤细胞的选择性低， 在损伤肿瘤细胞的同时， 对正常的组织细胞也有一定程度的损伤， 毒性明显， 安全范围较小。
The results showed that: In Table 5, the acute toxicity of zp-2-pl9 to KM mice showed that the safe range of zp-2 pl9 was larger, LD 5Q reached 419.08 mg.kg-Table 6, and cisplatin was small for KM. The acute toxicity of the mice showed that the safe range of cisplatin was small, LD 5 o was 15.029 mg.kg - in Table 7, the median lethal dose of zp-2 pl9 and cisplatin to KM mice showed that due to zp-2 Pl9 selectively binds specifically to integrin receptors and has less effect on normal organ tissues, so toxicity is significantly reduced and the safety range is large. As a traditional cytotoxic antitumor drug, cisplatin has low selectivity to tumor cells, and damages tumor cells at the same time, it also has a certain degree of damage to normal tissue cells, with obvious toxicity and a small safety range.
Claims
权 利 要 求 书 Claims
1. 一种铂配体， 其化学式如式 I所示: A platinum ligand having the chemical formula shown in formula I:
式中， m=2-5， Z为 C2~4的饱和碳链， X和 Y独立为 NH2、 NR'2、 SR'， COOH基团， 分 别连接在 Z的不同碳上， ！ '为 — 4烷基。 Where m = 2-5, Z is a saturated carbon chain of C 2 ~ 4 , and X and Y are independently NH 2 , NR' 2 , SR', COOH groups, respectively attached to different carbons of Z, ! '为-4 alkyl.
2. 根据权利要求 1所述的铂配体， 其特征在于： X和 Y独立为 NH2， SR'。 2. The platinum ligand according to claim 1, wherein X and Y are independently NH 2 , SR′.
3. 根据权利要求 2所述的铂配体， 其特征在于： X和 Y独立为 NH2。 The platinum coordination body according to claim 2, wherein: X and Y are independently NH 2.
4. 一种末端修饰的靶向多肽， 其通式如式 II所示： 4. A terminally modified targeting polypeptide having the general formula shown in Formula II:
式中， m=2-5， Z为 C2~4的饱和碳链， X和 Y独立为 NH2、 NR'2、 SR'、 COOH基团， 分 别连接在 Z的不同碳上， R为靶向识别序列， ！ '为 — 4烷基。 Where m = 2-5, Z is a saturated carbon chain of C 2 ~ 4 , and X and Y are independently NH 2 , NR' 2 , SR ', COOH groups, respectively attached to different carbons of Z, R is Targeting recognition sequences, ! '为-4 alkyl.
5 根据权利要求 4所述的末端修饰的靶向多肽， 其特征在于： R为靶向识别多肽序列。 The terminally modified targeting polypeptide according to claim 4, wherein R is a targeting recognition polypeptide sequence.
一种靶向试剂， 由上述末端修饰的靶向多肽与功能化合物配合而成。 A targeting agent is prepared by complexing a target polypeptide modified by the above terminal with a functional compound.
根据权利要求 6所述的靶向试剂， 其特征在于： 功能化合物选自抗肿瘤药物、 检测试剂。 根据权利要求 6所述的靶向试剂， 其特征在于： 抗肿瘤药物选自铂类抗肿瘤药物、 活性 抗肿瘤多肽， 其中， 配合得到的靶向含铂抗肿瘤药物的通式如式 III所示： The targeting agent according to claim 6, wherein the functional compound is selected from the group consisting of an antitumor drug and a detection reagent. The targeting agent according to claim 6, wherein the antitumor drug is selected from the group consisting of a platinum antitumor drug and an active antitumor polypeptide, wherein the compounded platinum-containing antitumor drug has the general formula of Formula III Show:
〇、 P 〇, P
\ // \ //
一 NH— (CH2)m— C\ One NH—(CH 2 ) m — C\
X -—- Z NH X -——- Z NH
R P R R P R
R2 式 （III) R2 type (III)
式中， m=2-5， Z为 C2~4的饱和碳链， X和 Y独立为 NH2、 NR'2、 SR'， COOH基团， 分 别连接在 Z的不同碳上， ！ '为 — 4烷基， R为靶向识别序列； Ri、 R2分别为独立的基团， 或 、 R2共价连接成环。 Where m = 2-5, Z is a saturated carbon chain of C 2 ~ 4 , and X and Y are independently NH 2 , NR' 2 , SR', COOH groups, respectively attached to different carbons of Z, ! ' is -4 alkyl, R is a targeting recognition sequence; Ri, R 2 are each an independent group, or R 2 is covalently linked to form a ring.
9. 根据权利要求 8所述的靶向试剂， 其特征在于： 抗肿瘤药物选自顺铂、 卡铂、 奥沙利铂。 9. The targeting agent according to claim 8, wherein the antitumor drug is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin.
10.根据权利要求 8所述的靶向试剂， 其特征在于： 、 R2独立为 C1或 H20。
The targeting agent according to claim 8, wherein: R 2 is independently C1 or H 2 0.
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| CN102311482A (en) * | 2010-05-20 | 2012-01-11 | 中国医学科学院药物研究所 | Aro-peptide and preparation method as well as medicinal combination and application of aro-peptide |
| CN102389102A (en) * | 2011-11-01 | 2012-03-28 | 南京农业大学 | Low-sodium compound salt |
| CN103288673A (en) * | 2013-05-28 | 2013-09-11 | 广东药学院 | Platinum ligand and coordination compound thereof |
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| US5110797A (en) * | 1985-10-14 | 1992-05-05 | Nippon Zoki Pharmaceutical Co., Ltd. | Peptide compound and a pharmaceutically acceptable salt thereof |
| CN102311482A (en) * | 2010-05-20 | 2012-01-11 | 中国医学科学院药物研究所 | Aro-peptide and preparation method as well as medicinal combination and application of aro-peptide |
| CN102389102A (en) * | 2011-11-01 | 2012-03-28 | 南京农业大学 | Low-sodium compound salt |
| CN103288673A (en) * | 2013-05-28 | 2013-09-11 | 广东药学院 | Platinum ligand and coordination compound thereof |
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| CN115068501A (en) * | 2022-05-25 | 2022-09-20 | 中国科学院深圳先进技术研究院 | Antineoplastic quadrivalent platinum complex prodrug and preparation method and application thereof |
| CN115068501B (en) * | 2022-05-25 | 2023-08-11 | 中国科学院深圳先进技术研究院 | Antitumor tetravalent platinum complex prodrug, and preparation method and application thereof |
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