CN110922349B - 一种抗肿瘤化合物的合成及其在多发性骨髓瘤中的应用 - Google Patents
一种抗肿瘤化合物的合成及其在多发性骨髓瘤中的应用 Download PDFInfo
- Publication number
- CN110922349B CN110922349B CN201911196800.4A CN201911196800A CN110922349B CN 110922349 B CN110922349 B CN 110922349B CN 201911196800 A CN201911196800 A CN 201911196800A CN 110922349 B CN110922349 B CN 110922349B
- Authority
- CN
- China
- Prior art keywords
- compound
- multiple myeloma
- tumor
- application
- tumor compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 29
- 206010035226 Plasma cell myeloma Diseases 0.000 title claims description 26
- 208000034578 Multiple myelomas Diseases 0.000 title claims description 14
- 230000000259 anti-tumor effect Effects 0.000 title abstract description 8
- 230000015572 biosynthetic process Effects 0.000 title description 4
- 238000003786 synthesis reaction Methods 0.000 title description 4
- 239000003814 drug Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 201000000050 myeloid neoplasm Diseases 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- -1 indole compound Chemical class 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- JTEJPPKMYBDEMY-UHFFFAOYSA-N 5-methoxytryptamine Chemical compound COC1=CC=C2NC=C(CCN)C2=C1 JTEJPPKMYBDEMY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 101710085938 Matrix protein Proteins 0.000 description 2
- 101710127721 Membrane protein Proteins 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000009982 effect on human Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- FXOSSGVJGGNASE-UHFFFAOYSA-N 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(N=C=S)=CC(C(F)(F)F)=C1 FXOSSGVJGGNASE-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940097276 5-methoxytryptamine Drugs 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002559 cytogenic effect Effects 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种抗肿瘤药如式Ⅰ所示及其在肿瘤治疗药物中的应用,属于抗肿瘤药学技术范围。本发明解决的技术问题是提供一种肿瘤抑制剂的化合物。该化合物包括如下所示的化合物及其在药学上可接受的盐,可以作为一种肿瘤抑制剂,具有一定的抗肿瘤活性。式Ⅰ
Description
技术领域
本发明公开一种新型抗肿瘤药的合成以及在肿瘤治疗中的应用,研究表明,该化合物对人骨髓瘤细胞U266具有较好的抑制作用,属于肿瘤治疗药物发现的技术领域,为***药开发提供依据。
背景技术
多发性骨髓瘤(MM)是一种恶性浆细胞病,属于B淋巴细胞淋巴瘤的范围,其肿瘤细胞起源于骨髓中的浆细胞,而浆细胞是B淋巴细胞发育到最终功能阶段的细胞。其特征为骨髓浆细胞异常增生伴有单克隆免疫球蛋白或轻链(M蛋白)过度生成,极少数患者可以是不产生M蛋白的未分泌型MM。临床表现多样,主要有贫血、骨痛、肾功能不全、感染、出血、神经症状、高钙血症、淀粉样变等。据统计多发性骨髓瘤发病率估计为2~3/10万,男女比例为1.6:1,40岁以上,特别是60岁以上的老年人为多发群体。
随着生物化学、分子生物学和细胞遗传学等学科的发展,越来越多的新的靶向多发性骨髓治疗的药物已经被识别并开始应用于临床取得了可喜的成果。目前,硼替佐米,伊沙佐米是临床上最广泛的靶向药。尽管如此,多发性骨髓瘤(MM)仍是一种不能治愈的血液***肿瘤。多发性骨髓瘤患者多数为不能耐受强烈化疗中老年人,而目前应用的药物大多为化学药剂。这些药物不仅对身体有毒副作用还引起药物耐药。因此,开发靶向性的新型小分子精准治疗药物是克服MM临床问题的关键,也是未来发展的趋势和热点。
本发明涉及的化合物是一个全新骨架化合物,该化合物拥有全新的骨架类型,目前没有关于活性的报道,对于本发明涉及的化合物在制备抑制U266细胞 (多发性骨髓瘤),但不限于U266细胞,抗肿瘤作用属于首次公开,而且由于骨架类型属于全新的骨架类型,不存在由其他化合物给出任何启示的可能,具备突出的实质性特点,同时用于多发性骨髓瘤(U266细胞)的抑制显然具有显著效果。
发明内容
本发明解决的问题是提供一种抗肿瘤的新化合物。
本发明的一个目的在于:提供一种具有骨髓瘤抑制作用的吲哚类化合物,该化合物能够有效抑制多发性骨髓瘤细胞U266细胞。
本发明的另一个目的在于:提供所述的吲哚类化合物在药学上可接受的盐。
本发明的再一个目的在于:提供所述吲哚类化合物的制备方法。
本发明的再一个目的在于:提供所述吲哚类化合物的应用。
附图说明
图1化合物浓度为20uM对不同肿瘤细胞的抑制率。
具体实施方式
实施例1化合物的合成如式Ⅰ所示化合物采用如下反应式合成:
在氯仿(20 mL) 溶液中加入5-甲氧基色胺 (3.0 mmol),逐滴加入三乙胺(6.0mmol),搅拌5min后,加入3,5-双(三氟甲基)苯基异硫氰酯(3.0 mmol)。搅拌回流8小时,混合液冷却至常温,用布氏漏斗过滤,每次用30ml的乙醇洗涤滤饼三次,收集滤液,并将其悬干,浓缩至干燥得到的固体再次经过经95%乙醇(30 mL)洗涤,过滤后为收集白色固体,得到终产物。
本发明还提供上述化合物或其药学上可接受盐在肿瘤抑制方面的用途。
本发明制备的化合物或其药学上可接受的盐,具有较明显的治疗骨髓瘤但不限于骨髓瘤的效果。
本发明制备的化合物或其药学上可接受的盐,具有较明显的治疗多发性骨髓瘤效果。
本发明还提供本发明所述的化合物的药学上可接受的盐,所述盐可以是磷酸盐,硝酸盐、硫酸盐或盐酸盐等。
实验证明,采用MTT法测试了该化合物对人多发性骨髓瘤U266、人小细胞肺癌SCLC-21H、人***细胞HL-60、淋巴瘤U698的抑制作用,对人多发性骨髓瘤U266的抑制作用比更强,因此发明化合物可用于制备治疗多发性骨髓瘤U266的药物。
本发明还提供上述化合物或其药学上可接受的盐在制备治疗骨髓瘤但不限于骨髓瘤药物中的用途。进一步的,所述化合物可以用于骨髓瘤但不限于骨髓瘤的相关治疗。
下面结合实施例对本发明的具体实施方式做进一步的描述,并不因此将本发明限制在所述的实施列范围之中。
1H-NMR (400 MHz, DMSO-d 6), δ(ppm): 10.68 (1H, brs), 10.14 (1H, brs),8.26 (2H, brs), 7.72 (1H, brs), 7.23 (1H, d, J = 8.8 Hz), 7.16 (1H, d, J =2.1 Hz), 6.73 (1H, dd, J = 8.8, 2.1 Hz), 3.80 (2H, m), 3.75 (3H, s), 2.98(2H, t, J = 7.2 Hz)。
13C-NMR (100 MHz, DMSO-d 6),δ(ppm): 180.9, 153.5, 142.4, 131.9, 131.9,130.6 (33.5 Hz), 130.6 (33.5 Hz), 128.1, 125.1, 124.0, 122.4, 122.4, 118.1(324.6 Hz), 118.1 (324.6 Hz), 112.5, 111.6, 100.9, 55.8, 44.9, 24.8。
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911196800.4A CN110922349B (zh) | 2019-11-29 | 2019-11-29 | 一种抗肿瘤化合物的合成及其在多发性骨髓瘤中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911196800.4A CN110922349B (zh) | 2019-11-29 | 2019-11-29 | 一种抗肿瘤化合物的合成及其在多发性骨髓瘤中的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110922349A CN110922349A (zh) | 2020-03-27 |
CN110922349B true CN110922349B (zh) | 2022-04-26 |
Family
ID=69847734
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911196800.4A Expired - Fee Related CN110922349B (zh) | 2019-11-29 | 2019-11-29 | 一种抗肿瘤化合物的合成及其在多发性骨髓瘤中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110922349B (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016191911A1 (en) * | 2015-05-29 | 2016-12-08 | Wuhu Eastinno Biotechnologies Co., Ltd. | Pharmaceutical composition and use thereof and methods of treating diseases mediated by hedgehog signaling pathway |
TW201739768A (zh) * | 2016-05-06 | 2017-11-16 | 艾伯維史坦森特瑞斯有限責任公司 | 新穎抗tnfrsf21抗體及使用方法 |
CN107820495A (zh) * | 2015-04-29 | 2018-03-20 | 桑福德-伯纳姆医学研究院 | 靶向epha4的配体结合域的新型epha4抑制剂 |
CN109516926A (zh) * | 2018-07-27 | 2019-03-26 | 四川大学 | 一种荜茇明碱衍生物的制备与抗肿瘤活性 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1874952A2 (en) * | 2005-04-11 | 2008-01-09 | Achillion Pharmaceuticals, Inc. | Pharmaceutical compositions for and methods of inhibiting hcv replication |
JP2011507910A (ja) * | 2007-12-21 | 2011-03-10 | ユニバーシティー オブ ロチェスター | 真核生物の寿命を変更するための方法 |
-
2019
- 2019-11-29 CN CN201911196800.4A patent/CN110922349B/zh not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107820495A (zh) * | 2015-04-29 | 2018-03-20 | 桑福德-伯纳姆医学研究院 | 靶向epha4的配体结合域的新型epha4抑制剂 |
WO2016191911A1 (en) * | 2015-05-29 | 2016-12-08 | Wuhu Eastinno Biotechnologies Co., Ltd. | Pharmaceutical composition and use thereof and methods of treating diseases mediated by hedgehog signaling pathway |
TW201739768A (zh) * | 2016-05-06 | 2017-11-16 | 艾伯維史坦森特瑞斯有限責任公司 | 新穎抗tnfrsf21抗體及使用方法 |
CN109516926A (zh) * | 2018-07-27 | 2019-03-26 | 四川大学 | 一种荜茇明碱衍生物的制备与抗肿瘤活性 |
Non-Patent Citations (1)
Title |
---|
褪黑素在眼科应用的最新进展;杨一涛等;《眼科新进展》;20090205(第02期);第146-151页 * |
Also Published As
Publication number | Publication date |
---|---|
CN110922349A (zh) | 2020-03-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2868660B1 (en) | Antitumor effect potentiator comprising an imidazooxazine compound | |
EA029707B1 (ru) | Гетероциклические ингибиторы глютаминазы | |
CA2574032A1 (en) | Compounds and methods for the treatment of cancer | |
TWI321566B (en) | Pyrido[2,3-d]pyrimidine derivatives, preparation thereof, therapeutic use thereof | |
AU2005286833B2 (en) | Sulfonyl hydrazines as hypoxia-selective antineoplastic agents | |
WO2016028225A1 (en) | Platinum complexes as anticancer agents | |
WO2018117177A1 (ja) | Brk阻害化合物 | |
US10781213B2 (en) | Methods for preparing bis-tetrahydroisoquinoline-containing compounds | |
EP2759547B1 (en) | Platinum compound having amino- or alkylamino-containing succinic acid derivatives as leaving group, preparation method therefor, and use thereof | |
CN110922349B (zh) | 一种抗肿瘤化合物的合成及其在多发性骨髓瘤中的应用 | |
RU2656485C2 (ru) | Дейтерированные соединения хиназолинона и содержащие их фармацевтические композиции | |
EP2740738B1 (en) | Platinum compounds for treating cell proliferative disease, preparation methods and uses thereof | |
WO2014075391A1 (zh) | 离去基团是含氨基或烷氨基的丙二酸衍生物的铂类化合物 | |
CN109081803B (zh) | 极性氨基酸修饰的吲哚乙醇衍生物,其合成,活性和应用 | |
CN107698484B (zh) | 一种来那度胺的衍生物的制备方法与应用 | |
CN112175014B (zh) | 一种一氧化氮供体型四价铂衍生物、制备方法及其医药用途 | |
CN109912589B (zh) | 谷氨酰胺酰氨基正己酰咔啉羧酸苄酯,其制备,活性和应用 | |
CN101712655B (zh) | 一种乙酰胺类衍生物及其在制药中的应用 | |
EP1674457A1 (en) | Derivatives of squaric acid with anti-proliferative activity | |
US20070142336A1 (en) | Treatment of cancer | |
CN109476605A (zh) | 具有抗肿瘤活性的苯并-n-羟基酰胺化合物 | |
CN116802175A (zh) | 新型谷氨酰胺类似物 | |
KR20120101798A (ko) | 신규한 6핵 아렌-루테늄 나노 프리즘 케이지 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 및 치료용 약학적 조성물 | |
JPS59101471A (ja) | 放射線療法の補助薬として有用な3−ニトロピラジンの2,6−ジ置換誘導体 | |
EP0270293A1 (en) | Substituted 3-nitrobenzenesulfonamides useful as adjuncts in radiation therapy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20220426 |
|
CF01 | Termination of patent right due to non-payment of annual fee |