CN114957244B - 一类呋咱NO供体型β-卡波林衍生物及应用 - Google Patents
一类呋咱NO供体型β-卡波林衍生物及应用 Download PDFInfo
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- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 239000002840 nitric oxide donor Substances 0.000 title claims abstract description 18
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000003107 substituted aryl group Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
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- 239000000543 intermediate Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 9
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- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
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- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- YTEFAALYDTWTLB-UHFFFAOYSA-N 2-(benzenesulfonyl)acetic acid Chemical compound OC(=O)CS(=O)(=O)C1=CC=CC=C1 YTEFAALYDTWTLB-UHFFFAOYSA-N 0.000 description 2
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
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- XFEFXBNEMPFTEX-UHFFFAOYSA-N [N]=O.C1(=CC=CC=C1)S(=O)(=O)C1=NON=C1S(=O)(=O)C1=CC=CC=C1 Chemical compound [N]=O.C1(=CC=CC=C1)S(=O)(=O)C1=NON=C1S(=O)(=O)C1=CC=CC=C1 XFEFXBNEMPFTEX-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 2
- 229940106681 chloroacetic acid Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000008098 formaldehyde solution Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 108091007914 CDKs Proteins 0.000 description 1
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 1
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
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- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 1
- 240000005523 Peganum harmala Species 0.000 description 1
- 235000005126 Peganum harmala Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- NELWQUQCCZMRPB-UBPLGANQSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(4-amino-5-ethenyl-2-oxopyrimidin-1-yl)-2-methyloxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1N1C(=O)N=C(N)C(C=C)=C1 NELWQUQCCZMRPB-UBPLGANQSA-N 0.000 description 1
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- 229940049706 benzodiazepine Drugs 0.000 description 1
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- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 230000001079 digestive effect Effects 0.000 description 1
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- 230000012010 growth Effects 0.000 description 1
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- 230000006882 induction of apoptosis Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一类呋咱NO供体型β‑卡波林衍生物及应用,属于天然药物及药物化学领域。具体涉及一系列具有抗肿瘤活性的呋咱NO供体型β‑卡波林衍生物的制备方法和在抗肿瘤药物方面新用途。本发明所述的呋咱NO供体型β‑卡波林衍生物及其药学上可接受的盐如通式I所示。其中,R和R1如权利要求书和说明书中所述。
Description
技术领域
本发明属于天然药物及药物化学领域,涉及一类呋咱NO供体型β-卡波林衍生物及应用,具体涉及一系列具有抗肿瘤活性的呋咱NO供体型β-卡波林衍生物的制备方法及其在抗肿瘤方面的用途。
背景技术
β-卡波林生物碱(β-carboline)于1841年首次从骆驼蓬(Peganum harmala L.)中分离得到,具有较好的抗肿瘤活性。主要通过三种作用机制来抑制肿瘤细胞增殖和诱导其凋亡。首先,β-卡波林生物碱可以与DNA相互作用,改变DNA的复制;另外,它能够抑制细胞周期素依赖激酶、拓扑异构酶和单胺氧化酶等;最后,它对苯二氮卓和5-羟色胺等受体具有高亲和力。很多研究者对β-卡波林生物碱进行结构修饰,获得活性更强、毒性更低、选择性更好的抗肿瘤候选化合物。
一氧化氮(NO)能够调控肿瘤细胞的生长、凋亡、代谢、转移和肿瘤诱导的免疫抑制等。一般来说,高浓度的一氧化氮会抑制细胞的生长,诱导细胞死亡,而低浓度的一氧化氮则会促进细胞的生长。因此,一氧化氮供体型药物的研究备受关注。
发明内容
本发明以β-卡波林生物碱为先导化合物,设计并合成了呋咱NO供体型β-卡波林衍生物,并测试了合成衍生物在抗肿瘤方面的生物活性。
本发明要解决的技术问题是寻找抗肿瘤活性好的呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐,并进一步提供一种药物组合物。
为解决上述技术问题,本发明提供如下技术方案:
一类呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐,具有如下I的结构通式:
其中,R为氢,或含有1-4个碳原子的烷基,或含有4-12个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-3个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-3个碳原子的烷氧基;R1为含有1-8个碳原子的烷基。
优选地,R为氢,或含有1-3个碳原子的烷基,或含有4-10个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-2个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-3个碳原子的烷氧基;R1为含有1-6个碳原子的烷基。
更优选地,R为氢,或含有1-2个碳原子的烷基,或含有4-8个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-2个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-2个碳原子的烷氧基;R1为含有2-4个碳原子的烷基。
进一步地,
本发明优选如下衍生物及其药学上可接受的盐的结构式如a~c所示:
本发明的衍生物可用下列方法制备得到:
化合物L-色氨酸1在NaOH溶液中与37%的甲醛溶液37℃反应,得中间体2a;L-色氨酸1在1,2-二氯乙烷中与乙醛或对甲氧基苯甲醛、三氟乙酸110℃反应得到中间体2b-c。然后将中间体2a-c溶解于甲醇中,在冰浴条件下滴加SOCl2,回流反应得到中间体3a-c。再将3a-c溶于N,N-二甲基甲酰胺中,与高锰酸钾室温反应得到中间体4a-c。最后4a-c在NaOH条件下进行水解得到化合物5a-c;
将75mL苯硫酚6(0.6mol)与78g(0.8mol)氯乙酸在碱性条件(3N NaOH溶液)下反应得40g苯硫乙酸7,然后经50mL 30%H2O2氧化生成苯磺酰乙酸8。30g化合物8在发烟HNO3存在下100℃加热环合成10g 3,4-二苯磺酰基呋咱氮氧化物9,360mg化合物9在NaH催化的条件下,以THF为反应溶剂与N-羟乙基哌嗪反应生成化合物10 150mg;
将化合物5a-c溶于无水二氯甲烷,依次加入EDCI、HOBt,分别与10室温反应得到目标化合物11a-c。
一种药物组合物,所述药物组合物含有治疗有效量的通式I所示的呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐和药学上可接受的载体。
通式I所示的呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐在制备***疾病的药物中的应用。
进一步地,所述的肿瘤为乳腺癌肿瘤或肝癌肿瘤。
一种药物组合物在制备***疾病的药物中的应用。
进一步地,所述的肿瘤为乳腺癌肿瘤或肝癌肿瘤。
药理试验证明,本发明的呋咱NO供体型β-卡波林衍生物具有很好的抗肿瘤细胞增殖作用,可以用于进一步制备抗肿瘤药物。
具体实施方式
下述非限定性实施例可以使本领域的普通技术人员更全面地理解本发明,但不以任何方式限制本发明。
本发明实施例的衍生物合成路线如下:
实施例1
(1)将5g化合物L-色氨酸1(24.51mmol)溶解于0.4N的NaOH溶液中,然后加入3mL37%甲醛溶液(36.97mmol),37℃反应三天。TLC监测,反应基本完全,冷却,然后加入冰乙酸,有沉淀生成,抽滤,烘干,得中间体2a 4.64g。将4.64g中间体2a(21.48mmol)溶解于无水甲醇中,在冰浴条件下滴加3.68mL SOCl2(50.67mmol),然后回流反应6h。TLC监测,反应完全,冷却,将反应液浓缩,然后加入50mL饱和的碳酸氢钠溶液,用乙酸乙酯萃取3次,饱和食盐水洗1次,无水硫酸钠干燥,过滤,浓缩,得中间体3a 3.5g。将3.5g中间体3a(15.22mmol)溶解于DMF中,在冰浴条件下加入7g高锰酸钾(44.3mmol),反应1h后转移至室温反应14h。TLC监测,反应完全,抽滤,将滤液旋干,用乙酸乙酯萃取3次,饱和食盐水洗1次,无水硫酸钠干燥,过滤,浓缩,得中间体4a 2.6g,硅胶柱色谱分离(DCM:MeOH=40:1),得纯中间体4a2.0g。将2.0g纯中间体4a溶解于甲醇/二氯甲烷中,加入5mL2N的NaOH溶液,加热反应2h。TLC监测,反应完全,冷却,然后加入4M的盐酸溶液调pH至4-5,有沉淀生成,抽滤,烘干,得化合物5a 1.8g。
(2)将苯硫酚6与氯乙酸在碱性条件(4N NaOH溶液)下反应得苯硫乙酸7,然后经30%H2O2氧化生成苯磺酰乙酸8。化合物8在发烟HNO3存在下100℃加热环合成3,4-二苯磺酰基呋咱氮氧化物9,化合物9在NaH催化的条件下,以THF为反应溶剂与N-羟乙基哌嗪反应生成化合物10。
(3)将90mg化合物5a(0.43mmol)用5mL无水DCM溶解,加入59mg HOBt(0.43mmol)、164mg EDCI(0.86mmol)搅拌30min,然后加入122mg化合物10(0.35mmol),室温搅拌8h,TLC监测,反应不继续进行,然后加入10mL蒸馏水,DCM萃取3次,饱和食盐水洗1次,无水硫酸钠干燥,过滤,浓缩,得粗产物77mg,硅胶柱色谱分离(DCM:MeOH=50:1),得化合物11a。灰白色固体,产率20%。
1H NMR(600MHz,CDCl3)δ:8.83(s,1H,1-CH),8.70(s,1H,Ar-NH),8.43(s,1H,4-CH),8.13(m,1H,Ar-H),8.05(m,2H,Ar-H),7.73(m,1H,Ar-H),7.57(m,4H,Ar-H),7.32(m,1H,Ar-H),4.58(t,2H,-OCH2),3.85(m,4H,-N(CH2)2),2.93(t,2H,-NCH2),2.70(m,4H,-N(CH2)2);13C NMR(150MHz,CDCl3)δ:168.90,159.06,143.59,140.84,138.24,136.14,135.81,131.83,129.84(×2),129.62,129.16,128.65(×2),122.17,121.70,120.92,116.48,111.91,110.64,69.32,61.58,56.28(×2),54.00,53.41;HRMS(ESI)m/z calcdfor C26H23N6O6S[M-H]+547.1400,found 547.1401。
实施例2
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与乙醛、三氟乙酸110℃反应得到中间体2b。
其余步骤参照实施例1的合成方法制备得化合物11b,灰白色固体,产率20%。
1H NMR(600MHz,CDCl3)δ:8.40(s,1H,Ar-NH),8.27(s,1H,4-CH),8.10(m,1H,Ar-H),8.06(m,2H,Ar-H),7.74(m,1H,Ar-H),7.61(m,2H,Ar-H),7.56(m,2H,Ar-H),7.31(m,1H,Ar-H),4.63(m,2H,-OCH2),3.81(m,4H,-N(CH2)2),2.83(s,3H,-CH3),2.69(m,2H,-NCH2),1.60(m,4H,-N(CH2)2);13C NMR(150MHz,CDCl3)δ:168.94,158.92,140.56,140.45,138.13,135.84(×2),134.89,129.85(×2),128.85,128.79,128.66(×2),122.19,122.14,120.85,114.45,111.97,110.62,68.92,56.25(×2),56.18,53.95,53.42,20.46;HRMS(ESI)m/z calcd for C27H27N6O6S[M+H]+563.1713,found 563.1702。
实施例3
实施例1步骤(1)中合成2a的步骤替换成:化合物L-色氨酸1在1,2-二氯乙烷中与对甲氧基苯甲醛、三氟乙酸110℃反应得到中间体2c。
其余步骤参照实施例1的合成方法制备得化合物11c,灰白色固体,产率33%。
1H NMR(600MHz,CDCl3)δ:9.08(s,1H,Ar-NH),8.35(s,1H,4-CH),8.08(m,1H,Ar-H),8.02(m,2H,Ar-H),7.89(d,J=8.65Hz,2H,Ar-H),7.68(m,1H,Ar-H),7.56(m,4H,Ar-H),7.30(m,1H,Ar-H),7.06(d,J=8.65Hz,2H,Ar-H),4.56(t,2H,-OCH2),3.88(m,4H,-N(CH2)2),3.83(s,3H,-OCH3),2.90(t,2H,-NCH2),2.68(m,4H,-N(CH2)2);13C NMR(150MHz,CDCl3)δ:168.75,160.36,159.01,143.39,140.85,140.75,138.16,135.76,133.54,130.67,130.38,129.78(×2),129.53(×2),128.81,128.52(×2),122.12,121.97,120.75,115.08,114.71(×2),111.99,110.57,69.45,56.22,55.50(×2),53.94,53.55,53.41;HRMS(ESI)m/z calcd for C33H31N6O7S[M+H]-655.1975,found 655.1982。
下面是本发明部分化合物的药理实验结果:
实验设备与试剂
实验方法
细胞抑制活性实验方法
细胞在37℃、5%CO2饱和湿度的培养箱中常规培养。培养液为含10%热灭活胎牛血清,青霉素100U/mL和链霉素100U/mL的高糖DMEM细胞培养基。48h更换培养液,细胞贴壁后,用0.25%胰蛋白酶消化传代。实验用细胞均处于对数生长期,CCK-8法表明细胞活力>95%。
取处于对数生长期状态良好的细胞一瓶,加入消化液(0.125%胰蛋白酶+0.01%EDTA)消化,计数2~4×104cell/mL,制成细胞悬液接种于96孔板上,100μL/孔,置恒温CO2培养箱中培养24小时。换液,加入受试药物,100μL/孔,培养72小时。将CCK-8加入96孔板中,50μL/孔,培养箱中孵育4小时。吸去上清液,加DMSO,200μL/孔,平板摇床上震荡10分钟。受试物考察0.001至100μM以十倍浓度递增的6个浓度,用酶联免疫监测仪在波长为450nm处测定每孔的吸光度,分别计算各浓度下的细胞抑制率。
抑制率计算方法:
药敏孔相对OD值=药敏孔绝对OD值﹣空白对照孔绝对OD值
实验结果
表1实施例对2种人乳腺癌和1种人胃癌细胞株抗增殖活性的IC50值(μM)
药理试验证明,本发明的目标衍生物具有更好的抗乳腺癌和肝癌细胞增殖活性,可以用于进一步制备抗肿瘤药物。
Claims (8)
1.通式I所示的呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐:
其中,R为氢,或含有1-4个碳原子的烷基,或含有4-12个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-3个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-3个碳原子的烷氧基;R1为含有1-8个碳原子的烷基。
2.根据权利要求1所述的通式I所示的呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐,其特征在于:
通式I中,R为氢,或含有1-3个碳原子的烷基,或含有4-10个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-2个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-3个碳原子的烷氧基;R1为含有1-6个碳原子的烷基。
3.根据权利要求1所述的通式I所示的呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐,其特征在于:
通式I中,R为氢,或含有1-2个碳原子的烷基,或含有4-8个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基,所述杂环芳基的芳杂环中包含1-2个N、O或S的杂原子,所述取代芳基或取代杂环芳基中的取代基为卤素或含有1-2个碳原子的烷氧基;R1为含有2-4个碳原子的烷基。
4.根据权利要求1-3中任一项所述的通式I所示的呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐,其特征在于:所述呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐的结构式如a~c所示:
5.一种药物组合物,其特征在于:所述药物组合物含有治疗有效量的权利要求1-4中任一项所述的通式I所示的呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐和药学上可接受的载体。
6.权利要求1-4中任一项所述的通式I所示的呋咱NO供体型β-卡波林衍生物及其药学上可接受的盐在制备***疾病的药物中的应用。
7.权利要求5所述的药物组合物在制备***疾病的药物中的应用。
8.根据权利要求6或7所述的应用,其特征在于:所述的肿瘤为乳腺癌肿瘤或胃癌肿瘤。
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