CN105481836B - 具有抗肿瘤活性的5-羟色氨酸甲酯衍生物及其制备方法和应用 - Google Patents
具有抗肿瘤活性的5-羟色氨酸甲酯衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN105481836B CN105481836B CN201510948875.9A CN201510948875A CN105481836B CN 105481836 B CN105481836 B CN 105481836B CN 201510948875 A CN201510948875 A CN 201510948875A CN 105481836 B CN105481836 B CN 105481836B
- Authority
- CN
- China
- Prior art keywords
- hydroxyryptophan
- butylbenzyl
- methyl ester
- triazole
- ter
- 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
- 150000004702 methyl esters Chemical class 0.000 title claims abstract description 26
- 238000009795 derivation Methods 0.000 title claims abstract description 17
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 11
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 10
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 230000012010 growth Effects 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 239000002994 raw material Substances 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- -1 4- t-butylbenzyl nitrine Chemical compound 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 210000004027 cell Anatomy 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 239000000284 extract Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 239000001963 growth medium Substances 0.000 claims description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- QZNQSIHCDAGZIA-UHFFFAOYSA-N 1-(bromomethyl)-4-tert-butylbenzene Chemical compound CC(C)(C)C1=CC=C(CBr)C=C1 QZNQSIHCDAGZIA-UHFFFAOYSA-N 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 claims description 5
- 239000012266 salt solution Substances 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- UGWKCNDTYUOTQZ-UHFFFAOYSA-N copper;sulfuric acid Chemical compound [Cu].OS(O)(=O)=O UGWKCNDTYUOTQZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 208000010749 gastric carcinoma Diseases 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 201000000498 stomach carcinoma Diseases 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 2
- 230000003698 anagen phase Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 210000004881 tumor cell Anatomy 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 4
- 150000003851 azoles Chemical class 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 201000006608 esophagus squamous cell carcinoma Diseases 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 230000004663 cell proliferation Effects 0.000 abstract description 3
- 150000002611 lead compounds Chemical class 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- 125000003352 4-tert-butyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 125000006487 butyl benzyl group Chemical group 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- DIEUGINJYISDCB-UHFFFAOYSA-N ethyl 6-amino-5-methoxy-1h-indole-2-carboxylate Chemical compound COC1=C(N)C=C2NC(C(=O)OCC)=CC2=C1 DIEUGINJYISDCB-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- SPAKMVQVTSVXES-UHFFFAOYSA-N methanol;oxolane;hydrate Chemical compound O.OC.C1CCOC1 SPAKMVQVTSVXES-UHFFFAOYSA-N 0.000 description 1
- KCUNTYMNJVXYKZ-JTQLQIEISA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-JTQLQIEISA-N 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- WQMOWDRIXRBJBW-UHFFFAOYSA-N phenyl(piperidin-1-yl)diazene Chemical compound C1CCCCN1N=NC1=CC=CC=C1 WQMOWDRIXRBJBW-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种具有抗肿瘤活性的5‑羟色氨酸甲酯衍生物及其制备方法和应用,具体为5‑羟基‑N‑[[1‑(4‑叔丁基苯甲基)‑1H‑1,2,3‑三氮唑‑4‑基]羰基]‑D‑色氨酸甲酯,其结构式为:
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种具有抗肿瘤活性的5-羟色氨酸甲酯衍生物及其制备方法和应用。
背景技术
恶性肿瘤是危害人类健康的重要疾病,其死亡率是仅次于心脑血管疾病的第二大疾病。目前恶性肿瘤的主要治疗方法仍以外科手术治疗为主,化疗、放疗、基因治疗及其他生物治疗等综合治疗为辅,但治疗效果仍不够理想,其中放疗和化疗是极其重要的非手术疗法,但是放疗和化疗在杀死肿瘤细胞的同时也对机体正常细胞产生严重损害。由于药物本身缺乏靶向性,因而使肿瘤部位药物有效浓度降低,全身毒副作用增强,出现治愈率低,多药耐药性、毒副作用大等治疗问题。因此我国已把抗癌药物的研究列为新药开发的最重要的战略性课题之一,研究新型具有高效、低毒和高选择性的抗癌药物成为我们长期的目标和任务。
发明内容
本发明解决的技术问题是提供了一种操作简单易行、原料廉价易得、反应效率较高且重复性好的具有抗肿瘤活性的5-羟色氨酸甲酯衍生物及其制备方法,制得的5-羟色氨酸甲酯衍生物能够用于制备抗癌药物。
本发明为解决上述技术问题采用如下技术方案,具有抗肿瘤活性的5-羟色氨酸甲酯衍生物,其特征在于该5-羟色氨酸甲酯衍生物为5-羟基-N-[[1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-基]羰基]-D-色氨酸甲酯,其结构式为:
。
本发明所述的具有抗肿瘤活性的5-羟色氨酸甲酯衍生物的制备方法,其特征在于具体步骤为:首先将4-叔丁基苄溴与叠氮化钠反应生成4-叔丁基苄基叠氮,该4-叔丁基苄基叠氮与丙炔酸甲酯发生Click反应制得N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸甲酯,N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸甲酯脱去甲氧基制得N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸,最后在N,N-二甲基甲酰胺、三乙胺、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐和1-羟基苯并三氮唑中,将5-羟色氨酸甲酯和N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸缩合制得目标产物5-羟基-N-[[1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-基]羰基]-D-色氨酸甲酯。
进一步限定,所述的具有抗肿瘤活性的5-羟色氨酸甲酯衍生物的制备方法,其特征在于具体步骤为:
(1)在500mL三颈瓶中加入44g 5-羟色氨酸和350mL甲醇,降温至-5℃滴加17.4mL氯化亚砜,滴加完毕后升温至35℃反应过夜,TLC检测原料消失停止反应,减压蒸馏除去甲醇,冷却后加入300mL乙酸乙酯搅拌,抽滤,烘干得到灰白色固体5-羟色氨酸甲酯;
(2)将2.27g 4-叔丁基苄溴溶解在10mL二甲基甲酰胺中,冰浴条件下加入0.975g叠氮化钠,室温条件下搅拌过夜,TLC检测原料消失停止反应,反应结束后加水溶解,依次用等量的乙酸乙酯进行萃取,分出有机层,用饱和食盐水洗涤,无水MgSO4干燥,过滤,浓缩得到油状液体4-叔丁基苄基叠氮;
(3)将926.1mg 4-叔丁基苄基叠氮和0.295mL丙炔酸甲酯溶解于5mL体积比为1:1的四氢呋喃和水的混合溶液中,冰浴条件下加入392mg催化剂硫酸铜和970.7mg左旋抗坏血酸钠,在室温条件下反应5h,TLC检测原料消失停止反应,反应结束后加水溶解,依次用等量的乙酸乙酯进行萃取,分出有机层,用饱和食盐水洗涤,无水MgSO4干燥,过滤,蒸去溶剂后得到淡黄色结晶性粉末N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸甲酯;
(4)将530.3mg N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸甲酯溶解于7mL体积比为4:2:1四氢呋喃、甲醇和水的混合溶液中,加入93mg氢氧化锂,室温条件下搅拌过夜,TLC检测原料消失停止反应,反应物加水溶解后,用盐酸溶液调节反应溶液的pH值至弱酸性,用乙酸乙酯萃取3次,乙酸乙酯相用水洗涤1次,饱和食盐水萃取1次,无水硫酸钠干燥,抽滤旋干得到棕色晶体N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸;
(5)将315mg N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸溶解于5mL二甲基甲酰胺中,再加入363mg 1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、249mg 1-羟基苯并三氮唑和0.4mL三乙胺,然后加入345.5mg 5-羟色氨酸甲酯,室温条件下搅拌过夜,TLC检测原料消失停止反应,反应物加水溶解后,用盐酸溶液调节反应溶液的pH值至中性,用乙酸乙酯萃取3次,乙酸乙酯相用水洗涤1次,饱和食盐水萃取1次,无水硫酸钠干燥,抽滤旋干,然后用体积比为6:1的二氯甲烷和乙酸乙酯混合溶液过硅胶柱色谱分离得到浅棕色晶体粉末5-羟基-N-[[1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-基]羰基]-D-色氨酸甲酯。
本发明所述的具有抗肿瘤活性的5-羟色氨酸甲酯衍生物在制备抗肿瘤药物中的应用,其中抗肿瘤药物由5-羟基-N-[[1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-基]羰基]-D-色氨酸甲酯和药学上可接受的载体或赋形剂制备而成,所述的肿瘤为脑瘤、肺癌、肝癌、乳腺癌、宫颈癌、食道癌、胃癌和结肠癌或者白血病。
经MTT实验发现,本发明合成的化合物有良好的体外抗肿瘤细胞增殖活性,对TE-1、MGC803、HCT116细胞生长均受到较明显的抑制,可作为抗肿瘤药物或先导化合物进一步开发。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明,但不应该将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例
5-羟基-N-[[1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-基]羰基]-D-色氨酸甲酯的合成方法:
a: NaN3, DMF, rt, 12h; b: CuSO4, Sodium ascobate, THF-H2O(1:1), rt, 5h; c: LiOH, THF-MeOH-H2O(4:2:1), rt, over night; d: SOCl2, MeOH, reflux, 5h;e: EDC·HCl, HOBt, DMF, triethylamine, rt, over night。
合成过程的具体步骤为:
1)5-羟色氨酸甲酯的合成
在500mL三颈瓶中加入5-羟色氨酸44.00g(0.2mol)和甲醇350mL,降温至-5℃,低温下缓慢滴加氯化亚砜17.4mL (0.24mol)。滴加完毕后升温至35℃反应过夜。TLC检测原料消失停止反应。减压蒸馏掉甲醇,冷却后加入300mL乙酸乙酯搅拌,抽滤,烘干得到灰白色固体43.53g(92.90%)。M.p.135-136℃;分子式:C12H14N2O3,HRMS(FAB)(m/z): 235.1060[M+H]+。
2)4-叔丁基苄基叠氮的合成
4-叔丁基苄溴2.27g(10mmol)溶解于10mL二甲基甲酰胺中,冰浴条件下分批加入叠氮化钠0.975g(15mmol),室温条件下搅拌过夜,TLC检测原料消失停止反应。反应结束后加水溶解,依次用等量的乙酸乙酯进行萃取,分出有机层,用饱和食盐水洗涤,无水MgSO4干燥,过滤,浓缩得到油状液体1.1719g(62%),分子式:C11H15N3,HRMS(FAB)(m/z):190.1060[M+H]+。
3) N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸甲酯的合成
取4-叔丁基苄基叠氮926.1mg(4.9mmol)和丙炔酸甲酯0.295mL(3.3mol)溶解于5mL四氢呋喃和水(体积比为1:1)溶液中,冰浴条件下分别加入催化剂硫酸铜392mg和左旋抗坏血酸钠970.7mg,继续在室温条件下反应5h,TLC检测原料消失停止反应。反应结束后加水溶解,依次用等量的乙酸乙酯进行萃取,分出有机层,用饱和食盐水洗涤,无水MgSO4干燥,过滤,蒸去溶剂后得到淡黄色结晶性粉末629.4mg(70%),分子式:C15H19O2N3,1H-NMR(400 MHz, DMSO-D6):δH 8.76(1H, s),7.39(2H, d, J=8Hz),7.27(2H, d, J=8Hz),5.59(2H, s),3.68(3H, s),1.24(3H×3, s)。
4) N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸的合成
N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸甲酯530.3mg(2.04mmol),溶解在7mL四氢呋喃、甲醇和水(体积比为4:2:1)的混合溶液中,分批加入93mg(4mmol)氢氧化锂,室温条件下搅拌过夜,TLC检测原料消失停止反应。反应物加水溶解后,用1mol/L的盐酸溶液调节反应溶液pH值至弱酸性,用乙酸乙酯萃取3次,乙酸乙酯相用水洗涤1次,饱和食盐水萃取1次,无水硫酸钠干燥,抽滤旋干得到棕色晶体488mg(97%),分子式:C14H17O2N3,1H-NMR (400 MHz, DMSO-D6):δH 8.76(1H, s),7.39(2H, d, J=8Hz),7.27(2H, d, J=8Hz),5.59(2H, s),1.24(3H×3, s)。
5)5-羟基-N-[[1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-基]羰基]-D-色氨酸甲酯的合成
N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸315mg(1.23mmol)溶解于5mL二甲基甲酰胺溶液中,加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl)363mg(1.845mmol)、1-羟基苯并三氮唑(HOBt)249mg(1.845mmol)和三乙胺0.4mL,然后加入5-羟色氨酸甲酯345.5mg(1.47mmol),室温条件下搅拌过夜。TLC检测原料消失停止反应,反应物加水溶解后,用1mol/L的盐酸溶液调节反应溶液pH值至中性,用乙酸乙酯萃取3次,乙酸乙酯相用水洗涤1次,饱和食盐水萃取1次,无水硫酸钠干燥,抽滤旋干,用二氯甲烷和乙酸乙酯(体积比为6:1)的混合溶液过硅胶柱色谱分离得到浅棕色晶体粉末368mg(77.8%)。分子式:C26H29O4N5,分子量:475.20。HRMS(FAB)(m/z):498.2119[M+Na]+,1H-NMR (400MHz, DMSO-D6):δH 9.88(1H, s, indole-NH),8.37 (1H, s),7.39(2H, d, J=8Hz),7.27(2H, d, J=8Hz),7.20(1H, d, J=8Hz),7.19(1H, s),6.97 (1H, s),6.70(1H, d, J=8Hz),5.59(2H,s),4.92(1H, m),3.68(3H, s),3.33(1H, dd, J=9.0, 15.0Hz ),2.91(1H, dd, J=4.8,15.0Hz),1.29(3H×3, s)。
实验例1
本试验例的目的是在研究本发明化合物的体外抗肿瘤细胞增值活性
取对数生长期的人食管鳞癌细胞(TE-1)、人胃癌细胞(MGC803)、人结肠癌细胞(HCT116)以6×103个/孔接种至96孔板中,培养24h后将培养基更换为含5-羟基-N-[[1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-基]羰基]-D-色氨酸甲酯的培养基,每个样品9个浓度,分别为128、64、32、16、8、4、2、1、0.5μg/mL,设空白对照组,继续培养72h。培养结束后,加MTT 20μL每孔,四个小时后甩掉培养基,每孔加150mL DMSO,震荡均匀后酶标仪490nm波长测其OD值,根据OD值利用SPSS软件计算化合物的IC50值。
实验结果表明:5-羟基-N-[[1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-基]羰基]-D-色氨酸甲酯作用72h后,TE-1、MGC803、HCT116细胞生长均受到较明显的抑制,IC50值分别为10.106μg/mL、9.836μg/mL、16.756μg/mL。
以上实施例描述了本发明的基本原理、主要特征及优点,本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明原理的范围下,本发明还会有各种变化和改进,这些变化和改进均落入本发明保护的范围内。
Claims (2)
1.具有抗肿瘤活性的5-羟色氨酸甲酯衍生物在制备抗肿瘤药物中的应用,其中抗肿瘤药物由5-羟色氨酸甲酯衍生物和药学上可接受的载体或赋形剂制备而成,肿瘤细胞为食管鳞癌细胞TE-1、人胃癌细胞MGC803或人结肠癌细胞HCT116,5-羟色氨酸甲酯衍生物的结构式为:
;
具体过程为:取对数生长期的人食管鳞癌细胞TE-1、人胃癌细胞MGC803、人结肠癌细胞HCT116以6×103个/孔接种至96孔板中,培养24h后将培养基更换为含5-羟色氨酸甲酯衍生物的培养基,每个样品9个浓度,分别为128μg/mL、64μg/mL、32μg/mL、16μg/mL、8μg/mL、4μg/mL、2μg/mL、1μg/mL、0.5μg/mL,设空白对照组,继续培养72h,培养结束后,加MTT 20μL每孔,四个小时后甩掉培养基,每孔加150mL DMSO,震荡均匀后酶标仪490nm波长测其OD值,根据OD值利用SPSS软件计算化合物的IC50值,5-羟色氨酸甲酯衍生物作用72h后,TE-1、MGC803、HCT116细胞生长均受到较明显的抑制,对应的IC50值分别为10.106μg/mL、9.836μg/mL、16.756μg/mL;
所述5-羟色氨酸甲酯衍生物的具体合成过程为:首先将4-叔丁基苄溴与叠氮化钠反应生成4-叔丁基苄基叠氮,该4-叔丁基苄基叠氮与丙炔酸甲酯发生Click反应制得N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸甲酯,N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸甲酯脱去甲氧基制得N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸,最后在N,N-二甲基甲酰胺、三乙胺、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐和1-羟基苯并三氮唑中,将5-羟色氨酸甲酯和N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸缩合制得目标产物5-羟基-N-[[1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-基]羰基]-D-色氨酸甲酯。
2.根据权利要求1所述的应用,其特征在于所述5-羟色氨酸甲酯衍生物的具体合成步骤为:
(1)在500mL三颈瓶中加入44g 5-羟色氨酸和350mL甲醇,降温至-5℃滴加17.4mL氯化亚砜,滴加完毕后升温至35℃反应过夜,TLC检测原料消失停止反应,减压蒸馏除去甲醇,冷却后加入300mL乙酸乙酯搅拌,抽滤,烘干得到灰白色固体5-羟色氨酸甲酯;
(2)将2.27g 4-叔丁基苄溴溶解在10mL二甲基甲酰胺中,冰浴条件下加入0.975g叠氮化钠,室温条件下搅拌过夜,TLC检测原料消失停止反应,反应结束后加水溶解,依次用等量的乙酸乙酯进行萃取,分出有机层,用饱和食盐水洗涤,无水MgSO4干燥,过滤,浓缩得到油状液体4-叔丁基苄基叠氮;
(3)将926.1mg 4-叔丁基苄基叠氮和0.295mL丙炔酸甲酯溶解于5mL体积比为1:1的四氢呋喃和水的混合溶液中,冰浴条件下加入392mg催化剂硫酸铜和970.7mg左旋抗坏血酸钠,在室温条件下反应5h,TLC检测原料消失停止反应,反应结束后加水溶解,依次用等量的乙酸乙酯进行萃取,分出有机层,用饱和食盐水洗涤,无水MgSO4干燥,过滤,蒸去溶剂后得到淡黄色结晶性粉末N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸甲酯;
(4)将530.3mg N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸甲酯溶解于7mL体积比为4:2:1四氢呋喃、甲醇和水的混合溶液中,加入93mg氢氧化锂,室温条件下搅拌过夜,TLC检测原料消失停止反应,反应物加水溶解后,用盐酸溶液调节反应溶液的pH值至弱酸性,用乙酸乙酯萃取3次,乙酸乙酯相用水洗涤1次,饱和食盐水萃取1次,无水硫酸钠干燥,抽滤旋干得到棕色晶体N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸;
(5)将315mg N-1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-羧酸溶解于5mL二甲基甲酰胺中,再加入363mg 1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、249mg 1-羟基苯并三氮唑和0.4mL三乙胺,然后加入345.5mg 5-羟色氨酸甲酯,室温条件下搅拌过夜,TLC检测原料消失停止反应,反应物加水溶解后,用盐酸溶液调节反应溶液的pH值至中性,用乙酸乙酯萃取3次,乙酸乙酯相用水洗涤1次,饱和食盐水萃取1次,无水硫酸钠干燥,抽滤旋干,然后用体积比为6:1的二氯甲烷和乙酸乙酯混合溶液过硅胶柱色谱分离得到浅棕色晶体粉末5-羟基-N-[[1-(4-叔丁基苯甲基)-1H-1,2,3-三氮唑-4-基]羰基]-D-色氨酸甲酯。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510948875.9A CN105481836B (zh) | 2015-12-18 | 2015-12-18 | 具有抗肿瘤活性的5-羟色氨酸甲酯衍生物及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510948875.9A CN105481836B (zh) | 2015-12-18 | 2015-12-18 | 具有抗肿瘤活性的5-羟色氨酸甲酯衍生物及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105481836A CN105481836A (zh) | 2016-04-13 |
CN105481836B true CN105481836B (zh) | 2019-02-22 |
Family
ID=55669155
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510948875.9A Expired - Fee Related CN105481836B (zh) | 2015-12-18 | 2015-12-18 | 具有抗肿瘤活性的5-羟色氨酸甲酯衍生物及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105481836B (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010042685A2 (en) * | 2008-10-08 | 2010-04-15 | Medical College Of Georgia Research Institute, Inc. | Inhibitors of the atb(0,+) transporter and uses thereof |
WO2015192099A1 (en) * | 2014-06-13 | 2015-12-17 | The University Of Kansas | Triazole modified coumarin and biphenyl amide-based hsp90 inhibitors |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7935843B2 (en) * | 2005-12-09 | 2011-05-03 | Bezwada Biomedical, Llc | Functionalized diphenolics and absorbable polymers therefrom |
CN101514192B (zh) * | 2009-04-02 | 2012-05-23 | 山东大学 | 具有逆转肿瘤细胞多药耐药活性的喹喔啉酮类衍生物及其制备方法 |
CN103936814B (zh) * | 2014-05-12 | 2015-11-18 | 南京惠特莱医药科技有限公司 | 一种色氨酸羟化酶-1抑制剂熊果酸类衍生物及其制备方法和应用 |
-
2015
- 2015-12-18 CN CN201510948875.9A patent/CN105481836B/zh not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010042685A2 (en) * | 2008-10-08 | 2010-04-15 | Medical College Of Georgia Research Institute, Inc. | Inhibitors of the atb(0,+) transporter and uses thereof |
WO2015192099A1 (en) * | 2014-06-13 | 2015-12-17 | The University Of Kansas | Triazole modified coumarin and biphenyl amide-based hsp90 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
CN105481836A (zh) | 2016-04-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104311536A (zh) | 一种制备来那度胺的方法 | |
CN102603743A (zh) | 抗肿瘤的氮杂苯并[f]薁衍生物其制备方法及其用途 | |
CN106632271A (zh) | 具有抗肿瘤活性的厄洛替尼衍生物及其制备方法和应用 | |
CN108117507A (zh) | 一种氮杂螺环己二烯酮的合成方法和用途 | |
CN112707833B (zh) | 组蛋白去乙酰酶抑制剂及其制备和应用 | |
CN106083850B (zh) | 一类嘧啶并萘酰亚胺衍生物及其制备方法和应用 | |
CN104045629B (zh) | Pyridostatin类化合物及其制备方法与应用 | |
CN106674242B (zh) | 一种具有抗肿瘤活性的莪术醇衍生物及其制备方法和应用 | |
WO2013107428A1 (zh) | 7-位取代的汉防己乙素衍生物、及其制备方法和应用 | |
CN105906602B (zh) | 2-(5,6-二甲基呫吨酮-4-基)-乙酸衍生物的制备方法 | |
CN113735828A (zh) | 一种靶向降解egfr的化合物及其制备方法和应用 | |
CN103922992B (zh) | 一种抗癌活性吲哚酮衍生物、合成方法及其用途 | |
CN105481836B (zh) | 具有抗肿瘤活性的5-羟色氨酸甲酯衍生物及其制备方法和应用 | |
CN107739381B (zh) | 莪术醇衍生物及其在制备抗肿瘤药物中的应用 | |
CN114605407B (zh) | 一种吲哚喹啉酮类化合物及其合成方法和应用 | |
CN109320583A (zh) | 一类具有抗肿瘤活性的脱氢枞酸苯并咪唑硫醚类杂环衍生物及其制备方法和应用 | |
CN113603694B (zh) | 一种1,2-二酮类化合物及其制备方法和应用 | |
CN105601618B (zh) | 芳香族酰亚胺类化合物及其制备方法与应用 | |
CN114835759A (zh) | 一种褪黑素-铂(iv)-碳氮长链配合物、制备方法及其在肿瘤药物中的应用 | |
CN106565657A (zh) | 一种具抗肿瘤活性的橙皮素肉桂酸酯类化合物及其合成方法 | |
CN104163772A (zh) | 一种取代二芳醚类化合物及其制备方法及应用 | |
CN113444095A (zh) | 一种三嗪取代的咪唑类化合物及其制备方法和应用 | |
CN108299291B (zh) | 酰基化喹啉或异喹啉衍生物的合成方法 | |
CN115057850B (zh) | 一种芦荟大黄素衍生物及其制备方法和应用 | |
CN115850276B (zh) | 苯并咪唑类苦参碱衍生物、制备方法及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into 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: 20190222 |