新型四氢苯并[4',5']噻吩并[3',2'∶5,6]吡啶并[4,3-d]嘧啶类化合物衍生物的合成及抗肿瘤活性

本文以环己酮为原料,通过氮杂Wittig反应合成了一系列结构新颖的取代四氢苯并噻吩并吡啶并嘧啶衍生物,并采用MTT法考察所合成目标化合物对CNE2、KB、MGC-803、MCF-7和PC3这5种肿瘤细胞的抑制活性。初步的生物活性结果表明,目标化合物对5种肿瘤细胞均有抑制活性,尤其是对胃癌MGC-803细胞展现出了更强的抑制活性。其中3-(4-氟苯基)-2-((4-氟苯基)氨基)-5-甲基-8,9,10,11-四氢苯并4',5']噻吩并3',2':5,6]吡啶并4,3-d]嘧啶-4(3H)-酮化合物8c,IC_(50)=(0. 9±0. 25)μmol·L~(-1)]对MGC-803的活性最强,是5-氟尿嘧啶IC_(50)=(18. 4±1. 43)μmol·L~(-1)]的20倍;同时,目标化合物对正常的胃黏膜上皮细胞GES-1没有毒性。四氢苯并4',5']噻吩并3',2':5,6]吡啶并4,3-d]嘧啶类化合物具有良好的抗肿瘤活性,值得进一步深入研究。

Synthesis and antitumor activity evaluation of novel tetrahydrobenzo[4

Objective To design and synthesize tetrahydrobenzo4'',5'']thieno3'',2'':5,6]pyrido4,3-d]pyrimidine derivatives and to investigate their anti-tumor activities in vitro. Methods A novel series of tetrahydrobenzo4'',5'']thieno3'',2'':5,6]pyrido4,3-d]pyrimidine derivatives were designed and synthesized via a tandem aza-Wittig reaction, their anti-tumor activities in vitro were evaluated for CNE2, KB, MGC-803, MCF-7 and PC3 cells by MTT assay. Results Twenty-five novel tetrahydrobenzo4'',5'']thieno3'',2'':5,6]pyrido4,3-d]pyrimidine derivatives were synthesized and the structures of compounds prepared were confirmed by the application of IR, 1H NMR, 13C NMR and HR-MS. The preliminary biological results showed that these conjugates displayed significant antiproliferative effect on these five cancer cells, especially for MGC-803. Compound 8c (IC50 = 0.9 ± 0.25 umol?L-1) stood out as the most potent against MGC-803, which was 20-fold more potent than 5-FU (IC50 = 18.4 ± 1.43 umol?L-1). Additionally, all compounds were nontoxic to health GES-1 and VERO cells, while 5-FU showed essential toxicity. Conclusion Tetrahydrobenzo4'',5''] thieno 3'',2'':5,6] pyrido4,3-d] pyrimidine compounds displayed promising antitumor activities, which is worth further being developed.