Mortimer Catriona G, Wells Geoffrey, Crochard Jean-Philippe, Stone Erica L, Bradshaw Tracey D, Stevens Malcolm F G, Westwell Andrew D
Cancer Research UK Experimental Cancer Chemotherapy Research Group, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, UK.
J Med Chem. 2006 Jan 12;49(1):179-85. doi: 10.1021/jm050942k.
A series of new 2-phenylbenzothiazoles has been synthesized on the basis of the discovery of the potent and selective in vitro antitumor properties of 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (8n; GW 610, NSC 721648). Synthesis of analogues substituted in the benzothiazole ring was achieved via the reaction of o-aminothiophenol disulfides with substituted benzaldehydes under reducing conditions. Compounds were evaluated in vitro in four human cancer cell lines, and compound 8n was found to possess exquisitely potent antiproliferative activity (GI(50) < 0.1 nM for MCF-7 and MDA 468). Potent and selective activity was also observed in the NCI 60 human cancer cell line panel. Structure-activity relationships established that the compound 8n stands on a pinnacle of potent activity, with most structural variations having a deactivating in vitro effect. Mechanistically, this new series of agents contrasts with the previously reported 2-(4-aminophenyl)benzothiazoles; compound 8n is not reliant on induction of CYP1A1 expression for antitumor activity.
基于2-(3,4-二甲氧基苯基)-5-氟苯并噻唑（8n；GW 610，NSC 721648）具有强大且选择性的体外抗肿瘤特性这一发现，合成了一系列新型2-苯基苯并噻唑。在还原条件下，通过邻氨基苯硫酚二硫化物与取代苯甲醛反应，实现了苯并噻唑环上取代类似物的合成。在四种人类癌细胞系中对化合物进行了体外评估，发现化合物8n具有极其强大的抗增殖活性（MCF-7和MDA 468的GI(50) < 0.1 nM）。在NCI 60人类癌细胞系面板中也观察到了强大且选择性的活性。构效关系表明，化合物8n处于强大活性的巅峰，大多数结构变化在体外具有失活作用。从机制上讲，这一系列新药物与先前报道的2-(4-氨基苯基)苯并噻唑不同；化合物8n的抗肿瘤活性不依赖于CYP1A1表达的诱导。
