设计、合成及 4-取代甲氧基苯甲酰基-芳基-噻唑类似物的构效关系研究作为有效及口服生物利用度的抗癌药物。
Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl-thiazoles analogues as potent and orally bioavailable anticancer agents.
机构信息
Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center, Memphis, Tennessee 38163, United States.
出版信息
J Med Chem. 2011 Jul 14;54(13):4678-93. doi: 10.1021/jm2003427. Epub 2011 Jun 7.
Abstract
In a continued effort to improve upon the previously published 4-substituted methoxybenzoyl-aryl-thiazole (SMART) template, we explored chemodiverse "B" rings and "B" to "C" ring linkage. Further, to overcome the poor aqueous solubility of this series of agents, we introduced polar and ionizable hydrophilic groups to obtain water-soluble compounds. For instance, based on in vivo pharmacokinetic (PK) studies, an orally bioavailable phenyl-amino-thiazole (PAT) template was designed and synthesized in which an amino linkage was inserted between "A" and "B" rings of compound 1. The PAT template maintained nanomolar (nM) range potency against cancer cell lines via inhibiting tubulin polymerization and was not susceptible to P-glycoprotein mediated multidrug resistance in vitro, and markedly improved solubility and bioavailability compared with the SMART template (45a-c (PAT) vs 1 (SMART)).
摘要
为了进一步改进先前发表的 4-取代甲氧基苯甲酰基-芳基噻唑（SMART）模板，我们探索了化学多样性的“B”环和“B”到“C”环连接。此外，为了克服该系列试剂的较差的水溶性，我们引入了极性和亲水可电离基团以获得水溶性化合物。例如，基于体内药代动力学（PK）研究，设计并合成了可口服生物利用的苯基-氨基-噻唑（PAT）模板，其中在化合物 1 的“A”和“B”环之间插入了氨基连接。PAT 模板通过抑制微管蛋白聚合，对癌细胞系保持纳摩尔（nM）范围的效力，并且不易受到体外 P 糖蛋白介导的多药耐药性的影响，与 SMART 模板相比，显著提高了溶解度和生物利用度（45a-c（PAT）与 1（SMART））。
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