Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia.
Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia.
复制标题
生物还原性可激活的苯他汀前药缀合物，旨在针对肿瘤缺氧。
DOI：
10.1016/j.bmcl.2016.11.093
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发表时间：
2017
影响因子：
2.7
通讯作者：
Pinney,KevinG
中科院分区：
文献类型：
--
作者：
Winn,BlakeA;Shi,Zhe;Carlson,GrahamJ;Wang,Yifan;Nguyen,BensonL;Kelly,EvanM;Ross4th,RDavid;Hamel,Ernest;Chaplin,DavidJ;Trawick,MaryL;Pinney,KevinG
多种实体瘤癌症含有显著的缺氧区域，这为有效抗癌剂的靶向提供了独特的挑战。生物还原活化的前药缀合物（BAPCs）代表了用于治疗干预的有前景的策略。BAPC被设计为生物惰性的，直到它们与低氧张力接触，此时还原酶介导的切割以肿瘤特异性方式释放母体抗癌剂。Phenstatin是一种有效的微管蛋白聚合抑制剂，模拟天然产物Combretastatin A-4的化学结构和生物活性。已经建立了用于酚他丁的硝基苄基、硝基咪唑、硝基呋喃基和硝基噻吩基前药的合成方法，包括所连接的硝基化合物的去甲、单甲基和偕二甲基变体。通过化学合成法制备了一系列基于酚他丁的BAPC，并对微管蛋白-微管蛋白系统进行了评价。在厌氧条件下的初步研究中，在NADPH细胞色素P450氧化还原酶的存在下，gem-二甲基硝基噻吩和gem-二甲基硝基呋喃类似物被证明进行有效的酶促裂解。本研究中评价的11种BAPC中的每一种均显示出与母体抗癌剂芬他汀相比对微管蛋白的抑制活性显著降低（IC 50 = 1.0 μM）。事实上，大多数BAPC（11种类似物中的7种）不是微管蛋白聚合的抑制剂（IC 50> 20 μM），这代表了这些前药的预期（和理想）属性，因为它们在酶介导的裂解释放苯他汀之前是生物学无活性的。
A variety of solid tumor cancers contain significant regions of hypoxia, which provide unique challenges for targeting by potent anticancer agents. Bioreductively activatable prodrug conjugates (BAPCs) represent a promising strategy for therapeutic intervention. BAPCs are designed to be biologically inert until they come into contact with low oxygen tension, at which point reductase enzyme mediated cleavage releases the parent anticancer agent in a tumor-specific manner. Phenstatin is a potent inhibitor of tubulin polymerization, mimicking the chemical structure and biological activity of the natural product combretastatin A-4. Synthetic approaches have been established for nitrobenzyl, nitroimidazole, nitrofuranyl, and nitrothienyl prodrugs of phenstatin incorporatingnor-methyl,mono-methyl, andgem-dimethyl variants of the attached nitro compounds. A series of BAPCs based on phenstatin have been prepared by chemical synthesis and evaluated against the tubulin-microtubule protein system. In a preliminary study using anaerobic conditions, thegem-dimethyl nitrothiophene andgem-dimethyl nitrofuran analogues were shown to undergo efficient enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase. Each of the eleven BAPCs evaluated in this study demonstrated significantly reduced inhibitory activity against tubulin in comparison to the parent anti-cancer agent phenstatin (IC50= 1.0 μM). In fact, the majority of the BAPCs (seven of the eleven analogues) were not inhibitors of tubulin polymerization (IC50> 20 μM), which represents an anticipated (and desirable) attribute for these prodrugs, since they are intended to be biologically inactive prior to enzyme-mediated cleavage to release phenstatin.