Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.
Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.
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DOI：
10.1021/jm400048v
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发表时间：
2013-06-27
影响因子：
7.3
通讯作者：
Njar VC
中科院分区：
文献类型：
--
作者：
Purushottamachar P;Godbole AM;Gediya LK;Martin MS;Vasaitis TS;Kwegyir-Afful AK;Ramalingam S;Ates-Alagoz Z;Njar VC
作为我们探索候选药物3β-（羟基）-17-（1H-苯并咪唑-1-基）-雄甾-5，16-二烯（galeterone，5）的小结构修饰对雄激素受体（AR）调节的影响的计划的一部分，我们制备并评价了一系列新的C-3、C-16和C-17类似物。使用结构活性分析，我们确定C-17处的苯并咪唑部分是必需的和最佳的，并且C-3处的亲水性和杂芳基增强抗增殖（AP）和AR降解（ARD）活性。最有效的抗增殖化合物是3β-（1H-咪唑-1-羧酸酯）-17-（1H-苯并咪唑-1-基）-雄甾-5，16-二烯（47），3-（（EZ）-羟肟基）-17-（1H-苯并咪唑-1-基）-雄甾-4，16-二烯（36），3β-（吡啶-4-羧酸酯）-17-（1H-苯并咪唑-1-基）-雄甾-5，16-二烯（43），GI 50值分别为0.87、1.91和2.57 μM。与5相比，化合物47在AP和ARD活性方面分别是4倍和8倍。重要的是，我们还发现我们的化合物，包括5、36、43和47，可以降解CWR 22 rv 1人前列腺癌细胞中的全长和截短的AR。有了这些活性，它们作为治疗所有形式前列腺癌的新药的潜力就显现出来了。
As part of our program to explore the influence of small structural modifications of our drug candidate, 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16 and C-17 analogs. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both anti-proliferative (AP) and AR degrading (ARD) activities. The most potent anti-proliferative compounds were 3β-(1H-imidazole-1-carboxylate)- 17-(1H-benzimidazol-1-yl)-androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1Hbenzimidazol- 1-yl)-androsta-4,16-diene (36), 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol- 1-yl)-androsta-5,16-diene (43), with GI50 values of 0.87, 1.91 and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43 and 47 could degrade both full-length and truncated AR in CWR22rv1 human prostate cancer cells. With these activities, their potential for development as new drugs for the treatment of all forms of prostate cancer.
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影响因子：
9.2
作者：
Guo Z;Qiu Y
通讯作者：
Qiu Y
影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
7.3
作者：
Brandt GE;Schmidt MD;Prisinzano TE;Blagg BS
通讯作者：
Blagg BS
影响因子：
2.7
作者：
Bruno RD;Vasaitis TS;Gediya LK;Purushottamachar P;Godbole AM;Ates-Alagoz Z;Brodie AM;Njar VC
通讯作者：
Njar VC
影响因子：
3.8
作者：
Fan, Meiyun;Rickert, Emily L.;Weatherman, Ross V.
通讯作者：
Weatherman, Ross V.