Design, synthesis, and biological activities of novel hexahydropyrazino[1,2-a]indole derivatives as potent inhibitors of apoptosis (IAP) proteins antagonists with improved membrane permeability across MDR1 expressing cells

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• 作者：Zenyu Shiokawa ; Kentaro Hashimoto ; Bunnai Saito ; Yuya Oguro ; Hiroyuki Sumi ; Masato Yabuki ; Mie Yoshimatsu ; Yohei Kosugi ; Yasuyuki Debori ; Nao Morishita ; Douglas R. Dougan ; Gyorgy P. Snell ; Sei Yoshida ; Tomoyasu Ishikawa
• 关键词：HATU ; O-(7-azabenzotriazol-1-yl)-N ; N ; N&prime ; N&prime ; -tetramethyluronium hexafluorophosphate ; DIPEA ; N-ethyldiisopropylamine ; Ac ; acetyl ; CDCl3 ; deuteratedchloroform ; DMF ; N ; N-dimethylformamide ; DMSO ; dimethyl sulfoxide ; DMT-MM ; 4-(4 ; 6-dimethoxy-1 ; 3 ; 5-triazin-2-yl)-4-methylmorpholinium chloride ; EDC ; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ; Et ; ethyl ; HOBT ; 1-hydroxybenzotriazole ; i ; iso ; mp ; melting point ; Me ; methyl ; Pd/C ; palladium on carbon ; Pd(OH)2/C ; palladium hydroxide on carbon ; P
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 December, 2013
• 年：2013
• 卷：21
• 期：24
• 页码：7938-7954
• 全文大小：2692 K

文摘

We previously reported octahydropyrrolo[1,2-a]pyrazine derivative class="boldFont">2 (T-3256336) as a potent antagonist for inhibitors of apoptosis (IAP) proteins. Because compound class="boldFont">2 was susceptible to MDR1 mediated efflux, we developed another scaffold, hexahydropyrazino[1,2-a]indole, using structure-based drug design. The fused benzene ring of this scaffold was aimed at increasing the lipophilicity and decreasing the basicity of the scaffold to improve the membrane permeability across MDR1 expressing cells. We established a chiral pool synthetic route to yield the desired tricyclic chiral isomers. Chemical modification of the core scaffold led to a representative compound class="boldFont">50, which showed strong inhibition of IAP binding (X chromosome-linked IAP [XIAP]: IC₅₀ 23 nM and cellular IAP [cIAP]: IC₅₀ 1.1 nM) and cell growth inhibition (MDA-MB-231 cells: GI₅₀ 2.8 nM) with high permeability and low potential of MDR1 substrate.