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

• Published in: Bioorganic & medicinal chemistry 2013-12, Vol.21 (24), p.7938-7954
• Main Authors: Shiokawa, Zenyu, Hashimoto, Kentaro, Saito, Bunnai, Oguro, Yuya, Sumi, Hiroyuki, Yabuki, Masato, Yoshimatsu, Mie, Kosugi, Yohei, Debori, Yasuyuki, Morishita, Nao, Dougan, Douglas R., Snell, Gyorgy P., Yoshida, Sei, Ishikawa, Tomoyasu
• Format: Article
• Language: English
• Subjects: antagonists; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; benzene; cell growth; Cell Line, Tumor; Cell Membrane Permeability - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; cIAP; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; drugs; growth retardation; Hexahydropyrazino[1,2-a]indole; Humans; hydrophobicity; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Inhibitor of Apoptosis Proteins - chemical synthesis; Inhibitor of Apoptosis Proteins - chemistry; Inhibitor of Apoptosis Proteins - pharmacology; Inhibitors of apoptosis proteins; inhibitory concentration 50; membrane permeability; Models, Molecular; Molecular Structure; proteins; Pyrazines - chemical synthesis; Pyrazines - chemistry; Pyrazines - pharmacology; stereoisomers; Structure-Activity Relationship; XIAP
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.09.067

We previously reported octahydropyrrolo[1,2-a]pyrazine derivative 2 (T-3256336) as a potent antagonist for inhibitors of apoptosis (IAP) proteins. Because compound 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 50, which showed strong inhibition of IAP binding (X chromosome-linked IAP [XIAP]: IC50 23nM and cellular IAP [cIAP]: IC50 1.1nM) and cell growth inhibition (MDA-MB-231 cells: GI50 2.8nM) with high permeability and low potential of MDR1 substrate.