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.
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 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.
['Shiokawa|Zenyu|Z|', 'Hashimoto|Kentaro|K|', 'Saito|Bunnai|B|', 'Oguro|Yuya|Y|', 'Sumi|Hiroyuki|H|', 'Yabuki|Masato|M|', 'Yoshimatsu|Mie|M|', 'Kosugi|Yohei|Y|', 'Debori|Yasuyuki|Y|', 'Morishita|Nao|N|', 'Dougan|Douglas R|DR|', 'Snell|Gyorgy P|GP|', 'Yoshida|Sei|S|', 'Ishikawa|Tomoyasu|T|']
D018435:ATP Binding Cassette Transporter, Subfamily B D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 D000970:Antineoplastic Agents D017209:Apoptosis D045744:Cell Line, Tumor D002463:Cell Membrane Permeability D049109:Cell Proliferation D002470:Cell Survival D018360:Crystallography, X-Ray D004305:Dose-Response Relationship, Drug D015195:Drug Design D004354:Drug Screening Assays, Antitumor D006801:Humans D007211:Indoles D051034:Inhibitor of Apoptosis Proteins D008958:Models, Molecular D015394:Molecular Structure D011719:Pyrazines D013329:Structure-Activity Relationship
Hexahydropyrazino[1,2-a]indole XIAP cIAP 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 1-hydroxybenzotriazole 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride Ac CDCl(3) DIPEA DMF DMSO DMT-MM EDC Et HATU HOBT Inhibitors of apoptosis proteins Me N,N-dimethylformamide N-ethyldiisopropylamine O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate Pd(OH)(2)/C Pd/C Pr Quant. TFA THF acetyl deuteratedchloroform dimethyl sulfoxide ethyl i iso melting point methyl mp palladium hydroxide on carbon palladium on carbon propyl quantitative yield satd saturated aqueous tert tertiary tetrahydrofuran trifluoroacetic acid