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

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

doi:10.1016/j.bmc.2013.09.067

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

Bioorg Med Chem. 2013 Dec 15;21(24):7938-54. doi: 10.1016/j.bmc.2013.09.067. Epub 2013 Oct 12.

Authors

Zenyu Shiokawa¹, 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

Affiliation

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: [email protected].

PMID: 24169315
DOI: 10.1016/j.bmc.2013.09.067

Abstract

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.

Keywords: 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; Hexahydropyrazino[1,2-a]indole; 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; XIAP; acetyl; cIAP; 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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cell Line, Tumor
Cell Membrane Permeability / drug effects*
Cell Proliferation / drug effects
Cell Survival / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Inhibitor of Apoptosis Proteins / chemical synthesis
Inhibitor of Apoptosis Proteins / chemistry
Inhibitor of Apoptosis Proteins / pharmacology*
Models, Molecular
Molecular Structure
Pyrazines / chemical synthesis
Pyrazines / chemistry
Pyrazines / pharmacology*
Structure-Activity Relationship

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Indoles
Inhibitor of Apoptosis Proteins
Pyrazines