Synthesis and anticancer activity of conformationally constrained Smac mimetics containing pseudo β turns

• Published in: Tetrahedron letters Vol. 59; no. 38; pp. 3473 - 3476
• Main Authors: Baravkar, Sachin B., Wagh, Mahendra A., Paul, Debasish, Santra, Manas, Sanjayan, Gangadhar J.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 19.09.2018; Elsevier
• Subjects: AVPI tetrapeptide; Benzoxazinone; Chemistry; Chemistry, Organic; MDA-MB-231; Physical Sciences; Science & Technology; Smac mimetics; Sulfonamide; Smac mimetics; Benzoxazinone; AVPI tetrapeptide; Sulfonamide; MDA-MB-231; SMAC/DIABLO; ANTAGONIST; DIABLO; CANCER; POTENT; THERAPY; INHIBITOR; PROTEINS; BINDING; PROMOTES APOPTOSIS
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2018.08.016

[Display omitted] •Smac mimetics containing reverse-turn inducing motifs are reported.•Reverse-turn incorporation is expected to improve structural stability.•Some of the analogs show better activity than the standard AVPI Smac tetrapeptide.•Sulfonamide counterparts outperform carboxamide analogs, in terms of activity. Herein, we report synthesis and in vitro anticancer activity of conformationally constrained Smac mimetics containing reverse turn inducing motifs “Ant-Pro” and “sAnt-Pro”. The synthesis of Smac analogs with diverse hydrophobic groups at the C-terminus was carried out using solution phase peptide synthesis. The synthesis of Ant-Pro containing analogs 3a–j was carried out by ring opening of benzoxazinones 7a–c, whereas, their sulfonamide counterparts 4a–h were synthesized by using routine acid-amine coupling reaction. In vitro anticancer studies against breast cancer cell line MDA-MB-231 revealed that some of the new analogs had better anticancer activity than the standard AVPI Smac tetrapeptide.