Synthesis, conformation and cytotoxic activity of short hybrid peptides containing conformationally constrained 1-(aminomethyl)cyclohexanecarboxylic acid and gabapentin.

The present work describes the synthesis,conformation and cytotoxic activities of short β/γ hybrid peptides, Boc-β2,2-Ac6c-Gpn-NHMe, BG1; Boc-(β2,2-Ac6c-Gpn)2-OMe, BG2; Boc-(β2,2-Ac6c-Gpn)3-OMe, BG3; H-β2,2-Ac6c-Gpn-NHMe, BG4; H-(β2,2-Ac6c-Gpn)2-OMe, BG5; H-(β2,2-Ac6c-Gpn)3-OMe, BG6, Boc-β2,2-Ac6c-Gpn-OMe, BG7 and H-β2,2-Ac6c-Gpn-OMe, BG8. Mixed C6/C7 conformations were observed for β/γ hybrid peptides. Further, BG1-BG8 were screened against MCF-7 (Breast cancer), A549 (Lung Cancer), PC-3 (Prostate cancer), HCT-116 (Colon cancer), and MDA-MB-231 (Breast cancer) cell lines. Among all, BG6 exhibited potent cytotoxicity against all cancer cell lines with IC50 ranging from 1.6 μM to 6.3 μM with relatively low cytotoxicity against normal epithelial breast cell line fR-2 and human embryonic kidney cell line HEK-293. Minimal hemolytic activity was observed for BG6 against human erythrocytes. Peptide BG6 displayed anti-migratory and anti-invasive potentials showing strong interactions with intrinsic apoptotic markers Bcl-2, Bax, and cleaved-PARP, as well as the induction of the mitochondria maladjustment mediated apoptosis.