Structure-activity study to develop cationic lipid-conjugated haloperidol derivatives as a new class of anticancer therapeutics.

Basic Information

ID: ALA1764983

Journal: J Med Chem

Title: Structure-activity study to develop cationic lipid-conjugated haloperidol derivatives as a new class of anticancer therapeutics.

Authors: Pal K, Pore S, Sinha S, Janardhanan R, Mukhopadhyay D, Banerjee R.

Abstract: Haloperidol (HP), a neuroleptic drug, shows high affinity toward σ receptors (SR). HP and reduced-HP at higher concentration were known to induce apoptosis in SR-overexpressing carcinomas and melanomas. Herein, we report the development of cationic lipid-conjugated haloperidol as a new class of anticancer therapeutics. In comparison to HP, the C-8 carbon chain analogue (HP-C8) showed significantly high, SR-assisted antiproliferative activity against cancer cells via caspase-3-mediated apoptosis and down-regulation of pAkt. Moreover, melanoma tumor aggressiveness in HP-C8-treated mice was significantly lower than that in HP-treated mice. HP-C8 simultaneously reduced Akt-protein level and increased Bax/Bcl-2 ratio in vascular endothelial cells, thereby indicating a possible protein kinase down-regulatory and apoptosis inducing role in tumor-associated vascular cells. In conclusion, we developed σ receptor-targeting cationic lipid-modified HP derivatives as a promising class of anticancer therapeutic that concurrently affects cancer and tumor environment associated angiogenic vascular cells through induction of apoptosis and Akt protein down-regulation.

CiteXplore: 21391684

DOI: 10.1021/jm101530j

Patent ID: ┄