European Journal of Medicinal Chemistry 2011-08-01

Design and synthesis of spiro derivatives of parthenin as novel anti-cancer agents.

Doma Mahendhar Reddy, Naveed A Qazi, Sanghpal D Sawant, Abid H Bandey, Jada Srinivas, Mannepalli Shankar, Shashank K Singh, Monika Verma, Gousia Chashoo, Arpita Saxena, Dilip Mondhe, Ajit K Saxena, V K Sethi, Subhash C Taneja, Gulam N Qazi, H M Sampath Kumar, Doma Mahendhar Reddy, Naveed A. Qazi, Sanghpal D. Sawant, Abid H. Bandey, Jada Srinivas, Mannepalli Shankar, Shashank K. Singh, Monika Verma, Gousia Chashoo, Arpita Saxena, Dilip Mondhe, Ajit K. Saxena, V.K. Sethi, Subhash C. Taneja, Gulam N. Qazi, H.M. Sampath Kumar

Index: Eur. J. Med. Chem. 46 , 3210-7, (2011)

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Abstract

Several novel spiro derivatives of parthenin (1) have been synthesized by the dipolar cycloaddition using various dipoles viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring (α-methylene-γ-butyrolactone). Majority of the compounds exhibited improved anti-cancer activity compared to the parthenin, when screened for their in vitro cytotoxicity against three human cancer cell lines viz., SW-620, DU-145 and PC-3. In vivo screening of select analog revealed improved anti-cancer activity with low mammalian toxicity as compared to parthenin. The results of the cytotoxicity pattern of these derivatives reveals the SAR of these sesquiterpinoid lactones and possible role of α,β-unsaturated ketone of parthenin in inhibiting NF-kB. A mechanistic correlation of anti-cancer activity along with in vivo and western blotting experiments has been described.Copyright © 2011 Elsevier Masson SAS. All rights reserved.