Synthesis and biological evaluation of amino analogs of Ludartin: potent and selective cytotoxic agents

Diverse amino analogs of Ludartin, a cytotoxic guaianolide and a position isomer of an Anticancer drug, Arglabin were prepared through Michael type addition at its highly active α-methylene-γ-lactone motif. The semisynthetic derivatives were subjected to sulphorhodamine B cytotoxicity assay against a panel of four different human Cancer cell lines viz. lung (A-549), leukemia (THP-1), prostate (PC-3) and colon (HCT-116) to look into structure-activity relationship. Few of the analogs displayed potent selective cytotoxicity compared to the parent molecule-Ludartin (1). (11R)-13-(Diethyl amine)-11,13-dihydroludartin (6) and (11R)-13-(piperidine)-11,13-dihydroludartin (10) showed almost same cytotoxicity against leukemia cell lines (THP-1) as that of parent molecule-Ludartin, but were more active against colon (HCT-116) Cancer cells. (11R)-13-(Morpholine)-11,13-dihydroludartin (11) displayed selectively better cytotoxicity against Leukemia Cancer cells (THP-1) exhibiting IC50 of 2.8 μM. (11R)-13-(6-Nitroindazole)-11,13-dihydroludartin (17) was four times more potent than Ludartin with selective cytotoxic effects against prostate Cancer cells (2.2 μM) while as (11R)-13-(6-nitroindazole)-11,13-dihydroludartin (18) exhibited three-fold selective cytotoxicity for Lung (A-549) Cancer cell lines exhibiting IC50 of 2.6 μM.

Amino analogs; Cytotoxicity; Ludartin; Michael-addition.