title: Synthesis and biological evaluation of amino analogs of Ludartin: potent and selective cytotoxic agents.
abstract: 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.
authors.affiliation: Bio-organic Chemistry Division, Indian Institute of Integrative Medicine, CSIR, Srinagar 190005, India.
authors.forename: Shabir H
authors.initials: SH
authors.lastname: Lone
authors.forename: Khursheed A
authors.initials: KA
authors.lastname: Bhat
authors.lastname: Shakeel-u-Rehman
authors.forename: Rabiya
authors.initials: R
authors.lastname: Majeed
authors.forename: Abid
authors.initials: A
authors.lastname: Hamid
authors.forename: Mohd A
authors.initials: MA
authors.lastname: Khuroo
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology*; D045789:Sesquiterpenes, Guaiane; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D003603:Cytotoxins; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C083346:arglabin
keywords: Amino analogs; Cytotoxicity; Ludartin; Michael-addition