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

详细信息    查看全文

• 作者：Shabir H. Lone ; Khursheed A. Bhat ; Shakeel-u-Rehman ; Rabiya Majeed ; Abid Hamid ; Mohd A. Khuroo
• 关键词：Ludartin ; Michael-addition ; Amino analogs ; Cytotoxicity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 September, 2013
• 年：2013
• 卷：23
• 期：17
• 页码：4931-4934
• 全文大小：1597 K

文摘

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 ¦Á-methylene-¦Ã-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 ICub>50ub> of 2.8 ¦ÌM. (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 ¦ÌM) while as (11R)-13-(6-nitroindazole)-11,13-dihydroludartin (18) exhibited three-fold selective cytotoxicity for Lung (A-549) cancer cell lines exhibiting ICub>50ub> of 2.6 ¦ÌM.