title: CLEFMA-an anti-proliferative curcuminoid from structure-activity relationship studies on 3,5-bis(benzylidene)-4-piperidones.
abstract: 3,5-Bis(benzylidene)-4-piperidones are being advanced as synthetic analogs of curcumin for anti-cancer and anti-inflammatory properties. We performed structure-activity relationship studies, by testing several synthesized 3,5-bis(benzylidene)-4-piperidones for anti-proliferative activity in lung adenocarcinoma H441 cells. Compared to the lead compound 1, or 3,5-bis(2-fluorobenzylidene)-4-piperidone, five compounds were found to be more potent (IC(50) < 30 microM), and 16 compounds possessed reduced cell-killing efficacy (IC(50) > 50 microM). Based on the observations, we synthesized 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] (29 or CLEFMA) as a novel analog of 1. CLEFMA was evaluated for anti-proliferative activity in H441 cells, and was found to be several folds more potent than compound 1. We did not find apoptotic cell population in flow cytometry, and the absence of apoptosis was confirmed by the lack of caspase cleavage. The electron microscopy of H441cells indicated that CLEFMA and compound 1 induce autophagic cell death that was inhibited by specific autophagy inhibitor 3-methyladenine. The results suggest that the potent and novel curcuminoid, CLEFMA, offers an alternative mode of cell death in apoptosis-resistant cancers.
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Lagisetty
authors.forename: Prachi
authors.initials: P
authors.lastname: Vilekar
authors.forename: Kaustuv
authors.initials: K
authors.lastname: Sahoo
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.forename: Vibhudutta
authors.initials: V
authors.lastname: Awasthi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D001597:Benzylidene Compounds / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D010881:Piperidones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C526290:3,5-bis(benzylidene)-4-piperidone; C572622:4-(3,5-bis(2-chlorobenzylidene)-4-oxopiperidine-1-yl)-4-oxo-2-butenoic acid; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D010881:Piperidones