CLEFMA—An anti-proliferative curcuminoid from structure–activity relationship studies on 3,5-bis(benzylidene)-4-piperidones

Abstract

Abstract3,5-bis(benzylidene)-4-piperidones are being advanced as synthetic analogs of curcumin for anticancer 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 μM), and sixteen compounds possessed reduced cell-killing efficacy (IC 50 > 50 μM). 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 antiproliferative 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.

Curcumin Induces Autophagy via Activating the AMPK Signaling Pathway in Lung Adenocarcinoma Cells

“…However, autophagy is a very complex process that requires multiple molecular methods for monitoring according to the guideline of autophagy study community (49). Therefore, the immunofluorescence and immunoblotting results from our study strongly support the finding from Lagisetty et al (48), that is, curcumin indeed induces autophagy in lung adenocarcinoma cells.…”

“…Curcumin was found to be able to activate autophagy in some types of cancer cells, including melanoma cells (29), colon cancer cells (30), and hepatocellular carcinoma cells (31). We noted that there was one previous report showing that H441 lung cancer cells displayed autophagic phenotype upon treatment of 3,5-bis(benzylidene)-4-piperidones, synthetic analogs of curcumin, under observation with electron microscopy (48). However, autophagy is a very complex process that requires multiple molecular methods for monitoring according to the guideline of autophagy study community (49).…”

Remediation of Hemorrhagic Shock-Induced Intestinal Barrier Dysfunction by Treatment with Diphenyldihaloketones EF24 and CLEFMA

“…EF24 and CLEFMA were synthesized in-house by the procedures published elsewhere (Lagisetty et al, 2009(Lagisetty et al, , 2010. Sterile solutions of these drugs were prepared in normal saline using poly(ethylene glycol) (PEG)-400 as a cosolvent (3 parts saline 1 1 part PEG400).…”

“…Another potent analog of EF24 is CLEFMA (4-[3,5-bis (2-chlorobenzylidene)-4-oxo-piperidine-1-yl]-4-oxo-2-butenoic acid) (Fig. 1A), which has bis-2-chloro in place of bis-2-fluoro functional groups and carries an additional maleic acid chain at the piperidonyl nitrogen (Lagisetty et al, 2010). In this study, we hypothesized that the salutary effects of diphenyldihaloketones in unresuscitated hemorrhagic shock would involve remediation of intestinal barrier function loss.…”

Synthesis of N-Substituted 3,5-Bis(arylidene)-4-piperidones with High Antitumor and Antioxidant Activity

“…The 1,5-diaryl-3-oxo-1,4-pentadienyl groups considered to react at a primary binding site, however the bioactivity will be influenced by others structural units: such as acylating piperidone nitrogen increased cytotoxic potencies and increasing the electron-withdrawing properties of substituents on aromatic ring has advantageous effect on cytotoxicity. [14][15][16][17][18] However, dimethylenbridge between C2-C6 atoms in piperidone was accompanied by reduction of cytotoxic properties exerting a steric impedance to alignment at one or more binding sites as well as variation of hydrophobicity and hence membrane transportation properties. 16 In general the DAP compounds were more effective than curcumin in inhibiting the proliferation of a variety of cancer cell lines.…”