Synthesis and evaluation of the anti-proliferative activity of diaryl-3-pyrrolin-2-ones and fused analogs

Abstract

Analogs containing a central 3-pyrrolin-2-one core with different methoxyphenyl and/or indole substituents were prepared and tested for anti-proliferative activity in U-937 cells. The most efficacious analogs were non-rigid, (non-fused) contained methoxyaryl groups located at the 4-position, and contained either methoxyaryl or indole groups located at the 3-position. Both the number of methoxy groups contained in the substituents and the particular location of the indole rings with respect to the lactam carbonyl had significant affects on anti-proliferative activity. This work provides a framework to better understand structure-activity relationships for inducing anti-proliferative activity in diaryl heterocyclic scaffolds.

Discovery of Highly Functionalized 5-hydroxy-2H-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen

“…Notably, treatment of E2-non-depleted cells with compounds 32 , 35 , 43 and 49 decreased the viability of ER+ cancer cells (i.e., MCF-7, MCF-7/BUS, T47D and Ishikawa cells) with IC 50 values lower than 10 μM. The antitumoral potency for compound 32 (IC 50 from 0.27 to 10 μM) or compound 35 (IC 50 from 1 to 5 μM) in ER+ cancer cells was relatively higher compared to several 5-hydroxy-2 H -pyrrol-2-one analogs with IC 50 values over 10 μM ( Table 1 ) and other reported pyrrolidone-type compounds [ 24 , 25 ]. Interestingly, compounds 32 and 35 also decreased the viability of ER− BC cells (i.e., SK-BR-3, BT-549, Hs-578T, MDA-MB-231), but with relatively lower potency than ER+ BC cells ( Table 1 ).…”

“…Pyrrol-2-ones belong to a class of biologically active compounds [ 24 , 25 , 26 , 27 ] that possess different types of pharmacological activities; among others, inhibition of plasminogen activator inhibitor-1 (PAI-1) [ 28 ], anti-inflammatory [ 29 ] or antitumoral effects [ 24 ] have been reported on ER− and ER+ BC cells. In this study, we synthesized and characterized a new chemical library of highly functionalized 5-hydroxy- 2H -pyrrol-2-ones by using an in-silico modeling approach [ 30 , 31 ] followed by phenotype- and ERα-based screening assays in ERα-positive breast and endometrial cancer cells in order to identify new therapeutic strategies that overcome major limitations of current ER+ BC treatments.…”

One‐Step Synthesis of 3,4‐Diphenyl‐2‐pyrrolinones by Solvent‐Free and Bi2O3‐Catalyzed Approaches and Cytotoxicity Screening Against Glioma Cells

“…In this way, these newly developed conditions afford practical access to multifunctionalized dihydro‐2‐pyrrolinones with two vicinal phenyl substituents in a simple way and are adequate for the purpose of synthesizing a small set of such δ‐lactam in a quick way for biological screening. In this case, among tested heterocycles, compound 7 was the most cytotoxic against U251 and C6 glioma cells and appears to be a new possibility as an antitumor scaffold , paving the way for diaryl‐dihydro‐2‐pyrrolinones to be further investigated in this aggressive brain tumor .…”

Synthesis, characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA, BSA interactions and molecular docking study

“…In vivo studies have shown that some pyrrolin-2-one derivatives had genotoxic effects on the mouse bone marrow [34]. There are also data on the antitumor effects of some diaryl-3-pyrroline-2-on derivatives on human malignant cells, such as U-937 histiocytic lymphoma cells [35]. Almost no data are available on the mechanism of action of these organic compounds, as well as the type of cell death they induce, so we examined whether cytotoxicity induced by tested compounds was due to apoptosis or cell cycle arrest.…”