Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives

D V Kaminskyy,R B Lesyk

doi:10.7124/bc.000150

Abstract

The aim of present research was investigation of anticancer activity of 4-azolidinone-3-carboxylic acids derivatives, and studies of structure–activity relationships (SAR) aspects. Methods. Organic synthesis; spectral methods; anticancer screening was performed according to the US NCI protocol (Developmental Therapeutic Program). Results. The data of new 4-thiazolidinone-3-alkanecarboxylic acids derivatives in vitro anticancer activity were described. The most active compounds which belong to 5-arylidene-2,4thia(imida)zolidinone-3-alkanecarboxylic acids; 5-aryl(heteryl)idenerhodanine-3-succinic acids derivatives were selected. Determination of some SAR aspects which allowed to determine directions in leadcompounds structure optimization, as well as desirable molecular fragments for design of potential anticancer agents based on 4-azolidinone scaffold were performed. 5-Arylidenehydantoin-3-acetic acids amides were identified as a new class of significant selective antileukemic agents. Possible pharmacophore scaffold of 5-ylidenerhodanine-3-succinic acids derivatives was suggested. Conclusions. The series of active compounds with high anticancer activity and/or selectivity levels were selected. Some SAR aspects were determined and structure design directions were proposed.

Highlights

Design of «small molecules» as innovative anticancer agents based on well-known scaffolds is one of the most commonly employed approaches in drug discovery
The row of 4-azolidinone-3-carboxylic acids derivatives with high affinity to «anticancer biotargets» was discovered. 5-Arylidenerhodanine-3-carboxylic acids are known as inhibitors of antiapoptic protein–protein interaction between Bcl-2 and Bax family and their interaction with receptors’ domains [7,8,9,10]; inhibitors of JSP-1 – «atypical» dual-specific phosphatases family member (JNK-stimulating phosphatase-1) [11]
Average values of panel cancer lines growth percent lay within 100 %, which provides evidence that nonspecific antimitotic action for studied 4-thiazolidinone derivatives

Summary

Introduction

Design of «small molecules» as innovative anticancer agents based on well-known scaffolds is one of the most commonly employed approaches in drug discovery. Nowadays the anticancer potential of 4-azolidinone-3-carboxylic acids (derivatives of rhodanine, 2,4-thiazolidindione or hydantoin with carboxylic acids in position N3) realized via influence on various metabolic pathways of cancer cells is described based on traditional and high-throughput screening [1, 2] (Fig. 1). The large group of mentioned heterocycles with known pharmacological activity (such as antioxidant, anti-inflammatory, hypoglycemic, immunomodulative, etc.) was established as promising anticancer agents as well. Another approach to search of anticancer substances is target-oriented drug design, which. The ligands of neuroimunofiline FK506-binding protein (FKBP) are structurally analogous to mentioned series

Methods

Results

Conclusion