Design, Synthesis, and Biological Evaluation of Novel N-Acylhydrazone Bond Linked Heterobivalent β-Carbolines as Potential Anticancer Agents.

Chen Chen,Guo Guo,Zhang Zhang,Ma Ma,Fan Fan

doi:10.3390/molecules24162950

Chen Chen, Guo Guo + Show 3 more

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https://doi.org/10.3390/molecules24162950

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Abstract

Utilizing a pharmacophore hybridization approach, we have designed and synthesized a novel series of 28 new heterobivalent β-carbolines. The in vitro cytotoxic potential of each compound was evaluated against the five cancer cell lines (LLC, BGC-823, CT-26, Bel-7402, and MCF-7) of different origin—murine and human, with the aim of determining the potency and selectivity of the compounds. Compound 8z showed antitumor activities with half-maximal inhibitory concentration (IC50) values of 9.9 ± 0.9, 8.6 ± 1.4, 6.2 ± 2.5, 9.9 ± 0.5, and 5.7 ± 1.2 µM against the tested five cancer cell lines. Moreover, the effect of compound 8z on the angiogenesis process was investigated using a chicken chorioallantoic membrane (CAM) in vivo model. At a concentration of 5 μM, compound 8z showed a positive effect on angiogenesis. The results of this study contribute to the further elucidation of the biological regulatory role of heterobivalent β-carbolines and provide helpful information on the development of vascular targeting antitumor drugs.

Highlights

Cancer remains a leading cause of death in developed and developing countries, much significant progress has been achieved recently [1]
Continuing our studies to develop effective cytotoxic agents, the objective of this study was to synthesize potential anticancer compounds that are hybrids of β-carboline and acylhydrazone fragments (Figure 3). We have evaluated their cytotoxic activities for the first time, and the study includes an investigation of the mechanism of action of these compounds for angiogenesis inhibition
The obtained carboxylic acid 2 reacted with thionyl chloride and ester 3, which subsequently reacted with sulfur in xylene to afford compounds 4a–g

Summary

Introduction

Cancer remains a leading cause of death in developed and developing countries, much significant progress has been achieved recently [1]. One of the successful and effective methods for the discovery of new anticancer drugs from natural products is synthesis of novel compounds through chemical structural modifications on the basis of leading compounds. Β-Carbolines are a large group of heterocyclic compounds with a 9H-pyrido[3,4-b]indole structural unit. They compose a class of alkaloids that are widely distributed in nature, including plants, foodstuffs, marine creatures, insects, mammals, human tissues, and body fluids [2]. In the last few decades, there have been intense research efforts in the design and development of β-carbolines as a new class of antitumor agents.

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