Synthesis and Biological Evaluation of S-, O- and Se-Containing Dispirooxindoles.

Maksim Kukushkin,Yan Ivanenkov,Nikolay Zyk,Alexander Majouga,Anna Moiseeva,Elena Beloglazkina,Radik Shafikov,Vadim Filatov,Vladimir Novotortsev,Dmitry Skvortsov,Mark Veselov

doi:10.3390/molecules26247645

Abstract

A series of novel S-, O- and Se-containing dispirooxindole derivatives has been synthesized using 1,3-dipolar cycloaddition reaction of azomethine ylide generated from isatines and sarcosine at the double C=C bond of 5-indolidene-2-chalcogen-imidazolones (chalcogen was oxygen, sulfur or selenium). The cytotoxicity of these dispiro derivatives was evaluated in vitro using different tumor cell lines. Several molecules have demonstrated a considerable cytotoxicity against the panel and showed good selectivity towards colorectal carcinoma HCT116 p53+/+ over HCT116 p53−/− cells. In particular, good results have been obtained for LNCaP prostate cell line. The performed in silico study has revealed MDM2/p53 interaction as one of the possible targets for the synthesized molecules. However, in contrast to selectivity revealed during the cell-based evaluation and the results obtained in computational study, no significant p53 activation using a reporter construction in p53wt A549 cell line was observed in a relevant concentration range.

Highlights

Design and development of novel potent anticancer therapeutics are the most important tasks of synthetic organic and medicinal chemistry
Among the compounds with antitumor action, an important place is occupied by the spiro and dispiro derivatives of indolinones, due to the conformational rigidity of spiro scaffold which allows the introduction into the molecules of functional groups necessary for interaction with biological targets in the required arrangement, and the indolinone fragment simulates the tryptophan moiety, in many cases involved in such interactions [1,2,3,4,5]
We present a series of novel compounds of the dispiro-indolinone series with a modified spiro-oxindole core (Figure 1) with promising anticancer activity

Summary

Introduction

Design and development of novel potent anticancer therapeutics are the most important tasks of synthetic organic and medicinal chemistry. Spiro-oxindole alkaloids, which were firstly derived from the families Apocynaceae and Rubiaceae [6] and latter were found in a wide range of complex natural products [7,8,9,10] have shown significant anticancer activity. These compounds contain the spiro ring fusion at position 3 of the indolinone core, with different substitutions around the pyrrolidine and indolinone moieties. The p53 protein, which is a tumor suppressor, is one of the potential targets of antitumor therapy.

Methods

Discussion

Conclusion