The structural optimization of [(2-R-quinazolin-4-ylidene)hydrazono]carboxylic acids and esters – approach for creating a new class of compounds with the anticancer activity

O. Yu. Voskoboynik, O. V. Karpenko, S. I. Kovalenko, G. G. Berest, V. V. Ivchuk, V. M. Shvets

Abstract


The strategies of the search of novel effective anticancer agents via optimization of [(2-R-quinazoline-4-ylydene) hydrazono]carboxylic acids and their esters are summarized in this article. To develop the most efficient synthetic approaches of initial substances the available information about chemical properties of [(2-R-quinazoline- 4-ylydene)hydrazono]carboxylic acids and their derivatives has been generalized and systematized. The basic approaches for optimization of the initial substances structure included variation of substituents in position 2, creation and removal of conformational constraints and introduction of substituents into the cyclisation products. It has been shown that (3H-quinazoline-4-ylydene)hydrazine easily interacts with α, β, γ-ketocarboxylic acids and their esters with formation of the corresponding hydrazonoderivatives. The given compounds are multicenter reagents, which are able to cyclize into the corresponding 3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones. 3-R- 2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones are a class of electron-deficient heterocyclic systems and may be cleaved under the action of strong nuleophiles, in particular hydrazine, followed by formation of the corresponding 3-(2-aminophenyl)-6-R-1,2,4-triazine-5(2H)-ones or 3’-(2-aminophenyl)-3-R-spiro[pirazoline-5,6’(1’H)-1,2,4- tiazine]-5’(4’H)-ones. A comparative description of spectral characteristics of the compounds synthesized has also been presented. The highest anticancer activities have been shown by compounds 2c, 3b and 3c against leukemia cell lines CCRF-CEM (logGI50 = -6.10; 6.05; 5.81, respectively), compound 3b and 3c against breast cancer cell lines HS 578T (logGI50 = -5.83; -6.43, respectively). The results of SAR-analysis have been discussed and directions of further modification of the structures studied have been proposed.


Keywords


quinazolines; structural optimization; anticancer; structure – activity relationship

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References


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DOI: https://doi.org/10.24959/ophcj.14.802

Abbreviated key title: Ž. org. farm. hìm.

ISSN 2518-1548 (Online), ISSN 2308-8303 (Print)