Design, synthesis and antitumor activity of coumarin, isoxazole, pyrazole, pyridine and pyrimidine compounds: 3β-hydroxypregn-5-ene-20-one derivatives

Abstract

In continuation of our reserach for synthesizing heterocyclic derivatives with a broad range of biological activities, the current research was performed to synthesize 3β-hydroxypregn-5-ene-20-one derivatives of coumarin, isoxazole, pyrazole, pyridine and pyrimidine and screen for antitumor activity. Synthesis of amino-thiopephen derivatives (1a-1b) was performed through reaction of 3β-hydroxypregn-5-ene-20-one with ethyl cyanoacetate or malononitrile and sulphur. 3β-Hydroxypregn-5-ene-20-one was reacted with ethyl cyanoacetate in the presence of hydrazine, urea or thiourea to obtain aminopyrazole (3), aminopyrimidine (4a-4b) derivatives, respectively. The amino-thiophene derivatives (1a-1b) further reacted with either phenylisothiocyanate or benzoylisothiocyanate to form fused thienopyrimidine derivatives (5a-5d). The products 1a and 1b were also treated with ethyl cyanoacetate to afford cyanoacetamidothiophene derivatives (6a-6b) which were converted to fused thienopyridone derivatives (7a-7b) through cyclization reaction. The compounds 6a and 6b were allowed to react with different carbonyl compounds including salicyaldehyde, cyclopentanone-sulphur mixture, acetylacetone and malonaldehyde to prepare coumarin (8a-8b), cyclopentylthiophene (9a-9b) and 2-pyridinone (10a-10d) derivatives respectively. Furthermore, the reactions of hydroxylamine hydrochloride and benzoylacetonitrile with the compounds 6a-6b separately afforded new aminoisoxazole (12a-12b) and phenylpyridone (14a-14b) derivatives, respectively. The structures of new products were established through IR, 1H NMR, 13C NMR spectroscopic and mass spectrometric analysis. The synthesized compounds (1a-1b to 14a-14b) displayed in-vitro antitumor activity against human cell-lines, including MCF-7 (breast adenocarcinoma), SF-268 (CNS cancer) and NCI-H460 (non-small lung cancer cell). The results suggested that all the screened products exhibited cell growth inhibitory activity in a dose-dependents manner. However, the compound 12a showed highest level of inhibition against all three cell-lines.