Design, synthesis, and biological activities of novel thiophene, pyrimidine, pyrazole, pyridine, coumarin and isoxazole: Dydrogesterone derivatives as antitumor agents

Abstract

Abstract On the basis of our consideration to design and to develop antitumor activities of heterocyclic compound derivatives, especially in fused ring system, we refer to the possibility of the heterocyclic extension of one of the most important steroid compounds used as a medicinal drug. The reaction of dydrogesterone with each of the malononitrile or ethylcyanoacetate containing elemental sulfur afforded thiophene derivatives 1a,b. Also, dydrogesterone was reacted with a mixture of ethylcyanoacetate–hydrazine, ethylcyanoacetae–urea, or ethylcyanoacetate–thiourea to produce pyrazole derivative 4 and pyrimidine derivatives 5a,b. Thienopyrimidine derivatives 2a–d were introduced from the reaction of thiophene derivatives 1a,b with either phenylisothiocyanate or benzoylisothioyanate. Furthermore, compounds 1a,b were directed toward the reaction with ethylcyanoacetate to produce compounds 6a,b, and the last compounds 6a,b were directed toward cyclization to obtain thienopyridine derivatives 7a,b. In addition, compounds 6a,b were subjected to react with different carbonyl compounds, such as salicylaldehyde, cyclopentanone-elemental sulfur, malonaldehyde, and acetylacetone to produce coumarin derivatives 8a,b, fused thiophene derivatives 9a,b, and pyridine derivatives 10a–d. Isooxazole derivatives 12a,b were afforded through the reaction of compounds 6a,b with hydroxylamine hydrochloride. Finally, 2-pyridone derivatives 14a,b were obtained through the reaction of compounds 6a,b with benzoylacetonitrile. Conformation structure of the synthesized compounds was established by applying IR, 1H NMR, 13C NMR, and mass spectrometry, and their antitumor activity was examined. Some compounds showed promising growth inhibitory effects on the three different cell lines.