Due to their unique pharmacological characteristics, methylxanthines are known as therapeutic agents in a fascinating range of medicinal scopes. In this report, we aimed to examine some biological effects of previously synthesized 8-alkylmercaptocaffeine derivatives. Cytotoxic and antioxidative activity of 8-alkylmercaptocaffeine derivatives were measured in malignant A549, MCF7, and C152 cell lines. Assessment of cGMP levels and caspase-3 activity were carried out using a colorimetric competitive ELISA kit. Computational approaches were employed to discover the inhibitory mechanism of synthesized compounds. Among the twelve synthesized derivatives, three compounds (C1, C5, and C7) bearing propyl, heptyl, and 3-methyl-butyl moieties showed higher and more desirable cytotoxic activity against all the studied cell lines (IC < 100 µM). Furthermore, C5 synergistically enhanced cisplatin-induced cytotoxicity in MCF-7 cells (CI < 1). Both C5 and C7 significantly increased caspase-3 activity and intracellular cGMP levels at specific time intervals in all studied cell lines (P  0.05) and exhibited no marked ameliorating effects on oxidative damage (P > 0.05). Computational studies showed that H-bond formation between the nitrogen atom in pyrazolo[4,3-D] pyrimidine moiety with Gln817 and creating a hydrophobic cavity result in the stability of the alkyl group in the PDE5A active site. We found that synthesized 8-alkylmercaptocaffeine derivatives induced cell death in different cancer cells through the cGMP pathway. These findings will help us to get a deeper insight into the role of methylxanthines as useful alternatives to conventional cancer therapeutics.
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