LAUSR

A novel series of homonucleosides and their double-headed analogs containing theophylline, 1,3,4-oxadiazole, and variant nucleobases was designed and synthesized. The new derivatives were fully characterized by HRMS, FT-IR, 1H NMR, and 13C NMR. The cytotoxic activities of all prepared compounds were screened in vitro against four cell lines, including fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A-549). The double-headed analogue 18 showed marked growth inhibition against all the cell lines tested, specifically in HT-1080, with an IC50 values of 17.08 ± 0.97 µM. The possible mechanism of apoptosis was investigated using Annexin V staining, caspase-3/7 activity, and analysis cell cycle progression. The compound 18 induced apoptosis through caspase-3/7 activation and cell-cycle arrest in HT-1080 and A-549 cells. The molecular docking confirms that the compound 18 activated caspase-3 via the formation of hydrogen bonds and hydrophobic interactions.