Synthesis and biological evaluation of novel fused pyridopyrimidine derivatives as topoisomerase I inhibitors and as potential antitumor agents: promising results in lung, ovary and gastric cancer

The topoisomerase I (TOP1) enzymatic inhibition was investigated using novel pyrimidine and quinazolinone derivatives. First, the synthesis of these compounds was performed by intramolecular cycloaddition reaction of functionalized aminoalcohols, aminoesters and aldimines, obtained by the condensation of 2-aminopyridine and unsaturated aldehydes, affording corresponding pyrido[1,2- a ]pyrimidine derivatives, pyrido[2,1- b ]quinazolin-11-one derivatives and hybrid chromeno[4,3- d ]pyrido[1,2- a ]pyrimidine compounds respectively with good to high general yields. The vast majority of prepared products showed notable and excellent activity as inhibitors of TOP1. The cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV-3), human gastric adenocarcinoma (AGS), human undifferentiated gastric adenocarcinoma derived from the metastatic lymph node (HGC27), and on non-cancerous lung fibroblasts cell line (MRC-5) was also screened. Dihydrochromeno[4,3- d ]pyrido[1,2- a ]pyrimidine 9b was the most cytotoxic compound with IC 50 values of 6.0±0.3 nM in the A549 cell line, and with IC 50 values of 4.67±0.02 μM in the SKOV-3 cell line. Compound 9p (LL123) also proved to be a good candidate in two human gastric carcinoma lines (HGC27 and AGS). Furthermore, none of the compounds with outstanding results showed toxicity against non-malignant lung fibroblasts (MRC-5). • Intramolecular cycloaddition enabled efficient synthesis of fused pyrido-pyrimidine scaffolds • Compounds showed strong TOP1 enzymatic inhibition • Hybrid chromeno[4,3-d]pyrido[1,2-a]pyrimidine derivatives active in several cancer lines • Selectivity against non-malignant MRC-5 fibroblasts • Activity extends beyond TOP1 inhibition to pro-apoptotic signaling and potential to modulate drug resistance mechanisms in cancer cells