Exploring phosphorus substitution in chromeno[4,3-d]pyrido[1,2-a]pyrimidines: new insights into Topoisomerase 1 inhibition and cytotoxicity.

Abstract

Phosphorylated chromeno[4,3-d]pyrido[1,2-a]pyrimidines were synthesized from functionalized 2-aminopyridines and evaluated as novel inhibitors of human DNA topoisomerase 1. Several compounds demonstrated potent enzymatic inhibition, and notable derivatives such as 8b and 10a exhibited selective antiproliferative activity against SKOV-3 ovarian carcinoma cells, with micromolar IC50 values and no toxicity in non-malignant MRC-5 fibroblasts. Furthermore, moderate to high EC50 values for many derivatives has been observed in their role as P-gp modulators. These results suggest that incorporating phosphorated substituents into the chromeno-pyridopyrimidine scaffold significantly affects both enzymatic potency and cellular activity, reflecting modified physicochemical and electronic properties allowing radical tuning of specific characteristics. This work extends previous findings on non-phosphorylated analogues and highlights phosphorous substitution as a viable strategy to enhance the biological profile of topoisomerase 1 inhibitors.