Synthesis and Biological Evaluation of Some Polymethoxylated Fused Pyridine Ring Systems as Antitumor Agents

A series of 3,5‐bis(arylidene)‐4‐piperidones like chalcone analogues carrying variety of methoxylated aryl groups, pyrazolo[4,3‐c]pyridines, pyrido[4,3‐d]pyrimidines, and pyrido[3,2‐c]pyridines, carrying an arylidene moiety, and some pyrano[3,2‐c]pyridines, like flavone and coumarin isosteres, were synthesized and screened for their in‐vitro antitumor activity at the National Cancer Institute (NCI, USA). The tested compounds 7, 9, 10, 12, 13, 15, 17, and 19 exhibited a broad spectrum of antitumor activity. Compounds belonging to the pyrazolo[4,3‐c]pyridine series proved to be more active than those of the pyrido[3,2‐c]pyridine and pyrano[3,2‐c]pyridine analogues, in which the monomethoxylated derivatives showed better antitumor activity when compared with their corresponding dimethoxylated congeners. Compound 7 is considered to be the most active member identified in this study with a broad spectrum of activity against 22 different tumor cell lines belonging to the nine subpanels employed, and a particular effectiveness against the breast cancer T‐47D cell line (GI 54.7%). The pyrano[3,2‐c]pyridine heterocyclic system 19 proved to be the most active antitumor agent among the six‐membered fused pyridines, with variable activity against 18 different tumor cell lines, and special activity against the non‐small cell lung cancer Hop‐92 and ovarian cancer OVCAR‐4 cell lines (GI values 63.9 and 48.5%, respectively).