Heterocyclic privileged medicinal scaffolds involving pyridine, 1,4-dihydropyridine, chromeno[2,3-b]pyridine, and dihydro-1,4-dithiepine frameworks are prepared via a single-step multicomponent reaction of structurally diverse aldehydes with various thiols and malononitrile. Mechanistic studies of the synthetic pathway leading to pyridines reveal that 1,4-dihydropyridines undergo oxidation by the intermediate Knoevenagel adducts rather than by air oxygen. The use of o,o'-disubstituted aromatic aldehydes leads to the corresponding 1,4-dihydropyridines, whereas salicylic aldehydes result in chromeno[2,3-b]pyridines. Reactions of ethanedithiol as a thiol component produce dimeric pyridines with sterically unencumbered aldehydes, while o,o'-disubstituted aromatic aldehydes give dihydro-1,4-dithiepines. Thus, depending on the aldehyde and thiol types, diverse libraries of medicinally relevant compounds can be prepared by a simple one-step process involving no chromatography.

Podophyllotoxin has been extensively used as a lead agent in the development of new anticancer drugs. On the basis of the previously reported simplified 4-aza-2,3-didehydro podophyllotoxin analogues, we implemented a bioisosteric replacement of the methylenedioxybenzene subunit with a pyrazole moiety to afford tetracyclic dihydropyridopyrazoles. Libraries of these structurally simple analogues are prepared by a straightforward one-step multicomponent synthesis and demonstrated to display antiproliferative properties in a number of human cancer cell lines. These new heterocycles potently induce apoptosis in cancerous Jurkat cells even after a short 24 h exposure. In contrast, no apoptosis is detected in primary lymphocytes under the same treatment conditions. The ease of synthesis and encouraging biological activities make the presented library of dihydropyridopyrazoles promising new leads in anticancer drug design.

Pyrano[3,2-c]pyridone and pyrano[3,2-c]quinolone structural motifs are commonly found in alkaloids manifesting diverse biological activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed compound libraries based on these privileged heterocyclic scaffolds. The selected library members display low nanomolar antiproliferative activity and induce apoptosis in human cancer cell lines. Mechanistic studies reveal that these compounds induce cell cycle arrest in the G2/M phase and block in vitro tubulin polymerization. Because of the successful clinical use of microtubule-targeting agents, these heterocyclic libraries are expected to provide promising new leads in anticancer drug design.