Monastrol is the best-known small compound from the dihydropyrimidinones/thiones (DHPMs) heterocycle family, a cell-permeable molecule recognized as an inhibitor of mitotic kinesin Eg5, that is over-expressed in tumor cells and is a very promising target for the development of new drugs for cancer. The lipophilic properties of the DHPMs have been demonstrated to be of pivotal importance in the design of new molecules. This work describes the synthesis and antitumoral activity of novel C5-substituted fatty-DHPMs against breast and gastric cancer cell lines. The compounds were synthesized via Biginelli multicomponent reaction from oleyl beta-ketoester in good yields (40-72%) using a simple approach catalyzed by nontoxic and free-metal sulfamic acid. Among the compounds tested, the compound 10c, derived from 3-hydroxybenzaldehyde and urea, exhibited 77% cellular viability to normal cells (C2C12) and was selected to be evaluated against tumoral breast (MCF-7) and gastric (AGS) cell lines. The results obtained afforded an IC50 of breast cancer cells of 2.3 mu M, qualifying the molecule as the most potent, and making it a promising compound for future experiments in vivo.