Effect of linkage geometry on biological activity in thiourea- and guanidine-substituted acridines and platinum–acridines

Novel thiourea- and guanidine-modified acridine-4-carboxamides (4, 7) and a corresponding platinum–intercalator conjugate (4′) have been synthesized and evaluated as cytotoxic agents in human promyelocytic leukemia, HL-60, and a non-small cell lung cancer, NCI-H460. Modification of thiourea sulfur in derivative 4 with a DNA platinating moiety, giving 4′, resulted in a pronounced cytotoxic enhancement, and the conjugate proved to be the most active of the newly synthesized compounds in NCI-H460 cells. Conjugate 4′ represents a new chemotype with potential applications in the treatment of chemoresistant tumors.