Design and synthesis of pyrroloquinoxaline based anticancer agents

Cancer is the leading cause of death worldwide. The most common malignancies in the US and European countries are lung, colorectal, breast and prostate. Therefore, despite is necessary to develop highly active, well tolerate, and easy to use new drugs, accurate and rapid detection of rapidly growing and metastatic tumors is of great importance for implementation of a tailored therapeutic regimen. With the recent advances in targeted therapeutics and the progress in new approaches in target identification, novel anticancer agents with new mechanisms of action are under intensive investigation. However, one major hurdle to overcome in a drug discovery program is the identification of suitable lead compound having desired biological activity. Salicylhydrazides represent a novel class of compounds with remarkable cytotoxicity activity in a panel of human cancer cell lines from different tumor origins.1 Several structural alterations were attempted in order to improve pharmacological profiles of original lead compounds. Recently, we have designed and synthesized a series of compounds bearing a hydrazide moiety linking a nitrogen containing polycyclic system to a heteroaroyl portion. Pyrroloquinoxalinyl based derivatives I were identified as the most promising in terms of potency and drug-like characteristics.2 Several of such derivatives (for example, cpd II) showed remarkable cytotoxic properties, with IC50 values in the low micromolar range, and promising in vivo activity in xenograft mice models of human ovarian cancer cell lines. In order to further explore the mode of action of these compounds and improve their physicochemical properties we have synthesized a new series of compounds by replacing the hydrazide linker of the parent compounds with different moieties (for example, cpds III). A pharmacophore model based on the cluster containing the highest number of frames to represent the most probable feature orientation was accordingly built.