Multi-target potentially antitumor agents for malignant melanoma: rational design, synthesis, and biological assays of novel benzofuroxan derivatives

Abstract

The study is based on previously findings observed for a series of substituted-[N'-(benzofuroxan-5-yl)methylene] benzohydrazides. These compounds, initially developed as anti-Trypanosoma cruzi agents, have shown potent cytotoxic effects against a variety of malignant tumor cells, that overexpressing MDMX protein. This protein is responsible for the deficiency of functional p53 in tumors such as melanoma, that even with wild type p53, this functionality has inhibited by MDMX. However, cancer is a multifactorial disease, which imposes the need to aggregate, in design of new drugs, different pharmacodynamic profiles capable of modulating distinct signaling pathways, in one molecule, creating drugs "multi-targets". Melanoma is the most aggressive form of skin cancer and it has been presented high resistance to many chemotherapy drugs therapeutically used, requiring the development of new therapeutic strategies. In this regard, the present proposal aims to identify antitumor drug candidates from the synthesis of a novel benzofuroxan-based library. Preliminary data obtained from lead compound, already indicate that, in addition to MDMX, BRAF protein (most promising therapeutic target in melanoma) is also affected in melanoma murine cell line B16F10. These observations indicate that these lead compound has potential to act on several tumor cell targets, suggesting that their use as structural template allied to the ligand-based drug design strategy aims the identification of novel analogs/derivatives with multi-target activity, therefore, with better probability of anticancer efficacy. (AU)