Medicinal Chemistry

Design, Synthesis, Molecular Modelling and Biological Evaluation of Novel α-Naphtholhydroxamate Derivatives as Potential Anticancer Agents

Abstract

Adel S Abdelrahim, Syam Mohan, Mohamed Albarrati, Hafiz Makeen and Safhi MM

Chemotherapy is one of the treatment options for cancer. A major problem in cancer chemotherapy is the lack of selective toxicity of many commonly used anti-cancer agents towards tumor tissue compared to normal tissue. Studies have shown that α-naphthol is selectively toxic to cultures of human tumor tissue compared to normal tissues in vitro. Hence, this study was conducted to synthesize a series of new hydroxamate derivatives containing α-naphthol nucleus by the reaction of naphthol acetic acid with amino acid methyl ester derivatives which were directly reacted with hydroxyl amine at room temperature. Structures of these compounds were confirmed by standard studies of IR, 1H NMR, 13 CNMR, MS and elemental analysis. The cytotoxicity of the synthesized compounds were studied using the MTT assay in four human cancer cell lines, including HepG2, PC-3, HT-29 and MCF-7. Among the compounds, compound 6g and 6h exhibited a significant cytotoxicity against almost all the used cells including the normal cells (WRL-68). Further studies have shown that the cell death observed was closely associated with generation of reactive oxygen species (ROS). In this study, other naphthol derivatives have shown significant increase in the level of ROS in concentration dependent manner in treated cells. In conclusion, the study has shown that among the synthesized compounds, compounds 6g , 6k and 6h hold the potential for further research. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, HDAC (PDB-code: 1T69).