The decline or leveling of the output of the R&D programs of the pharmaceutical companies may suffered recent changes when compared to earlier years of the 21st century. Although a major responsible for this increase is the immunopharmacology-based treatments, small molecules still play an important role. 1 Medicinal chemistry approaches to find a small molecule lead compound, which shows the desired pharmacological activity, continue to use as sources natural products, synthesis, and existing drugs.
In this communication, we will give examples of antitumor small molecules lead compounds obtained in our research group that arise from two existing drugs, lucanthone and mitoxantrone (MTX). One aim in medicinal chemistry is the study of drug metabolites, and very recently we engaged a project that intend to understand the influence of metabolites in the cardiotoxicity of an antitumor drug, MTX, approved in 1987 as an antitumor drug and in 2002 for use in multiple sclerosis. Although the main human MTX metabolites have been identified, their putative cardiotoxicity was not yet assessed.
Herein, we also exemplify MTX drug metabolites as potential sources of new drugs. Initially, the MTX-naphthoquinoxaline metabolite (NAPHT) was synthetized and studies on NAPHT cardiotoxicity revealed that the parent drug, MTX, caused a higher disruption in the energetic pathways in a cardiac model in vitro, whereas autophagy is involved in the toxicity of both compounds; 2 therefore, this metabolite should be regarded as a good option for a safer anticancer therapy since it is less cardiotoxic than MTX. Moreover, previous data has shown that NAPHT can have a potential role on MTX’s anticancer effects. The case studies presented herein are expected to contribute to a recent trend in drug discovery, with the involvement of old pharmaceuticals. To us, existing drugs will continue to provide a fruitful solution in drug discovery and development.
Acknowledgements: We thank FCT/MCTES and ERDF through the COMPETE–POFC programme, under the Strategic Funding UID/Multi/04423/2013, the project PTDC/MAR-BIO/4694/2014 (POCI-01-0145-FEDER-016790; 3599-PPCDT) and PTDC/DTP-FTO/1489/2014 (POCI-01-0145-FEDER-016790) in the framework of PT2020, to INNOVMAR (NORTE-01-0145-FEDER-000035, NOVELMAR), supported by NORTE 2020, under PORTUGAL 2020, through ERDF.
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