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

• Grant number: 17/01265-9
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: August 01, 2017
• End date: July 31, 2018
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Jose Alexandre Marzagão Barbuto
• Grantee: Salomão Dória Jorge
• Supervisor: Alexander Domling
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Groningen, Netherlands
• Associated to the scholarship: 14/14267-1 - Multi-target potentially antitumor agents for malignant melanoma: rational design, synthesis, and biological assays of novel benzofuroxan derivatives, BP.PD

Abstract

The study is based on previous findings on a series of substituted-[N'-(benzofuroxan-5-yl)methylene] benzohydrazides which have shown potent cytotoxic effects against a variety of malignant tumor cells that overexpress MDMX protein. MDMX is responsible for the functional deficiency of p53 in tumors, like melanoma, which show this deficiency even though they do not have mutations in p53. However, since cancer is a multifactorial disease, the design of new drugs should aggregate in one molecule, different pharmacodynamic profiles, able to modulate distinct signaling pathways, creating, thus, "multi-target" drugs. Melanoma is the most aggressive form of skin cancer that presents a high resistance to many chemotherapy agents currently in use, requiring the development of new therapeutic strategies. In this regard, the present proposal focuses on the elucidation of the molecular mechanism of action of two structural isomers, BFD-3A and BFD-4A, designed by LBDD to target MDMX and, by SBDD, to target BRAF (a very promising therapeutic target in melanoma). The project will characterize, the molecular mechanisms of direct anti-tumor action in MDMX, and the molecular mechanisms in PDL1 protein, since the previously data indicated effects of the compounds upon the immune system. These observations indicate that these novel compounds have a significant potential to act on several tumor cell targets, where they are likely to display multi-target activity, as one should expect from rationally designed new drugs. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MAMBELLI, LISLEY I.; TEIXEIRA, SARAH F.; JORGE, SALOMAO D.; KAWAMURA, BARBARA; MENEGUELO, RENATO; BARBUTO, JOSE A. M.; DE AZEVEDO, RICARDO A.; FERREIRA, ADILSON K.. Phosphoethanolamine induces caspase-independent cell death by reducing the expression of C-RAF and inhibits tumor growth in human melanoma model. BIOMEDICINE & PHARMACOTHERAPY, v. 103, p. 18-28, JUL 2018. (15/18528-7, 16/07519-0, 17/01265-9, 16/09392-7, 13/07273-2, 14/14267-1)