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Discovery of new bioactive ligands with anticancer properties

Grant number: 18/25289-7
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): August 01, 2019
Effective date (End): February 29, 2024
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Adriano Defini Andricopulo
Grantee:Matheus da Silva Souza
Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated research grant:13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID
Associated scholarship(s):22/00219-1 - Pathway toward catastrophe: cellular dynamics on hit-to-lead compound optimisation for current drug discovery pipelines, BE.EP.DR


Cancer consists of a group of diseases characterized by the disordered growth of abnormal cells capable of invading numerous tissues and organs. The World Health Organization (WHO) considers it to be the second leading cause of death worldwide, being responsible for almost 10 million of deaths in 2018. Although chemotherapy relies on an important arsenal of drugs, treatments are associated with high toxicity, and many are subject to low efficacy and resistance. In this context, the present PhD project aims at the identification, characterization, and planning of new bioactive ligands with anticancer properties. Series of heterocyclic derivatives based on the class of cyclopenta[b]indoles, indolizines and oxadiazoles will be planned, synthesized and evaluated for their anticancer activity in vitro and for their mechanism of action against tubulin, a validated molecular target of great scientific interest for the treatment of Cancer. The synthetic precursors of this new series of bioactive compounds were discovered by our research group through the application of biochemical screening strategies that led to the characterization of new tubulin modulators with pronounced cytotoxic action and high selectivity. The compounds selected in this new step will be quantitatively characterized by their properties of tubulin polymerization modulation and microtubule stabilization. In vitro cytotoxicity of the compounds will also be evaluated by viability assays and cell migration in tumoral strains, as well as their selectivity by assays with healthy human fibroblasts. Strategies in medicinal chemistry, such as multiple parameter optimization, will be applied in the design of new compounds. Thus, the prioritized compounds will be investigated by molecular modeling regarding the fundamental pharmacodynamic and pharmacokinetic parameters. In accordance with the experimental data of potency, affinity and selectivity, molecular docking analyses will be performed to characterize the binding mode of the compounds, and generate quantitative structure-activity relationships. In silico and in vitro pharmacokinetics studies will be performed to evaluate properties such as permeability, metabolism, and distribution coefficient (eLogD). Flow cytometry studies will be conducted for the analysis of cell cycle progression of the most promising compounds. The integration of these advanced experimental and computational methods will enable the discovery of candidates for new anticancer agents with optimized pharmacodynamic and pharmacokinetic profiles. This research project shares the main objectives of the Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), one of the CEPIDs of FAPESP (Process 13/076003). The work proposed herein will be developed in the Laboratory of Medicinal and Computational Chemistry (LQMC) of the Institute of Physics of São Carlos, University of São Paulo, which is the headquarters of CIBFar/CEPID. (AU)

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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)
DA SILVA, THIAGO SABINO; SOUZA, MATHEUS DA SILVA; ANDRICOPULO, ADRIANO DEFINI; COELHO, FERNANDO. Discovery of indolizine lactones as anticancer agents and their optimization through late-stage functionalization. RSC ADVANCES, v. 13, n. 29, p. 7-pg., . (18/02611-0, 22/00219-1, 13/07600-3, 18/25289-7)

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