Potential inhibitors of PI3K: synthesis of analogues of wortmannin planned by molecular simplification and selected by docking

• Grant number: 16/07984-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2016
• End date: September 30, 2017
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Roberto Parise Filho
• Grantee: Camila Felix de Carvalho
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cancer can be defined as an ensemble of diseases that have an uncontrolled and disseminated growth of cells as a common feature. This pathology is very concerning because of its high prevalence and mortality, representing about 13% of all annual deaths, with expectation of 70% new cases in the next two decades. According to this context, researches of new molecules that have antitumor activity are decisive, highlighting the importance of natural products as a significant source to the development of new molecules. Wortmannin is a fungal metabolite synthesized by Penicillium wortmanni and possess an important anti-prolific and selective action on neoplastic cells. Studies show that this selectivity occurs due to the inhibition of the enzyme phosphoinositide 3-kinase (PI3K), that is overexpressed on certain tumor cell lines. Nonetheless, as a result of toxicological, pharmacokinetics and/or physicochemical limitations, wortmannin was not inserted on therapy. Hence, this project proposes the synthesis of molecular fragments capable of inhibiting the enzyme PI3K. To achieve this, molecular fragments were proposed from the structure of wortmannin, using as a rational planning strategy the molecular modification, based on the concepts of bioisosterismo and molecular simplification. Firstly, to evaluate the existing complementarity of the fragments and the catalytic site of the enzyme, docking studies will be used. Following this step, the most promising fragments on the in silico studies will be synthesized and characterized.