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Synthesis of new antitumor phospholipids as inhibitors of the human enzyme cytidine triphosphate (CTP): phosphocholine cytidylyltransferase

Grant number: 18/22817-2
Support type:Scholarships in Brazil - Master
Effective date (Start): August 01, 2020
Effective date (End): August 31, 2021
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Daniel Fábio Kawano
Grantee:Xisto Antonio de Oliveira Neto
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Antitumor phospholipids are synthetic analogues of endogenous phosphatidylcholines with a remarkable ability: inducing the selective apoptosis of exponentially growing tumor cells. Concerning their mechanism of action, one hypothesis points to the inhibition of the enzyme cytidine triphosphate (CTP):phosphocholine cytidylyltransferase (CCT) as a key event related to the antitumor actions of these phospholipids, which, ultimately, would result from a significant suppression in phosphatidylcholine biosynthesis. The CCT enzyme catalyzes the conversion of choline phosphate to cytidine 5'-diphosphocholine (CDP-choline), which represents a source of phosphocholine for the synthesis of phosphatidylcholines. Phosphatidylcholine is a decisive element for cell cycle progression and its deficiency is recognized as a sign to trigger mechanisms that, eventually, will conduce to cell cycle arrest and apoptosis. Although several synthetic antitumor phospholipids are known inhibitors of the CCT enzyme (e.g. edelfosine, erucylphosphocholine, perifosine and miltefosine), none is extensively used in the clinical practice, highlighting an opportunity for optimization. In this context, herein we propose the syntheses of new antitumor phospholipids with an improved affinity for the human CCT enzyme, focusing on the development of new alternatives for cancer chemotherapy. (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)
NETO, XISTO ANTONIO DE OLIVEIRA; ALVES, ANNA CAROLINA SCHNEIDER; DIAS JUNIOR, REINALDO ANTONIO; RODRIGUES, RICARDO PEREIRA; LANCELLOTTI, MARCELO; ALMEIDA, WANDA PEREIRA; KAWANO, DANIEL FABIO. Molecular Docking Reveals the Binding Modes of Anticancer Alkylphospholipids and Lysophosphatidylcholine within the Catalytic Domain of Cytidine Triphosphate: Phosphocholine Cytidyltransferase. EUROPEAN JOURNAL OF LIPID SCIENCE AND TECHNOLOGY, v. 122, n. 7 JUN 2020. Web of Science Citations: 0.

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