Design and synthesis of new phospholipids that selectively induce the apoptosis of tumor cells via lipid rafts

• Grant number: 18/08585-1
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2019
• End date: December 31, 2021
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Daniel Fábio Kawano
• Grantee: Daniel Fábio Kawano
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Marcelo Lancellotti

Abstract

For more than 40 years, the fluid mosaic model of cellular membranes have supported our vision of an inert lipid bilayer containing membrane protein receptors that are randomly hit by extracellular molecules to trigger intracellular signaling events. However, the notion that compartmentalized cholesterol- and sphingomyelin-rich membrane microdomains known as lipid rafts spatially arrange receptors and effectors to promote kinetically favorable interactions necessary for signal transduction sounds much more realistic. Despite of their assumed importance in the dynamics of ligand-receptor interactions, lipid rafts and biomembranes as a whole remain less investigated than other classes of biomolecules because of the high variability and complexity of the phases of membranes, which rarely provide detailed atomic-level structural data in X-ray crystallography studies. The fact that some alkylphospholipids, namely edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) can selectively induce the apoptotic death of cancer cells by recruiting Fas death receptors and downstream signaling molecules into clusters of lipid rafts demonstrates that these potential drug targets deserve a more in-depth investigation. However, Phase II clinical studies have demonstrated that edelfosine has only a tumorostatic effect in humans, and not a cytotoxic action as it would be desirable for an antitumor drug. Therefore, herein we propose to synthesize edelfosine analogues that retain the ability to accumulate in lipid rafts, aiming the selective induction of apoptosis in tumor cells. The designed analogues will have their cytotoxic activities evaluated "in vitro". (AU)

Scientific publications

(6)

(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. (18/08585-1, 18/22817-2, 17/05876-2)

KRUMMENAUER, MARIA E.; LOPES, WILLIAM; GARCIA, ANE W. A.; SCHRANK, AUGUSTO; GNOATTO, SIMONE C. B.; KAWANO, DANIEL F.; VAINSTEIN, MARILENE H.. A Highly Active Triterpene Derivative Capable of Biofilm Damage to Control Cryptococcus spp.. BIOMOLECULES, v. 9, n. 12, DEC 2019. (18/08585-1)

FIORI-DUARTE, ANA THEREZA; DE OLIVEIRA GUARNIERI, JOAO PAULO; DE OLIVEIRA BORLOT, JESSICA RODRIGUES PEREIRA; LANCELLOTTI, MARCELO; RODRIGUES, RICARDO PEREIRA; KITAGAWA, RODRIGO REZENDE; KAWANO, DANIEL FABIO. In silico design and in vitro assessment of anti-Helicobacter pylori compounds as potential small-molecule arginase inhibitors. MOLECULAR DIVERSITY, JAN 2022. (18/08585-1)

DE SOUZA, VALERIA BARBOSA; KAWANO, DANIEL FABIO. Structural basis for the design of allosteric inhibitors of the Aurora kinase A enzyme in the cancer chemotherapy. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1864, n. 1, JAN 2020. (18/08585-1)

SCHNEIDER ALVES, ANNA CAROLINA; CARDOSO, RAQUEL SOARES; DE OLIVEIRA NETO, XISTO ANTONIO; KAWANO, DANIEL FABIO. Uncovering the Potential of Lipid Drugs: A Focus on Transient Membrane Microdomain-targeted Lipid Therapeutics. MINI-REVIEWS IN MEDICINAL CHEMISTRY, v. 22, n. 18, p. 14-pg., 2022-01-01. (18/08585-1, 18/22817-2, 22/01239-6, 17/05876-2)

KAWANO, DANIEL F.; COSTA, BRUNA Z.; ROMERO-OREJON, KATHERINE L.; LOUREIRO, HUGO C.; DE JESUS, DOSIL P.; MARSAIOLI, ANITA J.. The Enantiomeric Discrimination of 5-Hexyl-2-methyl-3,4-dihydro-2H-pyrrole by Sulfobutyl ether-beta-cyclodextrin: A Case Study. Molecules, v. 26, n. 9, p. 7-pg., 2021-05-01. (14/50249-8, 18/08585-1, 13/22127-2, 14/50867-3)