Design and synthesis of new phospholipids capable of selectively inducing apoptosis of tumor cells by acting in lipid rafts

Author(s)

Anna Carolina Schneider Alves

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Farmacêuticas
• Defense date: 2021-12-10

Examining board members

Daniel Fábio Kawano; Priscila Gava Mazzola; Paulo Sérgio Gonçalves Nunes; Vinicius Barreto da Silva; Maurício Ferreira Marcondes Machado

• Advisor: Daniel Fábio Kawano

Abstract

For more over than 40 years, the fluid mosaic model of cell membranes has reinforced our view of a lipid bilayer with dispersed membrane receptors that are randomly targeted by extracellular ligands to trigger intracellular signaling events. However, it is reasonable to think that this lipid bilayer has compartmentalized microdomains (known as lipid rafts) that promote the organization of receptors and ligands in a restricted physical space, in order to promote kinetically favorable interactions for receptor activation and intracellular signal transduction. Recently, increasing attention has been given to these structures after the observation that some phospholipids, mainly edelfosine (1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine), are able to recruit in vitro receptors of Fas death and the molecules necessary for its intracellular signaling in lipid rafts, triggering the process of cell death by apoptosis selectively for tumor cells, thus preserving healthy cells. However, Phase II clinical studies have shown that edelfosine has only a tumorostatic effect in humans, and not cytotoxic as would be expected from a good antitumor drug. In this sense, this work proposes to synthesize edelfosine analogues that retain the ability to accumulate in lipid rafts to selectively induce apoptosis in tumor cells and that potentially are more clinically active. The synthesis of these compounds was designed from a commercial reagent bathyl alcohol, being its primary hydroxyl selectively protected with the trityl group. Through phase transfer catalysis, the terminal alkyne was inserted into the secondary hydroxyl via Williamson synthesis. The resulting alkyne was then coupled to an organic azide, previously synthesized from an aromatic aniline, using the copper-catalyzed alkyne-azide cycloaddition reaction (CuAAC) (click chemistry), forming the nucleus 1,2,3 -triazole. The amines selected for this work have an aliphatic and an aromatic amine, and the aliphatic one was protected with the Boc group, in order to avoid azidation in the two amines, since it is not a selective reaction. Finally, insertion into phosphocholine in 1-hexadecanol was tested, before insertion into planned compounds (AU)

• FAPESP's process: 17/05876-2 - Design and synthesis of new phospholipids that selectively induce the apoptosis of tumor cells via lipid rafts
• Grantee: Anna Carolina Schneider Alves
• Support Opportunities: Scholarships in Brazil - Doctorate