Synthesis of 2-deoxyglycoside derivatives of anthracyclines

• Grant number: 16/21194-6
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): February 01, 2017
• Effective date (End): November 14, 2017
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Ivone Carvalho
• Grantee: Maristela Braga Martins Teixeira
• Supervisor abroad: Maria Carmen Galan
• Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Local de pesquisa : University of Bristol, England
• Associated to the scholarship: 15/10837-0 - Synthesis of novel anthracycline derivatives containing azido glycosides, BP.DR

Abstract

Doxorubicin is an anthracycline classified among the most effective chemotherapeutics against cancer. It is comprised by 3-amino-2,3,6-deoxy-L-fucose (daunosamine) linked to a quinone-hydroquinone system, and acts by DNA-intercalation, oxidative stress generation and topoisomerase II poisoning. Regardless of its therapeutic value, multidrug resistance and severe cardiotoxicity are important limitations consequential of doxorubicin treatment. To overcome these downsides, new generation analogues have been synthesized, with the carbohydrate moiety being the target of the most successful structural variations in terms of efficacy and toxicity. Based on chemical glyco-diversification, this project will exploit 2-deoxy and 3-amino-2,3-dideoxy glycosides, which are prevalent in many other bioactive natural products, to be combined with doxorubicin aglycone. Four novel glycosides are proposed, which will be prepared by a semi-synthesis approach. Protected doxorubicinone will be the acceptor for alpha-selective catalyzed glycosylations with conveniently manipulated glucals and galactals as glycosyl donors. The analogues prepared will be tested for anticancer activity in a panel of cancer cell lines (HeLa cervical cancer, breast cancer MCF-7 and MDA-MB31 and colon cancer E12 cells) and a model of healthy cells (human lung fibroblasts WI-38).

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)

PALO-NIETO, CARLOS; SAU, ABHIJIT; JEANNERET, ROBIN; PAYARD, PIERRE-ADRIEN; SALAME, AUDE; MARTINS-TEIXEIRA, MARISTELA BRAGA; CARVALHO, IVONE; GRIMAUD, LAURENCE; GALAN, M. CARMEN. Copper Reactivity Can Be Tuned to Catalyze the Stereoselective Synthesis of 2-Deoxyglycosides from Glycals. ORGANIC LETTERS, v. 22, n. 5, p. 1991-1996, MAR 6 2020. Web of Science Citations: 1.