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Total synthesis of anticancer pseudo-peptide tubulysin: application to the construction of chemically defined antibody-drug conjugates

Grant number: 16/18771-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): April 01, 2017
Effective date (End): December 31, 2019
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal researcher:Márcio Weber Paixão
Grantee:Barbara Bernardim de Souza
Home Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
Associated scholarship(s):17/13168-8 - Construction of chemically defined antibody-drug conjugates using carbonylacrylic reagents, BE.EP.PD


Common chemotherapeutic agents available in traditional anti-cancer treatments require administration at near the maximum tolerated dosage, lacking tumor selectivity and killing of proliferating normal cells. A recent class of therapy with considerable promise in the treatment of various cancers is the selective targeting of cytotoxic drugs to tumours by conjugating the drug to specific antibodies. This Antibody-Drug Conjugate (ADC) therapy is able to deliver a particularly toxic drug molecule that is conventionally excluded from use in chemotherapy directly to a target with minimal "off-target" toxicity. Studies demonstrated that first and second generation ADCs usually suffered from premature cleavage of the drug from the antibody, thus leading to associated toxicity. In addition, most of these ADCs were build using non-specific conjugations technologies resulting in poor pharmacokinetics and efficacy. Indeed, ADCs built with precise drug-to-antibody ratio(s) through the use site-specific methods have showed a significant improvement in efficacy. In this way, there is a considerable and progressive interest in the development of efficient methods for the preparation of ADCs in a site-specific fashion, controlling the ratio of drug to antibody. In this project, we propose to build stable ADCs with defined chemical properties based on the drug tubulysin using a bioconjugation protocol recently described by the group of Dr. Bernardes (University of Cambridge, UK). The tubulysin drug will be innovatively synthesized from fragments prepared via metal-free asymmetric catalysis and multicomponent approaches widely explored in the group of Prof. Dr. Márcio Paixão group (UFSCar). The strategy for the synthesis of this cytotoxin features a new proposal never explored before. This project aims to perform the total synthesis of tubulysin using a novel synthetic strategy followed by incorporation of this drug to antibodies and evaluation of the conjugate as ADC. (AU)