Project Details
Projekt
Photoredox-Catalyzed Reactions for Application in Medicinal Chemistry – A Novel Strategy for Difluoromethylation & Stable S–C(sp2) Linkers for Antibody-Drug Conjugates
Applicant
Dr. Alexander Lipp
Subject Area
Organic Molecular Chemistry - Synthesis and Characterisation
Term
from 2019 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 437535512
The objective of this work is the design of two photoredox-catalyzed transformations for application in medicinal chemistry. New strategies for the difluoromethylation of small molecules and for the construction of stable antibody-drug conjugates (ADCs) will be developed. Geminal difluorides are omnipresent in pharmaceuticals and agrochemicals. In the past years, many photoredox-catalyzed difluoromethylations were reported that rely on trapping of reductively generated difluoromethyl radicals with unsaturated substrates (e.g., alkynes, arenes, alkenes, isocyanides). In the first subproject, a complementary approach will be developed – trapping of oxidatively generated alkyl radicals with 1,1-difluoroethene. This new strategy will overcome previous limitations by enabling a radical difluoroalkylation using carboxylic acids, aldehydes (via dihydropyridines), alcohols (via oxalates) or alkyl trifluoroborates as radical precursors. However, since 1,1-difluoroethene is gaseous and prone to radical polymerization, a suitable surrogate is necessary. Vinylboronates, such as the commercially available vinyl-Bpin, appear to be promising candidates in this respect. Reaction of the latter with oxidatively generated alkyl radicals in the presence of Selectfluor with subsequent deboronation/fluorination should provide a one-pot access to the desired difluoroalkylated products. The utility of the devised method will be demonstrated in the synthesis of designed prostaglandin analogs from commercially available derivatives of Corey lactone. The second subproject aims at developing novel linkers for ADCs. Such immunoconjugates offer the chance to deliver a pharmaceutically active compound selectively to a specific cell type and are hence ideally suited for the harmful cytotoxins used in cancer therapy. In most cases, conjugation of the linker/cytotoxin unit to the antibody is accomplished through Michael reaction of cysteine side chains with maleimides. However, its reversibility limits the ADC’s circulation half-life and reduces the therapeutic window because of the systemic toxicity caused by released cytotoxins. In the course of this project, new linkers will be developed that enable the construction of stable S–C(sp2) conjugates through photoredox or nickel/photoredox dual catalysis. The reaction will be investigated using glutathione as cysteine-containing model substrate in combination with benzylamine and a short oligopeptide as cytotoxin-placeholders. The optimized conditions will then be applied to the functionalization of Trastuzumab, a commercially available antibody for targeting breast cancer cells. After fine-tuning the reaction conditions with an oligopeptide as cytotoxin-placeholder, a full ADC consisting of Trastuzumab and monomethyl auristatin E as cytotoxin will be assembled.
DFG Programme
Research Fellowships
International Connection
USA
