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Catalytic Enantioselective Diels Alder Reaction: Application in the Synthesis of Antiviral Agents

by Alessandro Grillo and Bruno Mattia Bizzarri

Catalysts 2022, 12(2), 150; https://doi.org/10.3390/catal12020150 - 25 Jan 2022

Cited by 1 | Viewed by 6932

The Diels–Alder reaction (DAR) is one of the most effective and reliable strategies for the construction of six-membered carbocyclic and heterocyclic rings, and it is widely used in the synthesis of organic molecules and drugs. Due to the high regio- and stereo-selectivity and its versatility, DARs have represented a powerful tool for organic chemistry for many years. In addition, the asymmetric DAR has become a fundamental synthetic approach in the preparation of optically active six-membered rings and natural compounds. The COVID-19-related pandemic requires continuous research; DAR represents an useful method to obtain optically active intermediates for the synthesis of antiviral agents under different catalytic conditions. We would like to highlight an intriguing synthetic procedure applied to the development of novel synthetic protocols that are potentially useful against a large panel of viruses and other unmet diseases. Full article

(This article belongs to the Special Issue Recent Advances in Nanostructured Catalysts)

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11 pages, 2273 KiB

Open AccessArticle

Design and Validation of Linkers for Site-Specific Preparation of Antibody–Drug Conjugates Carrying Multiple Drug Copies Per Cysteine Conjugation Site

by Amit Kumar, Shenlan Mao, Nazzareno Dimasi and Changshou Gao

Int. J. Mol. Sci. 2020, 21(18), 6882; https://doi.org/10.3390/ijms21186882 - 19 Sep 2020

Cited by 13 | Viewed by 4973

Abstract

First-generation cysteine-based site-specific antibody–drug conjugates (ADCs) are limited to one drug per cysteine. However, certain applications require a high drug to antibody ratio (DAR), such as when low-potency payloads are used. Higher drug load can be achieved using classical cysteine conjugation methods, but these result in heterogeneity, suboptimal efficacy and pharmacokinetics. Here, we describe the design, synthesis and validation of heterobifunctional linkers that can be used for the preparation of ADCs with a DAR of two, three and four in a site-specific manner per single cysteine conjugation site, resulting in site-specific ADCs with a DAR of four, six and eight. The designed linkers carry a sulfhydryl-specific iodoacetyl reactive group, and multiple cyclic diene moieties which can efficiently react with maleimide-carrying payloads through the Diels–Alder reaction. As a proof of concept, we synthesized site-specific DAR four, six and eight ADCs carrying tubulysin (AZ13601508) using engineered antibodies with a cysteine inserted after position 239 in the antibody CH2 domain. We evaluated and compared the in vitro cytotoxicity of ADCs obtained via the site-specific platform described herein, with ADCs prepared using classical cysteine conjugation. Our data validated a novel cysteine-based conjugation platform for the preparation of site-specific ADCs with high drug load for therapeutic applications. Full article

(This article belongs to the Special Issue Monoclonal Antibodies to Treat Cancer)

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