Synthesis, Table of Contents

Synthesis 2024; 56(04): 539-548
DOI: 10.1055/a-2004-5883

special topic

Synthetic Development of Key Intermediates and Active Pharmaceutical Ingredients (APIs)

A Robust, Gram-Scale and High-Yield Synthesis of MDP Congeners for Activation of the NOD2 Receptor and Vaccine Adjuvantation

Farooq-Ahmad Khan ∗

^aThird World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan

^bH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan

,

Sana Yaqoob‡

^aThird World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan

^bH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan

,

Muhammad Wasim Qasim‡

^aThird World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan

^bH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan

,

Shujaat Ali

^aThird World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan

^bH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan

,

Yan Wang∗

^bH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan

,

Zi-Hua Jiang∗

^cDepartment of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, Ontario, P7B 5E1, Canada

› Author Affiliations

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Abstract

The bacterial peptidoglycan (PGN) constituent muramyl dipeptide (MDP) and its congeners possess immuno-adjuvant activity, and find applications in vaccines to potentiate the immune response of antigens. It confers non-specific resistance towards pathogenic infections and defense against tumors. In this work, the parent MDP molecule is re-designed by replacing its carbohydrate moiety with an immunoregulatory xanthine scaffold, while conserving the l-d configuration of the pharmacophore. Alkyl chains are introduced at the C-terminus of d-isoglutamine to help the molecules access cytoplasmic NOD2 receptors and activate the innate immune system. Lipophilic MDP congeners are thus obtained by adopting a direct or indirect convergent synthetic route with overall yields of >50%. We found that an indirect approach can reliably be implemented on gram scale, thereby unlocking access to substantial amounts of pathogen-associated molecular patterns for in vivo studies, which will accelerate the development of NOD2 immuno-adjuvants against viral and bacterial infections.

Key words

Key words

NOD2 - vaccine - adjuvant - muramyl - peptides

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