The Synthesis and Biological Evaluation of Indolactam Alkaloids

Manuel Mendoza; Ryan Eom; Celeste Salas; Jeremy Haynes-Smith; Kelvin L. Billingsley

doi:10.1055/s-0039-1690198

Synthesis, Table of Contents

Synthesis 2019; 51(23): 4443-4451
DOI: 10.1055/s-0039-1690198

paper

The Synthesis and Biological Evaluation of Indolactam Alkaloids

Authors

Manuel Mendoza

^aDepartment of Chemistry and Biochemistry, California State University Fullerton, Fullerton, CA 92831, USA Email: kbillingsley@fullerton.edu
Ryan Eom

^bDepartment of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
Celeste Salas

^aDepartment of Chemistry and Biochemistry, California State University Fullerton, Fullerton, CA 92831, USA Email: kbillingsley@fullerton.edu
Jeremy Haynes-Smith

^cDepartment of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA
Kelvin L. Billingsley ∗

^aDepartment of Chemistry and Biochemistry, California State University Fullerton, Fullerton, CA 92831, USA Email: kbillingsley@fullerton.edu

Abstract

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Abstract

In this work, we execute a general synthetic strategy to access novel indolactam alkaloids, which are agonists of protein kinase C. This protocol allowed for the most efficient reported syntheses of indolactam V (ILV) stereoisomers, while also affording the large-scale production of natural product (–)-ILV. Structure–activity studies were conducted with these compounds to elucidate the elements necessary to promote PKC-mediated cellular response. EC₅₀ measurements in leukemia and lymphoma cell lines, as well as molecular docking analyses with the PKCδ C1B domain, provided the foundation for these studies. A distinct correlation between in vitro activity and the conformation of the macrocyclic lactam ring was discovered, which can guide design efforts for therapeutics that target the PKC regulatory domain.

Key words

natural products - synthesis - indolactams - amino acids - protein kinase C

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Supplementary Material

Supporting Information (PDF)