Design, synthesis and anti-malarial activities of synthetic analogs of biselyngbyolide B, a Ca2+ pump inhibitor from marine cyanobacteria

Eisuke Sato; Maho Morita; Haruo Ogawa; Masato Iwatsuki; Rei Hokari; Aki Ishiyama; Satoshi Ōmura; Arihiro Iwasaki; Kiyotake Suenaga

doi:10.1016/j.bmcl.2017.12.050

Design, synthesis and anti-malarial activities of synthetic analogs of biselyngbyolide B, a Ca²⁺ pump inhibitor from marine cyanobacteria

Bioorg Med Chem Lett. 2018 Feb 1;28(3):298-301. doi: 10.1016/j.bmcl.2017.12.050. Epub 2017 Dec 24.

Authors

Eisuke Sato¹, Maho Morita², Haruo Ogawa³, Masato Iwatsuki⁴, Rei Hokari⁴, Aki Ishiyama⁴, Satoshi Ōmura⁴, Arihiro Iwasaki¹, Kiyotake Suenaga⁵

Affiliations

¹ Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan.
² Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan; Institute of Molecular and Cellular Bioscience, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
³ Institute of Molecular and Cellular Bioscience, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
⁴ Research Center for Tropical Diseases, Kitasato Institute for Life Science, and Graduate School of Infection Control Science, Kitasato University, 5-9-1, Shirokane Minato-ku, Tokyo 108-8641, Japan.
⁵ Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan. Electronic address: suenaga@chem.keio.ac.jp.

PMID: 29292225
DOI: 10.1016/j.bmcl.2017.12.050

Abstract

Biselyngbyaside, an 18-membered macrolide glycoside from marine cyanobacteria, and its derivatives are known to be sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) inhibitors. Recently, a SERCA orthologue of the malaria parasite, PfATP6, has attracted attention as a malarial drug target. To provide a novel drug lead, we designed new synthetic analogs of biselyngbyolide B, the aglycone of biselyngbyaside, based on the co-crystal structure of SERCA with biselyngbyolide B, and synthesized them using the established synthetic route for biselyngbyolide B. Their biological activities against malarial parasites were evaluated.

Keywords: Biselyngbyaside; Biselyngbyolide; PfATP6; SERCA; Structure–activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis*
Antimalarials / chemistry
Antimalarials / pharmacology*
Calcium-Transporting ATPases / antagonists & inhibitors*
Calcium-Transporting ATPases / metabolism
Cell Line
Cell Proliferation / drug effects
Cyanobacteria / chemistry*
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Macrolides / chemical synthesis
Macrolides / chemistry
Macrolides / pharmacology*
Models, Molecular
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Plasmodium falciparum / enzymology
Structure-Activity Relationship

Substances

Antimalarials
Macrolides
biselyngbyolide B
Calcium-Transporting ATPases