Design, Synthesis, and Structure–Activity Optimization of Marine-Inspired Macrolactones as Nanomolar Anticancer Agents

Shan Qian; Haibo Qiu; Phillip R. Sanchez; Sarah A. Head; Ruth Hartke; Jun O. Liu; Wei Zheng; Zhendong Jin

doi:10.1021/acsmedchemlett.6c00222

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Design, Synthesis, and Structure–Activity Optimization of Marine-Inspired Macrolactones as Nanomolar Anticancer Agents

Journal article

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Design, Synthesis, and Structure–Activity Optimization of Marine-Inspired Macrolactones as Nanomolar Anticancer Agents

Shan Qian, Haibo Qiu, Phillip R. Sanchez, Sarah A. Head, Ruth Hartke, Jun O. Liu, Wei Zheng and Zhendong Jin

ACS medicinal chemistry letters

05/16/2026

DOI: 10.1021/acsmedchemlett.6c00222

PMCID: PMC13266650

PMID: 42305198

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Abstract

Inspired by the anticancer marine natural product superstolide A, we previously designed and synthesized a truncated analogue, designated ZJ-101, that retains the potent anticancer activity of the original natural product. In this study, using ZJ-101 as a lead compound, we conducted molecular design, convergent synthesis, and structure–activity optimization, resulting in the discovery of new analogues exhibiting anticancer activity approximately 30–80-fold more potent than ZJ-101, with IC50 values predominantly in the single-digit nanomolar range.

Drug Design

Superstolide A analogue

ZJ-101 analogue

anticancer agent

macrolide

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Details

Title: Subtitle: Design, Synthesis, and Structure–Activity Optimization of Marine-Inspired Macrolactones as Nanomolar Anticancer Agents
Creators: Shan Qian - University of Iowa
Haibo Qiu - University of Iowa
Phillip R. Sanchez - Johns Hopkins Medicine
Sarah A. Head - Johns Hopkins Medicine
Ruth Hartke - Johns Hopkins University
Jun O. Liu - Johns Hopkins University
Wei Zheng - National Institutes of Health
Zhendong Jin - University of Iowa
Resource Type: Journal article
Publication Details: ACS medicinal chemistry letters
DOI: 10.1021/acsmedchemlett.6c00222
PMID: 42305198
PMCID: PMC13266650
NLM abbreviation: ACS Med Chem Lett
ISSN: 1948-5875
eISSN: 1948-5875
Publisher: American Chemical Society; WASHINGTON
Grant note: National Center for Advancing Translational Sciences: NA Flight Attendant Medical Research Institute: NA InnoBioPharma, LLC: D2015070002 National Cancer Institute: 1R21CA204836-01
This work was made possible by the generous support of the funding from InnoBioPharma, LLC (D2015070002), a grant (1R21CA204836-01) from the National Institutes of Health, the Intramural Research Program of National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), and FAMRI.
Language: English
Electronic publication date: 05/16/2026
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9985164608502771

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