Linear (-)-Zampanolide: Flexibility in Conformation-Activity Relationships

Through an understanding of the conformational preferences of the polyketide natural product (-)-zampanolide, and the structural motifs that control these preferences, we developed a linear zampanolide analogue that exhibits potent cytotoxicity against cancer cell lines. This discovery provides a se...

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Bibliographic Details
Published in:ChemMedChem 2023-10, Vol.18 (19), p.e202300292-e202300292
Main Authors: Umaña, Christian A, Henry, Jeffrey L, Saltzman, Claire T, Sackett, Dan L, Jenkins, Lisa M, Taylor, Richard E
Format: Article
Language:English
Subjects:
Biological activity
Cytotoxicity
Flexibility
Macrolides - chemistry
Molecular Conformation
Natural products
Polyketides - chemistry
Protein structure
Reagents
Stabilizers (agents)
Structure-Activity Relationship
Tumor cell lines
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Summary:Through an understanding of the conformational preferences of the polyketide natural product (-)-zampanolide, and the structural motifs that control these preferences, we developed a linear zampanolide analogue that exhibits potent cytotoxicity against cancer cell lines. This discovery provides a set of three structural handles for further structure-activity relationship (SAR) studies of this potent microtubule-stabilizing agent. Moreover, it provides additional evidence of the complex relationship between ligand preorganization, conformational flexibility, and biological potency. In contrast to medicinal chemistry dogma, these results demonstrate that increased overall conformational flexibility is not necessarily detrimental to protein binding affinity and biological activity.
ISSN:1860-7179
1860-7187
1860-7187
DOI:10.1002/cmdc.202300292