Linear (-)-Zampanolide: Flexibility in Conformation-Activity Relationships.
conformation
linear analogues
macrocycles
polyketides
zampanolide
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
04 10 2023
04 10 2023
Historique:
revised:
20
07
2023
received:
05
06
2023
pmc-release:
04
10
2024
medline:
26
10
2023
pubmed:
8
8
2023
entrez:
8
8
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37552215
doi: 10.1002/cmdc.202300292
pmc: PMC10615712
mid: NIHMS1924132
doi:
Substances chimiques
zampanolide
0
Macrolides
0
Polyketides
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202300292Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM084922
Pays : United States
Organisme : NIH HHS
ID : GM084922
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM075762
Pays : United States
Informations de copyright
© 2023 Wiley-VCH GmbH.
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