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Design, Synthesis, and Biological Evaluation of Fluorinated Analogues of Salicylihalamide
- Source :
- Journal of Medicinal Chemistry. 52:798-806
- Publication Year :
- 2008
- Publisher :
- American Chemical Society (ACS), 2008.
-
Abstract
- Salicylihalamide A (SA), a benzolactone enamide compound, possesses potent cytotoxicity against human tumor cell lines. SA is a selective inhibitor of mammalian vacuolar type H(+)-ATPase (V-ATPase), and is distinct from previously known V-ATPase inhibitors such as bafilomycins and concanamycins that do not discriminate between mammalian and nonmammalian V-ATPases. Because of its potent antitumor activity and structural simplicity, SA is a promising candidate for an anticancer drug. Although a number of structure-activity relation studies using synthetic analogues have been reported, no fluorinated derivative of SA has been evaluated even though selective addition of a fluorine atom into a therapeutic small molecule candidate often enhances pharmacokinetic and physicochemical properties. We designed and synthesized fluorinated analogues of SA and evaluated their V-ATPase inhibitory activities. Compared to the natural product, the synthetic analogues were potent V-ATPase inhibitors, suggesting that these analogues are potential drug candidates and potential molecular probes for mode-of-action studies using fluorine-based analytical methods such as (19)F-NMR spectroscopy.
- Subjects :
- Vacuolar Proton-Translocating ATPases
Cell Survival
Swine
medicine.drug_class
Stereochemistry
Antineoplastic Agents
Carboxamide
Chemical synthesis
Structure-Activity Relationship
chemistry.chemical_compound
Chlorocebus aethiops
Drug Discovery
medicine
Animals
Chromaffin Granules
Cytotoxicity
chemistry.chemical_classification
Natural product
biology
Chemistry
Biological activity
Bridged Bicyclo Compounds, Heterocyclic
Small molecule
Enzyme inhibitor
Drug Design
COS Cells
biology.protein
Molecular Medicine
Lactone
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....194c9e079ce15e705330b33dc6180b23