trans-Fluorine Effect in Cyclopropane: Diastereoselective Synthesis of Fluorocyclopropyl Cabozantinib Analogs

Investigation of the trans-fluorine effect on the hydrolysis rate of diethyl 2-fluorocyclopropane-1,1-dicarboxylate provides synthetic access to both diastereomers of the fluorocyclopropyl analog of cabozantinib, a c-Met and VEGFR-2 inhibitor used as a first-line treatment for thyroid cancer and as...

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Bibliographic Details
Published in:ACS medicinal chemistry letters Vol. 11; no. 11; pp. 2146 - 2150
Main Authors: Veliks, Janis, Videja, Melita, Kinens, Artis, Bobrovs, Raitis, Priede, Martins, Kuka, Janis
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 12.11.2020
Subjects:
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
c-Met kinase inhibitors
fluorocyclopropane
VEGFR-2 kinase inhibitors
anticancer
cabozantinib
ISSN:1948-5875, 1948-5875
Online Access:Get more information
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Summary:Investigation of the trans-fluorine effect on the hydrolysis rate of diethyl 2-fluorocyclopropane-1,1-dicarboxylate provides synthetic access to both diastereomers of the fluorocyclopropyl analog of cabozantinib, a c-Met and VEGFR-2 inhibitor used as a first-line treatment for thyroid cancer and as a second-line treatment for renal cell carcinoma. Despite some known potent examples, there are only a few drug molecules that contain fluorocyclopropane moieties. Herein, we present a case study in which the monofluoro analog of a known cyclopropane-containing drug molecule displays an improved in vitro profile compared to the parent nonfluorinated structure. The fluorocyclopropane moiety may offer valuable fine-tuning options for lead optimization in drug discovery.
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ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.0c00220