TY - JOUR
T1 - Trans-Fluorine Effect in Cyclopropane
T2 - Diastereoselective Synthesis of Fluorocyclopropyl Cabozantinib Analogs
AU - Veliks, Janis
AU - Videja, Melita
AU - Kinens, Artis
AU - Bobrovs, Raitis
AU - Priede, Martins
AU - Kuka, Janis
N1 - Funding Information:
Financial support from the ERDF project Nr.1.1.1.5/17/A/003. The authors wish to thank Aigars Jirgensons and Maija Dambrova for scientific discussions; Renate Melngaile, Armands Kazia, and Arturs Sperga for the synthesis of reagent 2; Andulis Smidlers for technical assistance; and LIOS analytical service for NMR (Juris Popelis and Marina Petrova) and MS (Solveiga Grinberga, Dace Hartmane, Valerija Krizanovska, and Baiba Gukalova).
Publisher Copyright:
© 2020 American Chemical Society. All rights reserved.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/11/12
Y1 - 2020/11/12
N2 - 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.
AB - 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.
KW - anticancer
KW - c-Met kinase inhibitors
KW - cabozantinib
KW - fluorocyclopropane
KW - VEGFR-2 kinase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85099325516&partnerID=8YFLogxK
UR - https://www-webofscience-com.db.rsu.lv/wos/alldb/full-record/WOS:000592744800011
U2 - 10.1021/acsmedchemlett.0c00220
DO - 10.1021/acsmedchemlett.0c00220
M3 - Article
AN - SCOPUS:85099325516
SN - 1948-5875
VL - 11
SP - 2146
EP - 2150
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 11
ER -
