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

Janis Veliks; Melita Videja; Artis Kinens; Raitis Bobrovs; Martins Priede; Janis Kuka

doi:10.1021/acsmedchemlett.0c00220

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

Janis Veliks (Coresponding Author), Melita Videja, Artis Kinens, Raitis Bobrovs, Martins Priede, Janis Kuka

Faculty of Pharmacy

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	2146-2150
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	11
DOIs	https://doi.org/10.1021/acsmedchemlett.0c00220
Publication status	Published - 12 Nov 2020

Keywords*

anticancer
c-Met kinase inhibitors
cabozantinib
fluorocyclopropane
VEGFR-2 kinase inhibitors

Field of Science*

3.1 Basic medicine
1.4 Chemical sciences

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/acsmedchemlett.0c00220

Cite this

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title = "Trans-Fluorine Effect in Cyclopropane: Diastereoselective Synthesis of Fluorocyclopropyl Cabozantinib Analogs",

abstract = "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.",

keywords = "anticancer, c-Met kinase inhibitors, cabozantinib, fluorocyclopropane, VEGFR-2 kinase inhibitors",

author = "Janis Veliks and Melita Videja and Artis Kinens and Raitis Bobrovs and Martins Priede and Janis Kuka",

note = "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: {\textcopyright} 2020 American Chemical Society. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2020",

month = nov,

day = "12",

doi = "10.1021/acsmedchemlett.0c00220",

language = "English",

volume = "11",

pages = "2146--2150",

journal = "ACS Medicinal Chemistry Letters",

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publisher = "American Chemical Society",

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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

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

Abstract

Keywords*

Field of Science*

Publication Type*

UN SDGs

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