4‐O‐Substituted Glucuronic Cyclophellitols are Selective Mechanism‐Based Heparanase Inhibitors

ChemMedChem, vol. 18, pp. e202200580

Abstract

Degradation of the extracellular matrix (ECM) supports tissue integrity and homeostasis, but is also a key factor in cancer metastasis. Heparanase (HPSE) is a mammalian ECM-remodeling enzyme with β-D-endo-glucuronidase activity overexpressed in several malignancies, and is thought to facilitate tumor growth and metastasis. By this virtue, HPSE is considered an attractive target for the development of cancer therapies, yet to date no HPSE inhibitors have progressed to the clinic. Here we report on the discovery of glucurono-configured cyclitol derivatives featuring simple substituents at the 4-O-position as irreversible HPSE inhibitors. We show that these compounds, unlike glucurono-cyclophellitol, are selective for HPSE over β-D-exo-glucuronidase (GUSB), also in platelet lysate. The observed selectivity is induced by steric and electrostatic interactions of the substituents at the 4-O-position. Crystallographic analysis supports this rationale for HPSE selectivity, and computer simulations provide insights in the conformational preferences and binding poses of the inhibitors, which we believe are good starting points for the future development of HPSE-targeting antimetastatic cancer drugs.

Authors 9

1. Valentina Borlandelli Aachen Bio-organic Synthesis Leiden Institute of Chemistry Gorlaeus Laboratories

   Leiden University

   Affiliation as printed

   Bio-organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University Gorlaeus Laboratories Einsteinweg 55 2333 CC Leiden The Netherlands

   Bio-organic Synthesis, Leiden Institute of Chemistry (LIC), Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands

2. Zachary Armstrong Aachen Bio-organic Synthesis Leiden Institute of Chemistry Gorlaeus Laboratories

   Leiden University · University of York

   Affiliation as printed

   Bio-organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University Gorlaeus Laboratories Einsteinweg 55 2333 CC Leiden The Netherlands

   Department of Chemistry York Structural Biology Laboratory University of York Heslington YO10 5DD York UK

   Bio-organic Synthesis, Leiden Institute of Chemistry (LIC), Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands

   Department of Chemistry, York Structural Biology Laboratory, University of York, Heslington, YO10 5DD York, UK

3. Alba Nin‐Hill

   Universitat de Barcelona

   Affiliation as printed

   Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and Institut de Química Teòrica i Computacional (IQTCUB) Universitat de Barcelona Martí i Franquès 1 08028 Barcelona Spain

4. Jeroen D. C. Codée Aachen Bio-organic Synthesis Leiden Institute of Chemistry Gorlaeus Laboratories

   Leiden University

   Affiliation as printed

   Bio-organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University Gorlaeus Laboratories Einsteinweg 55 2333 CC Leiden The Netherlands

   Bio-organic Synthesis, Leiden Institute of Chemistry (LIC), Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands

5. Lluı́s Raich

   Universitat de Barcelona · Freie Universität Berlin

   Affiliation as printed

   Current address: Department of Mathematics and Computer Science Freie Universität Berlin 14195 Berlin Germany

   Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and Institut de Química Teòrica i Computacional (IQTCUB) Universitat de Barcelona Martí i Franquès 1 08028 Barcelona Spain

6. Marta Artola Aachen Bio-organic Synthesis Leiden Institute of Chemistry Gorlaeus Laboratories

   Leiden University

   Affiliation as printed

   Bio-organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University Gorlaeus Laboratories Einsteinweg 55 2333 CC Leiden The Netherlands

   Bio-organic Synthesis, Leiden Institute of Chemistry (LIC), Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands

7. Carme Rovira

   Universitat de Barcelona

   Affiliation as printed

   Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and Institut de Química Teòrica i Computacional (IQTCUB) Universitat de Barcelona Martí i Franquès 1 08028 Barcelona Spain

8. G.J. Davies corresponding

   University of York

   Affiliation as printed

   Department of Chemistry York Structural Biology Laboratory University of York Heslington YO10 5DD York UK

   Department of Chemistry, York Structural Biology Laboratory, University of York, Heslington, YO10 5DD York, UK

9. Herman S. Overkleeft corresponding Aachen Bio-organic Synthesis Leiden Institute of Chemistry Gorlaeus Laboratories

   Leiden University

   Affiliation as printed

   Bio-organic Synthesis Leiden Institute of Chemistry (LIC) Leiden University Gorlaeus Laboratories Einsteinweg 55 2333 CC Leiden The Netherlands

   Bio-organic Synthesis, Leiden Institute of Chemistry (LIC), Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands