Enantioselective synthesis of adamantylalanine and carboranylalanine and their incorporation into the proteasome inhibitor bortezomib

Gerjan de Bruin; Elliot D Mock; Sascha Hoogendoorn; Adrianus M C H van den Nieuwendijk; Jaroslaw Mazurek; Gijsbert A van der Marel; Bogdan I Florea; Herman S Overkleeft

doi:10.1039/c6cc01156j

Enantioselective synthesis of adamantylalanine and carboranylalanine and their incorporation into the proteasome inhibitor bortezomib

Chem Commun (Camb). 2016 Mar 14;52(21):4064-7. doi: 10.1039/c6cc01156j.

Authors

Gerjan de Bruin¹, Elliot D Mock¹, Sascha Hoogendoorn¹, Adrianus M C H van den Nieuwendijk¹, Jaroslaw Mazurek², Gijsbert A van der Marel¹, Bogdan I Florea¹, Herman S Overkleeft¹

Affiliations

¹ Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands. h.s.overkleeft@lic.leidenuniv.nl.
² Crystallics B.V., Meibergdreef 31, 1105 AZ Amsterdam, The Netherlands.

PMID: 26894389
DOI: 10.1039/c6cc01156j

Abstract

The incorporation of adamantylalanine and carboranylalanine at the P2 site of bortezomib is well tolerated and provided potent cell permeable proteasome inhibitors with increased off-rates compared to bortezomib. Adamantylalanine and carboranylalanine were synthesized enantioselectively by an asymmetric Strecker reaction on Ellmans tert-butyl sulfinimines.

MeSH terms

Adamantane / chemical synthesis*
Adamantane / chemistry
Boron Compounds / chemical synthesis*
Boron Compounds / chemistry
Bortezomib / chemistry*
Bortezomib / pharmacology*
Cell Line, Tumor
Humans
Phenylalanine / analogs & derivatives*
Phenylalanine / chemical synthesis
Phenylalanine / chemistry
Proteasome Endopeptidase Complex / chemistry*
Proteasome Endopeptidase Complex / metabolism
Proteasome Inhibitors / chemistry*
Proteasome Inhibitors / pharmacology*
Stereoisomerism
Sulfonium Compounds / chemistry

Substances

Boron Compounds
Proteasome Inhibitors
Sulfonium Compounds
Phenylalanine
carboranylalanine
Bortezomib
Proteasome Endopeptidase Complex
Adamantane