Thioxophosphoranyl aryl- and heteroaryloxiranes as the representants of a new class of metallocarboxypeptidase inhibitors.
A novel and potent family of metallocarboxypeptidase inhibitors based on thioxophosphoranyl oxiranes is presented. These compounds bear aryl or heteroaryl substituents with trans-stereochemistry with respect to the phosphorylated group and they have been synthesized by the addition of [bis(diisopropylamino)phosphino](trimethylsilyl)carbene to the corresponding aldehydes and the subsequent thiolation of the phosphine. These oxiranes contain a tetrahedral P atom harboring shielded N,N-groups. The screening of their biological activity as metallocarboxypeptidase inhibitors and some structural studies, as well as full experimental details for the new compounds, is disclosed. Thus, from the analysis of their activity against the prototypical metallocarboxypeptidases A and B (CPA and CPB), we have observed that hydrophobic phosphorylated oxiranes perform better as CPB inhibitors, reaching K(i) values comparable to classical synthetic carboxypeptidase inhibitors. X-ray diffraction analysis revealed that the packing in the structure of one phosphorylated oxirane is mediated mainly by hydrophobic contacts and that the N,N-groups are highly flexible. Consequently, phosphorylated oxiranes might constitute an attractive material for subsequent improvements in the design of novel inhibitors against human proteolytic enzymes with enhanced oral availability.
Fernández
Daniel
D
Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
Illa
Ona
O
Avilés
Francesc X
FX
Branchadell
Vicenç
V
Vendrell
Josep
J
Ortuño
Rosa M
RM
D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D002417:Cattle; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005027:Ethylene Oxide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry*; D010766:Phosphorylation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D013438:Sulfhydryl Compounds; D002268:Carboxypeptidases; D005027:Ethylene Oxide