Synthesis of macrocyclic trypanosomal cysteine protease inhibitors.
The importance of cysteine proteases in parasites, compounded with the lack of redundancy compared to their mammalian hosts makes proteases attractive targets for the development of new therapeutic agents. The binding mode of K11002 to cruzain, the major cysteine protease of Trypanosoma cruzi was used in the design of conformationally constrained inhibitors. Vinyl sulfone-containing macrocycles were synthesized via olefin ring-closing metathesis and evaluated against cruzain and the closely related cysteine protease, rhodesain.
Chen
Yen Ting
YT
Department of Chemistry, Scripps Florida, 5353 Parkside Drive, RE-2, Jupiter, FL 33458, USA.
Lira
Ricardo
R
Hansell
Elizabeth
E
McKerrow
James H
JH
Roush
William R
WR
D000818:Animals; D003546:Cysteine Endopeptidases / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives; D010879:Piperazines; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014105:Tosyl Compounds; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000201:enzymology*; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D010879:Piperazines; D015800:Protozoan Proteins; D013450:Sulfones; D014105:Tosyl Compounds; D014344:Trypanocidal Agents; D014753:Vinyl Compounds; C115125:morpholin- urea-phenylalanyl-homophenylalanyl-vinylsulfone-phenyl; C487484:N-pip-phenylalanine-homophenylalanine-vinyl sulfone phenyl; D010649:Phenylalanine; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; C446033:rhodesain