The 1,4-naphthoquinone scaffold in the design of cysteine protease inhibitors.
A series of 1,4-naphthoquinone derivatives diversely substituted at C-2, C-3, C-5 and C-8, prepared by reaction of amines, amino acids and alcohols with commercial 1,4-naphthoquinones, has been evaluated against papain and bovine spleen cathepsin B. These 1,4-naphthoquinone derivatives were found to be irreversible inhibitors for both cysteine proteases, with second-order rate constants, k(2), ranging from 0.67 to 35.4M(-1)s(-1) for papain, and from 0.54 to 8.03M(-1)s(-1) for cathepsin B. Some derivatives display a hyperbolic dependence of the first-order inactivation rate constant, k(obs), with the inhibitor concentration, indicative of a specific interaction process between enzyme and inhibitor. The chemical reactivity of the compounds towards cysteine as a model thiol is dependent on the naphthoquinone LUMO energy, whereas papain inactivation is not. The 1,4-naphthoquinone derivatives are inactive against the serine protease, porcine pancreatic elastase.
Valente
Cláudia
C
CECF, Faculty of Pharmacy, University of Lisbon, Avenida das Forças Armadas, Lisboa, Portugal.
Moreira
Rui
R
Guedes
Rita C
RC
Iley
Jim
J
Jaffar
Mohammed
M
Douglas
Kenneth T
KT
D002401:Cathepsin B / Q000737:chemistry / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry*; D010196:Pancreatic Elastase / Q000737:chemistry / Q000378:metabolism; D010206:Papain / Q000737:chemistry / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D009285:Naphthoquinones; D010196:Pancreatic Elastase; D002401:Cathepsin B; D010206:Papain; D003545:Cysteine; C035342:1,4-naphthoquinone