Effects of new ubiquinone-imidazo[2,1-b]thiazoles on mitochondrial complex I (NADH-ubiquinone reductase) and on mitochondrial permeability transition pore.
In this work we describe the synthesis of a series of imidazo[2,1-b]thiazoles and 2,3-dihydroimidazo[2,1-b]thiazoles connected by means of a methylene bridge to CoQ(0). These compounds were tested as specific inhibitors of the NADH:ubiquinone reductase activity in mitochondrial membranes. The imidazothiazole system when bound to the quinone ring in place of the isoprenoid lateral side chain, may increase the inhibitory effect (with an IC(50) for NADH-Q(1) activity ranging between 0.25 and 0.96 microM) whereas the benzoquinone moiety seems to lose the capability to accept electrons from complex I as indicated by very low maximal velocity elicited by the compounds tested. Moreover the low rotenone sensitivity for almost all of these compounds suggests that they are only partially able to interact with the physiological ubiquinone-reduction site. The compounds were investigated for the capability of increasing the permeability transition of the inner mitochondrial membrane in isolated mitochondria. Unlike CoQ(0), which is considered a mitochondrial membrane permeability transition inhibitor, the new compounds were inducers.
Dipartimento di Scienze Farmaceutiche, Universitá di Bologna, Via Belmeloro 6, 40126 Bologna, Italy. aldo.andreani@unibo.it
Aldo
A
Andreani
Massimiliano
M
Granaiola
Alberto
A
Leoni
Alessandra
A
Locatelli
Rita
R
Morigi
Mirella
M
Rambaldi
Maurizio
M
Recanatini
Giorgio
G
Lenaz
Romana
R
Fato
Christian
C
Bergamini
D000818:Animals; D002417:Cattle; D042967:Electron Transport Complex I / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014451:Ubiquinone / Q000737:chemistry / Q000494:pharmacology*
D007093:Imidazoles; D013844:Thiazoles; D014451:Ubiquinone; D042967:Electron Transport Complex I