A new series of thieno[3,2-h]cinnolinone analogues was synthesized which is structurally related to 2,3,4,4a,5,6-hexahydro thieno[3,2-h]cinnolin-3-one 1, a weak inhibitor of the matrix metalloproteinase MMP-8 (human neutrophil collagenase). Preliminary SAR studies have shown that while C-4a-methyl, C-7-acetylamino, C-7 and C-8-nitro substitution, and C-4-C-4a olefination provided no increase in activity relative to 1, Cs-acetylamino substitution as in 5 and 8 was favourable. Moreover, to predict how the thieno[3,3-h]cinnolinone inhibitors might bind to MMP-8, the unsubstituted compound 9 was docked into the MMP-8 crystal structure. These studies revealed that inhibitor 9 does not seem to be able to coordinate the catalytically-active zinc ion but preferably interact with the peptide-binding region of the active site.

Preparation of thieno[3,2-h]cinnolinones as matrix metalloproteinase inhibitors / Ga, Pinna; Mm, Curzu; G., Murineddu; G., Chelucci; G., Cignarella; E., Menta; Hw, Krell; Rastelli, Giulio; Am, Ferrari. - In: ARCHIV DER PHARMAZIE. - ISSN 0365-6233. - STAMPA. - 333:(2000), pp. 37-47. [10.1002/(SICI)1521-4184(200002)333:2/3<37::AID-ARDP37>3.0.CO;2-V]

Preparation of thieno[3,2-h]cinnolinones as matrix metalloproteinase inhibitors

RASTELLI, Giulio;
2000

Abstract

A new series of thieno[3,2-h]cinnolinone analogues was synthesized which is structurally related to 2,3,4,4a,5,6-hexahydro thieno[3,2-h]cinnolin-3-one 1, a weak inhibitor of the matrix metalloproteinase MMP-8 (human neutrophil collagenase). Preliminary SAR studies have shown that while C-4a-methyl, C-7-acetylamino, C-7 and C-8-nitro substitution, and C-4-C-4a olefination provided no increase in activity relative to 1, Cs-acetylamino substitution as in 5 and 8 was favourable. Moreover, to predict how the thieno[3,3-h]cinnolinone inhibitors might bind to MMP-8, the unsubstituted compound 9 was docked into the MMP-8 crystal structure. These studies revealed that inhibitor 9 does not seem to be able to coordinate the catalytically-active zinc ion but preferably interact with the peptide-binding region of the active site.
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37
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Preparation of thieno[3,2-h]cinnolinones as matrix metalloproteinase inhibitors / Ga, Pinna; Mm, Curzu; G., Murineddu; G., Chelucci; G., Cignarella; E., Menta; Hw, Krell; Rastelli, Giulio; Am, Ferrari. - In: ARCHIV DER PHARMAZIE. - ISSN 0365-6233. - STAMPA. - 333:(2000), pp. 37-47. [10.1002/(SICI)1521-4184(200002)333:2/3<37::AID-ARDP37>3.0.CO;2-V]
Ga, Pinna; Mm, Curzu; G., Murineddu; G., Chelucci; G., Cignarella; E., Menta; Hw, Krell; Rastelli, Giulio; Am, Ferrari
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/306152
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