Design and Biological Evaluation of Manganese- and Ruthenium-Based Hybrid CO-RMs (HYCOs).
Interest in the therapeutic effects of carbon monoxide (CO), a product of heme degradation catalyzed by the enzyme heme oxygenase-1 (HO-1), has led to the development of CO-releasing molecules (CO-RMs) for the controlled delivery of this gas in vivo. We recently proposed conjugating a cobalt-based CO-RM with various activators of nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor that regulates HO-1 expression, in order to exploit the beneficial effects of exogenous and endogenous CO. In this study, we describe the preparation of hybrid molecules (termed HYCOs) conjugating a fumaric acid derivative as an Nrf2 activator to a Mn- or a Ru-based CO-RM known to be pharmacologically active. With the exception of an acyl-manganese complex, these hybrids were obtained by associating the two bioactive entities by means of a linker of variable structure. X-ray diffraction analyses and preliminary biological investigations are also presented.
['Ollivier|Anthony|A|', 'Foresti|Roberta|R|0000-0002-0836-7937', 'El Ali|Zeina|Z|', 'Martens|Thierry|T|0000-0002-4156-0122', 'Kitagishi|Hiroaki|H|0000-0003-4682-7217', 'Motterlini|Roberto|R|0000-0003-2684-2612', 'Rivard|Michael|M|0000-0002-5487-1595']
D000818:Animals D002248:Carbon Monoxide D002460:Cell Line D018360:Crystallography, X-Ray D004305:Dose-Response Relationship, Drug D015195:Drug Design D005650:Fumarates D008345:Manganese D051379:Mice D008958:Models, Molecular D015394:Molecular Structure D051267:NF-E2-Related Factor 2 D009942:Organometallic Compounds D012428:Ruthenium D013329:Structure-Activity Relationship
biological activity drug design manganese medicinal chemistry ruthenium