Re(I) and Tc(I) Complexes for Targeting Nitric Oxide Synthase: Influence of the Chelator in the Affinity for the Enzyme. (7th May 2015)

• Record Type: Journal Article
• Authors: Oliveira, Bruno L.; Morais, Maurício; Mendes, Filipa; Moreira, Irina S.; Cordeiro, Carlos; Fernandes, Pedro A.; Ramos, Maria J.; Alberto, Roger; Santos, Isabel; Correia, João D. G.
• Is Part Of: Chemical biology & drug design. Volume 86:Number 5(2015:Nov.)
• Page Start: 1072
• Page End: 1086
• Publication Date: 2015-05-07
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12575
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12575-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Aiming to design <sup>99m</sup>Tc complexes for probing nitric oxide synthase (NOS) by SPECT, we synthesized conjugates (<bold>L4</bold>–<bold>L6</bold>) comprising a NOS‐recognizing moiety connected to a diamino‐propionic acid (dap) chelating unit. The conjugates led to complexes of the type <italic>fac</italic>‐[M(CO)<sub>3</sub>(ĸ<sup>3</sup>‐L)] (M = Re/<sup>99m</sup>Tc; <bold>Re4</bold>/<bold>Tc4</bold>: L = <bold>L4</bold>;<bold> Re5</bold>/<bold>Tc5</bold>: L = <bold>L5</bold>;<bold> Re6</bold>/<bold>Tc6</bold>: L = <bold>L6</bold>). Enzymatic studies showed that <bold>L4</bold> and <bold>L5</bold>, but not <bold>L6</bold>, gave complexes (<bold>Re4</bold> and <bold>Re5</bold>) that are less potent than the conjugates. To rationalize these results, we performed docking and molecular dynamics simulations. The high affinity of <bold>L4</bold> and <bold>L5</bold> is due to the strong interactions between the dap chelator and polar residues of the binding cavity. These interactions are hampered by metallation resulting in complexes with lower affinity. The higher potency of <bold>Re5</bold> compared to <bold>Re4</bold> was assigned to the increased bulkiness of <bold>Re5</bold> and the presence of additional anchoring groups that better fit the active site and provide more extensive contacts. In turn, <bold>Re6</bold> is too bulky and its organometallic tail is oriented toward the peripheral pocket of iNOS, leading to loss of contacts and a lower affinity. These results were compared with our previous results obtained with analogue complexes stabilized by a pyrazolyl‐diamine chelating unit.</p> </abstract>