Hydroxamate based inhibitors of adenylyl cyclase. Part 1: The effect of acyclic linkers on P-site binding

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Abstract

The adenylyl cyclases (ACs) are a family of enzymes that are key elements of signal transduction by virtue of their ability to convert ATP to cAMP. The catalytic mechanism of this transformation proceeds through initial binding of ATP to the purine binding site (P-site) followed by metal mediated cyclization with loss of pyrophosphate. Crystallographic analysis of ACs with known inhibitors reveals the presence of two metals in the active site. Presently, nine isoforms of adenylyl cyclase are known and unique isoform combinations are expressed in a tissue specific manner. The development of isoform specific inhibitors of adenylyl cyclase may prove to be a useful strategy toward the design of novel therapeutic agents. In order to develop novel AC inhibitors, we have chosen a design approach utilizing molecules with the adenine ring system joined to a metal-coordinating hydroxamic acid via flexible acyclic linkers. The designed inhibitors were assayed against type V AC with the size and heteroatom content of the linkers varied to probe the interaction of the nucleotide and metal binding sites within the enzyme.

The synthesis of potent acyclic adenylyl cyclase antagonists is reported.

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    Two other FSK-derivatives, 7-deacetyl-7-hydroxaminoFSK and 5,6-dehydroxy-7-deacetyl-7-nicotinoylFSK (FD3 and FD4, respectively, Fig. 4), are selective activators for AC3 with respect to AC2 and AC5 [82], and could be tested in dopaminergic neuronal migration. Among the P-site inhibitors with metal chelating properties (PMC), the derivative 1R,4R-3-(6-aminopurin-9-yl)-cyclopentane-carboxylic acid hydroxamide (PMC-6, Fig. 4) has been identified as a potent AC5 inhibitor that is selective with respect to AC2 and AC3 [88–90]. Moreover, the 2′(3′)-O-(N-methylanthraniloyl) (MANT) nucleotides, such as MANT-guanosine 5′-[γ-thio]triphosphate (MANT-GTPγS) and MANT-inosine 5′-[γ-thio]triphosphate (MANT-ITPγS, Fig. 4) have also been found to be potent AC inhibitors [91], showing weak AC5 selectivity with respect to AC2, but not with respect to AC1 and AC6 [92].

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