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

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 21; pp. 3085 - 3088
• Main Authors: Levy, Daniel E, Marlowe, Charles, Kane-Maguire, Kim, Bao, Ming, Cherbavaz, Diana B, Tomlinson, James E, Sedlock, David M, Scarborough, Robert M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 04-11-2002; Elsevier
• Subjects: Adenylyl Cyclase Inhibitors; Analytical, structural and metabolic biochemistry; Binding Sites; Biological and medical sciences; Cell Line; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrogen Bonding; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - pharmacology; Indicators and Reagents; Isoenzymes - antagonists & inhibitors; Kidney - drug effects; Kidney - enzymology; Lyases; Magnesium - chemistry; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Protein Conformation; Receptors, Purinergic - drug effects; Structure-Activity Relationship; Adenine derivatives; Purine derivatives; Enzyme; Phosphorus-oxygen lyases; Hydroxamic acid; Enzyme inhibitor; Lyases; Binding site; Alkaline earth metal Complexes; In vitro; Adenylate cyclase; Signal transduction; α-Aminoacid; Structure activity relation; Magnesium Complexes; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00653-4

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.