One-step, nonenzymatic synthesis of O-acetyl-ADP-ribose and analogues from NAD and carboxylates

O-Acetyl-ADP-ribose (OAADPR) is a metabolite produced from nicotinamide adenine dinucleotide (NAD) as a product of sirtuin-mediated protein deacetylation. We present here a simple, one-step, nonenzymatic synthesis of OAADPR from NAD and sodium acetate in acetic acid. We extended the reaction to other carboxylic acids, demonstrating that the reaction between NAD and nonaqueous carboxylate buffers produces mixtures of the corresponding 2'- and 3'-carboxylic esters.     

Synthesis of Carba-NAD and the Structures of Its Ternary Complexes with SIRT3 and SIRT5

Carba-NAD is a synthetic compound identical to NAD except for one substitution, where an oxygen atom adjacent to the anomeric linkage bearing nicotinamide is replaced with a methylene group. Because it is inert in nicotinamide displacement reactions, carba-NAD is an unreactive substrate analogue for NAD-consuming enzymes. SIRT3 and SIRT5 are NAD-consuming enzymes that are potential therapeutic targets for the treatment of metabolic diseases and cancers. We report an improved carba-NAD synthesis, including a pyrophosphate coupling method that proceeds in approximately 60% yield. We also disclose the X-ray crystal structures of the ternary complexes of SIRT3 and SIRT5 bound to a peptide substrate and carba-NAD. These X-ray crystal structures provide critical snapshots of the mechanism by which human sirtuins function as protein deacylation catalysts.     

Schmidt reaction of 4-substituted adamantanones

The Schmidt reaction of various 4^a - and 4^e -substituted adamantanones has been investigated. It is shown that the direction of the nitrogen insertion is not dominated by inductive substituent influences. The main reaction pathway involves the diazoiminium ion 3 and the intermediates 4 and 5 which prefer different reactions: 4 undergoes mainly fragmentation (8 and 9) whereas 5 gives mainly water addition products (7). The recyclisation of 8 and 9 is highly regloselective. The structure determinations of the products are based on their ¹H and ¹³C NMR data.