The Structure of Aristeromycin

Bisubstrate Inhibitors of Catechol O‐Methyltransferase (COMT): the Crucial Role of the Ribose Structural Unit for Inhibitor Binding Affinity

“…Thus, NMR investigations convincingly demonstrate that in analogy to adenosine, the solution conformations of aristeromycin can be described in terms of the twostate N/S equilibrium of the pseudorotational phase cycle in which the S-type conformation is adopted preferentially (P = 1308-1358), [40] roughly matching the conformation required by computer modeling for the binding of 13-20 to the active site of COMT (P = 1378-1998). In contrast, crystalline aristeromycin adopts an East-type conformation ( 1a E) (P = 89.28), [41] which suggests that the energy barrier of interconversion between Nand S-type conformers is easily reached at room temperature and can be overcome by crystal packing forces. Furthermore, the carbocyclic SAH analogue SAmH ("m" denotes the carbocyclic modification) was reported to possess inhibitory activity toward COMT similar to the parent natural counterpart (K i = 168 AE 39 mm and 36.3 AE 2.2 mm, for SAmH and SAH, respectively).…”

Carbocyclic nucleosides

“…The stable ( * )-2-azabicyclo[2.2.1]hept-S-ene-3-one (5) prepared earlier by Jagt and Van LeusenZ6 was used in several instances by Vince and Daluge since 1976 to prepare various carbocyclic nucleosides and aminonucleosides.2730 However, it was only in 1981 that they reported the direct osmylation of 5 which gave stereoselectively compound 14 after methanolysis of the lactam ringz3 When osmylation was performed earlier on the ring-opened hydrolyzed product of 5, regioselectivity was lost and a mixture of isomers was produced.30 From 14, acetylation, reduction, and reacetylation, gave the tetraacetate 15 from which racemic C-rib-NH2 (6) independently reported a nearly identical procedure which employed KMnO, as an efficient cis-hydroxylating reagent. 24 In a slmilar fashion as performed for the enantioselective synthesis of C-and N-nucleosides, which started with a non-carbohydrate moiety?'…”

Cyclic aristeromycin diphosphate ribose: A potent and poorly hydrolysable Ca2+‐mobilising mimic of cyclic adenosine diphosphate ribose

“…The product was purified by ion-exchange chromatography (40% yield) and quantified using UV analysis assuming the extinction coefficient to be the same as that of cADPR. This assumption was made based on the knowledge that the extinction coefficient of aristeromycin is the same as for adenosine [19]. The UV data for the final product was 2ma x = 260 nm with e = 14.3 x 103M -t. Full synthetic details will be reported elsewhere.…”