16975-94-3Relevant articles and documents
Conformationally restricted nucleosides. The reaction of adenosine deaminase with substrates built on a bicyclo[3.1.0]hexane template
Marquez, Victor E.,Russ, Pamela,Alonso, Randolph,Siddiqui, Maqbool A.,Shin, Kye-Jung,George, Clifford,Nicklaus, Marc C.,Dai, Fang,Ford Jr., Harry
, p. 521 - 530 (1999)
Adenosine deaminase (ADA) can discriminate between two distinct (North and South), conformationally rigid substrate conformers. (N)-methanocarba- 2'dA (4) is deaminated 100 times faster than the antipodal (S)-methanocarba- 2'dA (5), whereas a nonrigid analogue, aristeromycin (6), is deaminated at an intermediate rate. These results are in agreement with crystallographic data from ADA-ribonucleoside complexes showing the furanose ring of the bound purine in a C3'-endo (North) conformation. The data presented here suggests that 4 and 5 are useful probes to ascertain conformational preferences by purine metabolizing enzymes.
Synthesis of conformationally restricted carbocyclic nucleosides: The role of the O(4')-atom in the key hydration step of adenosine deaminase
Marquez, Victor E.,Russ, Pamela,Alonso, Randolph,Siddiqui, Maqbool A.,Hernandez, Susana,George, Clifford,Nicklaus, Marc C.,Dai, Fang,Ford Jr., Harry
, p. 2119 - 2129 (2007/10/03)
Conformationally restricted carbocyclic nucleosides with either a northern(N)-type conformation, i.e., N-type 2'-deoxy-methanocarba-adenosine 8 ((N)MCdAdo) or a southern(S)-type conformation, i.e. S-type 2'-deoxy- methanocarba-adenosine 9, ((S)MCdAdo), were used as substrates for adenosine deaminase (ADA) to assess the enzyme's preference for a fixed conformation relative to the flexible conformation represented by the carbocyclic nucleoside aristeromycin (10). Further comparison between the rates of deamination of these compounds with those of the two natural substrates adenosine (Ado: 1) and 2'-deoxyadenosine (dAdo; 2), as well as with that of the conformationally locked nucleoside LNA-Ado (11), which, like the natural substrates, has a furanose O(4') atom, helped differentiate between the roles of the O(4') anomeric effect and sugar conformation in controlling the rates of deamination by ADA. Differences in rates of deamination as large as 10000 can be attributed to the combined effect of the Q(4') atom and the enzyme's preference for an N-type conformation. The hypothesis proposed is that ADA's preference for N-type substrates is not arbitrary; it is rather the direct consequence of the conformationally dependent O(4') anomeric effect, which is more efficient in N-type conformers in promoting the formation of a covalent hydrate at the active site of the enzyme. The formation of a covalent hydrate at the active site of ADA precedes deamination. A new and efficient synthesis of the important carbobicyclic template 14a, a useful intermediate for the synthesis of (N)MCdAdo (8) and other conformationally restricted nucleosides is also reported.
Resolution of racemic carbocyclic analogues of purine nucleosides through the action of adenosine deaminase. Antiviral activity of the carbocyclic 2'-deoxyguanosine enantiomers
Secrist III.,Montgomery,Shealy,O'Dell,Clayton
, p. 746 - 749 (2007/10/02)
The action of adenosine deaminase on racemic carbocyclic analogues of 6-aminopurine nucleosides was investigated. When either racemic carbocyclic adenosine [(±)-C-Ado] or the racemic carbocyclic analogue [(±)-C-2,6-DAP-2'-dR] of 2,6-diaminopurine 2'-deoxyribofuranoside was incubated with this enzyme, approximately half of the material was deaminated rapidly. From the resulting solution, the D isomers of the deaminated carbocyclic analogues (D-carbocyclic inosine, D-C-Ino, or D-carbocyclic 2'-deoxyguanosine, D-2'-CDG) and the L isomers of the undeaminated carbocyclic analogues were isolated. At higher concentrations of the enzyme, deamination of (L)-C-Ado and (L)-C-2,6-DAP-2'dR proceeded slowly, thus also making the other enantiomers accessible. In tests in vitro against herpes simplex virus, types 1 and 2, D-2'-CDG was as active and potent as (±)-2'-CDG, whereas L-2'-CDG displayed only modest activity. In contrast to the previously reported high activity and potency of (±)-C-2,6-DAP-2'-dR against these two viruses, (L)-C-2,6-DAP-2'-dR was inactive.
