Adenosine derivatives

Roelen H, Veldman N, Spek AL, von Frijtag Drabbe Kiinzel JK, Mathot RAA, Ijzerman AP. /V6,C8-disubstitutcd adenosine derivatives as partial agonist for adenosine A receptors. J Med Chem 1996 39 1463-1471. 

Lorenzen A, Sebastiao AM, Sellink A, Vogt H, Schwabe U, Ribeiro JA, Ijzerman AP. Biological activities of /V6,C8-disubstitutcd adenosine derivatives as partial agonist at rat brain adenosine A, receptors. Eur J Pharmacol 1997 334 299-307. 

Figure 25. Shapes of five alkylated derivatives of adenosine and deoxyadenosine. (a) Adenosine derivative of DMBA (XXXII). (b) Deoxyadenosine derivative of DMBA (XXXIV). No hydrogen atom positions for this diagram, (c) Adenosine derivative of dimethyl anthracene (XXXI). Note the different conformation.

Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH]... 

Based on the experience mentioned previously, the Dimroth rearrangement was succesfully applied for the preparation of water-soluble macro-molecular adenosine derivatives of the redox enzymes 72 (NAD(H), NADP(H), and FAD) (Scheme IV.31) (86MI1 87MI3, 87MI2 88H1623 89MI1 90M11). 

As an alternative approach an adenosine-derived mustard was developed as a PRMT inhibitor by a strategy that was based on the mechanism of the enzyme. This compound is an alkylating agent which is covalently attached to a peptide substrate only upon incubation with PRMTl [80]. It is not very druglike and is more of a chemical tool. 

Julius Rebek and his group were also active at about the same time with enzyme-free self-replication of chemical structures. Unhke von Kiedrowski group, he did not use nucleotides, but a rephcator consisting of an adenosine derivative and a derivative of Kemp s acid (Rotello etal., 1991 Rebek, 1994). See also Figure 7.7 for a self-replicating system not based on nucleic-acid chemistry. There are several variations of this scheme, which are not illustrated here - for reviews see Sievers etal, 1994 Orgel, 1995. 

The enzyme catalyzes the deamination of a wide spectrum of naturally occurring adenosine derivatives including, in addition to the majority of compounds noted in Table VII, many other phosphorylated derivatives (75, 179). The Km values for adenosine, 5 -AMP, 3 -AMP, 3, 5 -cyclic AMP, and 2 -dAMP ranged from 0.1 to 0.5 mM. Except for 2 -dAMP, the relative rates of deamination for these compounds were similar. The 2 -monophosphate ester was not deaminated (75, 180). Oligomers of AMP such as ApA, ApAp, ApApA, and ApApApA (181) were also substrates deamination of the first residue of ApAp was more rapid than the second. Deamination of polyadenylic, polydeoxyadenylic, and the terminal residue of E. coli soluble RNA was not observed. 

Gao Z-G, Kim S-K, Biadatti T, Chen W, Lee K, Barak D, Kim S-G, Johnson CR, Jacobson KA (2002) Structural determinants of A3 adenosine receptor activation nucleoside ligands at the agonist/antagonist boundary. J Med Chem 445 4471-4484 Gao Z-G, Blaustein JB, Gross AS, Melman N, Jacobson KA (2003) M -Substituted adenosine derivatives selectivity, efficacy, and species differences at A3 adenosine receptors. Biochem Pharmacol 65 1675-1684... 

Recently, new potent and A3 selective M ,2-disubstitutcd adenosine derivatives have been reported. Volpini et al. (2007) made a series of V6-mcthoxy-2-alkyladcnosinc derivatives, of which 44b was the most potent and selective. This compound had a K. of 2.5 nM at the hA3AR and selectivity of 21,000 and 4,200 against A( and A2AARs respectively. 

Fig. 6.7 Conversion of adenosine derivatives into selective antagonists of the A3AR...

Cosyn L, Gao ZG, Van Rompaey P, Lu C, Jacobson KA, Van Calenbergh S (2006a) Synthesis of hypermodified adenosine derivatives as selective adenosine A3 receptor ligands. Bioorg Med Chem 14(5) 1403-1412... 

Elzein E, Palle V, Wu Y, Maa T, Zeng D, Zablocki J (2004) 2-Pyrazolyl-V6-substituted adenosine derivatives as high affinity and selective adenosine A3 receptor agonists. J Med Chem 47(19) 4766-4773... 

Gao ZG, Mamedova L, Chen P, Jacobson KA (2004) 2-Substituted adenosine derivatives affinity and efficacy at four subtypes of human adenosine receptors. Biochem Pharmacol 68(10) 1985-1993... 

Exploring distal regions of the A3 adenosine receptor binding site sterically-con-strained iV< -(2-phenylethyl)adenosine derivatives as potent ligands. Bioorg Med Chem 12(9) 2021-2034... 

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