29836-02-0Relevant academic research and scientific papers
Synthesis and primary evaluation of novel HIV-1 inhibitors
Safadi, Yazan El,Marquet, Roland,Aubertin, Anne-Marie,Vivet-Boudou, Valerie
, p. 1161 - 1165 (2007)
The overcoming of antiviral drug resistance is an important challenge in the treatment of HIV-1 infection. According to the theory of viral error catastrophe, slightly increasing the mutation rate could exceed the error threshold for viability of a viral population and kill it. Investigation of this mechanism could lead to the discovery of new antiviral agents capable of bypassing viral resistance. To this aim, we designed several modified nucleosides. We describe here the synthesis and partial evaluation of 8-amido-2′-deoxyadenosine. The supplementary amide group on the base should allow base-pairing with several natural nucleosides, thus creating supplementary mutations that would kill the virus. Copyright Taylor & Francis Group, LLC.
Structure-activity relationships of bisphosphate nucleotide derivatives as P2Y1 receptor antagonists and partial agonists
Nandanan, Erathodiyil,Camaioni, Emidio,Jang, Soo-Yeon,Kim, Yong-Chul,Cristalli, Gloria,Herdewijn, Piet,Secrist III, John A.,Tiwari, Kamal N.,Mohanram, Arvind,Harden, T. Kendall,Boyer, José L.,Jacobson, Kenneth A.
, p. 1625 - 1638 (2007/10/03)
The P2Y1 receptor is present in the heart, in skeletal and various smooth muscles, and in platelets, where its activation is linked to aggregation. Adenosine 3',5'- and 2',5'-bisphosphates have been identified as selective antagonists at the P2Y1 receptor (Boyer et al. Mol. Pharmacol. 1996, 50, 1323-1329) and have been modified structurally to increase receptor affinity (Camaioni et al. J. Med. Chem. 1998, 41, 183-190). We have extended the structure-activity relationships to a new series of deoxyadenosine bisphosphates with substitutions in the adenine base, ribose moiety, and phosphate groups. The activity of each analogue at P2Y1 receptors was determined by measuring its capacity to stimulate phospholipase C in turkey erythrocyte membranes (agonist effect) and to inhibit phospholipase C stimulation elicited by 10 nM 2-(methylthio)adenosine 5'-diphosphate (antagonist effect). 2'-Deoxyadenosine bisphosphate analogues containing halo, amino, and thioether groups at the 2-position of the adenine ring were more potent P2Y1 receptor antagonists than analogues containing various heteroatom substitutions at the 8-position. An N6-methyl-2-chloro analogue, 6, was a full antagonist and displayed an IC50 of 206 nM. Similarly, N6- methyl-2-alkylthio derivatives 10, 14, and 15 were nearly full antagonists of IC50 50 of 3 μM, i.e., similar in potency to ATP. 5'-Phosphate groups have been modified in the form of triphosphate, methyl phosphate, and cyclic 3',5'-diphosphate derivatives. The carbocyclic analogue had enhanced agonist efficacy, and the 5'-O-phosphonylmethyl modification was tolerated, suggesting that deviations from the nucleotide structure may result in improved utility as pharmacological probes. The N6-methoxy modification eliminated receptor affinity. Pyrimidine nucleoside 3',5'- bisphosphate derivatives were inactive as agonists or antagonists at P2Y receptor subtypes.
Hydrolysis of 2'-Deoxypurine Nucleosides. The Effect of Substitution at the C-8 Position.
Laayoun, Ali,Decout, Jean-Luc,Lhomme, Jean
, p. 4989 - 4990 (2007/10/02)
The hydrolytic stability of 2'-deoxypurine nucleosides is decreased by introduction of electronwithdrawing substituents at the C-8 position in the series of compounds 2-8, 10-14.The sulfone group causes a 2.9 x 104 rate acceleration for glycosidic, bond cleavage in compound 14.
