106060-89-3Relevant articles and documents
Potential lipophilic nucleotide prodrugs: Synthesis, hydrolysis, and antiretroviral activity of AZT and d4T acyl nucleotides
Bonnaffe, David,Dupraz, Bernadette,Ughetto-Monfrin, Joel,Namane, Abdelkader,Henin, Yvette,Dinh, Tam Huynh
, p. 895 - 902 (1996)
Three general methods for the synthesis of acyl nucleotides (mono-, di-, and triphosphates) have been developed and applied to different HIV inhibitors. These new types of compounds, where a fatty acid moiety is linked to the nucleotide phosphate chain by an acyl phosphate bond, were designed as lipophilic prodrugs of HIV inhibitors metabolites. Acyl nucleoside monophosphates 1a,b were prepared by acylation of the corresponding nucleoside monophosphates. Acyl nucleoside diphosphates 2a-c and 3a,b were synthesized directly from the free nucleosides using DCC activation of acyl pyrophosphates. Acyl nucleoside triphosphates 4a-c and 5a were obtained using phosphoromorpholidate chemistry and acyl pyrophosphates as nucleophiles. Hydrolysis of acyl nucleotides liberated the corresponding nucleotides by selective cleavage of the acyl phosphate bond, with half lives ranging from 51 to 185 h at 37°C in triethylammonium acetate buffer pH 7.0. Their antiretroviral activity, measured by the inhibition of cytopathogenicity and reverse transcriptase activity in the cultures supernatants, did not reveal any differences between an acyl nucleotide and its corresponding nucleotide. These results are explained in term of rapid aminolysis of the acyl phosphate bond in culture media.
Highly selective recognition of thymidine mono- and diphosphate nucleotides in aqueous solution by ditopic receptors zinc(II)-bis(cyclen) complexes (cyclen = 1,4,7,10-tetraazacyclododecane)
Aoki, Shin,Kimura, Eiichi
, p. 4542 - 4548 (2000)
Highly selective and efficient recognition of thymidine and uridine nucleotides such as 3'-dTMP (thymidine 3'-monophosphate), 5'-dTMP (thymidine 5'-monophosphate), 2'-UMP (uridine 2'-monophosphate), 3'-UMP (uridine 3'- monophosphate), 5'-UMP (uridine 5'-monophosphate), 5'-dTDP (thymidine 5'- diphosphate), 5'-dTTP (thymidine 5'-triphosphate), AZTMP (3'-azido-3'- deoxythymidine 5'-monophosphate), and AZTDP (3'-azido-3'-deoxythymidine 5'- diphosphate) with ditopic dimeric zinc(II) complexes of macrocyclic 12- membered tetramines, meta- and para-xylyl-bis(Zn2+-cyclen)s (Zn2L4 and Zn2L5) (cyclen = 1,4,7,10-tetraazacyclododecane) has been studied by potentiometric pH titration, isothermal titration calorimetry, UV spectrophotometric titration, and NMR titration. The apparent 1:1 complexation constants for 5'-dTMP, K(app) (= [(Zn2L)-(S--OPO32- )]/[Zn2L](free)[S-OPO32-](free) (M-1)), where S- denotes the imide- deprotonated thymine part), with Zn2L4 or Zn2L5 determined by potentiometric pH titration showed a more stable complex with Zn2L5 (log K(app) = 6.4) than with Zn2L4 (log K(app) = 5.5) at pH 7.6 with I = 0.1 (NaNO3) and 25 °C. These values are much greater than log K(app) (K(app) = [ZnL3-dT-]/[ZnL3](free)[dT](free) (M-1)) of 3.2 for a nucleoside thymidine (dT) complex with a monomeric Zn2+-benzylcyclen (ZnL3). The 1:1 complexation was confirmed by the FAB mass spectroscopic data for Zn2L with 3'- and 5'-dTMP. The combined data from the spectrophotometric UV titration and 1H NMR measurements of 5'-dTMP and 5'-dTDP with Zn2L5 in D2O at pD 7.8 and 35 °C indicated that the terminal phosphate dianion interacted with one of the (Zn2+-cyclen)s and the imide anion of dT bound to the other Zn2+-cyclen.
