Carbocyclic nucleosides

Márquez, Víctor E.; Lim, Mu-Ill

doi:10.1002/med.2610060102

Cited by 318 publications

(88 citation statements)

References 125 publications

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“…However, furanose and cyclopentane rings are expected to have similar conformation, theoretically these analogues can be substrates or inhibitors of enzymes involved in the nucleoside metabolic pathways. Many carbocyclic nucleosides have been reported to have anti-tumour and antiviral activities (Marquez and Lim, 1986).…”

Section: Carbocyclicmentioning

confidence: 99%

Stability of Carbovir, a Potent Inhibitor of HIV, to Phosphorolysis by Human Purine Nucleoside Phosphorylase

Marr¹,

Penn²

1992

Antivir Chem Chemother

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SummaryCarbovir, a carbocyclic guanosine analogue, is a selective and potent inhibitor of HIV-1 in vitro. The (-)enantiomer of carbovir has been shown, by spectrophotometric and high pressure liquid chromatography (HPLC) analysis, to be stable to phosphorolytic cleavage by purified human erythrocytic purine nucleoside phosphorylase. Thus depurination, and the salvage reaction via hypoxanthine-guanine phosphoribosyl transferase, would be unlikely to be involved in the metabolism of carbovir.lnhibition of purine nucleoside phosphorylase interferes with T-lymphocytic function and would be an undesirable activity for any potential antiviral agent. The present study also showed that carbovir, at concentrations up to 300 /-LM, did not inhibit purine nucleoside phosphorylase.

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Section: Carbocyclicmentioning

confidence: 99%

Stability of Carbovir, a Potent Inhibitor of HIV, to Phosphorolysis by Human Purine Nucleoside Phosphorylase

Marr¹,

Penn²

1992

Antivir Chem Chemother

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“…Earlier studies showed that these analogs, which lack the labile glycosidic bond, are stable to cleavage by phosphorylases and hydrolases while retaining the potential for therapeutically useful interaction with other enzymes involved in nucleotide metabolism (16). The chemical and biological properties of carbocyclic nucleosides has recently been reviewed (17).…”

mentioning

confidence: 99%

Potent and selective activity of a new carbocyclic nucleoside analog (Carbovir: NSC 614846) against human immunodeficiency virus In vitro

Vince

Mei

Brownell

et al. 1988

Biochemical and Biophysical Research Communications

223

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“…Such superposition indicates that unless the presence of a hydroxyl group at the 2' position of the 8 anomer is essential (4) and the 04' position is strongly sensitive to the steric interference, some biological activity from the a anomer 2b cannot be ruled out. It should be noted that carbocyclic nucleosides like neplanocin A (22) show considerable antitumor activity. Also, change in orientation of the ligand molecules at the binding site during structural modification is not uncommon.…”

Section: Methodsmentioning

confidence: 99%

Structural mimicry of adenosine by the antitumor agents 4-methoxy- and 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine as viewed by a molecular modeling method.

Ghose¹,

Viswanadhan²,

Sanghvi³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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A rationale for the antitumor activity of 4-methoxy-and 4-amino-8-(I8-D-ribofuranosylamino)pyrimido-[5,4-dlpyrimidine (fJ-MRPP and 13-ARPP, respectively) was studied by a molecular modeling method. Although these nucleoside analogues are structurally different from adenosine, they act as substrates for adenosine kinase. The molecular modeling method, which considered the three-dimensional structure and atom-based physicochemical properties of the nucleosides to quantify the molecular similarities, showed that certain low-energy conformations of the fJ anomers of a series of nucleosides including f-MRPP, 13-ARPP, and their 4-hydroxy, 4-amino-6-chloro, 4-methylthio-2,6-dichloro, 4,6-diamino, 4-dimethylamino, 4-methylamino, and 4-hydroxy-2,6-dichloro analogues have remarkable structural similarity to adenosine. The method also suggested that the selection of the reference compound adenosine in the structural comparison is of primary importance to gain insight into the observed antitumor activity. The success of the present method led to AMI (Austin model 1) molecular orbital calculations and experimental studies indicating that the antitumor activity of the a anomer of ARPP is probably due to equilibration to the 8 anomer. The AMI calculation of the protonation energy of N5 of pyrimido[5,4-dlpyrimidines, which occupies the same position in space as the Ni of adenosine, gave a direct correlation between the basicity of the nitrogen with a lone pair of electrons and the observed antitumor activity.We recently studied several exocyclic aminoribonucleosides such as 4-methoxy-and 4-amino-8-(,3-D-ribofuranosylamino)-pyrimido [5,tively; compounds la and lb, Fig. 1) and showed these nucleosides to be substrates of mammalian adenosine kinase (1-3). This conclusion was based on the resistance of adenosine kinase-deficient cells to the cytotoxic effects of the nucleosides la-li, 2a, and 2b with associated reductions in both the formation of their cellular monophosphates and the competitive inhibition of adenosine phosphorylation by adenosine kinase. These nucleosides structurally resemble inactive homoadenosine and violate the required spatial relationship between the 2'-OH of the pentofuranosyl and the aglycon moiety as established by Bennett and Hill (4) for a substrate of adenosine kinase. f3-MRPP (la), 13-ARPP (lb), and 4-amino-8-(a-D-ribofuranosylamino)pyrimido[5,4-d]-pyrimidine (2b) showed promising antitumor activity against L1210, WI-L2, and LoVo/L cells in culture and also against L1210 in mice (2). This activity was shown to be due to the inhibition of 5-phosphoribosyl-1-pyrophosphate synthetase (ribose-5-phosphate pyrophosphokinase, EC 2.7.6.1) by the monophosphates of la and lb (3). These results led us to investigate the reason for substrate recognition by adenosine kinase, using a computer-aided receptor modeling method (5, 6, t). In this method the low-energy conformations and atom-based physicochemical properties are exhaustively compared to find the structural similarities between two or more molecule...

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Carbocyclic nucleosides

Cited by 318 publications

References 125 publications

Stability of Carbovir, a Potent Inhibitor of HIV, to Phosphorolysis by Human Purine Nucleoside Phosphorylase

Stability of Carbovir, a Potent Inhibitor of HIV, to Phosphorolysis by Human Purine Nucleoside Phosphorylase

Potent and selective activity of a new carbocyclic nucleoside analog (Carbovir: NSC 614846) against human immunodeficiency virus In vitro

Structural mimicry of adenosine by the antitumor agents 4-methoxy- and 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine as viewed by a molecular modeling method.

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