Highly stacked dinucleoside monophosphate derived from adenine 8-cyclonucleosides

Ikehara, Morio; Uesugi, Seiichi; Yasumoto, M.

doi:10.1021/ja00718a046

Cited by 26 publications

(14 citation statements)

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“…Ikehara et al once reported that by activating the 5′-OH group with sodium hydride in dioxane, the resulting nucleophilic -O − species would attack the electron-deficient carbon at position 8 of 8-bromo-2′, 3′-O-isopropyllideneadenosine to give 5′-O, 8-cyclo-2′, 3′-Oisoprpylideneadenosine. 22 However, when we tried to follow this method to prepare compound 12 (see Scheme 1), we found we could not obtain compound 11 by bromination of compound 10 (which was prepared from compound 4) using bromine in the mixture of dioxane and 10% Na 2 HPO 4 (1:1) or bromine water in NaOAc buffer as reported in the literature for the synthesis of 8-bromo-2′, 3′-O-isopropylideneadenosine. 23,24,25 Instead, the product was identified to be compound 13 when bromine in dioxane/Na 2 HPO 4 (1:1) was used.…”

Section: Chemistrymentioning

confidence: 99%

Constrained NBMPR analogue synthesis, pharmacophore mapping and 3D-QSAR modeling of equilibrative nucleoside transporter 1 (ENT1) inhibitory activity

Zhu

Buolamwini

2008

Bioorganic & Medicinal Chemistry

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Conformationally constrained analogue synthesis was undertaken to aid in pharmacophore mapping and 3D QSAR analysis of nitrobenzylmercaptopurine riboside (NBMPR) congeners as equilibriative nucleoside transporter 1 (ENT1) inhibitors. In our previous study (Zhu et al., J. Med. Chem. 46, 831-837, 2003), novel regioisomeric nitro-1, 2, 3, 4-tetrahydroisoquinoline conformationally constrained analogues of NBMPR were synthesized and evaluated as ENT1 ligands. 7-NO 2 -1, 2, 3, 4-tetrahydroisoquino-2-yl purine riboside was identified as the analogue with the nitro group in the best orientation at the NBMPR binding site of ENT1. In the present study, further conformational constraining was introduced by synthesizing 5′-O, 8-cyclo derivatives. The flow cytometrically determined binding affinities indicated that the additional 5′-O, 8-cyclo constraining was unfavorable for binding to the ENT1 transporter. The structure-activity relationship (SAR) acquired was applied to pharmacophore mapping using the PHASE program. The best pharmacophore hypothesis obtained embodied an anti-conformation with three H-bond acceptors, one hydrophobic center, and two aromatic rings involving the 3′-OH, 4′-oxygen, the NO 2 group, the benzyl phenyl and the imidazole and pyrimidine portions of the purine ring, respectively. A PHASE 3D-QSAR model derived with this pharmacophore yielded an r 2 of 0.916 for four (4) PLS components, and an excellent external test set predictive r 2 of 0.78 for 39 compounds. This pharmacophore was used for molecular alignment in a comparative molecular field analysis (CoMFA) 3D-QSAR study that also afforded a predictive model with external test set validation predictive r 2 of 0.73. Thus, although limited, this study suggests that the bioactive conformation for NBMPR at the ENT1 transporter could be anti. The study has also suggested an ENT1 inhibitory pharmacophore, and established a predictive CoMFA 3D-QSAR model that might be useful for novel ENT1 inhibitor discovery and optimization.

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Section: Chemistrymentioning

confidence: 99%

Constrained NBMPR analogue synthesis, pharmacophore mapping and 3D-QSAR modeling of equilibrative nucleoside transporter 1 (ENT1) inhibitory activity

Zhu

Buolamwini

2008

Bioorganic & Medicinal Chemistry

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“…Some fifteen years ago, we found that a dinucleoside monophosphate of 8,2'-S-cycloadenosine (A"), NpN, takes a stable stacking conformation with a left-handed screw axis (5,6). Since then we have been working on the left-handed structure with high anti glycosidic conformation.…”

Section: Introductionmentioning

confidence: 99%

Hybrid Oligomer of Cyclonucleotides and Deoxynucleotides. A High Anti Left-handed Double Helical DNA Structure

Uesugi¹,

Lee²,

Ikehara³

et al. 1985

Journal of Biomolecular Structure and Dynamics

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It has been shown by us that oligonucleotides containing cyclonucleosides with a high anti glycosidic conformation take left-handed, single and double helical structures (S. Uesugi, J. Yano, E. Yano and M. Ikehara, J. Am. Chem. Soc. 99,2313 (1977) and references therein). In order to see whether DNA can adopt the high anti left-handed double helical structure or not, a self-complementary hexanucleotide containing 6,2'-O-cyclocytidine (C 0). 8,2'-O-cycloguanosine (G 0), deoxycytidine and deoxyguanosine, C 0 G 0 dCdGC 0 G 0, was synthesized. Corresponding hexanucleotide containing only cyclonucleosides, C 0 G 0 C 0 G 0 C 0 G 0, was also synthesized. Their conformation was examined by UV, CD and 1H NMR spectroscopy. C 0 G 0 C 0 G 0 C 0 G 0 forms an unusually stable, left-handed duplex. Imino proton NMR spectra and the results of nuclear Overhauser effect experiments strongly suggest that C 0 G 0 dCdGC0 G 0 take a left-handed double helical structure where the deoxynucleoside residues are involved in hydrogen bonding and take a high anti glycosidic conformation. Thus it is revealed that DNA could form a high anti, left-handed double helix which is different from that of Z-DNA under some constrained conditions.

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“…By slow evaporation of an acidic solution of A~pA ~ which was synthesized by the method described previously (Ikehara, Uesugi & Yasumoto, 1970), transparent prismatic crystals were obtained at 283 K. The space group and preliminary cell dimensions were determined by precession and Weissenberg photographs and then the cell dimensions were refined by the least-squares procedure using the (9 values of 32 reflections (29 ° < 2(9 < 38°; Mo Ka radiation) measured by a diffractometer.…”

Section: Methodsmentioning

confidence: 99%

The structure of a dinucleoside monophosphate having a high-anti conformation: 8,2'-S-cyclo-2'-thioadenylyl(3'-5')-8,2'-S-cyclo-2'-thioadenosine (AspAs) hydrochloride

Fujii¹,

Hamada²,

Miura³

et al. 1982

Acta Crystallogr Sect B

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Highly stacked dinucleoside monophosphate derived from adenine 8-cyclonucleosides

Cited by 26 publications

References 0 publications

Constrained NBMPR analogue synthesis, pharmacophore mapping and 3D-QSAR modeling of equilibrative nucleoside transporter 1 (ENT1) inhibitory activity

Constrained NBMPR analogue synthesis, pharmacophore mapping and 3D-QSAR modeling of equilibrative nucleoside transporter 1 (ENT1) inhibitory activity

Hybrid Oligomer of Cyclonucleotides and Deoxynucleotides. A High Anti Left-handed Double Helical DNA Structure

The structure of a dinucleoside monophosphate having a high-anti conformation: 8,2'-S-cyclo-2'-thioadenylyl(3'-5')-8,2'-S-cyclo-2'-thioadenosine (AspAs) hydrochloride

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