Structures of two dideoxynucleosides: 2',3'-dideoxyadenosine and 2',3'-dideoxycytidine

Silverton, J. V.; Quinn, F. R.; Haugwitz, R. D.; Todaro, Louis J.

doi:10.1107/s0108270187009910

Cited by 17 publications

(16 citation statements)

References 3 publications

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“…The two crystallographically independent molecules are very similar to each other. Bond lengths and angles for MMdCyd molecules are similar to those reported for 5-methoxymethyl-2'-deoxyuridine (MMdUrd) and are in the range reported for 2'-deoxycytidine nucleosides (15,(20)(21)(22)(23)(24)(25). Selected torsion angles for molecules A and B of MMdCyd compared to the corresponding angles in MMdUrd are shown in Table 3.…”

Section: X-ray Analysissupporting

confidence: 60%

Structure and conformation of 5-methoxymethyl-2′-deoxycytidine

Jia¹,

Tourigny²,

Delbaere³

et al. 1990

Can. J. Chem.

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Can. J. Chem. 68,836 (1990).The three-dimensional structure of the antiviral agent 5-methoxymethyl-2'-deoxycytidine (MMdCyd) was deduced by X-ray crystallographic analysis. MMdCyd crystallized in space group P2, with a = 7.9255(6) A; b = 16.1505(15) A, c = 10.1861 (5) A, P = 103.801(5)", and Z = 4 (2 molecules per asymmetric unit); R = 0.044 (R, = 0.046) for 2560 observed reflections with net I > 3u(I). The furanose ring adopts the C(3')-exo envelope conformation (3E) in molecule A and the C(2')-endo envelope conformation ( 2~) in molecule B. In the sugar ring of both crystallographically independent molecules A and B, the side chain at C(5') has the gi conformation. This appears to be a preferred geometry required for antiherpes activity in 2'-deoxyribonucleosides.The glycosyl linkage is anti with x = 213.7' for the A molecule and 222.2" for the B molecule. With respect to this anti conformation, the methoxy group at C(5) in molecules A and B exhibits different conformations; it is on the same side of the pyrimidine plane as the deoxyribofuranose ring oxygen (04') in molecule B and on the opposite side in molecule A.Key words: antiherpes agent, conformation, 5-methoxymethyl-2'-deoxycytidine, crystal structure. IntroductionThe discovery of 5-substituted-2'-deoxyuridines with selective activity against Herpes simplex virus was a major development in the area of viral chemotherapy (for reviews see refs. 1-3). The basis for selective antiherpes activity of 5-alkyl-2'-deoxyuridines is primarily due to the specific interaction with two virus-induced enzymes, the deoxythymidine-deoxycytidine (dThd/dCyd) kinase (viral-K) and the DNA polymerase. Cleavage of the N-glycosidic bond of many of these 5-substituted-2'-deoxyuridines by nucleoside phosphorylases rapidly leads to loss of biological activity (4-6). Thymidine phosphorylase (EC 2.4.2.4) is specific for the 2'-deoxyribosyl moiety of the nucleosides whereas uridine phosphorylase (EC 2.4.2.3) has broader substrate specificity (7-10). One possible approach to overcome this limitation is to use deoxycytidine analogs. The rationale for this hypothesis is (i) dCyd analogs are not substrates for thymidine and (or) uridine phosphorylase and (ii) in HSV-infected cells, dCyd analogs will be metabolized primarily by the virus-induced dCyd kinase -deoxycytidylate kinase pathway. Our findings on the biological activity of (E)-5-

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Section: X-ray Analysissupporting

confidence: 60%

Structure and conformation of 5-methoxymethyl-2′-deoxycytidine

Jia¹,

Tourigny²,

Delbaere³

et al. 1990

Can. J. Chem.

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“…2. Horner-Emmons reaction of 242 and 244 gave the corresponding dienone, which was transformed into the epimeric seco-acids 245. 3.2 Total Synthesis of Mycinolide v: [Hoffmann, 1986] (Scheme 20) [38] The Hoffmann mycinolide synthesis is based on the coupling of the Cl-C lO (227) and C l l -Cl5 (232) The allyl alcohol 236 was derived from meso-2,4-dimethylglutaric anhydride 235.…”

Section: The First Total Synthesis Of Mycinamicins IV and Viimentioning

confidence: 99%

Recent Progress in the Chemical Synthesis of Antibiotics

1990

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“…deoxythymidine (AZT) (Gurskaya, Tsapkina, Skaptsova, Kraevskil, Lindeman & Struchkov, 1986;Camerman, Mastropaolo & Camerman, 1987;Birnbaum, Giziewicz, Gabe, Lin & Prusoff, 1987;Dyer, Low, Tollin, Wilson & Howie, 1988) there are two crystallographically independent molecules of the nucleoside, one with the trans and one with the gauche + conformation, whereas in crystals of 2',3'-dideoxycytidine (DDC) (Birnbaum, Lin & Prusoff, 1988;Silverton, Quinn, Haugwitz & Todara, 1988) only the trans rotamer is observed. As in AZT, FIAC and other comparable nucleosides (Bimbaum, Blonski & Hruska, 1983;Birnbaum, Sadana, Blonski & Hruska, 1986) the gauche rotamer in the title compound is stabilized by an intramolecular C(6)--H(6)...O(5") hydrogen bond (Taylor & Kennard, 1982).…”

Section: (3) C(7)--c(8)---c(13) 1239 (3) C(9)--c(8)--c(i 3)mentioning

confidence: 99%