[X-ray structural study of 3'-O-methylthiomethylthymidine and 3'-O-methylsulfinylmethylthymidine--potential inhibitors of HIV]. / Rentgenostrukturnoe issledovanie 3'-O-metiltiometiltimidina i 3'-O-metilsul'finilmetiltimidina--potentsial'nykh ingibitorov VICh.

The molecular and crystalline structures of deoxiribonucleoside analogs: 3'-O-methylthiomethylthymidine monohydrate dT(CH2SMe).H2O and 3'-O-methylsulphinylmethylthymidine dT(CH2SOMe) were determined. The space group of dT(CH2SMe).H2O crystals is P2(1), the parameters of the elementary cell are a = 10.417(1), b = 4.912(2), c = 15.969(2) A, beta = 107.23(1) degrees, V = 780.5 A3, Z = 2, R = 3.8%. The crystals of dT(CH2SOMe have a space group P2(1)2(1)2(1), the elementary cell parameters are a = 8.858(2), b = 9.303(1), c = 17.698(2) A, V = 1458.3 A3, Z = 4, R = 2.8%. The dT(CH2SMe) and dT(CH2SOMe) molecules are characterized by an anti-conformation relative to the glycoside bond (angles chi (O4'-C1'-N1-C2) are equal to -116.2 degrees and -148.8 degrees), a gauche(+)-conformation relative to the exocyclic bond C4'-C5' (angles phi CO (C3'-C4'-C5'-O5') are equal to 52.1 degrees and 41.1 degrees). The conformation of the furanose cycle in the dT(CH2SMe) molecule is described by C2'-endo-C3'-exo (P = 167.8 degrees, psi m = 34.8 degrees) and in the dT(CH2SOMe) molecule by C2'-endo-C1'-exo (P = 148.4 degrees, psi m = 35.4 degrees). The structures studied were compared with 3'-azido-3'-deoxythymidine (AZT) and thymidine.

3'-C-branched 2'-deoxy-5-methyluridines: synthesis, enzyme inhibition, and antiviral properties.

A synthesis scheme for 3'-C-methyl-2'-deoxynucleosides and 3'-C-methylidene-2',3'-dideoxy-5-methyluridine has been proposed with 2-deoxyribose as the starting material. Methyl 5-O-benzoyl-2-deoxyribofuranose was oxidized and the mixture of the 3'-keto derivatives was separated into the alpha- and beta-anomers. The beta-keto derivative was converted by reaction with MeMgBr, and after reaction with thymine and subsequent deprotection 1-(3'-C-methyl-2'-alpha-deoxy-alpha-D-threo-pentofuranosyl)thymine and its beta-anomer were obtained. The same reactions with the alpha-keto sugar gave 1-(3'-C-methyl-2'-deoxy-alpha-D-erythro-pentofuranosyl)thymine and its beta-anomer. 1-(5-O-Benzoyl-3'-C-methyl-2'-deoxy-alpha-D-threo-pentofuranosyl)thymine was converted to a mixture of 3'-C-methylidene-2',3'-dideoxy-5-methyluridine and 3'-C-methyl-2',3'-dideoxy-2',3'-didehydro-5-methyluridine, which were separated. The stereoselectivity of the Grignard reagent's attachment to 2-deoxyfuranose 3-ulosides has been ruled by the substitute configuration at Cl. Also, the effect of the hydroxyl or OBz group configuration at C3 on the condensation stereoselectivity of 3-C-methyl-2-deoxyfuranosides with silylated thymine has been studied. The structure of the obtained compounds was proved by 1H NMR UV, 13C NMR, and CD spectroscopy, as well as elemental (C, H, N) analysis. The C2'-endo-C1'-exo conformation, the anti conformation of thymine in relation to the glycosidic bond, and the gauche+conformation in relation to the C4'-C5' bond are characteristic for the 3'-C-methyl-2'-deoxythymidine structure in the crystals. 3'-C-Methyl-2'-deoxythymidine 5'-triphosphate was synthesized and proved to be a competitive inhibitor, with respect to dTTP, of a number of DNA polymerases, including the reverse transcriptases of human immunodeficiency virus type 1 (HIV-1) and avian myeloblastosis virus (AMV). None of the DNA polymerases examined were able to incorporate this compound into the growing DNA chain. In contrast, 3'-C-methylidene-2',3'-dideoxy-5-methyluridine 5'-triphosphate was found to be incorporated at the 3'-end of the DNA chain by HIV-1 reverse transcriptase, albeit with very low efficiency. 3'-C-Methyl-2'-deoxy-5-methyluridine did not suppress HIV-1 replication in MT-4 cells at 500 microM while its 5'-phosphite derivative exhibited modest anti-HIV-1 activity.

[Molecular and crystalline structure of 3'-methylamino-2',3'-dideoxyribosylthymine--a potential inhibitor of HIV]. / Molekuliarnaia i kristallicheskaia struktura 3'-metilamino-2',3'-didezoksiriboziltimina--potentsial'nogo ingibitora VICh.

The structure of 3'-methylamino-2',3'-dideoxyribosylthymine [ddT(3'NHMe)] was determined by X-ray analysis. The space group is P2(1)2(1)2(1). Cell dimensions are: a 5.132(1), b 13.718(1), c 16.947(2) A, V 1193.2 A3, Z 4. The structure was solved by directed methods and refined by the full-matrix least square method to R 4.8%. The molecule of ddT(3'NHMe) has anti-conformation with respect to the glycosidic bond (chi (O4'-C1'-N1-C2) = -106.7 degrees), C3'-endo-C4'-exo puckering of the sugar moiety (P -28.8 degrees, psi m -31.5 degrees) and gauche-gauche conformation about exocyclic C4'-C5' bond (psi(C3'-C4'-C5'-O5') 45.8 degrees). The structure of ddT(3'NHMe) was compared with those of 3'-amino-3'-deoxythymidine, 3'-azido-3'-deoxythymidine and natural thymidine.

X-ray analysis of 2',3'-lyxoanhydrothymidine, a conformationally restricted inhibitor of retroviral reverse transcriptases.

2',3'-Lyxoanhydrothymidine (LAT), a conformationally restricted inhibitor of retroviral reverse transcriptases, has been studied by X-ray analysis. The unit cell contains two crystallographically independent molecules A and B. Their sugar moieties have an identical structure: an 04'-endo pucker of the furanose cycle and a trans conformation about the exocyclic C4'-C5' bond. The conformations of A and B molecules differ with respect to the N-glycosidic bond: chi A(04 'Cl' N1C2) = -121.9 degrees which is typical of a common anti conformation whereas chi B (04'Cl'N1C2) = 121.2 degrees corresponds to a rare high-syn conformation. All the conformation properties of LAT molecules stem from the presence of an epoxide cycle in their molecules.