Synthesis, biological properties and anti-HIV-1 activity of new pyrimidine P1,P2-dinucleotides.

New homo- and hetero-P(1),P(2)-dinucleotides were prepared with the use of multistep procedures starting from the monophosphates of 3'-fluoro-2-thiothymidine, 3'-fluoro-4-thiothymidine, AZT and 1-[(2-hydroxyethoxy)-methyl-5-propyl-6-phenylselenenyl]uracil. Anti-HIV properties of the synthesized P(1),P(2)-dinucleotides were evaluated against laboratory syncytia inducing strain HIV-1 in CEM-T4 cells. Anti-HIV activities were in the range of 5-45 nM, and therapeutic indexes were higher than 4666-14000. Interactions of the above mentioned compounds with recombinant HIV-1 reverse transcriptase were also investigated. The obtained results point to reverse transcriptase inhibition, with somewhat lower inhibitory activity than that of their parental nucleoside-5'-triphosphates. Compound 6 may be regarded as a potent anti-HIV/AIDS drug.

5'-O-ester prodrugs of potent and selective anti-HIV agent--2',3'-dideoxy-3'-fluoro-2-thiothymidine (S2FLT): synthesis and anti-HIV activity.

Novel synthesis of 2',3'-dideoxy-3'-fluoro-2-thiothymidine (SFLT) based on transformation of appropriately protected 1-beta-D-threo-ribofuranosylthymine is presented. The synthesis and evaluation of SFLT 5'-O-ester prodrugs enzymatic hydrolysis, as well as their anti-HIV activity, is also described.

5-Substituted N(4)-hydroxy-2'-deoxycytidines and their 5'-monophosphates: synthesis, conformation, interaction with tumor thymidylate synthase, and in vitro antitumor activity.

Convenient procedures are described for the synthesis of 5-substituted N(4)-hydroxy-2'-deoxycytidines 5a,b,d-h via transformation of the respective 5-substituted 3', 5'-di-O-acetyl-2'-deoxyuridines 1a-c,e-h. These procedures involved site-specific triazolation or N-methylimidazolation at position C(4), followed by hydroxylamination and deblocking with MeOH-NH(3). Nucleosides 5a,b,d-h were selectively converted to the corresponding 5'-monophosphates 6a,b,d-h with the aid of the wheat shoot phosphotransferase system. Conformation of each nucleoside in D(2)O solution, deduced from (1)H NMR spectra and confirmed by molecular mechanics calculations, showed the pentose ring to exist predominantly in the conformation S (C-2'-endo) and the N(4)-OH group as the cis rotamer. Cell growth inhibition was studied with two L5178Y murine leukemia cell lines, parental and 5-fluoro-2'-deoxyuridine (FdUrd)-resistant, the latter 70-fold less sensitive toward FdUrd than the former. With FdUrd-resistant L5178Y cells, 5-fluoro-N(4)-hydroxy-2'-deoxycytidine (5e) caused almost 3-fold stronger growth inhibition than FdUrd; 5e was only some 3-fold weaker growth inhibitor of the resistant cells than of the parental cells. Thymidylate synthase inhibition was studied with two forms of the enzyme differing in sensitivities toward 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), isolated from parental and FdUrd-resistant L1210 cell lines. All N(4)-hydroxy-dCMP (6a,b,d-h) and dUMP analogues studied were competitive vs dUMP inhibitors of the enzyme. Analogues 6b,d-h and 5-hydroxymethyl-dUMP, similar to N(4)-hydroxy-dCMP (6a) and FdUMP, were also N(5), N(10)-methylenetetrahydrofolate-dependent, hence mechanism-based, slow-binding inhibitors. 5-Chloro-dUMP, 5-bromo-dUMP, and 5-iodo-dUMP, similar to dTMP, did not cause a time-dependent inactivation of the enzyme. Instead, they behaved as classic inhibitors of tritium release from [5-(3)H]dUMP. 5-Bromo-dUMP and 5-iodo-dUMP showed substrate activity independent of N(5), N(10)-methylenetetrahydrofolate in the thymidylate synthase-catalyzed dehalogenation reaction. The =N-OH substituent of the pyrimidine C(4) prevented the enzyme-catalyzed release from the C(5) of Br(-) and I(-) (the same shown previously for H(+)). While FdUMP and 6a showed a higher affinity and greater inactivation power with the parental cell than FdUrd-resistant cell enzyme, an opposite relationship could be seen with 5-hydroxymethyl-dUMP.

[A case of Lambert-Eaton syndrome]. / Przypadek zespolu Lamberta-Eatona.

A case of the myasthenic syndrome developing in the course of microcellular bronchogenic carcinoma with involvement in the early period of the syndrome of muscles with bulbar innervation is described. Myasthenic symptoms responded well to choline esterase inhibitors.

[A case of severe reversible traumatic angiogenic brain stem damage with metabolic disorders]. / Przypadek odwracalnego, ciezkiego, urazowo-naczyniowego uszkodzenia pnia mózgu z zaburzeniami metabolicznymi.

A case of brain stem injury of vascular and traumatic origin, complicated with metabolic disturbances and with finally achieved cure is described.