A series of 23 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives that were highly potent inhibitors of wild-type human immunodeficiency virus type 1 strain IIIB (HIV-1/IIIB) replication in CEM cells were evaluated against a panel of HIV-1 mutant strains containing the replacement of leucine by isoleucine at position 100 (100-Leu-->Ile), 103-Lys-->Asn, 106-Val-->Ala, 138-Glu-->Lys, 181-Tyr-->Cys, 181-Tyr-->Ile, or 188-Tyr-->His in their reverse transcriptase (RT). A different structure-antiviral activity relationship was found, depending on the nature of the mutated amino acid in the HIV-1 RT. The results show that 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil, 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylphenylthio)uracil, and 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylphenylthio)-2-thiouracil remain active against the majority of viruses containing single mutations which confer resistance to nonnucleoside RT inhibitors.
Abstract Some new thiosemicarbazones containing benzimidazole moiety (VI) are synthesized and screened for their ability to inhibit the growth of 60 human cancer cell lines, in vitro replication on HIV virus strains as well as inhibition capacity for several bacterial strains.
We have previously described an animal model for the therapy of human immunodeficiency virus type 1 (HIV-1) infection with HIV-1-specific reverse transcriptase (RT) inhibitors based on a simian immunodeficiency virus (SIV), in which the RT gene of SIV was replaced by the RT gene of HIV-1. In vitro, replication of the hybrid virus, RT-SHIV, was delayed compared with parental SIV. RT-SHIV could induce AIDS-like symptoms and pathologic alterations in rhesus macaques. Characterization of re-isolates recovered from RT-SHIV-infected macaques one-half year after infection revealed that the re-isolates replicated with kinetics similar to those of SIV. Inefficient processing of the Gag-Pol precursor of RT-SHIV may be one reason for the retarded growth of RT-SHIV, because the protease cleavage site between the protease gene and the RT gene was frequently mutated in the RT-SHIV re-isolates. Adaptation of RT-SHIV to the growth in macaques did not result in a relevant loss of sensitivity to nonnucleoside RT inhibitors (NNRTIs). However, because a minor sub-population of the RT-SHIV re-isolates contained a mutation conferring low-level resistance to ddI and ddC, the RT-SHIV/macaque model may underestimate the efficacy of these drugs. Nevertheless, this report further supports the suitability, reliability, and usefulness of the RT-SHIV/macaque model to investigate the antiviral properties of most RT inhibitors in an in vivo setting.
A thymidylate (dTMP) synthetase-deficient murine mammary carcinoma cell line (FM3A/TS-), auxotrophic for thymidine (dThd), proved extremely useful for studying the dependence of cell growth on the exogenous supply of dThd, the relation between cell growth and DNA synthesis, and the ability of a series of 25 5-substituted 2'-deoxyuridines (dUrd) to substitute for dThd in sustaining cell growth. FM3A/TS-cells did not proliferate unless dThd was supplied to the cell culture medium. The 5-halogenated dUrd derivatives 5-chloro-dUrd, 5-bromo-dUrd and 5-iodo-d Urd also sustained FM3A/TS- cell growth. The extents of incorporation of [methyl-3H]dThd and 5-iodo-[6-3H]dUrd into DNA were closely correlated with their stimulatory effects on FM3A/TS- cell growth. This suggests that the stimulatory effects of the dUrd analogues on the growth rate of FM3A/TS- cells may be considered as evidence for their incorporation into host cell DNA. Based on this premise it is postulated that, in addition to 5-chloro-dUrd, 5-bromo-dUrd, 5-iodo-dUrd and dThd itself, the following dThd analogues are also incorporated into FM3A/TS- cell DNA (in order of the extent to which they are incorporated): 5-hydroxy-dUrd greater than 5-propynyloxy-dUrd greater than 5-ethyl-dUrd greater than 5-ethynyl-dUrd approximately 5-vinyl-dUrd. Thus, the dTMP synthetase-deficient FM3A/TS- cell line represents a unique system to dissociate the de novo and salvage pathways of dTMP biosynthesis and to distinguish those dUrd analogues that are incorporated into DNA from those that are not.
The idea to start the Rega Foundation was conceived in 1971 at an informal meeting organized by Prof. Piet De Somer (where Prof. Alfons Billiau, Prof. André Vlerick and I were also present), before the Foundation was formally created in 1972. From the early years some antiviral compounds, such as BVDU and the aminoacyl esters of acyclovir (from which ultimately valacyclovir evolved) originated. The advent of AIDS in 1981 and the discovery of the etiologic agent (HIV) thereof in 1983 have led to the identification of an avalanche of anti-HIV compounds in which the Rega Institute has played a primordial role. Foremost among these compounds was tenofovir, discovered in collaboration with Antonín Holý from the IOCB (Institute of Organic Chemistry and Biochemistry) in Prague. Tenofovir laid the basis for the treatment of HIV (AIDS) and hepatitis B virus (HBV) infections, and in combination with emtricitabine it was the first chemical ever approved by the US FDA (Food and Drug Administration) for the prophylaxis of HIV infections.
