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Biomedical subjects

J Balzarini

Publications and source records attributed to J Balzarini.

At least 505 records · Page 28Linked to original sources
PubMedDate not supplied

Potentiating effect of ribavirin on the anti-retrovirus activity of 3'-azido-2,6-diaminopurine-2',3'-dideoxyriboside in vitro and in vivo.

3'-Azido-2,6-diaminopurine-2',3'-dideoxyriboside (AzddDAPR) is a potent and selective inhibitor of human immunodeficiency virus (HIV) replication in vitro. It also inhibits Moloney murine sarcoma virus (MSV)-induced transformation of murine C3H/3T3 embryo fibroblasts. AzddDAPR causes a marked dose-dependent suppression of MSV-induced tumor formation and mortality therewith associated in newborn mice infected with MSV. Combination of AzddDAPR with ribavirin resulted in a marked potentiation of its anti-retrovirus activity in vitro and a significant enhancement of its inhibitory effect on MSV-induced tumor formation in vivo. A slight increase in the in vivo toxicity of AzddDAPR was noted when combined with ribavirin.

Animals↗
PubMedDate not supplied

Effect of antimetabolite drugs of nucleotide metabolism on the anti-human immunodeficiency virus activity of nucleoside reverse transcriptase inhibitors.

A number of attempts are currently underway to combine antimetabolite drugs of nucleotide metabolism with a nucleoside reverse transcriptase inhibitor (NRTI) targeting human immunodeficiency virus (HIV) to improve the antiviral efficacy of the NRTIs and to better control HIV drug resistance. Hydroxyurea, a ribonucleotide reductase inhibitor, is currently combined with the NRTI didanosine (2',3'-dideoxyinosine) in clinical trials. However, other cellular target enzymes, including thymidylate synthase, inosinate dehydrogenase, cytidine-5'-triphosphate synthetase, and other enzymes from the de novo nucleotide biosynthesis pathway, can also be considered to potentiate the antiviral action of NRTIs. The underlying reasons for the potentiation of the antiviral activity of the NRTIs by antimetabolite drugs of nucleotide metabolism can be multiple. Decreased endogenous 2'-deoxynucleoside-5'-triphosphate (dNTP) pools result in a better competition of the NRTI (as its triphosphate derivative), with the dNTPs for the virus-encoded reverse transcriptase to be recognized as a substrate for the DNA polymerization reaction and subsequently to be incorporated into the growing viral DNA chain. Also, an increased metabolism (phosphorylation) of the NRTI by stimulatory enzyme feedback mechanisms may result in the production of higher levels of NRTI triphosphate. Thus, higher intracellular ratios of NRTI-triphosphate/dNTP created by well-defined combinations of NRTIs and antimetabolite drugs enable a more profound inhibitory effect of the NRTI against the reverse transcriptase (and thus, against the virus) and a better suppression of resistant (mutant) virus strains. A profound evaluation of this relatively new concept in the clinical setting will reveal whether this approach will establish a place in future treatment modalities of HIV infections.

Antimetabolites↗
PubMedDate not supplied

A novel selective broad-spectrum anti-DNA virus agent.

A new compound has been found, (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA), that has potent and selective activity against a broad spectrum of DNA viruses, including herpes simplex virus (types 1 and 2); varicella zoster virus; thymidine kinase-deficient (TK-) mutants of herpes simplex and varicella zoster virus; human cytomegalovirus; phocid, simian, suid, bovid and equid herpesviruses; African swine fever virus; vaccinia virus; and human adenoviruses. It is also active against retroviruses. We also report that, in mice and rabbits in vivo, the compound is effective against both local and systemic infections with herpes simplex virus type 1, including herpetic keratitis caused by a TK- mutant which is resistant to the classical anti-herpes drugs.

Adenine↗
PubMedDate not supplied

3'-(N-hydroxyimino)-2',3-dideoxynucleosides and their derivatives: synthesis, broad spectrum antiviral properties and synthetical application for the preparation of other nucleoside analogues.

A series of 3'-(N-hydroxyimino)-2',3'-dideoxynucleosides bearing different nucleic bases has been prepared. In vitro antiviral activity studies showed that among these compounds the thymine derivative possesses significant activity against HIV, HSV, EBV and HBV. Conveniently 5'-protected 3'-(N-hydroxyimino)-2',3'-dideoxythymidine was further used as a synthon for the preparation of other nucleoside analogues.

Antiviral Agents↗
PubMedDate not supplied

Novel TSAO derivatives modified at positions 3" and 4" of the spiro moiety.

We have explored the introduction of different functional groups at positions 3" and 4" of the spiro moiety of TSAO-T. Alkylation of this spiro moiety afforded mixtures of N and/or C-alkylated derivatives, while acylation occurs, exclusively, on the amino group. Position 3" has been selectively functionalized by halogenation followed by Stille-cross coupling reaction with organostannanes under a variety of experimental conditions.

Spiro Compounds↗
PubMedDate not supplied

Antitumor potential of acyclic nucleoside phosphonates.

Acyclic nucleoside phosphonates such as HPMPC (cidofovir) and PMEA (adefovir) have been identified as broad-spectrum antiviral agents that are effective against herpes-, retro- and hepadnavirus infections (PMEA) and herpes-, pox-, adeno-, polyoma-, and papillomavirus infections (HPMPC). Here we show that HPMPC and PMEA also offer great potential as antitumor agents, through the induction of tumor cell differentiation (PMEA), inhibition of angiogenesis (HPMPC) and induction of apoptosis (HPMPC). In vivo tumor regressions have been noted for choriocarcinoma (PMEA) in rats, hemangioma (HPMPC) in rats and papillomatous lesions (HPMPC) in humans. Acyclic nucleoside phosphonates can be considered as a new dimension to the discipline of chemotherapy. They have a unique mode of action that is targeted at (viral or tumoral) DNA synthesis. They exhibit a pronounced and prolonged anti-viral and/or tumoral activity that can persist for days or weeks after a single administration. Most importantly, they have a uniquely broad spectrum of indications for clinical use, encompassing both DNA- and retrovirus infections, as well as various forms of cancer of both viral and non-viral origin.

Adenine↗
PubMedDate not supplied

An in situ pig liver esterase assay as a useful predictive tool for the likely in vitro anti viral activity of phosphoramidate pro-drugs.

The pig liver esterase (PLE) assay has been designed to "reproduce" in vitro the first step of the metabolism of phosphoramidate pro-drugs that generates the free amino acyl phosphoramidate intermediate which has been described as a key metabolite necessary but not sufficient for the biological activity. The method could be used as a predictive tool for the likely in vitro biological activity as well as for Structure-Activity Relationship establishment (SAR).

Animals↗
PubMedDate not supplied

Prodrugs of Ara-CMP and Ara-AMP with a S-acyl-2-thioethyl (SATE) biolabile phosphate protecting group: synthesis and biological evaluation.

The bis(S-pivaloyl-2-thioethyl) phosphotriesters of Ara-C and Ara-A were synthesized as potential bioreversible mononucleotide prodrugs. Some N- and O-acylated derivatives were also prepared with the aim to modify the lipophilicity of the title pronucleotides. Compounds were tested for their antitumor/antiviral activity against a variety of tumor cells and viruses.

Adenosine Monophosphate↗
PubMedDate not supplied

Synthesis, cytostatic activity and inhibition of ribonucleotide reductase by 5'-phosphoramidates and 5'-diphosphates, of 2'-O-allyl-arabinofuranosyl nucleosides.

The diphosphates of a series of 2'-O-allyl-1-beta-D-arabinofuranosyl derivatives, previously obtained by us, have been prepared and tested for their inhibitory activity in an in vitro assay using R1 and R2 subunits of the purified recombinant mouse ribonucleotide reductase (RNR). 2'-O-Allyl-araU diphosphate proved to be inhibitory, with an IC50 of 100 microM. The 5'-phosphoramidate pronucleotide of 2'-O-allyl-araU was also prepared and tested for inhibition of tumor cell proliferation.

Animals↗