Selective inhibition of herpes simplex virus ribonucleoside diphosphate reductase by derivatives of 2-acetylpyridine thiosemicarbazone

Turk, Steven R.; Shipman, Charles; Drach, John C.

doi:10.1016/0006-2952(86)90122-x

Cited by 51 publications

(24 citation statements)

References 30 publications

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“…The apparent inactivation ofthese enzymes is similar to that observed for A723U with HSV-1 and VZV ribonucleotide reductases (9,17). However, A111OU is about 30-fold more potent than A723U and is among the most potent inactivators of HSV ribonucleotide reductase reported to date (6,20,30).…”

Section: Methodssupporting

confidence: 67%

2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]-thiocarbonohydrazone (A1110U), a potent inactivator of ribonucleotide reductases of herpes simplex and varicella-zoster viruses and a potentiator of acyclovir.

Spector

Harrington²,

Morrison³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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(9) and to potentiate the antiherpetic activities of ACV. In addition to producing the expected decrease in the dGTP pool, A723U also caused the pool of ACVTP to increase by 10-fold (17).In the present study, the properties of 2-acetylpyridine 5-[(dimethylamino)thiocarbonyl]thiocarbonohydrazone (A111OU) were investigated. This compound was found to be considerably more potent than A723U. At submicromolar concentrations, A111OU inactivated the ribonucleotide reductases of these three herpes viruses. It also markedly potentiated the activity of ACV against the viruses in vitro. Furthermore, as reported elsewhere ( §, ¶), A111OU and ACV produced significantly synergistic therapy as topical treatment of HSV-infected animals. MATERIALS AND METHODSReagents. All reagents not described below were obtained as previously described (11).Synthesis of A111OU. A mixture of 24.2 g (0.203 mol) of 4,4-dimethylthiosemicarbazide, 26.6 g (0.220 mol) of 2-acetylpyridine, 2.5 ml of glacial acetic acid, and 100 ml of 95% (vol/vol) ethanol was refluxed for 1.5 hr and then incubated overnight at room temperature. Thick orange needles contaminated with a small amount of a light-colored solid were collected, washed with 20 ml of ethanol, and, while still damp, added to 450 ml of boiling methanol. After 10 min, the mixture was filtered. The undissolved solid was re-incubated with 50 ml of boiling methanol for 3 min and then filtered. After 15 min at room temperature, the yellow product recrystallized from the combined filtrates and was collected by filtration.

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Section: Methodssupporting

confidence: 67%

2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]-thiocarbonohydrazone (A1110U), a potent inactivator of ribonucleotide reductases of herpes simplex and varicella-zoster viruses and a potentiator of acyclovir.

Spector

Harrington²,

Morrison³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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“…O fato de as enzimas serem bioquimicamente distintas sugere que elas poderiam ser afetadas diferentemente por inibidores e, assim, a RDR do vírus seria um alvo para as drogas antivirais. De fato, foi demonstrado que a enzima do vírus é mais sensível à inibição por tiossemicarbazonas derivadas de 2-acetilpiridina do que a enzima celular homóloga 72 . Por outro lado, há evidências de efeitos tóxicos nas células nas concentrações usadas para inibir o vírus, o que põe em dúvida a seletividade dessas drogas 73 .…”

Section: Tiossemicarbazonas E Seus Complexos Com Outros Cátions Metálunclassified

Semicarbazonas e tiossemicarbazonas: o amplo perfil farmacológico e usos clínicos

Beraldo¹

2004

Quím. Nova

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Recebido em 31/7/03; aceito em 24/9/03 SEMICARBAZONES AND THIOSEMICARBAZONES: THEIR WIDE PHARMACOLOGICAL PROFILE AND CLINICAL APPLICATIONS. This article shows that thiosemicarbazones, semicarbazones and their metal complexes can exhibit target selectivity along with a wide pharmacological profile. Complexes of thiosemicarbazones with cytotoxic or antitumoral activity are presented, some of which show activity against cisplatinum-resistant cells. The inhibition mechanism of the enzyme ribonucleoside diphosphate reductase (RDR), involved in DNA syntheses, by α(N)-heterocyclic thiosemicarbazones is discussed. The encouraging results of clinical trials with the RDR inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone ("Triapine") against rapidly growing tumors are outlined. Examples are also given of thiosemicarbazones with antiviral and antimicrobial activity. The possible applications of semicarbazones as anticonvulsants with low toxicity and good therapeutic index are presented. . Ehrlich foi o fundador da quimioterapia e introduziu as primeiras idéias sobre relações estrutura-atividade e o conceito de índice terapêutico. Fez ainda uso de complexos metálicos, em especial os de arsênio, na preparação de drogas para o tratamento da sífilis 2 . Werner é considerado o pai da Química de Coordenação pelo desenvolvimento de sua teoria para explicar a estrutura e a ligação química nos complexos metálicos.Apesar da grande importância dos trabalhos desses e de outros pesquisadores, a Química Medicinal dedicou-se, durante muitos anos, principalmente ao estudo de compostos orgânicos e produtos naturais. A investigação a respeito do uso de complexos metálicos como fármacos teve início, de modo sistemático, apenas após a descoberta feita pelo físico Barnett Rosemberg, da atividade antitumoral do cis(diaminodicloro)platina(II), o "cisplatina" ou cis-ddp, em 1965 3 . Desde então, uma imensa variedade de complexos metálicos foi e tem sido investigada quanto às suas propriedades terapêuticas. É interessante observar que o primeiro número da revista Metal-Based Drugs apareceu em 1994.Tiossemicarbazonas e semicarbazonas (Figura 1) apresentam um amplo perfil farmacológico e constituem uma importante classe de compostos cujas propriedades têm sido extensivamente estudadas na Química Medicinal e, particularmente, na Química Medicinal Inorgânica, em razão de sua capacidade quelante e do papel da coordenação no seu mecanismo bioquímico de ação. Apesar da ampla versatilidade farmacológica desses compostos como uma classe, especificidades estruturais podem levar à manifestação de atividades específicas. Para os complexos metálicos, em alguns casos é possí-vel modular a atividade através do desenho do ligante ou através da escolha do metal, como veremos adiante.De modo geral pode-se dizer que tiossemicarbazonas e semicarbazonas agem, seja como inibidores de enzimas, através da complexação de metais endógenos ou através de reações de redox, seja através de interações com o ADN e da inibição da síntese do ADN. Além disso, alguns compl...

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“…We have shown that HSV type 1 (HSV-1) requires this increased synthesis of deoxynucleotides to replicate efficiently (22a). Inhibitors of the RR have been shown to potentiate the antiviral effects of ACV (21,(29)(30)(31) (32,33) and is also a potent inhibitor of HSV both in vitro and in vivo (27,28 (10). Previous experiments in our laboratory showed that this drug also potentiates the antiviral effects of ACV (20).…”

mentioning

confidence: 99%

Strategic design and three-dimensional analysis of antiviral drug combinations

Prichard

Shipman

1993

Antimicrob Agents Chemother

106

117

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The development of new drugs effective against human viral diseases has proven to be both difficult and time-consuming. Indeed, there are but 10 drugs licensed for such applications in the United States today. An attractive solution to this problem may be to optimize the efficacy and selectivity of existing antiviral drugs by combining them with agents that strategically block carefully selected metabolic pathways. This approach was used in the rational design of a three-drug combination to increase the apparent potency of acyclovir against herpes simplex virus. Recent advances in analytical techniques have made the evaluation of this complex drug strategy both possible and practical. A modified version of a previously described analytical method was used to identify optimal drug concentrations and to quantitate statistically significant synergy. Concentrations of 0.25 ,M 5-fluorodeoxyuridine, 3.6 ,uM 2-acetlpyridine thiosemicarbazone, and 0.3 ,uM acyclovir were determined to be optimal in terms of antiviral activity. The volume of synergy produced was nearly 2,000 ,uM3% at a 95% level of confidence (corresponding to a 186-fold decrease in the apparent 50%o inhibitory concentration of acyclovir with the addition of 0.25 ,uM 5-fluorodeoxyuridine and 3.6 ,uM 2-acetylpyridine thiosemicarbazone). We anticipate that this strategic approach and the supporting three-dimensional analytical method will prove valuable in designing and understanding multidrug therapies.Antiviral drugs derive their specificity through the preferential inhibition of virus-encoded enzymes present in infected cells (13). The usefulness of these agents is limited by the degree to which they concomitantly affect uninfected cells, producing untoward toxicity. Additionally, the emergence of drug-resistant mutants is a significant problem in single-drug therapy (3). Treatment with combinations of antiviral agents is generally thought to minimize drug resistance (1, 6, 14) but may or may not offer increased selectivity and efficacy. Traditionally, drug combinations have been chosen on the basis of the potency and/or efficacy of the individual agents. The component drugs often have been active against the same target, and detailed evaluations of drug interactions often have been lacking. Combiwitions of drugs that inhibit different targets, however, often offer surprising potency, even though one or more of the constituent c6mpounds may be weakly active. We now describe the rational design of an antiviral combination of three drugs that strategically inhibits the replication of herpes simplex virus (HSV) by blocking carefully chosen metabolic pathways. Evaluation of this strategy and the determination of optimal drug concentrations were made possible by recent advances in existing three-dimensional analytical procedures (21, 22).The rational design of a combination of drugs relies on a thorough understanding of drug metabolism in both virusinfected and uninfected cells. The antiherpesvirus drug acyclovir (ACV; Zovirax) is a potent inhibitor of HSV re...

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Selective inhibition of herpes simplex virus ribonucleoside diphosphate reductase by derivatives of 2-acetylpyridine thiosemicarbazone

Cited by 51 publications

References 30 publications

2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]-thiocarbonohydrazone (A1110U), a potent inactivator of ribonucleotide reductases of herpes simplex and varicella-zoster viruses and a potentiator of acyclovir.

2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]-thiocarbonohydrazone (A1110U), a potent inactivator of ribonucleotide reductases of herpes simplex and varicella-zoster viruses and a potentiator of acyclovir.

Semicarbazonas e tiossemicarbazonas: o amplo perfil farmacológico e usos clínicos

Strategic design and three-dimensional analysis of antiviral drug combinations

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