Synthesis and antiherpetic activity of (.+-.)-9-[[(Z)-2-(hydroxymethyl)cyclopropyl]methyl]guanine and related compounds

Ashton, Wallace T.; Meurer, Laura C.; Cantone, Christine L.; Field, Anjalie; Hannah, John; Karkas, John D.; Liou, Richard; Patel, Gool F.; Perry, Helen C.

doi:10.1021/jm00120a010

Cited by 91 publications

(32 citation statements)

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“…The authors concluded that there was no absolute correlation of either triphosphate formation or polymerase inhibition with in vitro antiviral activity against HSV-1. In fact, several compounds were found to be not phosphorylated at all by HSV thymidine kinase in their assay systems and yet exhibited modest antiviral activity (1). Conceivably their compounds as well as T01132 and T70072 may be phosphorylated by other cellular enzymes, or their antiviral activity may be unrelated to phosphorylation or DNA polymerase inhibition.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of human cytomegalovirus in culture by alkenyl guanine analogs of the thiazolo[4,5-d]pyrimidine ring system

Lewis

Drach

Fennewald

et al. 1994

Antimicrob Agents Chemother

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A series of alkyl and alkenyl guanine analogs containing a thiazolo [4,5-d]pyrimidine ring system were prepared by reaction of the appropriate alkyl halide with the sodium salt of the heterocycle. In preliminary antiviral efficacy evaluations against laboratory strains of both human cytomegalovirus (HCMV) and herpes simplex virus types 1 and 2, it was determined that two of the compounds (T70072 and T01132) were more active and less toxic in stationary-phase cell monolayers than were the other derivatives tested. T01132 and T70072, which have 2-pentenyl and 3-methyl-2-butenyl moieties attached to position 3 of the 5-aminothiazolo[4,5-dlpyrimidine-2,7-dione, respectively, were then more extensively evaluated for anti-HCMV activity.The concentrations of T01132 and T70072 required to inhibit HCMV by 50%o in plaque reduction assays were -0.5 and 6.8 ,iM, respectively. These two compounds inhibited the growth of KB, or Vero cells at concentrations of 75 to 150 ,uM, depending upon the cell line. In bone marrow progenitor cells T01132 was slightly less toxic than ganciclovir (DHPG). The 50%o inhibitory concentrations of T01132 against clinical isolates and DHPG-resistant strains of HCMV were approximately the same as those obtained for laboratory strains of HCMV (-0.5 jiM). When tested in combination with DHPG, the resultant antiviral activity was determined to be additive but not synergistic. Experiments performed using variations of the viral multiplicity of infection (MOI) demonstrated that T01132 was more active than DHPG at a low MOI (0.002 or 0.02). However, when a higher MOI (0.2 or 2.0) was used, DHPG was more efficacious than T01132. In experiments in which drug was added at various times post-viral infection, T01132 was most effective when added within the first 24 h post-HCMV infection while DHPG was able to protect cells in this assay system when added up to 48 h postinfection, indicating that T01132 is exerting its antiviral effect on events leading up to and possibly including viral DNA synthesis. The data presented in this report suggest that the antiviral activity of alkenyl-substituted thiazolopyrimidine derivatives may represent a mechanism of action against herpesviruses alternative to that of classical nucleoside analogs such as acyclovir or DHPG.

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Section: Discussionmentioning

confidence: 99%

Inhibition of human cytomegalovirus in culture by alkenyl guanine analogs of the thiazolo[4,5-d]pyrimidine ring system

Lewis

Drach

Fennewald

et al. 1994

Antimicrob Agents Chemother

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“…[OTf] could be isolated, in the case of ligands 6-9, the equilibrium between the trifluoroacetate (46-49) and hydride (54)(55)(56)(57) complexes is strongly shifted in favour of the trifluoroacetate complexes. In further contrast to the ALPHA/triflic acid system, the ethyl complexes 61-64 are only stable in the presence of an overpressure of ethene.…”

Section: A C H T U N G T R E N N U N G (Alpha)ha C H T U N G T R E N mentioning

confidence: 99%

Phosphine Ligands in the Palladium‐Catalysed Methoxycarbonylation of Ethene: Insights into the Catalytic Cycle through an HP NMR Spectroscopic Study

Fuente

Waugh

Eastham

et al. 2010

Chemistry A European J

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Novel cis-1,2-bis(di-tert-butyl-phosphinomethyl) carbocyclic ligands 6-9 have been prepared and the corresponding palladium complexes [Pd(O(3)SCH(3))(L-L)][O(3)SCH(3)] (L-L=diphosphine) 32-35 synthesised and characterised by NMR spectroscopy and X-ray diffraction. These diphosphine ligands give very active catalysts for the palladium-catalysed methoxycarbonylation of ethene. The activity varies with the size of the carbocyclic backbone, ligands 7 and 9, containing four- and six-membered ring backbones giving more active systems. The acid used as co-catalyst has a strong influence on the activity, with excess trifluoroacetic acid affording the highest conversion, whereas excess methyl sulfonic acid inhibits the catalytic system. An in operando NMR spectroscopic mechanistic study has established the catalytic cycle and resting state of the catalyst under operating reaction conditions. Although the catalysis follows the hydride pathway, the resting state is shown to be the hydride precursor complex [Pd(O(3)SCH(3))(L-L)][O(3)SCH(3)], which demonstrates that an isolable/detectable hydride complex is not a prerequisite for this mechanism.

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“…The other consequence of this structural change could be a conformational constraint (18). It has been shown that the introduction of a rigid structure into nucleosides can promote antiviral properties in certain compounds (1,2,5,18). For example, a conformationally constrained analogue of acyclovir was found to have potent antiherpetic properties (herpes simplex virus type 1 [HSV-1] and HSV-2) comparable to those of the nonconstrained acyclovir (2).…”

mentioning

confidence: 99%

“…It has been shown that the introduction of a rigid structure into nucleosides can promote antiviral properties in certain compounds (1,2,5,18). For example, a conformationally constrained analogue of acyclovir was found to have potent antiherpetic properties (herpes simplex virus type 1 [HSV-1] and HSV-2) comparable to those of the nonconstrained acyclovir (2). The structural rigidity of stavudine (D4T) also appears to play an important role in its antiviral activity (4,5).…”

mentioning

confidence: 99%

In Vitro Anti-Human Immunodeficiency Virus Activities of Z - and E -Methylenecyclopropane Nucleoside Analogues and Their Phosphoro- l -Alaninate Diesters

Uchida

Yoshimura

Maeda

et al. 1999

Antimicrob Agents Chemother

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Nucleoside analogues with a Z-or an E-methylenecyclopropane moiety were synthesized and examined for activity against human immunodeficiency virus type 1 (HIV-1) in vitro. The addition of a methyl phenyl phosphoro-L-alaninate moiety to modestly active analogues resulted in potentiation of their anti-HIV-1 activity. Two such compounds, designated QYL-685 (with 2,6-diaminopurine) and QYL-609 (with adenine), were most potent against HIV-1 in vitro, with 50% inhibitory concentrations of 0.034 and 0.0026 M, respectively, in MT-2 cell-based assays. Both compounds were active against zidovudine-resistant, didanosine-resistant, and multidideoxynucleoside-resistant infectious clones in vitro. Further development of these analogues as potential therapies for HIV-1 infection is warranted.

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Synthesis and antiherpetic activity of (.+-.)-9-[[(Z)-2-(hydroxymethyl)cyclopropyl]methyl]guanine and related compounds

Cited by 91 publications

References 0 publications

Inhibition of human cytomegalovirus in culture by alkenyl guanine analogs of the thiazolo[4,5-d]pyrimidine ring system

Inhibition of human cytomegalovirus in culture by alkenyl guanine analogs of the thiazolo[4,5-d]pyrimidine ring system

Phosphine Ligands in the Palladium‐Catalysed Methoxycarbonylation of Ethene: Insights into the Catalytic Cycle through an HP NMR Spectroscopic Study

In Vitro Anti-Human Immunodeficiency Virus Activities of Z - and E -Methylenecyclopropane Nucleoside Analogues and Their Phosphoro- l -Alaninate Diesters

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