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München, Germany

Aromatic aldehyde-derived thiosemicarbazones 4-6, the S-substituted modified thiosemicarbazones 7/8, and a vitamin A-derived (retinoid) thiosemicarbazone derivative 12 were investigated as inhibitors of human hepatitis C virus (HCV) subgenomic RNA replicon Huh7 ET (luc-ubi-neo/ET) replication. Compounds 4-6 and 12 were found to be potent suppressors of HCV RNA replicon replication. The trifluoromethoxy-substituted thiosemicarbazone 6 and the retinoid thiosemicarbazone derivative 12 were even superior in selectivity to the included reference agent recombinant human alpha-interferon-2b, showing potencies in the nanomolar range of concentration. In addition, compounds 5, 6, 8 and 12 were tested as inhibitors of cytopathic effect (CPE) induced by human varicella-zoster virus (VZV) and/or human cytomegalovirus (HCMV). Compounds 4-6, 8 and 12 were additionally examined as inhibitors of CPE induced by cowpox virus and vaccinia virus. Thiosemicarbazone 4 was inhibitory on cowpox and vaccinia virus replication comparable in potency and selectivity to the reference agent cidofovir. Retinoid thiosemicarbazone derivative 12 was active as micromolar inhibitor of VZV, HCMV, and, in addition, human immunodeficiency virus type 1 (HIV-1) replication. These results indicate that thiosemicarbazone derivatives are appropriate lead structures to be evaluated in targeted antiviral therapies for hepatitis C (STAT-C), and that the vitamin A-related thiosemicarbazone derivative 12 emerges as a broad-spectrum antiviral agent, co-suppressing the multiplication of important RNA and DNA viruses. © 2011 Elsevier Masson SAS. All rights reserved.

Schonleber A.,University of Bayreuth | Van Smaalen S.,University of Bayreuth | Weiss H.-C.,Currenta GmbH | Kesel A.J.,Chammunsterstr. 47
Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials | Year: 2014

At low temperatures the organic salt adamantan-1-ammonium 4-fluorobenzoate, C10H18N+·C7H 4FO2 -, possesses an incommensurately modulated crystal structure. The effect of the modulation on the atomic arrangement and intermolecular interactions is studied by analysing single-crystal X-ray diffraction data within the (3+1)-dimensional superspace approach and superspace group P21/n(α0γ)00. The modulation strongly affects the position of the atoms as well as their atomic displacement parameters. Nevertheless, the molecular cations and anions are built by rigid moieties, which vary their orientation with respect to each other as a function of the phase of the modulation t. Cations and anions are connected into slabs by dense N - H⋯O and C - H⋯F hydrogen-bonded networks, which are characterized by being rather rigid and which show only a little variation as a function of the phase of the modulation t. © 2014 International Union of Crystallography.

Kesel A.J.,Chammunsterstr. 47
Anti-Infective Agents | Year: 2012

The purpose of this contribution is to introduce an update on the bananins or trioxa-adamantane-triols (TATs), a class of anti-RNA-(corona)viral agents which are active against human severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and dengue virus type 2 (DENV-2). The prototype compound bananin (BN) inhibited replication of SARS-CoV through allosteric inhibition of SARS-CoV nsp13 ATPase/NTPase RNA/DNA helicase protein enzymatic function(s). The vanillinbananin (VANBA) blocked DENV-2 entry into host cells (Vero) by inhibiting endosome vacuole acidification, similar to concanamycin A. The structures of BN and VANBA were investigated by elemental analysis. It could be shown that both BN and VANBA matured after synthesis by poly-condensation of their 1,5,7-triol hydroxy groups, yielding brown to black colored powders. These high-polymer materials gave irregular NMR spectra, but re-constituted the monomeric TAT in aqueous media like cell culture and body fluids. Up to date eleven bananins [BN, IBNCA, ABNCA, ansaBN, euBN, VANBA, ethylVANBA, euVANBA, Ehrlich BN, [6]prismaneBN, nitrodiBN] were produced, four of which (BN, IBNCA, euBN, VANBA) inhibited both SARS-CoV replicase 1b protein nsp13 ATPase and DNA helicase enzymatic activity in vitro. The unique cage structure of the TATs was proved by NMR spectroscopy, IR spectroscopy, and UV/VIS spectrophotometry. Some modern two-dimensional NMR techniques (HH-COSY, gs-HMBC, gs-HSQC) and high resolution electrospray mass spectrometry (HR-ESI MS) were used to investigate the more complex bananins like [6]prismaneBN. The latter compound was reacted with all-trans-retinoic acid (ATRA) to yield the 12th TAT [6]prismaneBN-ATRA which served as tool for proving the general bananin structure(s) by HR-ESI MS. The group of TATs includes compounds with very unusual structures [ansaBN, [6]prismaneBN, nitrodiBN, [6]prismaneBN-ATRA], achieved only by skillful combination of organic synthetic achievements. The triazahexaprismane derivative [6]prismaneBN, and the dinitrohexaprismane derivative nitrodiBN, are the first successfully synthesized true hexaprismane [[6]prismane] derivatives. Because of theoretical considerations the bananins bear a great future intrinsic potential to inhibit RNA-viral replication of various RNA viruses, especially of hepatitis C virus (Flaviviridae), avian flu (influenza virus H5N1, Orthomyxoviridae), Ebola and Marburg virus (Filoviridae), Nipah and Hendra virus (Paramyxoviridae), Hantaan virus (Bunyaviridae), Lassa virus (Arenaviridae), yellow fever virus and dengue virus (Flaviviridae), tick-borne encephalitis virus (FSME virus, Flaviviridae), rabies virus (Rhabdoviridae), and, possibly, certain Picornaviridae (poliovirus, hepatitis A virus, coxsackievirus, echovirus, rhinovirus). Future work will be needed to define the true antiviral chemotherapeutic spectrum of the bananins which might in some way resemble the capacity of the first broad-spectrum virustatic drug ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), but, as to be expected, without exhibiting the pronounced host cell toxicity of ribavirin. © 2012 Bentham Science Publishers.

Kesel A.J.,Chammunsterstr. 47 | Day C.W.,Utah State University | Montero C.M.,Emory University | Montero C.M.,Veterans Affairs Medical Center | And 2 more authors.
Biochimica et Biophysica Acta - General Subjects | Year: 2016

Background Oxygen exists in two gaseous and six solid allotropic modifications. An additional allotropic modification of oxygen, the cyclooctaoxygen, was predicted to exist in 1990. Methods Cyclooctaoxygen sodium was synthesized in vitro from atmospheric oxygen, or catalase effect-generated oxygen, under catalysis of cytosine nucleosides and either ninhydrin or eukaryotic low-molecular weight RNA. Thin-layer chromatographic mobility shift assays were applied on specific nucleic acids and the cyclooctaoxygen sodium complex. Results We report the first synthesis and characterization of cyclooctaoxygen as its sodium crown complex, isolated in the form of three cytosine nucleoside hydrochloride complexes. The cationic cyclooctaoxygen sodium complex is shown to bind to nucleic acids (RNA and DNA), to associate with single-stranded DNA and spermine phosphate, and to be essentially non-toxic to cultured mammalian cells at 0.1-1.0 mM concentration. Conclusions We postulate that cyclooctaoxygen is formed in most eukaryotic cells in vivo from dihydrogen peroxide in a catalase reaction catalyzed by cytidine and RNA. A molecular biological model is deduced for a first epigenetic shell of eukaryotic in vivo DNA. This model incorporates an epigenetic explanation for the interactions of the essential micronutrient selenium (as selenite) with eukaryotic in vivo DNA. General significance Since the sperminium phosphate/cyclooctaoxygen sodium complex is calculated to cover the active regions (2.6%) of bovine lymphocyte interphase genome, and 12.4% of murine enterocyte mitotic chromatin, we propose that the sperminium phosphate/cyclooctaoxygen sodium complex coverage of nucleic acids is essential to eukaryotic gene regulation and promoted proto-eukaryotic evolution. © 2016 Elsevier B.V. All rights reserved.

Kesel A.J.,Chammunsterstr. 47 | Huang Z.,Southern Research Institute | Murray M.G.,Southern Research Institute | Prichard M.N.,University of Alabama at Birmingham | And 8 more authors.
Antiviral Chemistry and Chemotherapy | Year: 2014

Background: Human HBV and HIV integrate their retrotranscribed DNA proviruses into the human host genome. Existing antiretroviral drug regimens fail to directly target these intrachromosomal xenogenomes, leading to persistence of viral genetic information. Retinazone (RTZ) constitutes a novel vitamin A-derived (retinoid) thiosemicarbazone derivative with broad-spectrum antiviral activity versus HIV, HCV, varicella-zoster virus and cytomegalovirus. Methods: The in vitro inhibitory action of RTZ on HIV-1 strain LAI, human HBV strain ayw, HCV-1b strain Con1, enhanced green fluorescent protein-expressing Ebola virus Zaire 1976 strain Mayinga, wild-type Ebola virus Zaire 1976 strain Mayinga, human herpesvirus 6B and Kaposi's sarcoma-associated herpesvirus replication was investigated. The binding of RTZ to human glucocorticoid receptor was determined. Results: RTZ inhibits blood-borne human HBV multiplication in vitro by covalent inactivation of intragenic and intraexonic viral glucocorticoid response elements, and, in close analogy, RTZ suppresses HIV-1 multiplication in vitro. RTZ disrupts the multiplication of blood-borne human HCV and Ebola Zaire virus at nanomolar concentrations in vitro. RTZ has the capacity to bind to human glucocorticoid receptor, to selectively and covalently bind to intraexonic viral glucocorticoid response elements, and thereby to inactivate human genome-integrated proviral DNA of human HBV and HIV. Conclusions: RTZ represents the first reported antiviral agent capable of eradicating HIV and HBV proviruses from their human host. Furthermore, RTZ represents a potent and efficacious small-molecule in vitro inhibitor of Ebola virus Zaire 1976 strain Mayinga replication. © 2014 International Medical Press 1359-6535 (print) 2040-2066 (online).

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