Carcinostatic activity of thiosemicarbazones of formyl heteroaromatic compounds. VII. 2-Formylpyridine derivatives bearing additional ring substituents

French, Frederic A.; Blanz, Erwin J.; DoAmaral, Jefferson R.; French, D. A.

doi:10.1021/jm00300a025

Cited by 70 publications

(19 citation statements)

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“…This possibility is supported by the known affinity of thiosemicarbazones for Cu++ (8,9) and other cations of the first transition series (9). Biologically, Cu++ has been shown to be necessary for the antitumor activity of a thiosemicarbazone derivative (11) and is suspected to be involved in the antitumor activity of several other derivatives (16,17). More speculatively, the inhibition of the recently purified DNA polymerase of chick embryo cells by o-phenanthroline (18) could be due to a chelate since this compound strongly binds cupric ions.…”

Section: Resultsmentioning

confidence: 96%

Inhibition of RNA-Dependent DNA Polymerase of Rous Sarcoma Virus by Thiosemicarbazones and Several Cations

Levinson

Faras

Woodson

et al. 1973

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

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The RNA-dependent DNA polymerase of Rous -sarcoma virus is inhibited by N-methyl isatin j8-thiosemicarbazone and by thiosemicarbazide, but not by semicarbazide. These inhibitors also inactivate, upon contact with the virion, the transforming ability of Rous sarcoma virus. Sulfhydryl donors, such as 2-mercaptoethanol, can prevent these effects. The RNA-directed activity of the purified polymerase is inhibited to a greater degree than is the DNA-directed activity. N-methyl isatin g-thiosemicarbazone (Me-IBT) inhibits the growth of pox viruses (1, 2), and is effective in the prophylaxis of smallpox (3) and in the treatment of eczema vaccinatum, a complication of smallpox vaccination (4). Additional in vitro studies have extended the spectrum of action of this drug to include other groups of viruses, such as adenovirus, herpesvirus, picornavirus, reovirus, arbovirus, and myxo-and paramyxovirus viruses (5, 6). In these cases, inhibition of the virus was obtained by treatment of the cells after infection.In contrast, we have recently reported that Rous sarcoma virus (RSV) can be inactivated by exposure to the drug before infection (7). Other RNA tumor viruses, such as mouse sarcoma virus, and leukemia virus, and feline sarcoma virus, are similarly inactivated (unpublished observations). However, RNA-containing cytopathic viruses, including Newcastle disease virus, poliovirus, and vesicular stomatitis virus, are not affected (ref. 7, and unpublished results).In our previous paper (7), we described several negative attempts to determine the mechanism of inactivation (including inhibition of the RNA-dependent DNA polymerase). Subsequent experiments, reported here, have demonstrated that the RNA-dependent DNA polymerase of RSV is, indeed, inhibited by Me-IBT and that the presence of 2-mercaptoethanol prevented the action of IBT in our original experiments. The observation that a drug that inhibits the RNAdependent DNA polymerase also inactivates the transforming ability of the virus provides evidence for the importance of this enzyme to malignant transformation by RSV.Since thiosemicarbazones are strong chelators of copper (8, 9), a role for the cupric ion in the antiviral and antitumor activity of these drugs has been postulated and supported experimentally (10, 11). Therefore, we tested the effect of copper and several other cations on the transforming ability and on the RNA-dependent DNA polymerase activity of RSV. It was found that, at a concentration of 40 IAM, Cu++ and Hg++ inhibited both the transforming ability and the enzyme activity. In addition, low doses of Cu++ and Me-IBT, which had little effect on the virus, caused significant inhibition of enzyme activity and inactivation of transforming ability when mixed together. These findings lend support to the previously stated hypothesis that the action of thiosemicarbazones is related to their ability to chelate metallic ions (16).Other cations (Ag+, Co++, Zn++, Cd++, and Ni++) can significantly inactivate the RNA-dependent DNA polymerase but have a minor ...

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Section: Resultsmentioning

confidence: 96%

Inhibition of RNA-Dependent DNA Polymerase of Rous Sarcoma Virus by Thiosemicarbazones and Several Cations

Levinson

Faras

Woodson

et al. 1973

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

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“…N,N 0 -Disubstituted thiourea derivatives have attracted attention due to their coordination behaviour with transition metals (Schuster et al, 1990). The biological activities, such as antibacterial, antifungal, antitubercular, antithyroid and insecticidal, of complexes with thiourea derivatives have also been studied (Madan & Taneja, 1991;Frech et al, 1970). We present here the crystal structure of the title thiourea compound, (I).…”

Section: Commentmentioning

confidence: 99%

1-(3-Chlorobenzoyl)-3-phenylthiourea

2006

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“…These compounds and their chemical relatives have been shown to have marked antibacterial, antiviral, antifungal, and most intriguingly, antineoplastic activity 1 . Heterocyclic thiosemicarbazones are believed to exercise their beneficial therapeutic properties in mammalian cells by inhibiting ribonucleotide reductase in the synthesis of DNA precursors 2 . The non-heme iron subunit has been shown to be inhibited/inactivated by thiosemicarbazones 3 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of 2-pyridineformamide 3-pyrrolidinylthiosemicarbazone

Shakya

Yadav

2013

J. Nepal Chem. Soc.

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Carcinostatic activity of thiosemicarbazones of formyl heteroaromatic compounds. VII. 2-Formylpyridine derivatives bearing additional ring substituents

Cited by 70 publications

References 0 publications

Inhibition of RNA-Dependent DNA Polymerase of Rous Sarcoma Virus by Thiosemicarbazones and Several Cations

Inhibition of RNA-Dependent DNA Polymerase of Rous Sarcoma Virus by Thiosemicarbazones and Several Cations

1-(3-Chlorobenzoyl)-3-phenylthiourea

Synthesis and characterization of 2-pyridineformamide 3-pyrrolidinylthiosemicarbazone

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