Inhibition of RNA polymerase by captan at both DNA and substrate binding sites

Genetic toxicology of folpet and captan

“…injection, which increases bioavailability of folpet and limits the neutralizing actions of cellular thiols� Because i.p. injection bypasses the normal routes of exposure, it does not simulate anticipated human exposure� DNA polymerases, similar to histones, are integrally linked to DNA integrity� In vitro biochemical investigations have demonstrated that captan inhibits DNA polymerase by competing for the same site as the DNA while not interfering with the fidelity of the DNA polymerase I copy of the DNA template (Dillwith and Lewis, 1982)� Using captan as an inhibitor of viral reverse transcriptase, the differential effects of captan on DNA polymerase and RNase H activity could be determined Simmon et al, 1977Reassessment Jones et al 1984 In vitro Simmon et al, 1977Reassessment Jones et al 1984 In vitro (Freeman-Wittig et al�, 1986)� RNase H activity was 10-fold more sensitive to captan than either DNA-dependent or RNAdependent DNA polymerase� Based on the observation that dithiothreitol prevented captan inhibition, it was concluded that the trichloromethylthio moiety of captan was involved in the inhibitory action (Freeman-Wittig et al�, 1986)� Captan was subsequently found to be active at but not limited to the nucleoside triphosphate binding site and DNA binding site of the RNA polymerase (Luo and Lewis, 1992)� A number of in vitro studies have been conducted with the goal of elucidating key elements associated with folpet and captan's mutagenicity� The reactivity of folpet, captan, and thiophosgene is such that within an in vitro environment reactions will occur with available thiols� The in vitro environment is distinct from the intact animal� Although these mechanistic studies speak to possible modes of mutagenic action, they are not performed in systems comparable to the in vivo setting where captan and folpet mutagenicity is absent�…”

Redox-Regulated Inhibition of T7 RNA Polymerase via Establishment of Disulfide Linkages by Substituted Dppz Dirhodium(II,II) Complexes

“…It appears that several dirhodium complexes achieve transcription inhibition in vitro by binding to the RNA polymerase, 29 whereas cisplatin interferes with transcription primarily by forming 1,2-d(GpG) intrastrand cross-links with DNA, the result of which is the hijacking of various proteins to the platinated sites and disruption of their normal function. [32][33][34] It has been documented that apart from transcription inhibition by modification/damage to the DNA, [35][36][37] suppression of transcription can arise from drug binding to the active site of RNA Polymerase, from blocking of the DNA/RNA channel, 38,39 or from targeting of transcription factors. 40 The bacteriophage T7-RNA Polymerase (T7-RNAP) system is a relatively simple enzyme that carries out the transcription cycle in an identical manner to that of bacterial and eukaryotic RNAPs; 41,42 the single-subunit T7-RNAP protein (99 kDa) is capable of initiation, elongation, and termination.…”

“…Dirhodium compounds are also known to be potent inhibitors of transcription − and DNA replication in vitro. It appears that several dirhodium complexes achieve transcription inhibition in vitro by binding to the RNA polymerase, whereas cisplatin interferes with transcription primarily by forming 1,2-d(GpG) intrastrand cross-links with DNA, the result of which is the hijacking of various proteins to the platinated sites and disruption of their normal function. − It has been documented that apart from transcription inhibition by modification/damage to the DNA, − suppression of transcription can arise from drug binding to the active site of RNA Polymerase, from blocking of the DNA/RNA channel, , or from targeting of transcription factors …”

Effect of Axial Coordination on the Electronic Structure and Biological Activity of Dirhodium(II,II) Complexes

“…The principal mode of action of many antitumor drugs and antiviral agents takes place through the disruption of transcription and related processes. − These include anticancer agents such as actinomycin D, − anthracycline antibiotics, , daunorubicin, , and cisplatin, , among others. − In general, the inhibition of transcription by these drugs takes place through their interaction with, modification of, or damage to template DNA, − but in some cases the mechanism involves the binding of the drug to the active site of RNA polymerase, blocking of the DNA/RNA channel, , or by targeting transcription factors . The developed cellular resistance and the effectiveness of each agent against certain cancers but not others are limitations of the current drugs, which have prompted the search for new compounds. − …”