Development of novel inhibitor probes of DNA polymerase III based on dGTP analogs of the HPUra type: base, nucleoside and nucleotide derivatives of N2-(3,4-dichlorobenzyl)guanine
dc.contributor.author | Butler, Michelle Marie | |
dc.contributor.author | Dudycz, Lech W. | |
dc.contributor.author | Khan, Naseema N. | |
dc.contributor.author | Wright, George E. | |
dc.contributor.author | Brown, Neal C. | |
dc.date | 2022-08-11T08:08:52.000 | |
dc.date.accessioned | 2022-08-23T16:10:44Z | |
dc.date.available | 2022-08-23T16:10:44Z | |
dc.date.issued | 1990-12-25 | |
dc.date.submitted | 2008-08-14 | |
dc.identifier.citation | <p>Nucleic Acids Res. 1990 Dec 25;18(24):7381-7.</p> | |
dc.identifier.issn | 0305-1048 (Print) | |
dc.identifier.pmid | 2259629 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/33001 | |
dc.description.abstract | 6-(p-Hydroxyphenylhydrazino)uracil (H2-HPUra) is a selective and potent inhibitor of the replication-specific class III DNA polymerase (pol III) of Gr+ bacteria. Although formally a pyrimidine, H2-HPUra derives its inhibitory activity from its specific capacity to mimic the purine nucleotide, dGTP. We describe the successful conversion of the H2-HPUra inhibitor prototype to a bona fide purine, using N2-(benzyl)guanine (BG) as the basis. Structure-activity relationships of BGs carrying a variety of substituents on the aryl ring identified N2-(3,4-dichlorobenzyl)guanine (DCBG) as a nucleus equivalent to H2-HPUra with respect to potency and inhibitor mechanism. DCBdGTP, the 2'-deoxyribonucleoside 5'-triphosphate form of DCBG, was synthesized and characterized with respect to its action on wild-type and mutant forms of B. subtilis DNA pol III. DCBdGTP acted on pol III by the characteristic inhibitor mechanism and formally occupied the dNTP binding site with a fit which permitted its polymerization. | |
dc.language.iso | en_US | |
dc.relation | <p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2259629&dopt=Abstract ">Link to article in PubMed</a></p> | |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC332876/ | |
dc.subject | Base Sequence; Binding Sites; DNA Polymerase III; Deoxyguanine Nucleotides; Guanine; Molecular Sequence Data; Uracil | |
dc.subject | Life Sciences | |
dc.subject | Medicine and Health Sciences | |
dc.title | Development of novel inhibitor probes of DNA polymerase III based on dGTP analogs of the HPUra type: base, nucleoside and nucleotide derivatives of N2-(3,4-dichlorobenzyl)guanine | |
dc.type | Journal Article | |
dc.source.journaltitle | Nucleic acids research | |
dc.source.volume | 18 | |
dc.source.issue | 24 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/gsbs_sp/155 | |
dc.identifier.contextkey | 578119 | |
html.description.abstract | <p>6-(p-Hydroxyphenylhydrazino)uracil (H2-HPUra) is a selective and potent inhibitor of the replication-specific class III DNA polymerase (pol III) of Gr+ bacteria. Although formally a pyrimidine, H2-HPUra derives its inhibitory activity from its specific capacity to mimic the purine nucleotide, dGTP. We describe the successful conversion of the H2-HPUra inhibitor prototype to a bona fide purine, using N2-(benzyl)guanine (BG) as the basis. Structure-activity relationships of BGs carrying a variety of substituents on the aryl ring identified N2-(3,4-dichlorobenzyl)guanine (DCBG) as a nucleus equivalent to H2-HPUra with respect to potency and inhibitor mechanism. DCBdGTP, the 2'-deoxyribonucleoside 5'-triphosphate form of DCBG, was synthesized and characterized with respect to its action on wild-type and mutant forms of B. subtilis DNA pol III. DCBdGTP acted on pol III by the characteristic inhibitor mechanism and formally occupied the dNTP binding site with a fit which permitted its polymerization.</p> | |
dc.identifier.submissionpath | gsbs_sp/155 | |
dc.contributor.department | Department of Biochemistry and Molecular Pharmacology | |
dc.contributor.department | Graduate School of Biomedical Sciences | |
dc.source.pages | 7381-7 |