Benzothiazolyl and Benzoxazolyl Hydrazones Function as Zinc Metallochaperones to Reactivate Mutant p53
We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure–act...
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Published in | Journal of medicinal chemistry Vol. 64; no. 4; pp. 2024 - 2045 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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25.02.2021
Amer Chemical Soc |
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Abstract | We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure–activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated C1 to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified C85 as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 in vitro and in vivo. |
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AbstractList | We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure–activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated C1 to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified C85 as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 in vitro and in vivo. We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure–activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated C1 to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified C85 as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 in vitro and in vivo . We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure-activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 and . |
Author | Yu, Xin Carpizo, Darren R Blanden, Adam R Kimball, S. David Na, Bing Bencivenga, Anthony F Roberge, Jacques Y Blayney, Alan J Gilleran, John A Augeri, David J Loh, Stewart N |
AuthorAffiliation | Division of Surgical Oncology, Department of Surgery Department of Biochemistry and Molecular Biology Rutgers Molecular Design and Synthesis, Office of Research and Economic Development Program of Surgical Oncology, Rutgers Cancer Institute of New Jersey Department of Surgery, Robert Wood Johnson Medical School University of Rochester Medical Center Wilmot Cancer Center |
AuthorAffiliation_xml | – name: Department of Surgery, Robert Wood Johnson Medical School – name: Division of Surgical Oncology, Department of Surgery – name: Wilmot Cancer Center – name: Program of Surgical Oncology, Rutgers Cancer Institute of New Jersey – name: University of Rochester Medical Center – name: Rutgers Molecular Design and Synthesis, Office of Research and Economic Development – name: Department of Biochemistry and Molecular Biology |
Author_xml | – sequence: 1 givenname: John A surname: Gilleran fullname: Gilleran, John A organization: Rutgers Molecular Design and Synthesis, Office of Research and Economic Development – sequence: 2 givenname: Xin surname: Yu fullname: Yu, Xin organization: Department of Surgery, Robert Wood Johnson Medical School – sequence: 3 givenname: Alan J surname: Blayney fullname: Blayney, Alan J organization: Department of Biochemistry and Molecular Biology – sequence: 4 givenname: Anthony F surname: Bencivenga fullname: Bencivenga, Anthony F organization: Rutgers Molecular Design and Synthesis, Office of Research and Economic Development – sequence: 5 givenname: Bing surname: Na fullname: Na, Bing organization: Department of Surgery, Robert Wood Johnson Medical School – sequence: 6 givenname: David J surname: Augeri fullname: Augeri, David J organization: Rutgers Molecular Design and Synthesis, Office of Research and Economic Development – sequence: 7 givenname: Adam R surname: Blanden fullname: Blanden, Adam R organization: Department of Biochemistry and Molecular Biology – sequence: 8 givenname: S. David surname: Kimball fullname: Kimball, S. David organization: Rutgers Molecular Design and Synthesis, Office of Research and Economic Development – sequence: 9 givenname: Stewart N surname: Loh fullname: Loh, Stewart N organization: Department of Biochemistry and Molecular Biology – sequence: 10 givenname: Jacques Y orcidid: 0000-0002-7810-4139 surname: Roberge fullname: Roberge, Jacques Y organization: Rutgers Molecular Design and Synthesis, Office of Research and Economic Development – sequence: 11 givenname: Darren R surname: Carpizo fullname: Carpizo, Darren R email: darren.carpizo@urmc.rochester.edu organization: Wilmot Cancer Center |
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Keywords | 2-ACETYLPYRIDINE SITE 2-BENZOXAZOLYL THIOSEMICARBAZONES CHELATORS COPPER CONFORMATION BINDING ANTITUMOR MOLECULES |
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Notes | S.N.L, J.Y.R., and D.R.C. are co-senior authors. J.G., X.Y., and A.J.B. contributed equally to this work. Author Contributions |
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Snippet | We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc... |
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SubjectTerms | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Benzothiazoles - chemical synthesis Benzothiazoles - pharmacology Benzothiazoles - therapeutic use Benzoxazoles - chemical synthesis Benzoxazoles - pharmacology Benzoxazoles - therapeutic use Cell Line, Tumor Chelating Agents - chemical synthesis Chelating Agents - pharmacology Chelating Agents - therapeutic use Chemistry, Medicinal Humans Hydrazones - chemical synthesis Hydrazones - pharmacology Hydrazones - therapeutic use Life Sciences & Biomedicine Mice Mice, Nude Molecular Structure Neoplasms - drug therapy Pharmacology & Pharmacy Photosensitizing Agents - chemical synthesis Photosensitizing Agents - pharmacology Photosensitizing Agents - therapeutic use Science & Technology Structure-Activity Relationship Tumor Suppressor Protein p53 - drug effects Tumor Suppressor Protein p53 - metabolism Xenograft Model Antitumor Assays Zinc - metabolism |
Title | Benzothiazolyl and Benzoxazolyl Hydrazones Function as Zinc Metallochaperones to Reactivate Mutant p53 |
URI | http://dx.doi.org/10.1021/acs.jmedchem.0c01360 http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestApp=WOS&DestLinkType=FullRecord&UT=000624369300015 https://www.ncbi.nlm.nih.gov/pubmed/33538587 https://pubmed.ncbi.nlm.nih.gov/PMC9278656 |
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