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Research ArticleArticle

Diazonamide A and a Synthetic Structural Analog: Disruptive Effects on Mitosis and Cellular Microtubules and Analysis of Their Interactions with Tubulin

Zobeida Cruz-Monserrate, Hélène C. Vervoort, Ruoli Bai, David J. Newman, Stephen B. Howell, Gerrit Los, Jeffrey T. Mullaney, Michael D. Williams, George R. Pettit, William Fenical and Ernest Hamel
Molecular Pharmacology June 2003, 63 (6) 1273-1280; DOI: https://doi.org/10.1124/mol.63.6.1273
Zobeida Cruz-Monserrate
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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Hélène C. Vervoort
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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Ruoli Bai
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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David J. Newman
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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Stephen B. Howell
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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Gerrit Los
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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Jeffrey T. Mullaney
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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Michael D. Williams
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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George R. Pettit
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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William Fenical
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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Ernest Hamel
Screening Technologies Branch (Z.C.-M., R.B., E.H.) and Natural Products Branch (D.J.N.), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography (H.C.V., W.F.) and Department of Medicine and the Cancer Center (S.B.H., G.L.), University of California at San Diego, La Jolla, California; and Department of Chemistry and Biochemistry and Cancer Research Institute, Arizona State University, Tempe, Arizona (J.T.M., M.D.W., G.R.P.)
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Abstract

The marine ascidian Diazona angulata was the source organism for the complex cytotoxic peptide diazonamide A. The molecular structure of this peptide was recently revised after synthesis of a biologically active analog of diazonamide A in which a single nitrogen atom was replaced by an oxygen atom. Diazonamide A causes cells to arrest in mitosis, and, after exposure to the drug, treated cells lose both interphase and spindle microtubules. Both diazonamide A and the oxygen analog are potent inhibitors of microtubule assembly, equivalent in activity to dolastatin 10 and therefore far more potent than dolastatin 15. This inhibition of microtubule assembly is accompanied by potent inhibition of tubulin-dependent GTP hydrolysis, also comparable with the effects observed with dolastatin 10. However, the remaining biochemical properties of diazonamide A and its analog differ markedly from those of dolastatin 10 and closely resemble the properties of dolastatin 15. Neither diazonamide A nor the analog inhibited the binding of [3H]vinblastine, [3H]dolastatin 10, or [8-14C]GTP to tubulin. Nor were they able to stabilize the colchicine binding activity of tubulin. These observations indicate either that diazonamide A and the analog have a unique binding site on tubulin differing from the vinca alkaloid and dolastatin 10 binding sites, or that diazonamide A and the analog bind weakly to unpolymerized tubulin but strongly to microtubule ends. If the latter is correct, diazonamide A and its oxygen analog should have uniquely potent inhibitory effects on the dynamic properties of microtubules.

  • Received November 4, 2002.
  • Accepted February 24, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (6)
Molecular Pharmacology
Vol. 63, Issue 6
1 Jun 2003
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Research ArticleArticle

Diazonamide A and a Synthetic Structural Analog: Disruptive Effects on Mitosis and Cellular Microtubules and Analysis of Their Interactions with Tubulin

Zobeida Cruz-Monserrate, Hélène C. Vervoort, Ruoli Bai, David J. Newman, Stephen B. Howell, Gerrit Los, Jeffrey T. Mullaney, Michael D. Williams, George R. Pettit, William Fenical and Ernest Hamel
Molecular Pharmacology June 1, 2003, 63 (6) 1273-1280; DOI: https://doi.org/10.1124/mol.63.6.1273

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Research ArticleArticle

Diazonamide A and a Synthetic Structural Analog: Disruptive Effects on Mitosis and Cellular Microtubules and Analysis of Their Interactions with Tubulin

Zobeida Cruz-Monserrate, Hélène C. Vervoort, Ruoli Bai, David J. Newman, Stephen B. Howell, Gerrit Los, Jeffrey T. Mullaney, Michael D. Williams, George R. Pettit, William Fenical and Ernest Hamel
Molecular Pharmacology June 1, 2003, 63 (6) 1273-1280; DOI: https://doi.org/10.1124/mol.63.6.1273
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