PT  - JOURNAL ARTICLE
AU  - Zobeida Cruz-Monserrate
AU  - Hélène C. Vervoort
AU  - Ruoli Bai
AU  - David J. Newman
AU  - Stephen B. Howell
AU  - Gerrit Los
AU  - Jeffrey T. Mullaney
AU  - Michael D. Williams
AU  - George R. Pettit
AU  - William Fenical
AU  - Ernest Hamel
TI  - Diazonamide A and a Synthetic Structural Analog: Disruptive Effects on Mitosis and Cellular Microtubules and Analysis of Their Interactions with Tubulin
AID  - 10.1124/mol.63.6.1273
DP  - 2003 Jun 01
TA  - Molecular Pharmacology
PG  - 1273--1280
VI  - 63
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/63/6/1273.short
4100  - http://molpharm.aspetjournals.org/content/63/6/1273.full
SO  - Mol Pharmacol2003 Jun 01; 63
AB  - 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.