DIAZONAMIDE A

Molecular Weight: 765.64 g/mol
Molecular Formula: C₄₀H₃₄Cl₂N₆O₆

Source: The tunicate Diazona angulata (CHORDATA)
Activity: Tubulin interactive agent
Status: Preclinical

The marine natural product Diazonamide A was first reported in 1991. It was extracted from the Philippine ascidian Diazona angulata by the William Fenical Chemistry Lab at the Scripp's Institution of Oceanography.

In preliminary bioactivity screens the new compound killed lab-cultured colon cancer cells. More detailed characterization and biomedical evaluation was hindered by a lack of source material and failed efforts to locate and collect more of the rare species from which the compound was isolated.

The structural complexity of the molecule made laboratory synthesis difficult, but funding from organizations like the American Cancer Society and the efforts of more than a dozen organic chemistry labs working toward the goal ultimately proved fruitful. In the process, synthetic chemists discovered that the original structure reported for the natural product was incorrect. When they finally synthesized an analog and then compared it to the original marine-derived product using X-ray crystalography and NMR, the differences became apparent. Subsequent to this discovery, a synthetic molecule structurally identical to natural diazonamide A has also been produced. Both analogs possess potent microtubulin interactive activity.

Diazonamide A is an inhibitor of microtubule assembly, arresting the process of cell division in cultures exposed to treatment. Examination of treated cells reveals a loss of spindle microtubule assemblies and also microtubules associated with the interphase stage of the cell cycle.

The precise mechanism of action is still under investiggation, but it has been postulated that the drug may bind tubulin at a unique site (e.g., distinct from dolastatin 10, vinca alkaloid, and other known binding sites), or that it may bind only weakly to unpolymerized tubulin but very strongly to fully formed microtubules. If the latter hypothesis is correct, it suggests that diazonamide A (and synthesized variants) could hold promise as a chemotherapeutant with unique microtubule inhibiting ability.

NCBI PubChem compound summary page - [ LINK ]

NCBI PubMed biomedical literature citations and abstracts - [ LINK ]

References

Cruz-Monserrate Z, Vervoort HC, Bai R, Newman DJ, Howell SB, Los G, Mullaney JT, Williams MD, Pettit GR, Fenical W, and E Hamel. 2003. Diazonamide A and a Synthetic Structural Analog: Disruptive Effects on Mitosis and Cellular Microtubules and Analysis of Their Interactions with Tubulin. Mol Pharmacol 63:1273-1280.

Newman DJ, and GM Cragg. 2004. Advanced preclinical and clinical trials of natural products and related compounds from marine sources. Current Medicinal Chemistry 11:1693-1713.