User:Pepe.king.prawn/Diazonamide A

Diazonamide A

Diazonamide A is a chlorinated peptide natural product isolated from the marine invertebrate Diazona chinensis. It attracted attention as a result of errors in its initial structure assignment. The unprecedented structure and potent cytotoxicity of diazonamide A have prompted several total syntheses enabling elucidation of its true structure and further investigation into its potential use as an antineoplastic drug.

First total synthesis.

Reassignment of structure by Harran et al (2001)

Nicolaou 2002.

Nicolaou 2003.

Nicolaou 2004.

Synthesis Harran et al

AB-5, a C25 and C27 deschloro analogue of diazonamide A, shows high potency (IC50 < 10 nM) in vitro against numerous human cancer cell lines. Its cytotoxicity was found comparable to taxane or vinca alkaloid antimitotic drugs. AB-5 showed promising pharmacokinetic performance in vivo, and no overt toxicity was observed when administered intravenously to mice at 20 mg/kg.

History


The isolation and structure of diazonamide A was reported in 1991 by William Fenical, Jon Clardy and co-workers. It was isolated from Diazona chinensis, an ascidian, collected in the Philippines along the northwest coast of Siquijor. Diazonamide A was found to be a potent (IC50 < 15 ng/mL) cytotoxic agent when tested against HCT-116 human colon carcinoma and B-16 murine melanoma cell lines. The structural connectivity could not be completely assigned by correlation spectroscopy, and thus the structures of diazonamide A and B were inferred from an single crystal x-ray structure of a derivative of diazonamide B. The original structural assignments are shown at the left. In 2001, Harran and co-workers completed a total synthesis of the originally proposed structure, which proved to be unstable, prompting reassignment of the structure.