Antineoplastic Agents. 592. Highly Effective Cancer Cell Growth Inhibitory Structural Modifications of Dolastatin 10

Abstract

The dolastatin series of unique peptides, originally discovered as constituents of the sea hare Dolabella auricularia, is of increasing importance in providing biological leads, especially to new and useful anticancer drugs. Dolastatin 10 and three analogues, minor structural modifications designated auristatins, are currently in human cancer clinical trials. The present study was undertaken to explore delivery to the cancer sites by way of phosphate or quinoline modifications. The initial objectives, auristatin TP as sodium phosphate 3b (GI50 10−2–10−4 μg/mL), auristatin 2-AQ (4, GI50 10−2–10−3 μg/mL), and auristatin 6-AQ (5, GI50 10−4 μg/mL), exhibited superior cancer cell growth inhibitory properties.

Microtubule-Depolymerizing Agents Used in Antibody–Drug Conjugates Induce Antitumor Immunity by Stimulation of Dendritic Cells

“…The binding site is in close physical proximity to vinblastine, with dolastatins acting as noncompetitive inhibitors of vinblastine binding to tubulin (17). Of note, dolastatin 10 is a far more potent inhibitor of tumor growth in vitro and in vivo when compared with vinblastine (18). Subsequently, dolastatin 10 analogues, such as monomethylauristatin-E (MMAE), have been synthesized, which share an identical chemical structure of the core region, and therefore, display the same molecular mode of action, but have been functionalized in the terminal domains (19).…”

Current Status of Marine-Derived Compounds as Warheads in Anti-Tumor Drug Candidates

“…Then, in 2011, his group reported modifications [14] with increased water solubility, whilst still maintaining significant potency against tumor lines (10–100 pM depending upon the lines used). The syntheses and structures of other modifications are given at length in the papers referred to above [6,7,8,14].…”

Antitumour bioactive peptides isolated from marine organisms

“…synthesized a structural analogue of dolastatin 10, auristatin TP, and, based on phosphorylation and quinoline modification, explored the process of drug transportation to the tumour site. The results indicate that the novel auristatin compound exerts a strong inhibitory effect on the growth of a panel of tumour cells …”