Biostructural Features of Additional Jasplakinolide (Jaspamide) Analogues

• Published in: Journal of natural products (Washington, D.C.) Vol. 74; no. 3; pp. 341 - 351
• Main Authors: Watts, Katharine R, Morinaka, Brandon I, Amagata, Taro, Robinson, Sarah J, Tenney, Karen, Bray, Walter M, Gassner, Nadine C, Lokey, R. Scott, Media, Joseph, Valeriote, Frederick A, Crews, Phillip
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society and American Society of Pharmacognosy 25.03.2011; Amer Chemical Soc; American Society of Pharmacognosy
• Subjects: Actins - metabolism; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Cytotoxins - chemistry; Cytotoxins - isolation & purification; Cytotoxins - pharmacology; Depsipeptides - chemistry; Depsipeptides - isolation & purification; Depsipeptides - pharmacology; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fiji; General pharmacology; HCT116 Cells; HeLa Cells; Humans; Life Sciences & Biomedicine; Marine Biology; Medical sciences; Molecular Structure; National Cancer Institute (U.S.); Peptides, Cyclic; Pharmacognosy. Homeopathy. Health food; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plant Sciences; Science & Technology; Stereoisomerism; United States; Fiji; Melanesia; Oceania; United States; BREAST-CANCER CELLS; F-ACTIN; (+)-JASPLAKINOLIDE JASPAMIDE; SPONGE JASPIS-SPLENDANS; ACTIN-TARGETING DEPSIPEPTIDES; CONFIGURATIONAL ASSIGNMENT; NATURAL CYCLODEPSIPEPTIDE JASPAMIDE; CHONDROMYCES-CROCATUS MYXOBACTERIA; GEODIAMOLIDE-A; MARINE SPONGE; Antineoplastic agent; Human; Solid tumor; Peptides; Cyclic peptides; Pharmacognosy; Tripeptide; Animal origin; Cytotoxicity; Uterine cervix; In vitro; Hela cell line; Biological activity; Marine environment; Cell line; Depsipeptide; Porifera; Isolation; Colon; Invertebrata; Tumor cell; Structural analysis
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np100721g

The cyclodepsipeptide jasplakinolide (1) (aka jaspamide), isolated previously from the marine sponge Jaspis splendens, is a unique cytotoxin and molecular probe that operates through stabilization of filamentous actin (F-actin). We have recently disclosed that two analogues of 1, jasplakinolides B (3) and E, were referred to the National Cancer Institute’s (NCI) Biological Evaluation Committee, and the objective of this study was to reinvestigate a Fijian collection of J. splendens in an effort to find jasplakinolide congeners with similar biological properties. The current efforts have afforded six known jasplakinolide analogues (4−7, 9, 10), two structures requiring revision (8 and 14), and four new congeners of 1 (11−13, 15) including open-chain derivatives and structures with modified β-tyrosine residues. Compounds were evaluated for biological activity in the NCI’s 60 cell line screen and in a microfilament disruption assay in both HCT-116 and HeLa cells. These two phenotypic screens provide evidence that each cytotoxic analogue, including jasplakinolide B (3), operates by modification of microfilaments. The new structure jasplakinolide V (13) has also been selected for study by the NCI’s Biological Evaluation Committee. In addition, the results of a clonogenic dose−response study on jasplakinolide are presented.