Biostructural features of additional jasplakinolide (jaspamide) analogues

Abstract

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.

Figure 1

Clarifying the bromination regiochemistry for 8 (this work) vs. literature.

Figure 2

Choosing between catechol and hydroquinone substructures of 13 and 14 using ¹H shifts (14. CD₃OD, 600 MHz) and selected gHMBC correlations (CD₃OD, DMSO-d₆).

Figure 3

Conversion of 14 to 15 with 1% TFA-d.

Figure 4

Anti-microfilament effects of compounds 1, 3, 8, 11 and 13 in HCT-116 and HeLa cells. F-actin is colored red and nuclei and chromosomes are colored green. Jasplakinolide (1) is used as a positive control, and negative controls are treated with DMSO. Screens were performed in duplicate and representative images are shown. Multiple images of control wells are included to demonstrate experiment variability.

Figure 5

Results of a clonogenic dose-response study with jasplakinolide (1) in HCT-116 cells. Cells were exposed to different concentrations of 1 for either 2 hrs, 24 hrs, or 7 days (continuous exposure).