Linda A. Morris

Metal binding of Lissoclinum patella metabolites. Part 1: Patellamides A, C and ulithiacyclamide A

Abstract Studies on three Thz, and Oxn containing cyclic peptides, patellamide A and C (1, 3) and ulithiacyclamide A (9) isolated from the Indo-Pacific ascidian (seasquirt) Lissoclinum patella have delineated their metal binding selectivity. Patellamide C (3) shows extreme selectivity for Cu2+ even in the presence of an excess of Zn2+ and shows no binding at all to Co2+, Ni2+ and Hg2+. Patellamide A (1) is less selective for Cu2+, whereas ulithiacyclamide A (9) shows selectivity similar to that of patellamide C (3). The selectivity was studied by circular dichroism spectroscopy and mass spectrometry. The CD spectra obtained whilst patellamide C was slowly titrated with Cu2+ show one isosbestic point indicating the Cu2+ binding involves only two conformations. These studies indicate that Cu2+, not Zn2+ is the biologically relevant metal for these compounds and point towards a potential ecological function of these complexes.

Axinellin C, a proline-rich cyclic octapeptide isolated from the Fijian marine sponge Stylotella aurantium

The structure of a new cyclic octapeptide, axinellin C, (cyclo[Thr1-Val2-Pro3-Trp4-Pro5-Phe6-Pro7-Leu8]), with all-trans peptide bond geometry, was elucidated by a combination of 2D NMR methods and tandem mass spectrometry. The solution state conformation was determined by ROE restrained molecular dynamics calculations. The structural features were found to be similar to those of the crystal structure of the cyclic decapeptide, phakellistatin 8, despite differing peptide sequences.

Wainunuamide, a histidine-containing proline-rich cyclic heptapeptide isolated from the Fijian marine sponge Stylotella aurantium

The isolation and structure determination of an unusual cyclic heptapeptide, wainunuamide, from a Fijian marine sponge, Stylotella aurantium, is reported. The peptide contains three proline residues and a histidine residue, which is rare in cyclic peptides and has only previously been reported in a cyclic peptide isolated from the cyanobacterium Oscillatoria agardhii, suggesting a possible source of the peptide. Wainunuamide is found to have weak cytotoxic activity.

Structure Determination and MSn Analysis of Two New Lissoclinamides Isolated from the Indo–Pacific Ascidian Lissoclinum patella: NOE Restrained Molecular Dynamics Confirms the Absolute Stereochemistry Derived by Degradative Methods

Abstract Two new lissoclinamides, lissoclinamides 9 and 10 were isolated from an Indonesian collection of the ascidian Lissoclinum patella along with the known patellamide C. The structures of the lissoclinamides were determined by a combination of 2D NMR, selective 1D TOCSY, MS and MSn techniques. The assignment of absolute stereochemistry was achieved by the hydrolysis of lissoclinamides 9 and 10 followed by chiral TLC. In the case of lissoclinamide 9, NOE restrained molecular dynamics studies were also performed confirming the proposed stereochemistry.

Metal binding of Lissoclinum patella metabolites. Part 2: Lissoclinamides 9 and 10

Abstract Studies on the Thz, Thn and Oxn containing cyclic peptides, lissoclinamides 9 ( 9 ) and 10 ( 10 ) isolated from the Indo-Pacific ascidian (seasquirt) Lissoclinum patella have delineated their metal binding selectivity. MS and CD competition studies show that lissoclinamide 10 ( 10 ) shows selectivity for Cu 2+ in the presence of an excess of Zn 2+ whereas lissoclinamide 9 ( 9 ) is less selective for Cu 2+ . Comparison of the solution state conformations derived from nOe restrained molecular dynamics and additional Monte–Carlo conformational searches suggested binding environments for the Cu 2+ which confirmed the MS measurements and suggested a reason for the selectivity in the case of lissoclinamides 9 and 10.

The capnellenes revisited: New structures and new biological activity

Abstract Three capnellanes have been isolated from the soft coral Capnella imbricata , one known ( 1 ) and two new structures ( 9, 10 ). Their structures were determined by a mixture of spectroscopic methods and comparisons to the previous literature. Cytotoxicity against a panel of cancer cell lines was determined for all the compounds with compound 1 showing an IC 50 of 0.7 μM against K562 leukaemia. In addition compound 9 was cytotoxic to promyelogenous leukaemia and 10 was active against renal leiomyoblastoma cells.

Conformational studies of free and Li+ complexed jasplakinolide, a cyclic depsipeptide from the Fijian marine sponge Jaspis splendens

The complexation of Li+ to jasplakinolide, a marine sponge derived cyclic depsipeptide showed preferential binding to two out of four carbonyl oxygens (C-10, C-14) and the electrons of the aromatic system of the beta-tyrosine amino acid residue. This is in contrast to previous results obtained by others who proposed complexation to three out of four available carbonyl oxygens (C-1, C-10, C-14). The structure of the complex in CD3CN was determined by NOE restrained molecular dynamic calculations. Structures of the uncomplexed jasplakinolide were calculated in CDCl3 and CD3CN for comparison.

Conformational change in the thiazole and oxazoline containing cyclic octapeptides, the patellamides. Part 2. Solvent dependent conformational change

Solvent dependent conformational change of the thiazole and oxazoline containing cyclic peptides, the patellamides, is examined by a combination of experimental and theoretical methods. A mechanism for the simultaneous formation of two type-II β-turns in the patellamides is proposed based on molecular dynamics and NOE restrained molecular dynamics studies as well as literature evidence. The effect of the solvent and desymmetrisation of the patellamides is crucial, with symmetrical patellamides in polar solvents giving the open type-I conformation, whereas symmetrical patellamides in non-polar solvents and asymmetrical patellamides in both polar and non-polar solvents give rise to the folded type-II conformation.

Conformational change in the thiazole and oxazoline containing cyclic octapeptides, the patellamides. Part 1. Cu2+ and Zn2+ induced conformational change

Conformational change during the binding of Cu2+ and Zn2+ to the thiazole and oxazoline containing cyclic octapeptides, the patellamides, is examined by a combination of experimental and theoretical methods. Circular dichroism and NOE-restrained molecular dynamics studies indicate that upon complexing with one equivalent of Cu2+, patellamide C undergoes a change in conformation which pre-organises a second Cu2+ binding site, and that the binding of a second Cu2+ induces no further conformational change. The binding of Zn2+ induces little conformational change in patellamide C. A restrained conformational search shows that the conformational change induced by the addition of one equivalent of Cu2+ to patellamide C is an intrinsic design feature of the system. Electronic structure calculations indicate that the patellamides provide an ideal coordination environment for Cu2+. On the basis of the evidence gathered, it can be proposed that Cu2+ is the biologically relevant metal for the patellamides.