Stellatolides, a New Cyclodepsipeptide Family from the Sponge Ecionemia acervus: Isolation, Solid-Phase Total Synthesis, and Full Structural Assignment of Stellatolide A

Abstract

The marine environment is a rich source of metabolites with potential therapeutic properties and applications for humans. Here we describe the first isolation, solid-phase total synthesis, and full structural assignment of a new class of cyclodepsipeptides from the Madagascan sponge Ecionemia acervus that shows in vitro cytotoxic activities at submicromolar concentrations. Seven structures belonging to a new family of compounds, given the general name stellatolides, were characterized. The sequence and stereochemistry of all the amino acids in these molecules were established by a combination of spectroscopic analysis, chemical degradation, and derivatization studies. Furthermore, the complete structure of stellatolide A was confirmed by an efficient solid-phase method for the first total synthesis and the full structural assignment of this molecule, including the asymmetric synthesis of the unique β-hydroxy acid moiety (Z)-3-hydroxy-6,8-dimethylnon-4-enoic acid.

Drugs and Drug Candidates from Marine Sources: An Assessment of the Current “State of Play”

“…The authors suggested that as a result of these findings, these three agents might be useful clinically in "Fanconizing" cancer cells in order to gain sensitivity against other antitumor drugs. The same year, Romano et al [50,51] reported that in in vitro and in vivo models, no relationship was found between the in vitro cytotoxic potency and in vivo antitumor activity in syngeneic mouse models, suggesting that there might well be a host response in these models. Also, the pharmacokinetics differ, even between the quite similar trabectedin and lurbinectedin in humans, and as expected due to the differences in structure, Zalypsis ® has been shown to differ in pharmacokinetics in humans [52].…”

“…The PharmaMar group recently presented data at the 2014 EORTEC meeting that demonstrated activity in these three modified marine-derived compounds (l " Fig. 7) [51,116,117]. Irvalec was pulled from clinical trials by PharmaMar at the Phase II level, so it is interesting that they are now reporting on it and the other two [118].…”

Marine Natural Peptides: Determination of Absolute Configuration Using Liquid Chromatography Methods and Evaluation of Bioactivities

“…Furthermore, the stereochemistry determination of amino acid residues in pipecolidepsins A ( 178 ) and B ( 179 ), isolated from the marine sponge Homophymia lamellose , confirmed the presence of several l and d amino acid residues, besides the (3 S ,4 R ) diMe- l -Glu and (2 S ,3 S )-EtO-Asp present in both peptides [ 148 ]. Stellatolide A ( 180 ), a cyclic depsipeptide isolated from Ecionemia acervus , was found to have N -Me- d -Ser and d - allo -Thr, among other l -configured amino acids [ 149 ]. The amino acid constituents of the cyclic depsipeptides cyclolithistide A ( 181 ) and nagahamide A ( 182 ), both isolated from the sponge Theonella swinhoei , were all found to have the S or l -configuration, and the 3-amino-5-hydroxybenzoic acid (AHBA) residue in nagahamide A ( 182 ) was established to have 3 S configuration [ 150 , 151 ].…”

Efficient total syntheses and biological activities of two teixobactin analogues

“…It is to be noted that excess Ile and base were required to drive the reaction to completion. 12 This was succeeded by (f) amide bond formation using Arg and subsequent (g) cleavage from the resin using 95 : 2.5 : 2.5 TFA : TIS : H 2 O. The final step was (h) the amide bond formation between Arg and Ala which proceeds smoothly yielding the desired cyclised fragment.…”