83030-43-7Relevant academic research and scientific papers
Fluorescent analogs of the marine natural product psammaplin A: Synthesis and biological activity
Hentschel, Fabia,Sasse, Florenz,Lindel, Thomas
experimental part, p. 7120 - 7133 (2012/09/22)
The symmetrical disulfide psammaplin A from the marine sponge Pseudoceratina sp. was synthesized and structurally altered by replacement of one of the α-(hydroxyimino)acyl units by a fluorescent 4-coumarinacetyl moiety. Thus, the first fluorescent analogs of psammaplin A were obtained. Structural variation also covered the substitution pattern of the phenyl ring. Cytotoxicity of psammaplin A against the mouse fibroblast cell line L-929 (IC50 0.42 μg mL-1) was about two-fold higher than that of the fluorescent hybrid compounds, whereas the disulfide containing two 4-coumarinacetyl moieties was inactive. Fluorescence microscopy revealed uptake of the 4-coumarinacetyl-α-(hydroxyimino)acyl hybrids into the cytoplasm leading to fluorescence in close proximity of the nuclear envelope, most likely in the Golgi apparatus. We did not observe strong fluorescence inside the nucleus, where most of the target histone deacetylases are located. We conclude that reduction of the disulfide probably takes place outside the nucleus. The psammaplin-derived thiol exhibited potent activity against histone deacetylase in the low nanomolar range, but diminished cytotoxicity. Antimicrobial activity of the new derivatives was also determined.
Epigenetic profiling of the antitumor natural product psammaplin A and its analogues
Garcia, Jose,Franci, Gianluigi,Pereira, Raquel,Benedetti, Rosaria,Nebbioso, Angela,Rodriguez-Barrios, Fatima,Gronemeyer, Hinrich,Altucci, Lucia,Lera, Angel R. De
experimental part, p. 3637 - 3649 (2011/08/03)
A collection of analogues of the dimeric natural product psammaplin A that differ in the substitution on the (halo)tyrosine aryl ring, the oxime and the diamine connection has been synthesized. The effects on cell cycle, induction of differentiation and apoptosis of the natural-product inspired series were measured on the human leukaemia U937 cell line. Epigenetic profiling included induction of p21WAF1, effects on global H3 histone and tubulin acetylation levels as well as in vitro enzymatic assays using HDAC1, DNMT1, DNMT3A, SIRT1 and a peptide domain with p300/CBP HAT activity. Whereas the derivatives of psammaplin A with modifications in the length of the connecting chain, the oxime bond and the disulfide unit showed lower potency, the analogues with changes on the bromotyrosine ring exhibited activities comparable to those of the parent compound in the inhibition of HDAC1 and in the induction of apoptosis. The lack of HDAC1 activity of analogues modified on the disulfide bond suggests that its cleavage must occur in cells to produce the monomeric Zn2+-chelating thiol. This assumption is consistent with the molecular modelling of the complex of psammaplin A thiol with h-HDAC8. Only a weak inhibition of DNMT1, DNMT3A and residual activities with SIRT1 and a p300/CBP HAT peptide were measured for these compounds.
TOTAL SYNTHESIS OF BASTADINS
Nishiyama, Shigeru,Yamamura, Shosuke
, p. 1281 - 1284 (2007/10/02)
Bastadins-1, -2 and -3, the novel metabolites originated from four bromotyrosine units, were synthesized, and each geometry at the oxime C=N double bonds was unambiguously determined to be anti.
