Fluorescent analogs of the marine natural product psammaplin A: synthesis and biological activity

Abstract

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 (IC(50) 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.

Marine Compounds and Cancer

“…and could be interesting for treatment approaches targeting epigenetic alterations, since it showed potent inhibition of histone deacetylases (HDAC, IC50 4.2 ± 2.4 nM) [143]. The psammaplin-derived thiol (125, Figure 30) exhibited potent activity against histone deacetylases in a low nanomolar range, but showed low cytotoxicity [144]. Five HDAC1 inhibitors, trichostatin A (126, Figure 30 Ten extracts from various marine sponges were identified as containing inhibitors of the transcription factor HIF-2 which has been shown to play a distinct role in tumorigenesis.…”

“…Cancer preventive compounds may stimulate anticancer immunity, inhibit inflammation, angiogenesis and tumor invasion, or protect from UV-radiation damage [144][145][146][147]. Preincubation with mytilan, a polysaccharide isolated from the mussel Crenomytilus grayanus, was followed by a normalization of the activity indicators of human peripheral blood lymphocytes and by a reduction of the number of morphological defects of the marine invertebrates larvae after UV-irradiation [148].…”

“…One of the transcription factor regulated by fatty acids is the peroxisome proliferator-activated receptors (PPARs), which are members of the nuclear hormone receptor family, the largest family of transcription factors [142]. Three PPAR have been identified including PPAR , PPAR / , and PPAR [143], all of them can be activated by naturally occurring fatty acids or fatty acid derivatives [144]. Their functions underlie a multitude of cellular and physiological processes by directly modulating target gene expression and indirectly modulating other transcription factors [142,143].…”

<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

“…According to the synthesis of 4a and b, 2 (100 mg, 0.51 mmol) was selectively converted to (E)-oxime 44) 5a (63.5 mg, 50%) as a colorless powder and (E)-oxime-methyl ester 5b (31.6 mg, 24%) as a colorless powder, respectively (Chart 5). …”

Triggering of Suicidal Erythrocyte Death by Psammaplin A

“…Psammaplin A, a symmetrical bromotyrosine-derived disulfide isolated from marine sponges [1][2][3][4][5], has previously been shown to trigger apoptosis of tumor cells [6][7][8][9] and is considered a potential drug for the treatment of malignancy [6][7][8][9][10][11][12][13][14]. Psammaplin A inhibits histone deacetylase and proved to be a powerful epigenetic modifier [3,6,10,[15][16][17][18][19][20][21].…”