Psammaplin A

Psammaplin A (208) Symmetrical bromotyrosine- derived disulfide Panobinostat (LBH-589) (209) Oncology Inhibits histone deacetylase (HDAC) Phase T/IT/ITT Novartis 945,946... 

Table 4. Chemical structures of natural product Psammaplin A through J, with HD AC and DNA methyltransferase (DNTB) inhibition values. Not tested shown as nt.

Ahn MY, Jung JH, Na YJ, Kim HS. (2008) A natural histone deacetylase inhibitor, Psammaplin A, induces cell cycle arrest and apoptosis in human endometrial cancer cells. Gynecol Oncol 108 27-33. 

McCulloch MWB, Coombs GS, Banerjee N, Bugni TS, Cannon KM, Harper MK, Veltri CA, Virshup DM. (2009) Psammaplin A as a general activator of cell-based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives. Bioorg Med Chem 17 2189-2198. 

Nicolaou, K.C. Hughes, R. Pfefferkom, J.A. Barluenga, S, (2001) Optimization and mechanistic studies of psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus. Angew. Chem. Int. Ed. Engl., 40,4296-310. 

There have been three reports of the same dimeric disulfide. It was first isolated from an unidentified sponge from Guam and the structure elucidated by analysis of spectral data. The (E,E) stereochemistry of the disulfide (500) was defined by comparing the I3C NMR spectroscopic data with those of the (E,Z)-isomer (501) that was obtained as an unstable minor product [425]. Compound 500 was isolated from a species of Psammaplysilla and was called psammaplin A [426]. It was also isolated from Thorectopsamma xana, collected from the same location in Guam, together with a minor dimeric metabolite bisaprasin (502). Both compounds inhibited growth of Staphylococcus aureus and Bacillus subtilis [427]. Psammaplin A (bisprasin) (500) was later isolated from a Dysidea species of sponge and shown to act on Ca2+-induced Ca2+ release channels of skeletal muscle [428]. 

Four minor metabolites, psammaplins B-D (503-505) and presammaplin A (506) were isolated from Psammaplysilla purpurea, in addition to psammaplin A (500). Psammaplin B (503) is a thiocyanate bromotyrosine derivative, while psammaplin C (502) is a sulfanamide. Psammaplin D (505) displayed antimicrobial activity and mild tyrosine kinase inhibition [429]. The psammaplins Ai (507) and A2 (508) and aplysinellins A (509) and B (510) were isolated from Aplysinella rhax from both Pohnpei and Palau. These compounds inhibit famesyl protein transferase and leucine aminopeptidase [430]. Another sample of A. rhax from the Great Barrier Reef, Australia contained psammaplin A 11 -sulfate (511) and bisaprasin ll -sulfate (512), both of which inhibited [3H]-l,3-dipropyl-8-cyclopentylxanthine binding to rat brain adenosine Ai receptors [431]. 

Pham NB, Butler MS, Quinn RJ (2000) Isolation of Psammaplin A 11 -Sulfate and Bisaprasin 11 -Sulfate from the Marine Sponge Aplysinella rhax. J Nat Prod 63 393... 

Tabudravu JN, Eijsink VGH, Gooday GW, Jaspars M, Komander D, Legg M, Synstad B, van Aalten DMF (2002) Psammaplin A, a Chitinase Inhibitor Isolated from the Fijian Marine Sponge Aplysinella rhax. Bioorg Med Chem 10 1123... 

Although biodiversity in terrestrial environments is extraordinary, oceans covering more than 70% of our planet represent a greater diversity of life. A small number of marine plants, animals, and microbes have already yielded over 12 000 novel compounds [10]. Among them, a great number of substances of marine origin have been reported to possess antimicrobial activity such as loloatins A-D, myticins A and B, psammaplin A, etc., which have been covered in several excellent reviews [10-12],... 

A second example of an activated chemical defense concerns the Indo Pacific sponge Aplysinella rhax, in which tissue damage results in the rapid enzymatic transformation of psammaplin A sulfate 63 into psammaplin A 64 exposure of 63 to tissue from other sponges does not result in any conversion. Compound 63 deters feeding by reef fish, but when offered a choice between psammaplin A and its sulfate, both foods were avoided. In aquarium assays with C. solandri, extracts of damaged tissue were more deterrent than extracts from intact tissue, but both treatments were less palatable than control foods. In choice experiments, C. solandri preferred food treated with 63 over 64.104... 

The isolation of psammaplin derivatives from the sponge PsammaplysiUa purpurea, in particular the only nonhalogenated analog, prepsammaplin A (105), allowed Jimenez and Crews to propose a biogenesis for this family of amino acid derivatives in which psammaplin A is formed by the linear combination of two bromotyrosine oxime derivatives and two rearranged cysteines [102]. 

Bromotyrosine-derived metabolites are often encountered in marine sponges of the families Aplysinidae and Pseudocer-atidae, in particular Pseudoceratina (= Psammaplysilla) purpurea. They show a variety of biological activities, which include antimicrobial, enzyme inhibitory, and antifouling activities. Psammaplysin A (47) is antimicrobial, cytotoxic, and antifouling, whereas psammaplin A (48) is an inhibitor of histone deacetylase (2). The marine sponge lanthella basta synthesizes at least 25 bastadins that are linear or cyclic peptides composed of four bromotyrosine residues [bastadin 5 (49)] and show antimicrobial, cytotoxic, and enzyme inhibitory activities as well as interaction with Ca + channels (21). 

Mora FD, Jones DK, Desai PV, et al. Bioassay for the identification of natural product-based activators of peroxisome proliferator-activated receptor-y (PPARy) the marine sponge metabolite psammaplin A activates PPARy and induces apoptosis in human breast cancer cells. J Nat Prod 2006 69 547-522. 

One of the earliest researchers in the area of natural product-like libraries is K.C. Nicolaou. Inspired by the total synthetic efforts of his group on many important natural product targets and coupled with his interest in synthetic methodology and chemical biology, Nicolaou reported a number of elegant examples (see Chapter 11) that include natural product-like libraries based upon Taxol, " sarcodictyins, epothiolones, vancomycin, muscone, and psammaplin a. ... 

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