From a collection of marine cyanobacteria made in the Coiba National Park along the Pacific coast of the Republic of Panama a novel cyclic depsipeptide, given the trivial name medusamide A, has been isolated and fully characterized. Medusamide A contains four contiguous β-amino acid (2R,3R)-3-amino-2-methylhexanoic acid (Amha) residues. This is the first report of multiple Amha residues and contiguous β-amino acid residues within a single cyclic peptide-type natural product. Stereochemical assignment of the Amha residues was completed following the synthesis of reference standards for this β-amino acid and the subsequent derivatization with Marfey’s reagent and LC–MS analysis.

Santacruzamate A (SCA) is a natural product isolated from a Panamanian marine cyanobacterium, previously reported to have potent and selective histone deacetylase (HDAC) activity. To optimize the enzymatic and cellular activity, 40 SCA analogues were synthesized in a systematic exploration of the zinc-binding group (ZBG), cap terminus, and linker region. Two cap group analogues inhibited proliferation of MCF-7 breast cancer cells, with analogous increased degranulation of cytotoxic T cells (CTLs), while one cap group analogue reduced CTL degranulation, indicative of suppression of the immune response. Additional testing of these analogues resulted in reevaluation of the previously reported SCA mechanism of action. These analogues and the resulting structure–activity relationships will be of interest for future studies on cell proliferation and immune modulation.

A dark brown tuft-forming cyanobacterium, morphologically resembling the genus Symploca, was collected during an expedition to the Coiba National Park, a UNESCO World Heritage Site on the Pacific coast of Panama. Phylogenetic analysis of its 16S rRNA gene sequence indicated that it is 4.5% divergent from the type strain for Symploca and thus is likely a new genus. Fractionation of the crude extract led to the isolation of a new cytotoxin, designated santacruzamate A (1), which has several structural features in common with suberoylanilide hydroxamic acid [(2), SAHA, trade name Vorinostat], a clinically approved histone deacetylase (HDAC) inhibitor used to treat refractory cutaneous T-cell lymphoma. Recognition of the structural similarly of 1 and SAHA led to the characterization of santacruzamate A as a picomolar level selective inhibitor of HDAC2, a Class I HDAC, with relatively little inhibition of HDAC4 or HDAC6, both Class II HDACs. As a result, chemical syntheses of santacruzamate A as well as a structurally intriguing hybrid molecule, which blends aspects of both agents (1 and 2), were achieved and evaluated for their HDAC activity and specificity.

Ethnopharmacological relevanceScutellaria barbata is a common herb in Traditional Chinese Medicine (TCM) most often used to treat cancer. S. barbata has been found to exhibit efficacy both in vitro and in vivo on a variety of cancer types. Similarly encouraging results have been shown in patients with metastatic breast cancer from Phase Ia and Ib clinical trials. This study aims to elucidate the current use of S. barbata by TCM practitioners and in current Western research.Materials and methodsSemi-structured interviews were conducted with fifteen TCM practitioners in Beijing and Nanjing, China to understand their clinical use of S. barbata. Practitioners were also asked to comment on the future development of TCM using Western research methods and the potential for integration of the two types of medicine in clinical therapy. Statistical analyses were conducted to compare use of S. barbata by disease and in conjunction with other herbs.ResultsCurrent Western research related to S. barbata is focused on cancer treatment, which corresponds to the most common use of S. barbata by TCM practitioners. Other common uses that practitioners reported included infection and inflammation, for which Beijing practitioners reported use of S. barbata more often than Nanjing practitioners (p<0.05). Hedyotis diffusa was found to be the most commonly cited herb to pair with S. barbata for cancer treatment (p<0.05). When compared to Western clinical trials of BZL101, an S. barbata extract, TCM practitioners reported using smaller doses of S. barbata in shorter durations, in combination with numerous other herbs with the goal to potentiate therapeutic efficacy and mitigate side effects. In addition, TCM practitioners repeatedly emphasized symptom differentiating as the key to achieving maximum therapeutic potential of S. barbata, a factor typically overlooked in Western research.ConclusionSimilarities and differences in diagnosis and treatment regimens between TCM practitioners and Western research have the potential to shed light on possible new avenues of research. Additional research may prove beneficial on possible synergistic effects of herbs commonly used with S. barbata, such as Hedyotis diffusa and Lobelia chinensis.Download high-res image (156KB)Download full-size image