Discovery and Synthesis of Caracolamide A, an Ion Channel Modulating Dichlorovinylidene Containing Phenethylamide from a Panamanian Marine Cyanobacterium cf. Symploca Species

Abstract

A recent untargeted metabolomics investigation into the chemical profile of 10 organic extracts from cf. Symploca spp. revealed several interesting chemical leads for further natural product drug discovery. Subsequent target-directed isolation efforts with one of these, a Panamanian marine cyanobacterium cf. Symploca sp., yielded a phenethylamide metabolite that terminates in a relatively rare gem-dichlorovinylidene moiety, caracolamide A (1), along with a known isotactic polymethoxy-1-alkene (2). Detailed NMR and HRESIMS analyses were used to determine the structures of these molecules, and compound 1 was confirmed by a three-step synthesis. Pure compound 1 was shown to have in vitro calcium influx and calcium channel oscillation modulatory activity when tested as low as 10 pM using cultured murine cortical neurons, but was not cytotoxic to NCI-H460 human non-small-cell lung cancer cells in vitro (IC > 10 μM).

Marine natural products

“…137 A dichlorovinylidenephenethylamide containing NP, caracolamide A 262, was iden-tied and synthesised using a three-step process. 138 Caracolamide A 262 showed in vitro calcium inux and calciumchannel oscillation modulatory activity against murine cortical neurons at concentrations as low as 10 pM. Two chlorinated fatty acid amide derivatives, columbamides D 263 and E 264, were isolated from Moorea bouilloni, collected near Mantanani Island, Sabah, Malaysia.…”

Marine Pharmacology in 2016–2017: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

“…Finally, and as shown in Table 2, several marine compounds (226)(227)(228)(229)(230)(231)(232)(233)(234) affected the nervous system, but their detailed molecular mechanisms of action remained undetermined at the time of publication: a novel Indonesian Aplysinellidae sponge-derived bromotyrosine araplysillin X (226) that inhibited the aspartic protease BACE1 involved in AD [247]; a novel Panamanian marine cyanobacterium cf. Symploca sp.-derived terpene caracolamide A (227) with in vitro calcium influx and calcium channel oscillation modulatory activity [248]; a Mexican marine cone snail Conus spurius peptide conorfamide-Sr3 (228) shown to block Shaker subtype voltage-gated potassium channels [249]; a new conopeptide contryphan-Bt (229) isolated from the South China Sea cone snail Conus betulinus shown to be neurotoxic to mice [250]; acetylcholinesterase inhibitory activity in two know meroterpenoids, dehydroaustin (230) isolated from the Chinese mangrove endophytic fungus Aspergillus sp. 16-5c [251], and terreulactone C (233) isolated from the South China Sea mangrove-derived endophytic fungus Penicillium sp.…”

Advances in the Biotechnological Potential of Brazilian Marine Microalgae and Cyanobacteria

“…In addition to participating in cell photoprotection, when stimulated by some biotic or abiotic factor, the secondary metabolism of microalgae and cyanobacteria is aroused for the production of some metabolites that may have biological activities of great biotechnological importance, such as sterols, toxins and some amino acids that have the ability to activate viral capsule structures, preventing their cell multiplication, thereby marking an antiviral agent ( Figure 2 ) [ 7 , 19 , 29 ].…”