Intramolecular Modulation of Serine Protease Inhibitor Activity in a Marine Cyanobacterium with Antifeedant Properties

Extracts of the Floridian marine cyanobacterium Lyngbya cf. confervoides were found to deter feeding by reef fish and sea urchins (Diadema antillarum). This antifeedant activity may be a reflection of the secondary metabolite content, known to be comprised of many serine protease inhibitors. Further chemical and NMR spectroscopic investigation led us to isolate and structurally characterize a new serine protease inhibitor 1 that is formally derived from an intramolecular condensation of largamide D (2). The cyclization resulted in diminished activity, but to different extents against two serine proteases tested. This finding suggests that cyanobacteria can endogenously modulate the activity of their protease inhibitors

Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria

Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2

Nonhalogenated organic molecules from Laurencia algae

The marine red algae of the genus Laurencia have produced more 700 secondary metabolites and exhibited high molecular diversity and intriguing bioactivity. Since the halogenated structures have been comprehensively reviewed previously, this review, covering up to the end of 2012, mainly focuses on the source, structure elucidation, and bioactivity of nonhalogenated organic molecules from Laurencia spp. as well as the relationship between nonhalogenated and halogenated products. Overall, 173 new or new naturally occurring compounds with 58 skeletons, mainly including sesquiterpenes, diterpenes, triterpenes, and C15-acetogenins, are described.The marine red algae of the genus Laurencia have produced more 700 secondary metabolites and exhibited high molecular diversity and intriguing bioactivity. Since the halogenated structures have been comprehensively reviewed previously, this review, covering up to the end of 2012, mainly focuses on the source, structure elucidation, and bioactivity of nonhalogenated organic molecules from Laurencia spp. as well as the relationship between nonhalogenated and halogenated products. Overall, 173 new or new naturally occurring compounds with 58 skeletons, mainly including sesquiterpenes, diterpenes, triterpenes, and C-15-acetogenins, are described

Novel naphthoquinones from Conospermum incurvum

During the reisolation of the trimeric naphthoquinone derivative conocurvone [1] from an extract of the Australian shrub Conospermum incurvum, six monomeric naphthoquinones were isolated. These include three novel 1,4-naphthoquinone derivatives: 3-methyl-14,15-dihydro-15-hydroxyteretifolione B [3], 3-methyl-14,15-dihydro-15-hydroxyteretifolione B methyl ether [4], and 2,3-dimethyl-6-hydroxy-7-methoxy-1,4-naphthoquinone [5]. In addition, the previously reported compounds 3-methylteretifolione B [6], 3-methylteretifolione B methyl ether [7], and 8-geranyl-2,7-dihydroxy-3-methyl-1,4-naphthoquinone [8] were isolated and identified. The structures of the novel 1,4-naphthoquinones were elucidated by spectral methods. While conocurvone [1] is a potent inhibitor of HIV-1-induced cell killing, all of the monomeric naphthoquinone derivatives were inactive against HIV-1