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Terpenoids are among the most ubiquitous and diverse secondary metabolites observed in nature. Although actinomycete bacteria are one of the primary sources of microbially derived secondary metabolites, they rarely produce compounds in this biosynthetic class. The terpenoid secondary metabolites that have been discovered from actinomycetes are often in the form of biosynthetic hybrids called hybrid isoprenoids (HIs). HIs include significant structural diversity and biological activity and thus are important targets for natural product discovery. Recent screening of marine actinomycetes has led to the discovery of a new lineage that is enriched in the production of biologically active HI secondary metabolites. These strains represent a promising resource for natural product discovery and provide unique opportunities to study the evolutionary history and ecological functions of an unusual group of secondary metabolites. [ABSTRACT FROM AUTHOR]

Abstract: The discovery of the anticancer agent salinosporamide A (NPI-0052) resulted from the exploration of new marine environments and a commitment to the potential of the ocean to yield new natural products for drug discovery and development. Driving the success of this process was the linkage of academic research together with the ability and commitment of industry to undertake drug development and provide the resources and expertise to advance the entry of salinosporamide A (NPI-0052) into human clinical trials. This paper offers a chronicle of the important events that facilitated the rapid clinical development of this exciting molecule. [Copyright &y& Elsevier]

Abstract: Zygosporamide (1), a new cyclic pentadepsipeptide, was isolated from the seawater-based fermentation broth of a marine-derived fungus identified as Zygosporium masonii. The structure of 1, which is composed of α-hydroxyleucic acid and both d- and l-amino acids, was determined by combined spectral and chemical methods. Despite a simple structure, zygosporamide illustrated significant cytotoxicity in the NCI’s 60 cell line panel (median GI50 =9.1μM), with highly enhanced selectivity against the CNS cancer cell line SF-268 (GI50 =6.5nM) and the renal cancer cell line RXF 393 (GI50 ⩽5.0nM). [Copyright &y& Elsevier]

Two metabolites, phomoxin and phomoxide, as well as the previously synthesized antibiotic eupenoxide, have been isolated from the fermentation broth of a marine-derived fungus of the genus Phoma (strain CNC-651). The new compounds are highly oxygenated polyketides of a new structural class. Phomoxin contains an unusual cyclic carbonate functionality that is rare among natural products. The structures of the new metabolites were assigned by spectroscopic methods that relied heavily on 2D NMR spectroscopic analysis. [Copyright &y& Elsevier]

Seriniquinone (SQ) was initially described by our group as an antimelanoma drug candidate and now also as an antifungal drug candidate. Despite its promising in vitro effects, SQ translation has been hindered by poor water-solubility. In this paper, we described the challenging nanoformulation process of SQ, which culminated in the selection of a phosphatidylcholine-based lamellar phase (PLP1). Liposomes and nanostructured lipid carriers were also evaluated but failed to encapsulate the compound. SQ-loaded PLP1 (PLP1-SQ) was characterized for the presence of sedimented or non-dissolved SQ, rheological and thermal behavior, and irritation potential with hen's egg test on the chorioallantoic membrane (HET-CAM). PLP1 influence on transepidermal water loss (TEWL) and skin penetration of SQ was assessed in a porcine ear skin model, while biological activity was evaluated against melanoma cell lines (SK-MEL-28 and SK-MEL-147) and C. albicans SC5314. Despite the presence of few particles of non-dissolved SQ (observed under the microscope 2 days after formulation obtainment), PLP1 tripled SQ retention in viable skin layers compared to SQ solution at 12 h. This effect did not seem to relate to formulation-induced changes on the barrier function, as no increases in TEWL were observed. No sign of vascular toxicity in the HET-CAM model was observed after cutaneous treatment with PLP1. SQ activity was maintained on melanoma cells after 48 h-treatment (IC 50 values of 0.59–0.98 µM) whereas the minimum inhibitory concentration (MIC) against C. albicans after 24 h-treatment was 32-fold higher. These results suggest that a safe formulation for SQ topical administration was developed, enabling further in vivo studies. [Display omitted] [ABSTRACT FROM AUTHOR]

HPLC-UV guided isolation of the culture broth of a marine bacterium Saccharomonospora sp. CNQ-490 has led to the isolation of two new natural products, lodopyridones B and C ( 1 and 2 ) along with the previously reported lodopyridone A ( 3 ). Their chemical structures were established from the interpretation of 2D NMR spectroscopic data and the comparison of NMR data with the lodopyridone A ( 3 ). Lodopyridones B and C ( 1 and 2 ) possess the thiazole, and chloroquinoline groups which are characteristic features of these molecules. Lodopyridones A–C show weak inhibitory activities on the β-site amyloid precursor protein cleaving enzyme 1 (BACE1). [ABSTRACT FROM AUTHOR]

Six cytotoxic and antimicrobial metabolites of a new bromo-phenazinone class, the marinocyanins A-F ( 1 – 6 ), were isolated together with the known bacterial metabolites 2-bromo-1-hydroxyphenazine ( 7 ), lavanducyanin ( 8, WS-9659A) and its chlorinated analog WS-9659B ( 9 ). These metabolites were purified by bioassay-guided fractionation of the extracts of our MAR4 marine actinomycete strains CNS-284 and CNY-960. The structures of the new compounds were determined by detailed spectroscopic methods and marinocyanin A ( 1 ) was confirmed by crystallographic methods. The marinocyanins represent the first bromo-phenazinones with an N -isoprenoid substituent in the skeleton. Marinocyanins A-F show strong to weak cytotoxicity against HCT-116 human colon carcinoma and possess modest antimicrobial activities against Staphylococcus aureus and amphotericin-resistant Candida albicans . [ABSTRACT FROM AUTHOR]

Two actinomycetes, a member of the rare halophilic genus Streptomonospora and a Nocardiopsis sp. (Nocardiopsaceae), strains CNQ-082 and CNQ-675, respectively, were isolated from marine sediments collected off shore near La Jolla, California. HPLC-UV guided fractionations of the extracts of these strains yielded marinopyrones A–D ( 1 – 4 ), the structures of which were elucidated by interpretation of 1D and 2D NMR and HRMS spectroscopic data. Oxidative ozonation, followed by conversion of the acid product to an α-naphthyl amide, provided the absolute configuration at the chiral center on the side-chain. Marinopyrones A–D were examined for the inhibitory activity on nitric oxide production in LPS-activated mouse macrophage cells (RAW 264.7); marinopyrone D ( 4 ) was inhibitory with an IC 50 value of 13 μM. To our knowledge, marinopyrones A–C are only the second reported natural products from the rare halophilic genus Streptomonospora . [ABSTRACT FROM AUTHOR]

HPLC–UV guided isolation for the culture broth extract of the marine-derived bacterium Streptomyces sp. has led to the two 14-membered macrolides, 4 Z - ( 1 ) and 4 E -12-dehydroxykromycins ( 2 ). The chemical structures of compounds 1 and 2 were elucidated by spectral data, while the absolute stereochemistry of 1 and 2 were determined by application of circular dichroism (CD) and analysis of X-ray crystallographic data. [ABSTRACT FROM AUTHOR]

Abstract: Three new depsipeptides, fijimycins A–C (1–3), together with the known etamycin A (4), were isolated and identified from the fermentation broth of strain CNS-575, a Streptomyces sp. cultured from a marine sediment sample collected off Nasese, Fiji. The planar structures of the new fijimycins were assigned by combined interpretation of NMR and MS/MS spectroscopic data. These assignments were complicated by the fact that 1–3 occurred as complex amide conformational mixtures. The absolute configurations of the component amino acids were established using the Marfey’s method. Fijimycins A–C, and etamycin A, were shown to possess significant in vitro antibacterial activity against three methicillin-resistant Staphylococcus aureus (MRSA) strains with MIC100 values between 4 and 16μgmL−1. [Copyright &y& Elsevier]

Abstract: Reported herein is the isolation and structure elucidation of three highly modified peptides, actinoramides A–C (1–3), which are produced by a marine bacterium closely related to the genus Streptomyces. The planar structures of the actinoramides, which are composed of the unusual amino acids 2-amino-4-ureidobutanoic acid and 4-amino-3-hydroxy-2-methyl-5-phenylpentanoic acid, were assigned by chemical transformations and by interpretation of spectroscopic data, while the absolute configuration of these new peptides were defined by application of the advanced Marfey’s and Mosher’s methods. [Copyright &y& Elsevier]

Abstract: The synthesis and in vivo anti-inflammatory activity of a series of pseudopterosin analogues are presented. Synthetic tricyclic catechol aglycons with different substitution patterns were monofucosylated or -xylosylated. Anti-inflammatory activity was conserved over a wide range of structural modifications. The most active synthetic compound 33 reduced phorbol myristate acetate (PMA)-induced inflammation in the mouse ear by 72% at 50μg/ear. This corresponds to 80% of the activity of natural pseudopterosin A. [ABSTRACT FROM AUTHOR]

Abstract: Two new cyclic peptides, microsporins A and B (7 and 8), were isolated from culture extracts of the marine-derived fungus Microsporum cf. gypseum obtained from a sample of the bryozoan Bugula sp. collected in the U.S. Virgin Islands. The structures of the new compounds were determined by extensive interpretation of 2D NMR data and by chemical methods. Microsporins A and B are potent inhibitors of histone deacetylase and demonstrate cytotoxic activity against human colon adenocarcinoma (HCT-116), as well as against the National Cancer Institute 60 cancer cell panel. The total synthesis of microsporin A on solid-phase is also reported. [Copyright &y& Elsevier]

Abstract: Chemical investigation of the culture broth extracts of the marine-derived fungus Massarina sp. (strain CNT-016) has yielded two secondary metabolites, spiromassaritone (1) and massariphenone (2), as well as the previously reported fungal metabolites 6-epi-5′-hydroxy-mycosporulone (3) and enalin A (4). The structures of these compounds were established by a variety of one- and two-dimensional NMR experiments, while the relative configuration of spiromassaritone (1) was determined by X-ray crystallographic methods. The fungal strain was isolated as a sterile mycelium from an ocean mud sample and identified using ITS sequence analysis. [Copyright &y& Elsevier]

Abstract: Four cytotoxic meroterpenoids, tropolactones A–D, were isolated from the whole broth extract of a marine-derived fungus of the genus Aspergillus. The structures of the meroterpenoids were established through a variety of two-dimensional NMR techniques. The absolute configuration of tropolactone A was determined using the modified Mosher method. Tropolactones A–C contain an interesting substituted 2,4,6-cycloheptatriene (tropone) ring, which presumably arises through an oxidative ring expansion from tropolactone D. Tropolactones A, B and C showed in vitro cytotoxicity against human colon carcinoma (HCT-116) with IC50 values of 13.2, 10.9 and 13.9μg/mL. [Copyright &y& Elsevier]

Abstract: The induction of biosynthesis of four new diterpenoids was observed following the addition of a marine α-proteobacterium to an established culture of the marine-derived fungus Libertella sp. The fungal strain and the marine bacterium, cultured alone, do not produce diterpenoid metabolites. The induced diterpenoids, libertellenones A–D, are cross-conjugated ketones of the pimarane class. The libertellenones show varying levels of cytotoxicity against the HCT-116 human adenocarcinoma cell line with libertellenone D being the most potent (IC50 =0.76μM). [Copyright &y& Elsevier]

The mechanism by which marine algae show resistance to pathogenic microorganisms remains poorly understood. To examine the possible role that algal secondary metabolites play in the prevention of infection, we examined the abundant green alga Penicillus capitatus, one of the major shallow water algae found in the Tropical Atlantic Ocean. Both aqueous and EtOAc extracts of this alga were found to be potent inhibitors of the well-known marine algal pathogen Lindra thallasiae. Using L. thallasiae in bioassay-guided fractionation, we isolated two new triterpene sulfate esters, capisterones A () and B (). The capisterones are potent inhibitors of L. thallasiae at natural and below natural concentrations. The structures of the capisterones, with relative stereochemistry only, were assigned by comprehensive spectral analyses that relied heavily on 2D NMR methods. [Copyright &y& Elsevier]

Marine micro-organisms represent an under explored resource for the discovery of novel antiviral agents. Here, we describe a series of peptides designated halovirs A–E (1–5) that are produced during the saline fermentation of a marine-derived fungus of the genus Scytalidium. These lipophilic, linear peptides are potent in vitro inhibitors of the herpes simplex viruses 1 and 2. Evidence is presented that the halovirs directly inactivate herpes viruses, a mechanism of action that could be applicable in the prevention of HSV transmission. The total structures of these new compounds were established by a combination of spectral and chemical techniques. Salient structural features of the halovir hexapeptides include a nitrogen terminus acylated by myristic (C14) or lauric (C12) acid, an unusual Aib-Hyp dipeptide segment, and a carboxyl terminus reduced to a primary alcohol. A qualitative analysis of the secondary structures of these molecules using variable temperature NMR experiments and NOE analyses is also reported. [Copyright &y& Elsevier]

Human immunodeficiency virus (HIV) replication requires integration of viral cDNA into the host genome, a process mediated by the viral enzyme integrase. We describe a new series of HIV integrase inhibitors, thalassiolins A–C (1–3), isolated from the Caribbean sea grass Thalassia testudinum. The thalassiolins are distinguished from other flavones previously studied by the substitution of a sulfated β-d-glucose at the 7-position, a substituent that imparts increased potency against integrase in biochemical assays. The most active of these molecules, thalassiolin A (1), displays in vitro inhibition of the integrase catalyzed strand transfer reaction (IC50=0.4 μM) and an antiviral IC50 of 30 μM. Molecular modeling studies indicate a favorable binding mode is probable at the catalytic core domain of HIV-1 integrase. [Copyright &y& Elsevier]

Seriniquinone is a secondary metabolite isolated from a rare marine bacterium of the genus Serinicoccus. This natural quinone is highlighted for its selective cytotoxic activity toward melanoma cancer cells, in which rapid metastatic properties are still a challenge for clinical treatment of malignant melanoma. The progress of seriniquinone as a promising bioactive molecule for drug development requires the assessment of its clinical interaction potential with other drugs. This study aimed to investigate the in vitro inhibitory effects of seriniquinone on the main human CYP450 isoforms involved in drug metabolism. The results showed strong inhibition of CYP1A2, CYP2E1 and CYP3A, with IC 50 values up to 1.4 μM, and moderate inhibition of CYP2C19, with IC 50 value >15 μM. Detailed experiments performed with human liver microsomes showed that the inhibition of CYP450 isoforms can be explained by competitive and non-competitive inhibition mechanisms. In addition, seriniquinone demonstrated to be an irreversible and time-dependent inhibitor of CYP1A2 and CYP3A. The low inhibition constants values obtained experimentally suggest that concomitant intake of seriniquinone with drug metabolized by these isoforms should be carefully monitored for adverse effects or therapeutic failure. • Seriniquinone may cause undesired interactions with drugs in humans. • Seriniquinone is a moderate inhibitor of CYP2C19. • Seriniquinone is a strong, reversible and competitive inhibitor of CYP2E1. • Seriniquinone is a strong and time-dependent inhibitor of CYP1A2 and CYP3A. [ABSTRACT FROM AUTHOR]

Streptomyces sp. CNQ-509 is a marine actinomycete belonging to the MAR4 streptomycete lineage. MAR4 strains have been linked to the production of diverse and otherwise rare meroterpenoid compounds. The genome sequence of Streptomyces sp. CNQ-509 was found to contain 29 putative gene clusters for the biosynthesis of secondary metabolites, some of them potentially involved in the formation of meroterpenoid molecules. [ABSTRACT FROM AUTHOR]