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β-lactams are a chemically diverse group of molecules with a wide range of biological activities. Having recently observed curious trends in 2 J HH coupling values in studies on this structural class, we sought to obtain a more comprehensive understanding of these diagnostic NMR parameters, specifically interrogating 1 J CH , 2 J CH , and 2 J HH , to differentiate 3- and 4-monosubstituted β-lactams. Further investigation using computational chemistry methods was employed to explore the geometric and electronic origins for the observed and calculated differences between the two substitution patterns., (© 2024 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.)

A simple empirical method is described that allows the assignment of absolute configurations of natural products containing chiral vicinal bromochloro (VBC) units, including the bromochloro substituted isoprenyl units present in the structures of antiproliferative halomon ( 1a ) and its halogen-swapped isomer iso -halomon ( 1b ) from the red alga, Portieria hornemannii , and callophycols A ( 3 ) and B ( 4 ) from Callophycus serratus . The relative configurations of 3 and 4 , published in 2007, were incomplete: C-16 was left unassigned. It is now shown that the additivity of molar rotations, [ M ] D (herein, abbreviated [ M ])─a consequence of van't Hoff's principle of optical superposition─could be used to deconvolute rotatory contributions, designated as [ M X ] and [ M Y ] of the two remotely spaced chiral substructures within 3 and 4 using simple arithmetic. Input of proxy values, [ M Y 1 ] and [ M Y 2 ], for the two different VBC units in two equations for [ M X ] and application of a "conditional test" returns the same value for [ M X ] only when a proxy with the correct configuration is included. It is revealed that 3 and 4 have opposite configurations at the C-16 stereocenter: 16 S and 16 R , respectively. Two important implications lie in these findings: 3 and 4 appear to qualify as paired-regioisomers, coupled through a putative dyotropic rearrangement (DR), and the biosyntheses of other Callophycus secondary metabolites, now numbering over 50, are tightly controlled by stereoelectronic considerations including neighboring group interactions of the DR. It now appears, counter to earlier suggestions, that the chirality of Callophycus secondary metabolites, despite their high chemodiversity, are surprisingly highly conserved. Enantiofacial halogenation additions to the C═C double bonds of precursor alkenes appear to direct the formation of the remaining stereocenters at both the halogenated benzoate-decalin core and the distal VBC of 3 and 4 . A consistent hypothesis is proposed to account for macrolactonizations in other Callophycus natural products including bromophycolides A and B. The conditional test of molar rotations was applied in a different context to understand the chiroptical properties and trends observed in the highly iodinated meroditerpenes, iodocallophycols A-E, also from Callophycus sp., resulting in the revision of the configuration of callophycol E from (10 R ,14 R ) to (10 S ,14 S ).

Culture-based microbial natural product discovery strategies fail to realize the extraordinary biosynthetic potential detected across earth's microbiomes. Here we introduce Small Molecule In situ Resin Capture (SMIRC), a culture-independent method to obtain natural products directly from the environments in which they are produced. We use SMIRC to capture numerous compounds including two new carbon skeletons that were characterized using NMR and contain structural features that are, to the best of our knowledge, unprecedented among natural products. Applications across diverse marine habitats reveal biome-specific metabolomic signatures and levels of chemical diversity in concordance with sequence-based predictions. Expanded deployments, in situ cultivation, and metagenomics facilitate compound discovery, enhance yields, and link compounds to candidate producing organisms, although microbial community complexity creates challenges for the later. This compound-first approach to natural product discovery provides access to poorly explored chemical space and has implications for drug discovery and the detection of chemically mediated biotic interactions., (© 2024. The Author(s).)

Protecting groups (PGs) in peptide synthesis have inspired advanced design principles that incorporate "orthogonality" for selective C- and N-terminus and side-chain deprotections. The conventionally acid-stable 9-fluorenylmethoxycarbonyl (Fmoc) group is one of the most widely used N-protection groups in solid- and solution-phase synthesis. Despite the versatility of Fmoc, deprotection by the removal of the Fmoc group to unmask primary amines requires the use of a basic secondary amine nucleophile, but this stratagem poses challenges in sensitive molecules that bear reactive electrophilic groups. An expansion of PG versatility, a tunable orthogonality, in the late-stage synthesis of peptides would add flexibility to the synthetic design and implementation. Here, we report a novel Fmoc deprotection method using hydrogenolysis under mildly acidic conditions for the synthesis of Z-Arg-Lys-acyloxymethyl ketone (Z-R-K-AOMK). This new method is not only valuable for Fmoc deprotection in the synthesis of complex peptides that contain highly reactive electrophiles, or other similar sensitive functional groups, that are incompatible with traditional Fmoc deprotection conditions but also tolerant of N-Boc groups present in the substrate., Competing Interests: The authors declare the following competing financial interest(s): Dr. Vivian Hook has an equity position at American Life Science Pharmaceuticals (ALSP) and is a founder and advisor to ALSP. V. Hook’s spouse, G. Hook, is co-founder with an equity position at ALSP. VHs conflict has been disclosed and is managed by her employer, the University of California, San Diego., (© 2024 The Authors. Published by American Chemical Society.)

Petrosamine ( 1 )-a colored pyridoacridine alkaloid from the Belizean sponge, Petrosia sp., that is also a potent inhibitor of acetylcholine esterase (AChE)-was investigated by spectroscopic and computational methods. Analysis of the petrosamine-free energy landscapes, p K a and tautomerism, revealed an accurate electronic depiction of the molecular structure of 1 as the di-keto form, with a net charge of q = +1, rather than a dication ( q = +2) under ambient conditions of isolation-purification. The pronounced solvatochromism (UV-vis) reported for 1 , and related analogs were investigated in detail and is best explained by charge delocalization and stabilization of the ground state (HOMO) of 1 rather than an equilibrium of competing tautomers. Refinement of the molecular structure 1 by QM methods complements published computational docking studies to define the contact points in the enzyme active site that may improve the design of new AChE inhibitors based on the pyridoacridine alkaloid molecular skeleton.

Geobarrettin D ( 1 ), a new bromoindole alkaloid, was isolated from the marine sponge Geodia barretti collected from Icelandic waters. Its structure was elucidated by 1D, and 2D NMR (including 1 H- 15 N HSQC, 1 H- 15 N HMBC spectra), as well as HRESIMS data. Geobarrettin D ( 1 ) is a new 6-bromoindole featuring an unusual purinium herbipoline moiety. Geobarrettin D ( 1 ) decreased secretion of the pro-inflammatory cytokine IL-12p40 by human monocyte derived dendritic cells, without affecting secretion of the anti-inflammatory cytokine IL-10. Thus, compound 1 shows anti-inflammatory activity.

Nine bromotyrosine alkaloids (BTAs), including debromoianthelline ( 1 ), pseudoceratinic acid ( 2a ), methyl pseudoceratinate ( 2b ), 13-oxo-ianthelline ( 3 ), aiolochroiamides A-D ( 4a , b and 5a , b) , and 7-hydroxypurealidin J ( 6 ), were isolated from a Bahamian Aiolochroia crassa (Hyatt; previously, Pseudoceratina crassa ). The structures of 1 - 6 were established from 1 H, 13 C, and 2D NMR spectra, IR, and mass spectrometry data. Compounds 2 - 4 comprise an O -methyl-2,6-dibromotyrosyl ketoxime (subunit A) amide linked to variable groups (subunit B). Compound 1 is debromoianthelline, and 2a and 2b are amides of 3-aminopropanoic acid and methyl 3-aminopropanoate, respectively. BTAs 3 and 4 are linked to 5-(2-aminoethyl)-2-iminoimidazolidin-4-one and a hexahydropyrrolo[2,3- d ]imidazol-2(1 H )-imine nucleus, respectively, whereas 5 is a self-dimerization motif of an aryl pyruvamide. Alkaloid 6 contains a spirocyclohexadienyl-isoxazoline-carboxamide amide coupled to 2-aminohistamine similar to that found in purealidin J and aerophobin-1 but with hydroxylation at C-7. The 2,4-diaminobutanoic acid residue in 3 was determined to be a 2:1 L- and D- mixture based on hydrolysis followed by derivatization with L-FDTA and LCMS. Diastereomeric pairs, 4a , b and 5a , b , were racemic. The relative configurations of 4a , 4b , 5a , and 5b were assigned by comparison of 1 H and 13 C chemical shifts with those calculated by DFT. Compounds 5a , b , ningalamide B ( 9 ), and ianthelline ( 7 ) moderately inhibited butyrylcholinesterase and Candida and Cryptococcus spp.

Examination of the MeOH extract of the sponge, Pseudoceratina cf. verrucosa , Berquist 1995 collected near Ningaloo Reef, Western Australia for selective acetylcholinesterase (AChE) inhibitors, yielded five new bromotyrosine alkaloids, methyl purpuroceratates A and B ( 1b and 2b ), purpuroceratic acid C ( 3a ), and ningalamides A and B ( 4 and 5 ). The structures of 1 - 4 share the dibromo-spirocyclohexadienyl-isoxazoline (SIO) ring system found in purealidin-R, while ketoxime 5 is analogous to ianthelline and purpurealidin I. The planar structures of all five compounds were obtained from analysis of MS, 1D and 2D NMR data, and the absolute configuration of the spiroisoxazoline (SIO) unit was assigned by electronic circular dichroism (ECD) and comparison with standards prepared by total synthesis of methyl purpuroceratate C, (±)- 3b . Compound 4 is the most complex SIO described, to date. The configuration of the homoserine module ( C ) in 4 was ascertained, after acid hydrolysis, by derivatization of an l-tryptophanamide derivative based on Marfey's reagent. Chiral-phase HPLC, with comparison to synthetic standards, revealed that most SIOs isolated from P. cf. verrucosa were configurationally heterogeneous; some, essentially racemic. Chiral-phase HPLC, with UV-ECD detection, is demonstrated as a superlative method for configurational assignment and quantitation of the enantiomeric composition of SIOs. Two SIOs─aerophobin-1 and aplysinamisine II─emerged as selective inhibitors of AChE over butyrylcholinesterase (BuChE, IC 50 ratio >10), while aplysamine-2 moderately inhibited both cholinesterases (ChEs, IC 50 , (AChE) 0.46 μM; IC 50 , (BuChE) 1.03 μM). SIO alkaloids represent a potential new structural manifold for lead-discovery of new therapeutics for treatment of Alzheimer's disease.

As part of a collaborative biomedical investigation of actinomycete bacteria isolated from sediments collected along the northern coast of Egypt (Mediterranean Sea), we explored the antibacterial metabolites from a bacterium identified as a Streptomyces sp., strain EG32. HPLC analysis and antibacterial testing against methicillin-resistant Staphylococcus aureus (MRSA) resulted in the identification of six compounds related to the resistoflavin and resistomycin class. Two of these metabolites were the chlorine-containing analogues chlororesistoflavins A ( 1 ) and B ( 2 ). The absolute configurations of the lone stereogenic center (C-11b) in these metabolites were assigned by analysis of their ECD spectra. Interestingly, the ECD spectrum of chlororesistoflavin A ( 1 ) shows a Cotton effect of the n-π* transition antipodal to that of the parent natural product, a consequence of 1,3-allylic strain induced by the adjacent bulky chlorine atom that distorts the coplanarity of the carbonyl group with the π-system. The chiroptical analysis thus resolves the paradox and uniformly aligns the configuration of all analogues as identical to that reported for natural resistoflavin. Chlororesistoflavins A ( 1 ) and B ( 2 ) exhibited antibacterial activity against MRSA with a minimum inhibitory concentration of 0.25 and 2.0 μg/mL, respectively.

Oceanalin B ( 1 ), an α,ω-bipolar natural product belonging to a rare family of sphingoid tetrahydoisoquinoline β-glycosides, was isolated from the EtOH extract of the lyophilized marine sponge Oceanapia sp. as the second member of the series after oceanalin A ( 2 ) from the same animal. The compounds are of particular interest due to their biogenetically unexpected structures as well as their biological activities. The structure and absolute stereochemistry of 1 as a α,ω-bifunctionalized sphingoid tetrahydroisoquinoline β-glycoside was elucidated using NMR, CD and MS spectral analysis and chemical degradation. Oceanalin B exhibited in vitro antifungal activity against Candida glabrata with a MIC of 25 μg/mL.

Oceanapiside (OPS), a marine natural product with a novel bifunctional sphingolipid structure, is fungicidal against fluconazole-resistant Candida glabrata at 10 μg/mL (15.4 μM). The fungicidal effect was observed at 3 to 4 h after exposure to cells. Cytological and morphological studies revealed that OPS affects the budding patterns of treated yeast cells with a significant increase in the number of cells with single small buds. In addition, this budding morphology was found to be sensitive in the presence of OPS. Moreover, the number of cells with single medium-sized buds and cells with single large buds were decreased significantly, indicating that fewer cells were transformed to these budding patterns, suggestive of inhibition of polarized growth. OPS was also observed to disrupt the organized actin assembly in C. glabrata , which correlates with inhibition of budding and polarized growth. It was also demonstrated that phytosphingosine (PHS) reversed the antifungal activity of oceanapiside. We quantified the amount of long chain-bases (LCBs) and phytoceramide from the crude extracts of treated cells using LC-ESI-MS. PHS concentration was elevated in extracts of cells treated with OPS when compared with cells treated with miconazole and amphotericin B. Elevated levels of PHS in OPS-treated cells confirms that OPS affects the pathway at a step downstream of PHS synthesis. These results also demonstrated that OPS has a mechanism of action different to those of miconazole and amphotericin B and interdicts fungal sphingolipid metabolism by specifically inhibiting the step converting PHS to phytoceramide.

Chemical investigation of the marine bryozoan Flustra foliacea collected in Iceland resulted in isolation of 13 new bromotryptamine alkaloids, flustramines Q-W ( 1 - 7 ) and flustraminols C-H ( 8 - 13 ), and two new imidazole alkaloids, flustrimidazoles A and B ( 14 and 15 ), together with 12 previously described compounds ( 16 - 27 ). Their structures were established by detailed spectroscopic analysis using 1D and 2D NMR and HRESIMS. Structure 2 was verified by calculations of the 13 C and 1 H NMR chemical shifts using density functional theory. The relative and absolute configurations of the new compounds were elucidated on the basis of coupling constant analysis, NOESY, [α] D , and ECD spectroscopic data, in addition to chemical derivatization. The compounds were tested for in vitro anti-inflammatory activity using a dendritic cell model. Eight compounds ( 1 , 3 , 5 , 13 , 16 , 18 , 26 , and 27 ) decreased dendritic cell secretion of the pro-inflammatory cytokine IL-12p40, and two compounds ( 4 and 14 ) increased secretion of the anti-inflammatory cytokine IL-10. Deformylflustrabromine B ( 27 ) showed the most potent anti-inflammatory effect (IC 50 2.9 μM). These results demonstrate that F. foliacea from Iceland expresses a broad range of brominated alkaloids, many without structural precedents. The potent anti-inflammatory activity in vitro of metabolite 27 warrants further investigations into its potential as a lead for inflammation-related diseases.

Chlorocyclopropanes (CCPs) conjugated to alk-yn-enes occur in a unique family of polyketide natural products from marine sponges. Synthesis of several optically enriched analogs of CCPs and measurement of their UV-vis spectra and electronic circular dichroism (ECD) spectra reveal unusually strong hyperconjugation that constrains and aligns the cyclopropyl C-C bond with the π-plane of the distal ene-bond. This alignment imposes a barrier to rotation of at least 5.0 kcal·mol -1 . Comparison of red-shifted Cotton effects in chiral CCPs show the barrier is independent of alkene substituent and establishes an empirical rule for assignment of other CCP-containing natural products., (© 2020 Wiley Periodicals LLC.)

Three new bromotyrosine spiroisoxazoline alkaloids, lacunosins A and B ( 1 and 2 ) and desaminopurealin ( 3 ), were isolated from a MeOH extract of the marine sponge Aplysina lacunosa that showed modest α-chymotrypsin inhibitory activity. The structures of 1 - 3 share the spirocyclohexadienyl-isoxazoline ring system found in purealidin-R and several other Verongid sponge secondary metabolites. Compounds 1 and 2 are coupled to a glycine and an isoserine methyl ester, respectively. Alkaloid 3 is linked, contiguously, to an O -1-aminopropyl 3,5-dibromotyrosyl ether and, finally, to histamine through an amide bond. The planar structures of all three compounds were obtained from analysis of MS and 1D and 2D NMR data. The absolute configuration of the SIO unit of 1 - 3 was assigned by electronic circular dichroism (ECD). The isoserine amino acid residue in 2 was found to be a 1:1 mixture of epimers using a new Marfey's type reagent, derived from Trp-NH 2 . Allylic O -naphthoylation of the SIO subunit enhances the ECD spectrum of SIOs and improves discrimination of enantiomorphs. A unifying hypothesis is proposed that links the biosynthesis of several of the new compounds with previously reported analogues.

The 2 S configuration of the marine natural product distaminolyne A was recently disputed based upon total synthesis, yet paradoxically supported by a second independent total synthesis from a different research group. We now verify the 2 S configuration of distaminolyne A by extensive chiroptical studies and support the veracity of the EC ECD method originally used to prove it. The origin of the apparent paradox appears to lie in the limits of precision of polarimetry in the context of weakly rotatory molecules, which strikes a cautionary note on the reliability of "reassignment" of natural product configurations based solely on specific rotation.

Bengazoles A⁻G from the marine sponge Jaspis sp. exhibit potent in vitro antifungal activity against Candida spp. and other pathogenic fungi. The mechanism of action (MOA) of bengazole A was explored in Candida albicans under both liquid culture and surface culture on Mueller-Hinton agar. Pronounced dose-dependent synergistic antifungal activity was observed with bengazole A in the presence of bengamide A, which is also a natural product from Jaspis sp. The MOA of bengazole A was further explored by monitoring the sterol composition of C. albicans in the presence of sub-lethal concentrations of bengazole A. The GCMS of solvent extracts prepared from liquid cultures of C. albicans in the presence of clotrimazole-a clinically approved azole antifungal drug that suppresses ergosterol biosynthesis by the inhibition of 14α-demethylase-showed reduced cellular ergosterol content and increased concentrations of lanosterol and 24-methylenedihydrolanosterol (a shunt metabolite of ergosterol biosynthesis). No change in relative sterol composition was observed when C. albicans was cultured with bengazole A. These results eliminate an azole-like MOA for the bengazoles, and suggest that another as-yet unidentified mechanism is operative.

Correction for 'The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research' by James B. McAlpine et al., Nat. Prod. Rep., 2018, DOI: .

Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

Sample configurations of distaminolyne A ( 1a ); isolated from the ascidians Pseudodistoma opacum and P. cereum , and collected at different sites in New Zealand, were investigated by two methods: Exciton coupled electronic circular dichroism (EC ECD) of the corresponding N , O -dibenzoyl derivative 1b ; and chiral reagent derivatization of 1a with ( S )- and ( R )-α-methoxyphenylacetic acid (MPA), followed by ¹H-NMR analysis. Configuration and optical purity of 1a (%ee) was found to vary depending on the geographic distribution of ascidian colonies. An improved method for preparing N , O -diarenoyl derivatives of 1a was optimized. The EC ECD method was found to be complementary to the MPA-NMR method at different ranges of %ee.

Three decahydroisoquinoline alkaloids, lepadins I-K, were isolated from a specimen of Didemnum sp. collected in the Bahamas. The structures of the new compounds were assigned by an integrated analysis of MS, IR, and 1 H, 13 C, and 2D NMR spectra. Like previously reported lepadins, the structures of the new compounds contain a decahydroquinoline heterocyclic core in lepadin I, and a new variation, an octahydroquinoline in lepadin J, but differ from earlier reported compounds by acylation of the 3-hydroxyl group by a rare 3'-methylthioacrylate. The absolute configuration of lepadin I was solved by interpretation of NOE measurements, and exciton coupled circular dichroism (ECCD) of the corresponding N- p-bromobenzoyl derivative. The latter constitutes a general method for determination of absolute configuration of the entire lepadin family. The configuration of the remote side-chain secondary carbinol was solved by the modified Mosher's esters method. Lepadin I inhibited butyrylcholineesterase (BuChE, IC 50 3.1 μM), but only weakly inhibited acetylcholineesterase (AChE) (10% at 100 μM).

An UPLC-qTOF-MS-based dereplication study led to the targeted isolation of seven bromoindole alkaloids from the sub-Arctic sponge Geodia barretti . This includes three new metabolites, namely geobarrettin A⁻C ( 1 ⁻ 3 ) and four known compounds, barettin ( 4 ), 8,9-dihydrobarettin ( 5 ), 6-bromoconicamin ( 6 ), and l-6-bromohypaphorine ( 7 ) . The chemical structures of compounds 1 ⁻ 7 were elucidated by extensive analysis of the NMR and HRESIMS data. The absolute stereochemistry of geobarrettin A ( 1 ) was assigned by ECD analysis and Marfey's method employing the new reagent l- N α -(1-fluoro-2,4-dinitrophenyl)tryptophanamide (l-FDTA). The isolated compounds were screened for anti-inflammatory activity using human dendritic cells (DCs). Both 2 and 3 reduced DC secretion of IL-12p40, but 3 concomitantly increased IL-10 production. Maturing DCs treated with 2 or 3 before co-culturing with allogeneic CD4⁺ T cells decreased T cell secretion of IFN-γ, indicating a reduction in Th1 differentiation. Although barettin ( 4 ) reduced DC secretion of IL-12p40 and IL-10 (IC 50 values 11.8 and 21.0 μM for IL-10 and IL-12p40, respectively), maturing DCs in the presence of 4 did not affect the ability of T cells to secrete IFN-γ or IL-17, but reduced their secretion of IL-10. These results indicate that 2 and 3 may be useful for the treatment of inflammation, mainly of the Th1 type.

The new pyrrole-imidazole and pyrrole-guanidine alkaloids 4-debromooroidin (1), 4-debromougibohlin (2), 5-debromougibohlin (3), and 5-bromopalau'amine (4), along with the known hymenidin (5) and (+)-monobromoisophakellin (6), have been isolated from a Dictyonella sp. marine sponge, collected at the Amazon River mouth. The bromine-substitution pattern observed for compounds 1, 2 and 4 is unusual among bromopyrrole alkaloids isolated from marine sponges. The 20S proteasome inhibitory activities of compounds 1-6 have been recorded, with 5-bromopalau'amine (4) being the most active in this series.

Atropisomeric cyclic catechol ethers are notoriously difficult to resolve by classical chiral phase high-performance liquid chromatography. Here, we show the first application of sulfatase enzymes for the kinetic resolution of O -sulfato-catechol ethers with enantioselectivities ranging from 30 to 65% ee, as determined by preparation of their Marfey's ether derivatives. Substrate-structure dependence was briefly explored., Competing Interests: The authors declare no competing financial interest.

Bastadin-6-34-O-sulfate ester (8) was isolated from methanol extracts of Ianthella basta. The structure of 8 was characterized by analysis of MS and NMR data, and conversion through acid hydrolysis, to the parent compound, bastadin-6, which was identical by HPLC, MS and NMR with an authentic sample. An improved procedure for procurement of pure samples of bastadins-4 (4), -5 (5) and -6 (6) is described., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Six new cyclopenta[g]indoles were isolated from a West Australian sponge, Trikentrion flabelliforme Hentschel, 1912, and their structures elucidated by integrated spectroscopic analysis. The compounds are analogues of previously described trikentrins, herbindoles, and trikentramides from related Axinellid sponges. The assignment of absolute configuration of the new compounds was carried out largely by comparative analysis of specific rotation, calculated and measured ECD, and exploiting van't Hoff's principle of optical superposition. Five of the new compounds were chemically interconverted to establish their stereochemical relationships, leading to a simple chiroptical mnemonic for assignment of the this family of chiral indoles. The first biosynthetic hypothesis is advanced to explain the origin of the trikentrin-herbinole family and proposes a pyrrole-carboxylic thioester-initiated polyketide synthase mechanism.

Liposomal circular dichroism (L-CD) of acyclic amino alcohols exhibit amplification of Cotton effects when measured in highly uniform, unilamellar liposomes. The effect is likely due to intermolecular associations-H-aggregates-that self-assemble spontaneously within the lipid bilayer, and persists over long time scales. L-CD spectra of N , O , O '-tri-(6'methoxy-2'-naphthoyl)-d- erythro -sphingosine, or the corresponding dihydro-derivative (sphinganine), shows ~10-fold amplification of magnitudes of Cotton effects over conventional CD spectra recorded in isotropic solution., Competing Interests: The authors declare no conflict of interest.

This review discusses the chemistry of cyclic azole-homologated peptides (AHPs) from the marine sponges, Theonella swinhoei, other Theonella species, Calyx spp. and Plakina jamaicensis. The origin, distribution of AHPs and molecular structure elucidations of AHPs are described followed by their biosynthesis, bioactivity, and synthetic efforts towards their total synthesis. Reports of partial and total synthesis of AHPs extend beyond peptide coupling reactions and include creative construction of the non-proteinogenic amino acid components, mainly the homologated heteroaromatic and α-keto-β-amino acids. A useful conclusion is drawn regarding AHPs: despite their rarity, exotic structures and the potent protease inhibitory properties of some members, their synthesis is under-developed and beckons solutions for outstanding problems towards their efficient assembly.

Two dimerized cyclic hexapeptides, antatollamides A (1) and B (2), were isolated from the colonial ascidian Didemnum molle collected in Pohnpei. The amino acid compositions and sequences were determined by interpretation of MS and 1D and 2D NMR data. Raney Ni reduction of antatollamide A cleaved the dimer to the corresponding monomeric cyclic hexapeptide with replacement of Cys by Ala. The amino acid configuration of 1 was established, after total hydrolysis, by derivatization with a new chiral reagent, (5-fluoro-2,4-dinitrophenyl)-N α -l-tryptophanamide (FDTA), prepared from l-Trp, followed by LCMS analysis; all amino acids were found to be l-configured except for d-Ala.

Symplocin A, a linear peptide possessing N-terminal N,N -dimethylisoleucine, statine, and valic acid residues, has been synthesized for the first time employing our previously established ' one-pot intramolecular tandem protocol '. Moreover, the stereochemistry of natural symplocin A was unambiguously revised through the confirmation by 1D NMR, 2D NMR, and HPLC comparisons with authentic natural product.

Ultra-high resolution band-selective HSQC (bsHSQC) has been employed for detection of 35 Cl- 37 Cl isotope shifted 13 C NMR signals for assignment of regioisomerism in bromo-chloro natural products. Optimum pulse sequence and instrumental parameters for maximization of detection of the isotope shifts were explored. The chlorine isotope shifts (Δδ) were detected within crosspeaks and were shown to vary with hybridization of 13 C, substitution of 13 C, presence of β-chloro substituents, and their relative configuration. Deconvolution of Cl-substituted CH bsHSQC crosspeaks may provide other useful information, including a potentially MS-independent method for quantitating 37 Cl/ 35 C isotopic fractionation during the biosynthesis of halogenated natural products. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Structure-activity relationships of the antifungal aminobisabolene natural product, 1 isolated from Halichondria sp., and synthetic analogs were explored, in parallel with the antidermatophytic allylamine, Terbinafine®, against a panel of pathogenic fungi: Candida spp., Cryptococcus spp. and Trichophyton rubrum. Interpretation of the results suggest different modes of action in antifungal activity for the two classes of compounds., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A novel technique that allows efficient measurement of the 35,37 Cl isotope pattern for any 13 C resonance has been developed. The band-selective CLIP-HSQMBC experiment is reliable and universally applicable for the indirect measurement of the 35,37 Cl isotope shift of 13 C resonances. The experiment provides advantages over conventional 1D 13 C NMR and the recently developed bs-HSQC experiments. The utility and performance of the bs-CLIP-HSQMBC experiment is demonstrated for polyhalogenated synthons in a synthetic route and for a polyhalogenated marine natural product.

A new cyclic peptide, jamaicensamide A, composed of six amino acids, including a thiazole-homologated amino acid, was isolated from the Bahamian sponge Plakina jamaicensis, along with known compounds bitungolide A and franklinolide A. The structure of the title peptide was solved by integrated analysis of MS, 1D and 2D NMR data, oxidation-hydrolyses to α-amino acids, and their stereodetermination by Marfey's method. The close structural resemblance of Western Atlantic-derived jamaicensamide A to known Western Pacific-derived peptides of lithistid sponges in the genus Theonella and Discodermia suggests a common origin: the symbiotic bacterium Entotheonella sp., a so-called "talented producer" responsible for biosynthesis of most Theonella-associated peptides. Similar natural products from sponges of disparate genera evince the likelihood that these invertebrates harbor the same or a very similar symbiont.

Cryptococcus gattii is a human pathogen and causative agent of a pernicious, sometimes fatal, disseminated fungal disease. Investigation of antifungal extracts of the marine sponge association Plakortis halichondrioides-Xestospongia deweerdtae and the sponge Plakortis zyggompha from the Bahamas led to the discovery and isolation of 6-epi-7,8-dihydroplakortide K (1), plakortide AA (2), and three new plakinic acids, N-P (4-6; unstable 1,2-dioxolanes bearing benzyl-substituted conjugated dienes), along with known plakinic acids L, K, and M.5 Chiroptical comparisons and DFT calculations of (13)C NMR chemical shifts were used to assign the absolute stereostructure of 4. The stereospecific base-promoted rearrangement-saponification of 1 to 10 was briefly investigated and showed tight kinetic control and stereospecific formation of the new C-2 stereocenter with inversion at C-3. Plakinic acid M and plakortides 9 and 11 exhibited antifungal activity against C. gattii (MIC90 = 2.4 to 36 μM), but plakinic acids N-P were inactive under the same conditions.

Four new chlorobromohydrins, mollenynes B-E, were isolated from the marine sponge Spirastrella mollis collected from Hogsty Reef, Bahamas. Their structures were elucidated by integrated analysis of NMR, MS, and computational methods. A high-resolution band-selective HSQC experiment was developed to identify (13)C NMR signals in samples at the nanomole-scale that arise from Cl-substituted (13)C by exploiting the (35)Cl/(37)Cl isotope shift.

Objectives: Marine sponges are among the most promising sources of chemically diversified fatty acids (FAs). In addition, several studies have shown the effect of polyunsaturated FAs on cancer therapy. This research carried out a biological and chemical evaluation of the sponge Scopalina ruetzleri collected on the South Brazilian coastline., Methods: Bioassay-guided fractionation of S. ruetzleri was performed in human glioma (U87) and neuroblastoma (SH-SY5Y) cell lines, and the in-vitro effects on free radicals were evaluated., Key Findings: The ethyl acetate fraction of S. ruetzleri showed promising cytotoxic effects in cancer cell lines, with IC50  < 20 μg/ml. Fingerprint (1) H Nuclear Magnetic Resonance (NMR) analysis showed that this fraction is mainly constituted of FAs. Through FA methyl ester analysis, it was possible to identify 32 FAs. In addition, some minor unusual FAs for the marine biosphere were identified. The results of conjugated dienes method showed that FAs fraction, at concentrations above 50 μg/ml, has a pro-oxidant effect, indicating that lipid peroxidation may be partially responsible for the mechanism of cytotoxicity on cancer cells., Conclusion: This work also contributes to studies that focus on the application of FAs on cancer therapy as a new adjuvant to radio or chemotherapy, or as a chemotherapeutic agent., (© 2015 Royal Pharmaceutical Society.)

Investigation of antifungal natural products from the marine sponge Pseudaxinella reticulata from the Bahamas led to the discovery of new crambescin homologues (1, 2) and enantiomers (3, 4) of known natural products. The cyclic-guanidine structures were solved through analysis of 2D NMR, MS-MS, and CD data. The absolute configurations of 1-4 were established as 13R-opposite of known homologues reported from Crambe crambe obtained from the Mediterranean Sea-by comparison of their CD spectra with predicted Cotton effects obtained from DFT calculations. Antifungal activities of 1-4 against the pathogenic strains Candida albicans and Cryptococcus sp. were observed to correlate potency (MIC50 and MIC90) with the length of the alkyl side chain.

Salvadenosine, (1) a rare 5'-deoxy-5'-(methylthio) nucleoside, was isolated from the deep-water Bahaman tunicate Didemnum sp. The structure was solved by integrated analysis of MS and 1D and 2D NMR data. We revise the structure of the known natural product, hamiguanosinol, which is a constitutional isomer of 1, to 5 by interpretation of the spectroscopic data and comparison with synthesized nucleosides.

Background and Purpose: Inositol 1,4,5-trisphosphate receptors (IP3 Rs) are intracellular Ca(2+) channels. Interactions of the commonly used antagonists of IP3Rs with IP3R subtypes are poorly understood., Experimental Approach: IP3-evoked Ca(2+) release from permeabilized DT40 cells stably expressing single subtypes of mammalian IP3R was measured using a luminal Ca(2+) indicator. The effects of commonly used antagonists on IP3-evoked Ca(2+) release and (3) H-IP3 binding were characterized., Key Results: Functional analyses showed that heparin was a competitive antagonist of all IP3R subtypes with different affinities for each (IP3R3 > IP3R1 ≥ IP3R2). This sequence did not match the affinities for heparin binding to the isolated N-terminal from each IP3R subtype. 2-aminoethoxydiphenyl borate (2-APB) and high concentrations of caffeine selectively inhibited IP3R1 without affecting IP3 binding. Neither Xestospongin C nor Xestospongin D effectively inhibited IP3-evoked Ca(2+) release via any IP3R subtype., Conclusions and Implications: Heparin competes with IP3, but its access to the IP3-binding core is substantially hindered by additional IP3R residues. These interactions may contribute to its modest selectivity for IP3R3. Practicable concentrations of caffeine and 2-APB inhibit only IP3R1. Xestospongins do not appear to be effective antagonists of IP3Rs., (© 2014 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Chronic lymphocytic leukemia (CLL) is the most common lymphoid neoplasia in Western societies and is currently incurable. Multiple treatment options are practiced, but the available small molecule drugs suffer from dose-limiting toxicity and undesirable side effects. The need for new, less toxic treatments is a pressing concern. Here, we demonstrate that (-)-agelastatin A (1a), a pyrrole-imidazole alkaloid obtained from a marine sponge, exhibits potent in vitro activity against primary cell lines of CLL and disclose the synthesis of several analogues that are equipotent or exceed the potency of the natural product. The novel synthetic analogue, 13-debromo-13-trifluoromethyl agelastatin A (1j), showed higher activity than the natural product when tested against the same cell lines and is the most potent agelastatin derivative reported to date. A detailed in vitro structure-activity relationship of 1a in CLL compared to that of 22 synthetic analogues is described along with preliminary in vivo pharmacokinetic and metabolism studies on the most potent compounds.

Two new peptides, stylissamides G and H, were isolated from extracts of a sample of Stylissa caribica collected in deep waters of the Caribbean Sea. A single sample of S. caribica among a collection of 10 samples that were examined by LC-MS appeared to be a different chemotype from the others in that it lacked the familiar pyrrole-2-aminoimidazole alkaloids, stevensine and oroidin, and contained peptides of the stylissamide class. The structures of the title compounds were solved by integrated analysis of the MS and NMR spectra and chemical degradation. The solution conformation of stylissamide G was briefly examined by electronic circular dichroism and temperature-dependent (1)H NMR chemical shifts of amide NH signals, which supported a conformationally rigid macrocycle.