The Paradox of Antimalarial Terpenoid Isonitrile Biosynthesis Explained. Proposal of Cyanoformate as an NC Delivery Vector.

Marine sponge diterpenoid isonitriles are exceptional nitrogenous natural products that exhibit antiplasmodial activity. Their biosynthesis presents a biosynthetic puzzle: how do the elements of NC engage terpenyl carbocations in isoprenoid secondary metabolism, and what is the biosynthetic precursor of the NC group? Cyanoformic acid (NC-COOH, ) is proposed as a plausible delivery vehicle of NC that resolves a paradox in the commonly held proposition that an inorganic cyanide anion, CN, terminates terpenoid isonitrile (TI) biosynthesis. DFT calculations of NC-COOH and its conjugate base, cyanoformate, NC-COO (), support high nucleophilicity at N and explain bond-forming constitutionality: attack at N and formation of an isonitrile over its nitrile isomer.

Empirical Chiroptical Analyses of Vicinal Bromochloro Natural Products by van't Hoff's Principle of Optical Superposition: Assignment of the C-16 Configurations of Callophycols A and B.

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 () and its halogen-swapped isomer -halomon () from the red alga, , and callophycols A () and B () from . The relative configurations of and , published in 2007, were incomplete: C-16 was left unassigned. It is now shown that the additivity of molar rotations, [] (herein, abbreviated [])─a consequence of van't Hoff's principle of optical superposition─could be used to deconvolute rotatory contributions, designated as [] and [] of the two remotely spaced chiral substructures within and using simple arithmetic.

Small molecule in situ resin capture provides a compound first approach to natural product discovery.

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.

DFT investigation of coupling constant anomalies in substituted β-lactams.

β-lactams are a chemically diverse group of molecules with a wide range of biological activities. Having recently observed curious trends in J coupling values in studies on this structural class, we sought to obtain a more comprehensive understanding of these diagnostic NMR parameters, specifically interrogating J, J, and J, 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.

Orthogonal Deprotection Strategy of Fmoc Provides Improved Synthesis of Sensitive Peptides: Application to Z-Arg-Lys-AOMK.

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.

Petrosamine Revisited. Experimental and Computational Investigation of Solvatochromism, Tautomerism and Free Energy Landscapes of a Pyridoacridinium Quaternary Salt.

Petrosamine ()-a colored pyridoacridine alkaloid from the Belizean sponge, 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 and tautomerism, revealed an accurate electronic depiction of the molecular structure of as the di-keto form, with a net charge of = +1, rather than a dication ( = +2) under ambient conditions of isolation-purification.

Small Molecule Resin Capture - A Compound First Approach to Natural Product Discovery.

Microbial natural products remain an important resource for drug discovery. Yet, commonly employed discovery techniques are plagued by the rediscovery of known compounds, the relatively few microbes that can be cultured, and laboratory growth conditions that do not elicit biosynthetic gene expression among myriad other challenges. Here we introduce a culture independent approach to natural product discovery that we call the Small Molecule In situ Resin Capture (SMIRC) technique.

Geobarrettin D, a Rare Herbipoline-Containing 6-Bromoindole Alkaloid from .

Geobarrettin D (), a new bromoindole alkaloid, was isolated from the marine sponge collected from Icelandic waters. Its structure was elucidated by 1D, and 2D NMR (including H-N HSQC, H-N HMBC spectra), as well as HRESIMS data. Geobarrettin D () is a new 6-bromoindole featuring an unusual purinium herbipoline moiety.

Bioactive Bromotyrosine Alkaloids from the Bahamian Marine Sponge . Dimerization and Oxidative Motifs.

Nine bromotyrosine alkaloids (BTAs), including debromoianthelline (), pseudoceratinic acid (), methyl pseudoceratinate (), 13-oxo-ianthelline (), aiolochroiamides A-D (, and ,, and 7-hydroxypurealidin J (), were isolated from a Bahamian (Hyatt; previously, ). The structures of - were established from H, C, and 2D NMR spectra, IR, and mass spectrometry data. Compounds - comprise an -methyl-2,6-dibromotyrosyl ketoxime (subunit A) amide linked to variable groups (subunit B).

Spiroisoxazoline Inhibitors of Acetylcholinesterase from . Quantitative Chiroptical Analysis of Configurational Heterogeneity, and Total Synthesis of (±)-Methyl Purpuroceratate C.

Examination of the MeOH extract of the sponge, cf. , Berquist 1995 collected near Ningaloo Reef, Western Australia for selective acetylcholinesterase (AChE) inhibitors, yielded five new bromotyrosine alkaloids, methyl purpuroceratates A and B ( and ), purpuroceratic acid C (), and ningalamides A and B ( and ). The structures of - share the dibromo-spirocyclohexadienyl-isoxazoline (SIO) ring system found in purealidin-R, while ketoxime is analogous to ianthelline and purpurealidin I.

Chlororesistoflavins A and B, Chlorinated Benzopyrene Antibiotics Produced by the Marine-Derived Actinomycete sp. Strain EG32.

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 sp., strain EG32. HPLC analysis and antibacterial testing against methicillin-resistant (MRSA) resulted in the identification of six compounds related to the resistoflavin and resistomycin class.

Oceanalin B, a Hybrid α,ω-Bifunctionalized Sphingoid Tetrahydroisoquinoline β-Glycoside from the Marine Sponge sp.

Oceanalin B (), 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 sp. as the second member of the series after oceanalin A () from the same animal. The compounds are of particular interest due to their biogenetically unexpected structures as well as their biological activities.

Oceanapiside, a Marine Natural Product, Targets the Sphingolipid Pathway of Fluconazole-Resistant .

Oceanapiside (OPS), a marine natural product with a novel bifunctional sphingolipid structure, is fungicidal against fluconazole-resistant at 10 μg/mL (15.4 μM). The fungicidal effect was observed at 3 to 4 h after exposure to cells.

Bromotryptamine and Imidazole Alkaloids with Anti-inflammatory Activity from the Bryozoan .

Chemical investigation of the marine bryozoan collected in Iceland resulted in isolation of 13 new bromotryptamine alkaloids, flustramines Q-W (-) and flustraminols C-H (-), and two new imidazole alkaloids, flustrimidazoles A and B ( and ), together with 12 previously described compounds (-). Their structures were established by detailed spectroscopic analysis using 1D and 2D NMR and HRESIMS. Structure was verified by calculations of the C and H NMR chemical shifts using density functional theory.

Synchronous bond molecular dynamics of conjugated chlorocyclopropyl alk-yn-enes revealed by ECD and UV-vis.

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.

Bromo-spiroisoxazoline Alkaloids, Including an Isoserine Peptide, from the Caribbean Marine Sponge .

Three new bromotyrosine spiroisoxazoline alkaloids, lacunosins A and B ( and ) and desaminopurealin (), were isolated from a MeOH extract of the marine sponge that showed modest α-chymotrypsin inhibitory activity. The structures of - share the spirocyclohexadienyl-isoxazoline ring system found in purealidin-R and several other Verongid sponge secondary metabolites. Compounds and are coupled to a glycine and an isoserine methyl ester, respectively.

The Configuration of Distaminolyne A is S: Quantitative Evaluation of Exciton Coupling Circular Dichroism of N, O- Bis-arenoyl-1-amino-2-alkanols.

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.

Synergistic Anti- Activity of Bengazole A in the Presence of Bengamide A †.

Bengazoles A⁻G from the marine sponge sp. exhibit potent in vitro antifungal activity against spp. and other pathogenic fungi.

Enantiomeric Variability of Distaminolyne A. Refinement of ECD and NMR Methods for Determining Optical Purity of 1-Amino-2-Alkanols.

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

Correction: The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

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.

6-Bromoindole Derivatives from the Icelandic Marine Sponge : Isolation and Anti-Inflammatory Activity.

An UPLC-qTOF-MS-based dereplication study led to the targeted isolation of seven bromoindole alkaloids from the sub-Arctic sponge . This includes three new metabolites, namely geobarrettin A⁻C (⁻) and four known compounds, barettin (), 8,9-dihydrobarettin (), 6-bromoconicamin (), and l-6-bromohypaphorine () The chemical structures of compounds ⁻ were elucidated by extensive analysis of the NMR and HRESIMS data. The absolute stereochemistry of geobarrettin A () was assigned by ECD analysis and Marfey's method employing the new reagent l--(1-fluoro-2,4-dinitrophenyl)tryptophanamide (l-FDTA).

Bromopyrrole Alkaloid Inhibitors of the Proteasome Isolated from a Dictyonella sp. Marine Sponge Collected at the Amazon River Mouth.

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.

Lepadins I-K, 3- O-(3'-Methylthio)acryloyloxy-decahydroquinoline Esters from a Bahamian Ascidian Didemnum sp. Assignment of Absolute Stereostructures.

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 H, C, and 2D NMR spectra.

Resolution of Atropisomeric Cyclic Catechol Monoether -Sulfate Esters by a Molluscan Sulfatase.

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 -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.

The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

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.