A Survey of Recently Discovered Naturally Occurring Organohalogen Compounds.

The discovery of naturally occurring organohalogen compounds has increased astronomically in the 55 years since they were first discovered─from fewer than 50 in 1968 to a combined 7,958 described examples in three comprehensive reviews. The present survey, which covers the period 2021-2023, brings the number of known natural organohalogens to approximately 8,400. The organization is according to species origin, and coverage includes marine and terrestrial plants, fungi, bacteria, marine sponges, corals, cyanobacteria, tunicates, and other marine organisms.

Naturally Occurring Organohalogen Compounds-A Comprehensive Review.

The present volume is the third in a trilogy that documents naturally occurring organohalogen compounds, bringing the total number-from fewer than 25 in 1968-to approximately 8000 compounds to date. Nearly all of these natural products contain chlorine or bromine, with a few containing iodine and, fewer still, fluorine. Produced by ubiquitous marine (algae, sponges, corals, bryozoa, nudibranchs, fungi, bacteria) and terrestrial organisms (plants, fungi, bacteria, insects, higher animals) and universal abiotic processes (volcanos, forest fires, geothermal events), organohalogens pervade the global ecosystem. Newly identified extraterrestrial sources are also documented. In addition to chemical structures, biological activity, biohalogenation, biodegradation, natural function, and future outlook are presented.

The Generation of Indole-2,3-quinodimethanes from the Deamination of 1,2,3,4-Tetrahydropyrrolo[3,4-b]indoles.

A novel generation of indole-2,3-quinodimethanes via the deamination of 1,2,3,4-tetrahydropyrrolo[s3,4-b]indoles is reported.

7-Chloro-3-(4-methyl-benzene-sulfon-yl)pyrrolo[1,2-c]pyrimidine.

In the title compound, C14H11ClN2O2S, the dihedral angle between the pyrrolo-[1,2-c]pyrimidine ring system (r.m.s. deviation = 0.008 Å) and the benzene ring is 80.2 (9)°. In the crystal, inversion dimers linked by pairs of C-H⋯O inter-actions generate R 2 2(16) loops. Several aromatic π-π stacking inter-actions between the pyrrolo-[1,2-c]pyrimidine rings, as well as separately between the pyrrolo and pyrimidine groups [shortest centroid-centroid separation = 3.5758 (14) Å], help to consolidate the packing.

First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors.

Genetic activation of the bacterial two-component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives, and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a ∼30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli.

A Modified ToxT Inhibitor Reduces Vibrio cholerae Virulence in Vivo.

We have previously designed and synthesized small-molecule inhibitors that reduce Vibrio cholerae virulence in vitro by targeting the transcription factor ToxT. Here we report the synthesis and biological activity of derivatives of our previous bicyclic, fatty acid-like inhibitors. All of the synthesized derivatives show antivirulence activity in vitro. For the most potent compounds, a concentration of 5 µM completely inhibited ToxT-mediated tcpA expression as measured in the ß-galactosidase assay. One indole compound, 3-(1-butyl-1 H-indol-7-yl)propanoic acid (8), was also effective at inhibiting intestinal colonization in the infant mouse. These modified compounds may serve as good candidates for further anti-cholera drug development.

Design, synthesis, and biological activity of second-generation synthetic oleanane triterpenoids.

We report the synthesis and biological activity of C-24 demethyl CDDO-Me 2 and the C-28 amide derivatives 3 and 4, which are analogues of the anti-inflammatory synthetic triterpenoid bardoxolone methyl (CDDO-Me) 1. Demethylation of the C-24 methyl group was accomplished via "abnormal Beckmann" rearrangement and subsequent ring A reformation. Amides 3 and 4 were found to be potent inhibitors of the production of the inflammatory mediator NO in vitro.

A new class of inhibitors of the AraC family virulence regulator Vibrio cholerae ToxT.

Vibrio cholerae is responsible for the diarrheal disease cholera that infects millions of people worldwide. While vaccines protecting against cholera exist, and oral rehydration therapy is an effective treatment method, the disease will remain a global health threat until long-term solutions such as improved sanitation and access to clean water become widely available. Because of this, there is a pressing need for potent therapeutics that can either mitigate cholera symptoms, or act prophylactically to prevent the virulent effects of a cholera infection. Here we report the design, synthesis, and characterization of a set of compounds that bind and inhibit ToxT, the transcription factor that directly regulates the two primary V. cholerae virulence factors. Using the folded structure of the monounsaturated fatty acid observed in the X-ray structure of ToxT as a template, we designed ten novel compounds that inhibit the virulence cascade to a greater degree than any known inhibitor. Our findings provide a structural and functional basis for the development of viable antivirulence therapeutics that combat cholera and, potentially, other forms of bacterial pathogenic disease.

Photo-degradation of 2,4-dinitroanisole (DNAN): An emerging munitions compound.

The US military is developing insensitive munitions (IM) that are less sensitive to shock and high temperatures to minimize unintentional detonations. DNAN (2,4-dinitroanisole) is one of the main ingredients of these IM formulations. During live-fire training, chunks of IM formulations are scattered by partial detonations and, once on the soil, they weather and dissolve. DNAN changes color when exposed to sunlight suggesting that it photodegrades into other compounds. We investigated the photo-degradation of DNAN both as a pure solid and as part of solid IM formulations, IMX101, IMX104 and PAX21. The concentrations of degradation products found were small, <1%, relative to DNAN concentrations. We saw transient peaks in the chromatograms indicating intermediate, unstable products but we consistently found methoxy nitrophenols and methoxy nitroanilines. We also found one unknown in most of the samples and other unknowns less frequently.

Synthesis of a Masked 2,3-Diaminoindole.

A three-step synthesis of masked 2,3-diaminoindole 1 from 2-iodo-3-nitro-1-(phenylsulfonyl)indole (2) has been developed. Treatment of 1 with trifluoroacetic acid generates the unstable 2,3-diamino-1-(phenylsulfonyl)indole (3), which can be trapped with α-dicarbonyl compounds to afford 5H-pyrazino[2,3-b]indoles 7-10.

Triple Benzannulation of Naphthalene via a 1,3,6-Naphthotriyne Synthetic Equivalent. Synthesis of Dibenz[a,c]anthracene.

A new synthesis of dibenzo[a,c]anthracene (4) is described that features the generation, from tetrabromo-bis-triflate 1 and phenyllithium, of a 1,3,6-naphthotriyne (2) synthetic equivalent that is trapped with 3 equiv of furan to form Diels-Alder tris-adduct 3. A subsequent two-step deoxygenation of 3 represents the first synthesis of dibenz[a,c]anthracene (4) that involves a tandem aryne Diels-Alder cycloaddition-deoxygenation strategy.

Novel synthetic pyridyl analogues of CDDO-Imidazolide are useful new tools in cancer prevention.

Two new analogues of CDDO-Imidazolide (CDDO-Im), namely 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole ("CDDO-2P-Im") and 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-3-yl)-1H-imidazole ("CDDO-3P-Im") have been synthesized and tested for their potential use as chemopreventive drugs. At nanomolar concentrations, they were equipotent to CDDO-Im for inducing differentiation and apoptosis in U937 leukemia cells. As inflammation and oxidative stress contribute to carcinogenesis, we also assessed their cytoprotective potential. The new compounds suppressed inducible nitric oxide synthase (iNOS) expression in RAW264.7 macrophage-like cells and significantly elevated heme oxygenase-1 (HO-1) and quinone reductase (NQO1) mRNA and protein levels in various mouse tissues in vivo. Most importantly, pharmacokinetic studies performed in vitro in human plasma and in vivo showed that each new analogue was more stable than CDDO-Im. Much higher concentrations of the new derivatives were found in mouse liver, lung, pancreas and kidney after gavage in contrast to CDDO-Im. Because of their better bioavailability and their excellent anti-inflammatory profile in vitro, CDDO-2P-Im and CDDO-3P-Im were tested for prevention in a highly relevant mouse lung cancer model, in which A/J mice develop lung carcinomas after injection of vinyl carbamate, a potent carcinogen. CDDO-2P-Im and CDDO-3P-Im were as effective as CDDO-Im for reducing the size and the severity of the lung tumors.

Biological Activity of Recently Discovered Halogenated Marine Natural Products.

This review presents the biological activity-antibacterial, antifungal, anti-parasitic, antiviral, antitumor, antiinflammatory, antioxidant, and enzymatic activity-of halogenated marine natural products discovered in the past five years. Newly discovered examples that do not report biological activity are not included.

Syntheses of 1-Bromo-8-methylnaphthalene and 1-Bromo-5-methylnaphthalene.

The Diels-Alder reaction between 2-methylfuran and 3-bromobenzyne (3), which was generated under mild conditions from 1,3-dibromobenzene and lithium diisopropylamide (LDA), gives a mixture of regioisomeric 1,4-dihydro-1,4-epoxynaphthalenes 4 and 5. A subsequent two-step deoxygenation affords the corresponding 1-bromo-8-methylnaphthalene (1) and 1-bromo-5-methylnaphthalene (2) in high yields.

An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester): analogues, biological activities, and comparison with oleanolic acid derivatives.

An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester) from commercially available ursolic acid, which features an oxidative ozonolysis-mediated C-ring enone formation, and provides the first access to ursolic acid-derived cyano enone analogues with C-ring activation. These new ursolic acid analogues show potent biological activities, with potency of approximately five-fold less than the corresponding oleanolic acid derivatives.

Methyl 1-benzyl-5-methyl-2,4-diphenyl-1H-pyrrole-3-carboxyl-ate.

In the title compound, C26H23NO2, the dihedral angles between the pyrrole ring and the two phenyl rings are 58.1 (6) and 71.5 (5)°. The mean planes of the 5-methyl-benzene ring and the carboxyl group are twisted by 89.5 (3) and 22.1 (9)°, respectively, from the pyrrole ring. In the crystal, weak C-H⋯O inter-actions lead to supra-molecular layers in the ab plane.

Synthesis and biological evaluation of amino acid methyl ester conjugates of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid against the production of nitric oxide (NO).

2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO, 2) was condensed with various amino acid methyl esters at the C-28 carboxylic acid. The new amide conjugates were evaluated for their inhibition of nitric oxide (NO) production in RAW264.7 cells stimulated with interferon-γ (IFNγ). Of these new compounds, CDDO conjugates with alanine, valine, and serine are nearly equipotent to CDDO-ethyl amide (4), a triterpenoid with promising biological activity in numerous disease models. Some of these conjugates also induce the in vitro expression of heme oxygenase-1, and inhibit the proliferation of Panc-1343 pancreatic cells.

Synthesis of a dicyano abietane, a key intermediate for the anti-inflammatory agent TBE-31.

The synthesis of dicyano abietane 11, a potential precursor to the biologically active tricyclic bis-cyano enone 6 (TBE-31), was accomplished in eight steps from epoxide 13. The synthesis features a Lewis acid promoted stereoselective cyclization of epoxide 13 to generate the tricyclic ring system 12 in one step.

Bruceolline J: 2-hy-droxy-3,3-dimethyl-2,3-di-hydro-cyclo-penta-[b]indol-1(4H)-one.

The 12-membered cyclo-penta-[b]indole ring system in the title compound, C13H13NO2, deviates only slightly from planarity (r.m.s. deviation = 0.051 Å). In the crystal, N-H⋯O and O-H⋯O hydrogen bonds link the mol-ecules into sheets parallel to (100). The five-membered cyclopentanone ring is in slightly distorted envelope conformation with the C atom bearing the hydroxy substituent as the flap.