Precursor-Directed Biosynthesis of Antialgal Fluorinated Bacillamide Derivatives in Bacillus atrophaeus.

The bacillamides are a class of indole alkaloids produced by the Bacillus genus that possess significant antialgal activity. Incorporation of fluorine into the bacillamides was carried out using a precursor-directed biosynthesis approach, with 4-, 5-, and 6-fluorotryptophan added to growing cultures of Bacillus atrophaeus IMG-11. This yielded the corresponding fluorinated analogues of bacillamides A and C, in addition to new derivatives of the related metabolite N-acetyltryptamine, thus demonstrating a degree of plasticity in the bacillamide biosynthetic pathway. The bacillamide derivatives were tested for activity against bloom-forming algae, which revealed that fluorination could improve the antialgal activity of these compounds in a site-specific manner, with fluorination at the 6-position consistently resulting in improved activity.

Synergistic effect of tryptamine-urea derivatives to overcome the chromosomally-mediated colistin resistance in Klebsiella pneumoniae.

Colistin is considered as the last-resort antibiotics to treat multi-drug resistant Gram-negative bacterial infections in humans. However, the clinical use of colistin was limited because of the apparition of chromosomal mutations and mobile colistin resistance genes in bacterial isolates. One promising strategy is to combine existing antibiotics with promising non-antibiotics to overcome the widespread emergence of antibiotic-resistant pathogens. Moreover, colistin resistance would be regulated by two component systems PhoP/PhoQ which leads to permanent synthesis of cationic groups compensating for Mg2+ deficiency. In this study, the synthesis of a small library of tryptamine urea derivatives was carried out. In addition, antibiotic susceptibility, antibiotic adjuvant screening and checkerboard assays were used to investigate the antibacterial activity of these synthesized compounds and the potential synergistic activity of their combination with colistin. Conformational analysis of the docked binding modes of the active compound in the predicted binding pocket of bacterial response regulator PhoP were carried out, to see if the active compound inhibits PhoP which is involved in colistin resistance. Finally, hemolytic activity studies have been conducted on the most active compound.

Copper-catalyzed cascade reaction of tryptamines with diazo compounds to access hexahydropyrroloindoline derivatives.

A domino reaction sequence of cyclopropanation/ring-opening/iminium cyclization of tryptamine derivatives with donor-acceptor diazo compounds is developed to furnish pyrroloindolines, creating three consecutive stereogenic centers in a single step. The copper-catalyzed reaction provides pyrroloindolines at room-temperature with good substrate scope.

Electrophilic Thiocyanation of Tryptamine Derivatives: Divergent Synthesis of SCN-Containing Indole Compounds.

A tandem dearomative electrophilic thiocyanation/cyclization/acylation of indoles was developed for the first time, which is enabled by acyl chloride. A variety of 3-SCN pyrroloindolines were obtained with moderate to excellent yields. Interestingly, following replacement of acyl chloride with methanesulfonic acid, 2-SCN tryptamines were obtained using the same starting substrates and reagents. Furthermore, catalytic enantioselective manner of thiocyanation/cyclization/acylation reaction was also studied. An enantiomer self-disproportionation effect of 3-SCN pyrroloindolines was discovered. A series of chiral 3-SCN pyrroloindolines were obtained with high enantioselectivities.

Synthesis of Tryptamines from Radical Cyclization of 2-Iodoaryl Allenyl Amines and Coupling with 2-Azallyls.

An efficient synthesis of tryptamines is developed. Indole structures were constructed using 2-iodoaryl allenyl amines as electron acceptors and radical cyclization precursors. Radical-radical coupling of indolyl methyl radicals and azaallyl radicals led to the tryptamine derivatives. The utility and versatility of this method are showcased by the synthesis of 22 examples of tryptamines in ≤88% yield. In each case, indole formation is accompanied by in situ removal of the Boc protecting group.

ß-Methyltryptamine Provoking the Crucial Role of Strictosidine Synthase Tyr151-OH for Its Stereoselective Pictet-Spengler Reactions to Tryptoline-type Alkaloids.

Strictosidine synthase (STR), the gate enzyme for monoterpenoid indole alkaloid biosynthesis, catalyzes the Pictet-Spengler reaction (PSR) of various tryptamine derivatives with secologanin assisted by "indole sandwich" stabilization. Continuous exploration with ß-methyltryptamine (IPA) stereoselectively delivered the C6-methylstrictosidines and C6-methylvincosides by enzymatic and nonenzymatic PSR, respectively. Unexpectedly, the first "nonindole sandwich" binding mode was witnessed by the X-ray structures of STR1-ligand complexes. Site-directed mutagenesis revealed the critical cryptic role of the hydroxyl group of Tyr151 in IPA biotransformation. Further computational calculations demonstrated the adjustable IPA position in STR1 upon the binding of secologanin, and Tyr151-OH facilitates the productive PSR binding mode via an advantageous hydrogen-bond network. Further chemo-enzymatic manipulation of C6-methylvincosides successfully resulted in the discovered antimalarial framework (IC50 = 0.92 µM).

Design, synthesis, and biological evaluation of carbamate derivatives of N-salicyloyl tryptamine as multifunctional agents for the treatment of Alzheimer's disease.

In this study, we designed, synthesized, and evaluated a series of carbamate derivatives of N-salicyloyl tryptamine as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). After screening the acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitory activities, target compound 1g stood out as a mixed type reversible dual inhibitor of AChE and BChE. In addition, molecular docking studies were conducted to explore the actions on AChE and BChE. The results showed that 1g could decrease the level of pro-inflammatory cytokines NO, iNOS, IL-6, TNF-α, and ROS, increase the level of anti-inflammatory cytokines IL-4, and inhibit the aggregation of Aß1-42. Moreover, the administration of 1g suppressed the activity of AChE in the brain. In a word, the compound 1g is effective for improving learning and memory behavior, blood-brain barrier permeation, pharmacokinetics, ChE inhibition, and anti-neuroinflammation. It may be considered as a promising multi-functional therapeutic agent for further investigation for the treatment of AD.

The photoredox-catalyzed hydrosulfamoylation of styrenes and its application in the novel synthesis of naratriptan.

The hydrosulfamoylation of diverse aryl olefins provides facile access to alkylsulfonamides. Here we report a novel protocol utilizing radical-mediated addition and a thiol-assisted strategy to achieve the hydrosulfamoylation of diverse styrenes in modest to excellent yields under mild and economic reaction conditions. The methodology was found to provide an efficient and convenient approach for the synthesis of the anti-migraine drug naratriptan and it also can be used for the late-stage functionalization of natural products or medicines.

N-salicyloyl tryptamine derivatives as potential therapeutic agents for Alzheimer's disease with neuroprotective effects.

Alzheimer's disease (AD) has become a serious threat to the developed nations with burgeoning patients and annual costs on health care system in modern society. Neuroinflammation, as one of the specific biochemical factors in the progress of neurodegeneration diseases, performs a crucial role in the pathogenesis and development of AD. Therefore, it is of great significance to develop effective anti-neuroinflammatory strategies for the treatment of AD. N-salicyloyl tryptamine derivatives were previously reported and demonstrated that possessed great potential anti-neuroinflammatory effects and favorable blood-brain barrier (BBB) permeation. Herein, a series of novel N-salicyloyl tryptamine derivatives were synthesized and their anti-AD potential was evaluated both in vitro and in vivo. Among them, L7 performed well anti-neuroinflammatory effects and excellent neuroprotective effects, as well as little toxicity. To lucubrate its potential for the treatment of AD, behavior tests including morris water maze (MWM), eight-arm radial maze, open field test and novel object recognition (NOR) test were carried out and the results showed that L7 could remarkably improve Aß-induced cognitive impairment. Moreover, the mechanism of action of L7 on improving Aß-induced AD was preliminarily investigated, and the results uncovered that the neuroprotective effects of L7 was might exerte via intervening Aß-induced pyroptosis through NLRP3-caspase-1-GSDMD axis and ameliorating neuronal apoptosis by mitochondrial apoptosis pathway. Besides, the distribution of Aß plaques in brain tissues were detected by immunohistochemical (IHC) assay and the results indicated that L7 could significantly attenuate the deposition of Aß plaques in the brain.

Effect of Chemical Penetration Enhancer-Adhesive Interaction on Drug Release from Transdermal Patch: Mechanism Study Based on FT-IR Spectroscopy, 13C NMR Spectroscopy, and Molecular Simulation.

Chemical penetration enhancers (CPEs) are commonly added into transdermal patches to impart improved skin permeation of drug. However, significant unexplained variability in drug release kinetics in transdermal patches is possible as a result of the addition of CPEs; investigations into the underlying mechanisms are still limited. In the present study, a diverse set of CPEs was employed to draw broad conclusions. Solubility parameters of CPEs and acrylate pressure-sensitive adhesive were calculated by molecular dynamics simulation and Fedors group contribution method to evaluate drug-adhesive miscibility. CPE-adhesive interaction was characterized by FT-IR study, 13C NMR spectroscopy, and molecular docking simulation. Results showed that release enhancement ratio (ERR) of CPEs for zolmitriptan was rank ordered as isopropyl myristate > azone > Plurol Oleique® CC497 > Span® 80 > N-methylpyrrolidone > Transcutol® P. It was found that solubility parameter difference (Δδ) between CPE and adhesive was negatively related with ERR. It was proved that hydrogen bonding between CPE and adhesive would increase drug release rate, but only if the CPE showed good miscibility with adhesive. CPE like isopropyl myristate, which had good miscibility with adhesive, could decrease drug-adhesive interaction leading to the release of drug from adhesive.

Decatungstate-Catalyzed C(sp3)-H Sulfinylation: Rapid Access to Diverse Organosulfur Functionality.

Here we report the direct conversion of strong, aliphatic C(sp3)-H bonds into the corresponding alkyl sulfinic acids via decatungstate photocatalysis. This transformation has been applied to a diverse range of C(sp3)-rich scaffolds, including natural products and approved pharmaceuticals, providing efficient access to complex sulfur-containing products. To demonstrate the broad potential of this methodology for the divergent synthesis of pharmaceutically relevant molecules, procedures for the diversification of the sulfinic acid products into a range of medicinally relevant functional groups have been developed.

Design, synthesis and biological evaluation of N-anthraniloyl tryptamine derivatives as pleiotropic molecules for the therapy of malignant glioma.

COX-2 and STAT3 are two key culprits in the glioma microenvironment. Herein, to inhibit COX-2 and block STAT3 signaling, we disclosed 27 N-anthraniloyl tryptamine compounds based on the combination of melatonin derivatives and N-substituted anthranilic acid derivatives. Among them, NP16 showed the best antiproliferative activity and moderate COX-2 inhibition. Of note, NP16 decreased the level of p-JAK2 and p-STAT3, and blocked the nuclear translocation of STAT3 in GBM cell lines. Moreover, NP16 downregulated the MMP-9 expression of BV2 cells in a co-culture system of BV2 and C6 glioma cells, abrogated the proliferative/invasive/migratory abilities of GBM cells, induced apoptosis by ROS and the Bcl-2-regulated apoptotic pathway, and induced obvious G2/M arrest in glioma cells in vitro. Furthermore, NP16 displayed favorable pharmacokinetic profiles covering long half-life (11.43 ± 0.43 h) and high blood-brain barrier permeability. Finally, NP16 effectively inhibited tumor growth, promoted the survival rate, increased the expression of E-cadherin and reduced overproduction of PGE2, MMP-9, VEGF-A and the level of p-STAT3 in tumor tissue, and improved the anxiety-like behavior in C6 glioma model. All these evidences demonstrated N-anthraniloyl tryptamine derivatives as multifunctional anti-glioma agents with high potency could drain the swamp to beat glioma.

N-Acetyl-α-hydroxy-ß-oxotryptamine, a racemic natural product isolated from Streptomyces sp. 80H647.

N-acetyl-α-hydroxy-ß-oxotryptamine (1) along with N-acetyl-ß-oxotryptamine (2) and pimprinine (3) were isolated from the culture broth of Streptomyces sp. 80H647. Compound 1 was found to be a racemate via X-ray diffraction analysis and the enantiomers were successfully purified by chiral-phase HPLC. The absolute configuration was assigned by comparison of the calculated and experimental ECD spectra. The α-hydroxy moiety of 1 was vital for cytotoxicity against different cancer cell lines.

Chemistry and Toxicology of Major Bioactive Substances in Inocybe Mushrooms.

Mushroom poisoning has always been a threat to human health. There are a large number of reports about ingestion of poisonous mushrooms every year around the world. It attracts the attention of researchers, especially in the aspects of toxin composition, toxic mechanism and toxin application in poisonous mushroom. Inocybe is a large genus of mushrooms and contains toxic substances including muscarine, psilocybin, psilocin, aeruginascin, lectins and baeocystin. In order to prevent and remedy mushroom poisoning, it is significant to clarify the toxic effects and mechanisms of these bioactive substances. In this review article, we summarize the chemistry, most known toxic effects and mechanisms of major toxic substances in Inocybe mushrooms, especially muscarine, psilocybin and psilocin. Their available toxicity data (different species, different administration routes) published formerly are also summarized. In addition, the treatment and medical application of these toxic substances in Inocybe mushrooms are also discussed. We hope that this review will help understanding of the chemistry and toxicology of Inocybe mushrooms as well as the potential clinical application of its bioactive substances to benefit human beings.

Synthesis of Novel Tryptamine Derivatives and Their Biological Activity as Antitumor Agents.

We synthesized five novel tryptamine derivatives characterized by the presence of an azelayl chain or of a 1,1,1-trichloroethyl group, in turn connected to another heterocyclic scaffold. The combination of tryptamin-, 1,1,1-trichloroethyl- and 2-aminopyrimidinyl- moieties produced compound 9 identified as the most active compound in hematological cancer cell lines (IC50 = 0.57-65.32 µM). Moreover, keeping constant the presence of the tryptaminic scaffold and binding it to the azelayl moiety, the compounds maintain biological activity. Compound 13 is still active against hematological cancer cell lines and shows a selective effect only on HT29 cells (IC50 = 0.006 µM) among solid tumor models. Compound 14 loses activity on all leukemic lines, while showing a high level of toxicity on all solid tumor lines tested (IC50 0.0015-0.469 µM).

Alkaloids and phenylpropanoid from Rhizomes of Arundo donax L.

A new bis-indole alkaloid, named arundaline (1), a new phenylpropanoid, named arundalcohol (2), and four known alkaloids, N-acetyltryptamine (3), trans-N-(p-coumaroyl)serotonin (4), trans-N-feruloylserotonin (5), and tuberosine B (6), were isolated from 70% aqueous ethanol extracts of the rhizomes of Arundo donax L. Their structures were elucidated by spectroscopic analysis and comparison of the data with literature values. Compounds 3-6 were isolated from the genus Arundo for the first time.

Toxicology and Analysis of Psychoactive Tryptamines.

Our understanding of tryptamines is poor due to the lack of data globally. Tryptamines currently are not part of typical toxicology testing regimens and their contribution to drug overdoses may be underestimated. Although their prevalence was low, it is increasing. There are few published data on the many new compounds, their mechanisms of action, onset and duration of action, toxicity, signs and symptoms of intoxication and analytical methods to identify tryptamines and their metabolites. We review the published literature and worldwide databases to describe the newest tryptamines, their toxicology, chemical structures and reported overdose cases. Tryptamines are 5-HT2A receptor agonists that produce altered perceptions of reality. Currently, the most prevalent tryptamines are 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), 5-methoxy-N,N- diallyltryptamine (5-MeO-DALT) and dimethyltryptamine (DMT). From 2015 to 2020, 22 new analytical methods were developed to identify/quantify tryptamines and metabolites in biological samples, primarily by liquid chromatography tandem mass spectrometry. The morbidity accompanying tryptamine intake is considerable and it is critical for clinicians and laboratorians to be informed of the latest data on this public health threat.

Quality by Design Approach for Preparation of Zolmitriptan/Chitosan Nanostructured Lipid Carrier Particles - Formulation and Pharmacodynamic Assessment.

PURPOSE: Zolmitriptan (ZT) is a selective serotonin agonist that is used for the treatment of migraine. It belongs to BCS class III with high solubility and low permeability. Besides, the drug is subjected to pre-systemic metabolism. Accordingly, new Zolmitriptan/chitosan nanostructured lipid carriers (ZT/CT NLCs) coated with Tween 80 (stealthy layer) have been developed to overcome such demerits. METHODS: The NLCs were developed by combining ultrasonication and double emulsion (w/o/w) techniques. The lipids were Gelucire and Labrasol. Herein, the quality by design (23 full factorial design) was scrupulously followed, where critical process parameters and critical quality attributes were predefined. The optimized formulation (F8) was fully characterized with respect to entrapment efficiency (%EE), percentage yield (% yield), particle size, size distribution (PDI), zeta potential (ZP), morphological appearance (TEM). In vitro release, stability study and pharmacodynamic evaluations were also assessed. The optimized freeze dried formula was dispensed in in situ gelling hard gelatin capsule encompassing pectin and guar gum for further in vitro and pharmacodynamic evaluations. RESULTS: The optimized spherical nanoparticles experienced high percentage EE and yield (78.14% and 60.19%, respectively), low particle size and PDI (343.87 nm and 0.209, respectively), as well as high negative ZP (-25.5 mV). It showed good physical stability at refrigerated conditions. The NLCs dispensed in in situ gelling hard gelatin capsule comprising pectin and guar gum experienced sustained release for 30 h and significantly maintained the pharmacological effect in mice up to 8 h (p < 0.001). CONCLUSION: ZT, a BCS class III drug that suffers from poor permeability and pre-systemic metabolism, was successfully maneuvered as nanostructured lipid carrier particles (NLCs). The incorporation of the NLCs in in situ gelling hard gelatin capsules fulfilled a dual function in increasing permeability, as well as sustaining the pharmacodynamic effect. This result would open new vistas in improving the efficacy of other class III drugs.

Comparative assessment of in vitro/in vivo performances of orodispersible electrospun and casting films containing rizatriptan benzoate.

The electrospinning process is a promising approach to produce various drug-loaded orodispersible films (ODFs) with a rapid onset of their actions. However, there is only limited number of studies comparing the pharmacological performances of electrospun ODFs (eODFs) with traditional casting films (CFs). In this study, rizatriptan benzoate (RB), a pain relieving agent was formulated with PVP and PVA into ODFs using electrospinning and casting methods. The ODFs were subsequently characterized with respect to their morphology, solid state properties and mechanical characteristics. The uniformity of the dosage units, disintegration behavior and dissolution patterns of the ODFs were also evaluated prior to the pharmacokinetic study. The obtained CFs and eODFs were semitransparent and white in appearance, respectively. The scanning electron microscopy revealed that the eODFs contained nanoporous structure, while the CFs showed no observable pores. RB was amorphously dispersed in both these films without drug-polymer interactions. The uniformity of dosage units for both eODFs and CFs was complied with European Pharmacopeia. As compared to the CFs, the eODFs were more flexible and lesser rigid in nature and showed faster disintegration and dissolution rates. In addition, the eODFs exhibited a higher bioavailability with a shorter Tmax relative to the CFs and commercial RB tablets. This study demonstrated that eODFs were superior to CFs with respect to in vivo pharmacological effects, which could be attributed to the submicron structure of eODFs obtained through the electrospinning process.

Discovery and Total Synthesis of a Bis(cyclotryptamine) Alkaloid Bearing the Elusive Piperidinoindoline Scaffold.

Bis(cyclotryptamine) alkaloids have been popular topics of study for many decades. Five possible scaffolds for bis(cyclotryptamine) alkaloids were originally postulated in the 1950s, but only four of these scaffolds have been observed in natural products to date. We describe synthetic access to the elusive fifth scaffold, the piperidinoindoline, through syntheses of compounds now termed "dihydropsychotriadine" and "psychotriadine". The latter of these compounds was subsequently identified in extracts of the flower Psychotria colorata. Our synthetic route features a stereospecific solid-state photodecarbonylation reaction to introduce the key vicinal quaternary stereocenters.