Novel thiosemicarbazide-based ß-carboline derivatives as α-glucosidase inhibitors: Synthesis and biological evaluation.

In the quest for potent α-glucosidase inhibitors to combat diabetes, a series of novel thiosemicarbazide-based ß-carboline derivatives (CTL1∼36) were synthesized and evaluated. CTL1∼36 exhibited remarkable inhibitory effects against α-glucosidase, with IC50 values ranging from 2.81 to 12.40 µM, significantly surpassing the positive control acarbose (IC50 = 564.28 µM). Notably, CTL26 demonstrated the most potent inhibition (IC50 = 2.81 µM) and was characterized as a non-competitive inhibitor. Through a combination assay with fluorescence quenching, 3D fluorescence spectra, CD spectra, and molecular docking, we elucidated that CTL26 formed a complex with α-glucosidase via hydrogen bondings and hydrophobic interactions, leading to α-glucosidase conformation changes that impaired enzymatic activity. In vivo studies revealed that oral administration of CTL26 (25 and 50 mg/kg/d) reduced fasting blood glucose levels, enhanced glucose tolerance, and ameliorated lipid abnormalities in diabetic mice. These findings positioned CTL26 as a promising candidate for the development of α-glucosidase inhibitors with anti-diabetic potential.

Effects and mechanisms of using "clean" smoke particles in the smoking process on the formation of ß-carboline heterocyclic amines (ß-CHAs) in smoked meat patties.

ß-Carboline heterocyclic amines (ß-CHAs), known for their synergistic neurotoxic and carcinogenic effects, are predominantly produced by humans through cigarette smoke and food and are found particularly in meats cooked at high temperatures. Few studies have explored the differences in the mechanisms of accumulation of ß-CHAs in smoked meat and meat processed at high temperatures. In this research, the concentration of ß-CHAs in smoked meats prepared using a variety of wood materials was measured using LCMS/MS. Additionally, key volatile organic compound markers associated with ß-CHAs accumulation in smoke were identified through GCMS and multivariate statistical analysis and subsequently confirmed in a chemical simulation system. Three types of strainers, each with a distinct aperture size, were used to assess the efficacy of particle filtration in reducing ß-CHAs levels in smoked meat. The findings indicated that smoke exposure indeed increases the ß-CHAs content of meat. However, only the strainer capable of filtering PM2.5-sized particles reduced the amount of ß-CHAs present compared to the control group. In contrast, strainers with larger pore sizes facilitated excessive accumulation of ß-CHAs. The presence of aldehydes such as 1 H-pyrrole-2-carboxaldehyde, 5-methylfurfural, benzaldehyde, furfural, and nonanal exhibited a positive correlation with the accumulation of ß-CHAs. Conversely, phenolic compounds, including 2-methoxy-4-vinylphenol, 2-methoxy-5-methylphenol, p-cresol, phenol, 2-methoxy-4-(1-propenyl)-, (Z)-, phenol, 3-ethyl-, and phenol, 4-ethyl-2-methoxy-, showed a negative correlation. Thus, filters made from chelated carbonyl trap materials both chemically and physically disrupt the buildup of ß-CHAs in smoked meats. The use of this approach will not only improve the quality of these products but will also contribute to decreasing the amount of inhalation pollutants released into the environment.

Synthesis and biological evaluation of novel 1,2,3,4-tetrahydro-ß-carboline derivatives as potential antibacterial agents.

The quest for novel antibacterial agents is imperative in the face of escalating antibiotic resistance. Naturally occurring tetrahydro-ß-carboline (THßC) alkaloids have been highlighted due to their significant biological derivatives. However, these structures have been little explored for antibacterial drugs development. In this study, a series of 1,2,3,4-THßC derivatives were synthesized and assessed for their antibacterial prowess against both gram-positive and gram-negative bacteria. The compounds exhibited moderate to good antibacterial activity, with some compounds showing superior efficacy against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), to that of Gentamicin. Among these analogs, compound 3k emerged as a hit compound, demonstrating rapid bactericidal action and a significant post-antibacterial effect, with significant cytotoxicity towards human LO2 and HepG2 cells. In addition, compound 3k (10 mg/kg) showed comparable anti-MRSA efficacy to Ciprofloxacin (2 mg/kg) in a mouse model of abdominal infection. Overall, the present findings suggested that THßC derivatives based on the title compounds hold promising applications in the development of antibacterial drugs.

Multimechanism biological profiling of tetrahydro-ß-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease.

With the intensive research on the pathogenesis of Alzheimer's disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-ß-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 selectively inhibited HDAC6 with IC50 of 15.2 nM and markedly increased acetylated alpha-tubulin levels. In cellular assay, 15 showed excellent neurotrophic effect by increasing the expression of GAP43 and Beta-3 tubulin markers. Besides, 15 showed neuroprotective effects in PC12 or SH-SY5Y cells against H2O2 and 6-OHDA injury through activation of Nrf2, catalase and Prx II, and significantly reduced H2O2-induced reactive oxygen species (ROS) production. In vivo, 15 significantly attenuated zebrafish anxiety-like behaviour and memory deficits in a SCOP-induced zebrafish model of AD. To sum up, multifunctional 15 might be a good lead to develop novel tetrahydrocarboline-based agents for the treatment of AD.

In Vitro Effect of 9,9'-Norharmane Dimer against Herpes Simplex Viruses.

Herpes simplex virus (HSV) infections are highly widespread among humans, producing symptoms ranging from ulcerative lesions to severe diseases such as blindness and life-threatening encephalitis. At present, there are no vaccines available, and some existing antiviral treatments can be ineffective or lead to adverse effects. As a result, there is a need for new anti-HSV drugs. In this report, the in vitro anti-HSV effect of 9,9'-norharmane dimer (nHo-dimer), which belongs to the ß-carboline (ßC) alkaloid family, was evaluated. The dimer exhibited no virucidal properties and did not impede either the attachment or penetration steps of viral particles. The antiviral effect was only exerted under the constant presence of the dimer in the incubation media, and the mechanism of action was found to involve later events of virus infection. Analysis of fluorescence lifetime imaging data showed that the nHo-dimer internalized well into the cells when present in the extracellular incubation medium, with a preferential accumulation into perinuclear organelles including mitochondria. After washing the host cells with fresh medium free of nHo-dimer, the signal decreased, suggesting the partial release of the compound from the cells. This agrees with the observation that the antiviral effect is solely manifested when the alkaloid is consistently present in the incubation media.

Development of Novel ß-Carboline/Furylmalononitrile Hybrids as Type I/II Photosensitizers with Chemo-Photodynamic Therapy and Minimal Toxicity.

Chemo-photodynamic therapy is a treatment method that combines chemotherapy and photodynamic therapy and has demonstrated significant potential in cancer treatment. However, the development of chemo-photodynamic therapeutic agents with fewer side effects still poses a challenge. Herein, we designed and synthesized a novel series of ß-carboline/furylmalononitrile hybrids 10a-i and evaluated their chemo-photodynamic therapeutic effects. Most of the compounds were photodynamically active and exhibited cytotoxic effects in four cancer cells. In particular, 10f possessed type-I/II photodynamic characteristics, and its 1O2 quantum yield increased by 3-fold from pH 7.4 to 4.5. Most interestingly, 10f exhibited robust antiproliferative effects by tumor-selective cytotoxicities and hypoxic-overcoming phototoxicities. In addition, 10f generated intracellular ROS and induced hepatocellular apoptosis, mitochondrial damage, and autophagy. Finally, 10f demonstrated extremely low acute toxicity (LD50 = 1415 mg/kg) and a high tumor-inhibitory rate of 80.5% through chemo-photodynamic dual therapy. Our findings may provide a promising framework for the design of new photosensitizers for chemo-photodynamic therapy.

[4 + 2] Cyclization or Lossen Rearrangement: Rhodium-Catalyzed Divergent Synthesis of Carboline Derivatives with Anticancer Activity.

An unusual rhodium-catalyzed C-H activation/Lossen rearrangement/oxa-Michael addition tandem cyclization has been achieved along with a tunable well-known C-H activation/[4 + 2] annulation, leading to regio-, chemo-, and diastereoselective access to diverse pentacyclic α-carbolines and ß-carboline-1-one derivatives in moderate to good yields with significant anticancer activity.

A ß-Carboline Derivate PAD4 Inhibitor Reshapes Neutrophil Phenotype and Improves the Tumor Immune Microenvironment against Triple-Negative Breast Cancer.

Triple-negative breast cancer is a highly aggressive and heterogeneous breast cancer subtype characterized by early metastasis, poor prognosis, and high recurrence. Targeting histone citrullination-mediated chromatin dysregulation to induce epigenetic alterations shows great promise in TNBC therapy. We report the synthesis, optimization, and evaluation of a novel series of ß-carboline-derived peptidyl arginine deiminase 4 inhibitors that exhibited potent inhibition of TNBC cell proliferation. The most outstanding PAD4 inhibitor, compound 28, hindered the PAD4-H3cit-NET signaling pathway and inhibited the growth of solid tumors and pulmonary metastatic nodules in the 4T1 in situ mouse model. Furthermore, 28 improved the tumor immune microenvironment by reshaping neutrophil phenotype, upregulating the proportions of dendritic cells and M1 macrophages, and reducing the amount of myeloid-derived suppressor cells. In conclusion, our work offered 28 as an efficacious PAD4 inhibitor that exerts a combination of conventional chemotherapy and immune-boosting effects, which represents a potential therapy strategy for TNBC.

Anticancer mechanisms of ß-carbolines.

ß-Carboline nucleus is therapeutically valuable in medicinal chemistry for the treatment of varied number of diseases, most importantly cancer. The potent and wide-ranging activity of ß-carboline has established them as imperative pharmacological scaffolds especially in the cancer treatment. Numerous derivatives such as Tetrahydro ß-carbolines, metal complexed ß-carbolines, mono, di and tri substituted ß-carbolines have been reported to possess dynamic anticancer activity. These different substituted ß-carboline derivatives had shown different mechanism of action and plays important role in anticancer drug discovery and development. The review is an update of the chemistry of ß-carbolines, both synthetic and natural origin acting through various targets against cancerous cells. In addition to this, studies of multitarget molecules designed by coupling ß-carbolines along with other mechanisms for treatment of neoplasm are also summarized.

3-Amide-ß-carbolines block the cell cycle by targeting CDK2 and DNA in tumor cells potentially as anti-mitotic agents.

ß-Carboline alkaloids are natural and synthetic products with outstanding antitumor activity. C3 substituted and dimerized ß-carbolines exert excellent antitumor activity. In the present research, 37 ß-carboline derivatives were synthesized and characterized. Their cytotoxicity, cell cycle, apoptosis, and CDK2- and DNA-binding affinity were evaluated. ß-Carboline monomer M3 and dimer D4 showed selective activity and higher cytotoxicity in tumor cells than in normal cells. Structure-activity relationships (SAR) indicated that the amide group at C3 enhanced the antitumor activity. M3 blocked the A549 (IC50 = 1.44 ± 1.10 µM) cell cycle in the S phase and inhibited A549 cell migration, while D4 blocked the HepG2 (IC50 = 2.84 ± 0.73 µM) cell cycle in the G0/G1 phase, both of which ultimately induced apoptosis. Furthermore, associations of M3 and D4 with CDK2 and DNA were proven by network pharmacology analysis, molecular docking, and western blotting. The expression level of CDK2 was downregulated in M3-treated A549 cells and D4-treated HepG2 cells. Moreover, M3 and D4 interact with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes, which means that the favorable entropy change (ΔS > 0) overcomes the unfavorable enthalpy change (ΔH > 0) and drives the spontaneous reaction (ΔG < 0). Overall, these results clarified the antitumor mechanisms of M3 and D4 through disrupting the cell cycle by binding DNA and CDK2, which demonstrated the potential of M3 and D4 as novel antiproliferative drugs targeting mitosis.

ß-Carboline alkaloids from the roots of Peganum harmala L.

This study reports the isolation of four new ß-carboline alkaloids (1-4) and six previously identified alkaloids (5-10) from the roots of Peganum harmala L. Among these compounds, 1 and 2 were characterized as rare ß-carboline-quinazoline dimers exhibiting axial chirality. Compound 3 possessed a unique 6/5/6/7 tetracyclic ring system with an azepine ring, and compound 4 was a novel annomontine ß-carboline. The structures of these compounds were elucidated by spectroscopic data and quantum mechanical calculations. The biosynthetic pathways of 1-3 were proposed. Additionally, the cytotoxicity of some isolates against four cancer cell lines (HL-60, A549, MDA-MB-231, and DU145) was evaluated. Notably, compound 4 exhibited significant cytotoxicity against HL-60, A549, and DU145 cells with IC50 values of 12.39, 12.80, and 30.65 µmol·L-1, respectively. Furthermore, compound 2 demonstrated selective cytotoxicity against HL-60 cells with an IC50 value of 17.32 µmol·L-1.

Distribution of photoactive ß-carboline alkaloids across Passiflora caerulea floral organs.

This study reports valuable information regarding the presence and concentration of a series of photoactive ß-carboline (ßCs) alkaloids (norharmane, harmane, harmine, harmol, harmaline, and harmalol) and their distribution across the floral age and organs of Passiflora caerulea. UHPLC-MS/MS data reported herein reveal that the ßCs' content ranged from 1 to 110 µg kg-1 , depending on the floral organ and age. In certain physiologically relevant organs, such as anthers, ßCs' content was one order of magnitude higher than in other organs, suggesting a special role for ßCs in this specific organ. ßCs' content also varied in a structure-dependent manner. Alkaloids bearing a hydroxyl group at position C(7) of the main ßC ring were present at concentrations one order of magnitude higher than other ßC derivatives investigated. UV-visible and fluorescence spectroscopy of the flower extracts provided complementary information regarding other biologically relevant groups of chromophores (phenolic/indolic derivatives, flavonoids/carotenes, and chlorophylls). Since flowers are constantly exposed to solar radiation, the presence of photoactive ßCs in floral organs may have several (photo)biological implications that are further discussed.

Cryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir.

Positron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [18F]-Flortaucipir is the only approved PET tracer compound for the visualisation of tau aggregation. Here, we describe cryo-EM experiments on tau filaments in the presence and absence of flortaucipir. We used tau filaments isolated from the brain of an individual with Alzheimer's disease (AD), and from the brain of an individual with primary age-related tauopathy (PART) with a co-pathology of chronic traumatic encephalopathy (CTE). Unexpectedly, we were unable to visualise additional cryo-EM density for flortaucipir for AD paired helical or straight filaments (PHFs or SFs), but we did observe density for flortaucipir binding to CTE Type I filaments from the case with PART. In the latter, flortaucipir binds in a 1:1 molecular stoichiometry with tau, adjacent to lysine 353 and aspartate 358. By adopting a tilted geometry with respect to the helical axis, the 4.7 Å distance between neighbouring tau monomers is reconciled with the 3.5 Å distance consistent with π-π-stacking between neighbouring molecules of flortaucipir.

Chromatography-Free Synthesis of ß-Carboline 1-Hydrazides and an Investigation of the Mechanism of Their Bioactivity: The Discovery of ß-Carbolines as Promising Antifungal and Antibacterial Candidates.

Agrochemical science prioritizes the discovery and effective synthesis of innovative and promising lead compounds. Herein, we developed an efficient column chromatography-free synthesis for ß-carboline 1-hydrazides via a mild CuBr2-catalyzed oxidation and investigated the antifungal and antibacterial activities and mechanisms for these compounds. In our study, compounds 4de (EC50 = 0.23 µg·mL-1) and 4dq (EC50 = 0.11 µg·mL-1) displayed the best efficacy, demonstrating enhancements in inhibitory activity of more than 20-fold against Ggt compared to silthiopham (EC50 = 2.39 µg·mL-1). Additionally, compound 4de (EC50 = 0.21 µg·mL-1) demonstrated outstanding in vitro antifungal activities as well as in vivo curative activities against Fg. According to preliminary mechanistic studies, ß-carboline 1-hydrazides led to the accumulation of reactive oxygen species, destruction of cell membranes, and dysregulation of histone acetylation. Furthermore, several substances exhibited antibacterial activity against Psg and Cms by preventing the development of bacterial biofilms.

Review of ß-carboline and its derivatives as selective MAO-A inhibitors.

As flavin adenine dinucleotide (FAD)-dependent enzymes, monoamine oxidases (MAOs) catalyze the oxidative deamination of various endogenous and exogenous amines. MAO-A inhibitors are thought to be effective therapeutic agents for treating neurological diseases including depression and anxiety. Due to the academic challenge of developing new human (h) MAO-A inhibitors and the potential for discovering substances with remarkable properties compared to existing MAO-A inhibitors, numerous research groups are looking into novel classes of chemical compounds that may function as selective hMAO-A inhibitors. ß-Carbolines are reported to be a prominent class of bioactive molecules exhibiting MAO-A inhibition. Chemically, ß-carboline is a tricyclic pyrido-3,4-indole ring. It has only recently been discovered that this chemotype has highly effective and specific MAO-A inhibitory activity. In this review, structure-activity relationship studies included in particular research publications from the 1960s to the present are discussed with regard to ß-carboline and its analogs. This comprehensive information helps to design and develop a new family of MAO-A inhibitors for the management of depressive disorders.

Current development of ß-carboline derived potential antimalarial scaffolds.

ß-Carboline alkaloids are an eminent class of nitrogen-based natural alkaloids and therapeutic molecules which exert various pharmacological activities through diverse mechanisms. A lot of attention has recently been directed towards this moiety in order to develop effective antimalarial drugs. "Malaria", an acute febrile illness caused by diverse Plasmodium parasites, is a continuing and escalating problem that devastates economically less developed countries by significantly increased morbidity and mortality rates. The mounting parasite resistance towards the antimalarial drugs and augmenting the 'habitat of the insect vector' are creating a catastrophe, indicating an urgent need for new efficacious therapeutics to combat this tropical disease. This article comprehensively encapsulates the clinical and preclinical antimalarial scaffolds comprising ß-carboline moiety in their structure. Herein, various classes of natural and semi-synthetic analogues of ß-carbolines reported in the last decade (2011-2021) have been extensively studied and illustrated. This review will help the readers to develop an insight into the ß-carboline based antimalarials and molecular mechanisms lying behind their mode of action, which is anticipated to be beneficial for the future development of new ß-carboline based therapeutics.

A bivalent ß-carboline derivative inhibits macropinocytosis-dependent entry of pseudorabies virus by targeting the kinase DYRK1A.

Pseudorabies virus (PRV) has become a "new life-threatening zoonosis" since the human-originated PRV strain was first isolated in 2020. To identify novel anti-PRV agents, we screened a total of 107 ß-carboline derivatives and found 20 compounds displaying antiviral activity against PRV. Among them, 14 compounds showed better antiviral activity than acyclovir. We found that compound 45 exhibited the strongest anti-PRV activity with an IC50 value of less than 40 nM. Our in vivo studies showed that treatment with 45 significantly reduced the viral loads and protected mice challenged with PRV. To clarify the mode of action of 45, we conducted a time of addition assay, an adsorption assay, and an entry assay. Our results indicated that 45 neither had a virucidal effect nor affected viral adsorption while significantly inhibiting PRV entry. Using the FITC-dextran uptake assay, we determined that 45 inhibits macropinocytosis. The actin-dependent plasma membrane protrusion, which is important for macropinocytosis, was also suppressed by 45. Furthermore, the kinase DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) was predicted to be a potential target for 45. The binding of 45 to DYRK1A was confirmed by drug affinity responsive target stability and cellular thermal shift assay. Further analysis revealed that knockdown of DYRK1A by siRNA suppressed PRV macropinocytosis and the tumor necrosis factor alpha-TNF-induced formation of protrusions. These results suggested that 45 could restrain PRV macropinocytosis by targeting DYRK1A. Together, these findings reveal a unique mechanism through which ß-carboline derivatives restrain PRV infection, pointing to their potential value in the development of anti-PRV agents.

Inspired by bis-ß-carboline alkaloids: Construction and antitumor evaluation of a novel bis-ß-carboline scaffold as potent antitumor agents.

Bis-ß-carboline alkaloids are widely distributed in natural products and represent a promising drug-like scaffold for discovering drugs and bioactive molecules. In this study, we utilized the structural simplification strategy to construct a novel bis-ß-carboline scaffold via "one-pot" condensation-Mannich reaction. The simplified bis-ß-carboline derivatives were obtained in good yield. Antitumor evaluation revealed most compounds, especially 3m, displayed potent antitumor activity (IC50 values for 3m: 0.96 µM âˆ¼ 1.52 µM). More importantly, 3m displayed valuable antitumor properties including anti-migration and anti-invasion activity against cancer cells, antiangiogenic and vascular-disrupting properties. Mechanistic studies revealed 3m potently inhibited both Top1 and Top2 activity, thus interfering with DNA synthesis in cancer cells. Taken together, this study developed a new synthetic methodology to construct a novel bis-ß-carboline scaffold, which represents a promising lead structure for antitumor drug discovery.

Effect of acrolein on the formation of harman and norharman in chemical models and roast beef patties.

Harman and norharman were the most abundant ß-carboline-type heterocyclic amines (HCAs) detected in various foodstuffs. Unsaturated fatty acids in foods may undergo rapid oxidative deterioration during transportation, storage and heat treatment, forming reactive carbonyl species (RCS). This work studied the effects of acrolein, a highly reactive RCS, on the formation of harman and norharman in the tryptophan model system. Results showed that 0.005, 0.01, 0.015, 0.02, 0.05, 0.1 and 0.2 mmol of acrolein led to harman production increased by 528 %, 752 %, 981 %, 1172 %, 1375 %, 1288 % and 768 % respectively, and led to norharman formation increased by 116 %, 129 %, 152 %, 169 %, and 197 %, 185 % and 157 %, respectively. Furthermore, acrolein addition reduced the residue of tryptophan (up to 63.19 %), but increased the level of the intermediates including formaldehyde (up to 352 %), acetaldehyde (up to 491 %), (1S,3S)-1-Methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid (MTCA, up to 1936 %), and 1,2,3,4-tetrahydro-ß-carboline-3-carboxylicacid (THCA, up to 2142 %) in the tryptophan model system. Acrolein might react with tryptophan, harman and norharman to eliminate them directly. These data suggested that acrolein may contribute to harman and norharman formation through participating in the above complex chemical reactions. In addition, the content of harman and norharman produced in roast beef patties made of minced beef oxidized for 2, 4, 6, 8, and 10 days increased by 118 %, 188 %, 267 %, 137 %, and 48 %, respectively, and led to norharman formation increased by 140 %, 132 %, 90 %, 86 %, and 74 %, respectively compared with those made of fresh minced beef, which further illustrated that lipid oxidation products potentially contributed to harman and norharman formation.

ß-Carboline alkaloids from Picrasma quassioides and their 3D-QSAR study on anti-inflammation in LPS-induced RAW 264.7 cells.

Two new ß-carboline alkaloids (1-2), 1-pyrrolidone propionyl-ß-carboline (1) and 1-(3-hydroxy-2-oxopiperidine-1-ethyl)-4,8-dimethoxyl-ß-carboline (2), named kumujantine W and J respectively, together with ten known compounds (3-12) were isolated from the stems of Picrasma quassioides (D. Don) Benn. Their structures were elucidated from spectral data including 1D and 2D NMR, UV, IR, HR-ESI-MS spectroscopic analysis and ECD calculations as well as by comparison to the reference databases or literature. The anti-inflammatory effects of these alkaloids (1-12) and six other ß-carboline alkaloids (13-18) in LPS-induced RAW 264.7 cells were evaluated by measuring nitric oxide (NO) concentrations. Among them, compounds 1, 3, 6, 15, and 17 could inhibit the secretion of NO, displaying significant anti-inflammatory activity without affecting cell viability in vitro, and 3D-QSAR analysis further revealed the influence of groups on the activity in ß-carboline alkaloids.