harmine and Neoplasms

Anticancer agents are critical for the cancer treatment, but side effects and the drug resistance associated with the currently used anticancer agents create an urgent need to explore novel drugs with low side effects and high efficacy. 1,2,3-Triazole is privileged building block in the discovery of new anticancer agents, and some of its derivatives have already been applied in clinics or under clinical trials for fighting against cancers. Hybrid molecules occupy an important position in cancer control, and hybridization of 1,2,3-triazole framework with other anticancer pharmacophores may provide valuable therapeutic intervention for the treatment of cancer, especially drug-resistant cancer. This review emphasizes the recent advances in 1,2,3-triazole-containing hybrids with anticancer potential, covering articles published between 2015 and 2019, and the structure-activity relationships, together with mechanisms of action are also discussed.

Topics: Antineoplastic Agents; Humans; Molecular Structure; Neoplasms; Structure-Activity Relationship; Triazoles

Even though one is moving towards the success in the discovery of efficient anti-cancer molecules, the drugs used in the treatment of various malignancies are found to possess toxicity and adverse reactivity in the human body that limit their use. The scientists all over the world are engaged in bringing up strategies that aim to develop small molecules that target the abnormal epigenetic factors. The discovery of the role of Histone deacetylases (HDACs) has promised to be a turning point in the treatment of various malignancies. Thus, the invention of potent and safe anticancer therapeutics agents with minimal adverse and side effects are still a major topic of concern and a huge number of research works have been reported in the past few years. This review has been written to discuss on the influence of Histone Deacetylases in cancer malignancies. We have tried to embrace majority of the developments made till date in the field of HDAC and its inhibitors herein. The drugs that are clinically applied, synthesis and SAR study that highlight the chemical groups responsible for evoking the HDAC inhibition and potential of various new classes of HDAC inhibitors (synthetic, hybrid and natural) have also been included.

Topics: Animals; Antineoplastic Agents; Biological Products; Chemistry Techniques, Synthetic; Drug Discovery; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Models, Molecular; Molecular Targeted Therapy; Neoplasms; Structure-Activity Relationship

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Protein kinases are one of the most studied drug targets in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. Dual-specificity Tyrosine phosphorylation-Regulated Kinase 1A (DYRK1A) has been much less studied compared to many other kinases. DYRK1A primary function occurs during early development, where this protein regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells. Although most extensively characterised for its role in brain development, DYRK1A is over-expressed in a variety of diseases including a number of human malignancies, such as haematological and brain cancers. Here we review the accumulating molecular studies that support our understanding of how DYRK1A signalling could underlie these pathological functions. The relevance of DYRK1A in a number of diseases is also substantiated with intensive drug discovery efforts to develop potent and selective inhibitors of DYRK1A. Several classes of DYRK1A inhibitors have recently been disclosed and some molecules are promising leads to develop DYRK1A inhibitors as drugs for DYRK1A-dependent diseases.

Topics: Alternative Splicing; Alzheimer Disease; Apoptosis; Benzothiazoles; Cell Cycle; Cell Differentiation; Down Syndrome; Dyrk Kinases; Enzyme Activation; Gene Dosage; Harmine; Humans; Indoles; Neoplasms; Neurodegenerative Diseases; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyridazines; Receptors, Notch; Signal Transduction

Topics: Animals; Breast Neoplasms; Carbolines; Carcinogens, Environmental; Cattle; Colonic Neoplasms; Cooking; Food; Harmine; Head and Neck Neoplasms; Humans; Imidazoles; Male; Meat; Mutagens; Neoplasms; Nitrates; Nitrites; Nitrosamines; Prostatic Neoplasms

Overexpression of histone deacetylases (HDACs) are observed in different types of cancers, but histone deacetylase inhibitors (HDACIs) have not shown significant efficacy as monotherapy against solid tumors. Recently, studies demonstrated that it is promising to combine HDACIs with DNA damage agents to improve DNA damage level to gain better effect on treating solid tumor. Harmine has been demonstrated to cause DNA damage by intercalating DNA. Therefore, we designed a series of harmine-based inhibitors targeting HDAC and DNA with multi-target strategy, the most potential compound 27 could bind to DNA and cause DNA damage. Furthermore 27 caused cells apoptosis through p53 signaling pathway, and exhibited significant anti-proliferation effects against HCT-116 cells (IC

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; DNA; Harmine; Histone Deacetylase Inhibitors; Histone Deacetylases; Neoplasms

DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1a) is highly expressed in glioma, an aggressive brain tumor, and has been proposed as a therapeutic target for cancer. In the current study, we have used an optimized and validated time-resolved fluorescence energy transfer (TR-FRET)-based DYRK1A assay for high-throughput screening (HTS) in 384-well format. A small-scale screen of the FDA-approved Prestwick drug collection identified the β-carboline, harmine, and four related analogs as DYRK1A inhibitors. Hits were confirmed by dose response and in an orthogonal DYRK1A assay. Harmine's potential therapeutic use has been hampered by its off-target activity for monoamine oxidase A (MAO-A) which impacts multiple nervous system targets. Selectivity profiling of harmine and a broader collection of analogs allowed us to map some divergent SAR (structure-activity relationships) for the DYRK1A and MAO-A activities. The panel of harmine analogs had varying activities in vitro in glioblastoma (GBM) cell lines when tested for anti-proliferative effects using a high content imaging assay. In particular, of the identified analogs, harmol was found to have the best selectivity for DYRK1A over MAO-A and, when tested in a glioma tumor xenograft model, harmol demonstrated a better therapeutic window compared to harmine.

Topics: Antineoplastic Agents; Carbolines; Dyrk Kinases; Harmine; High-Throughput Screening Assays; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neoplasms; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases

Harmine and its analogs have long been considered as anticancer agents. In vitro analyses suggested that intercalating DNA or inhibiting topoisomerase might contribute to the cytotoxic effect of this class of compound. However, this idea has not been rigorously tested in intact cells. By synthesizing novel derivatives, here we demonstrate that harmines did not activate the DNA damage response, a cellular signaling commonly induced by agents that intercalate DNA or inhibit topoisomerase. These findings suggest that mechanisms other than DNA intercalating or topoisomerase inhibiting contribute to the toxicity of harmines in vivo. Using a novel N

Topics: Apoptosis; Autophagy; Cell Cycle; Cell Line, Tumor; Cell Proliferation; DNA Damage; Harmine; Humans; Mass Spectrometry; Neoplasms

There is little information available on the monoamine oxidase isoform selectivity of N-alkyl harmine analogs, which exhibit a myriad of activities including MAO-A, DYRK1A and cytotoxicity to several select cancer cell lines.. Compounds 3e and 4c exhibited an IC

Topics: Antineoplastic Agents; Click Chemistry; Harmine; Humans; Kinetics; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neoplasms; Protein Isoforms; Structure-Activity Relationship; Triazoles

Alternative splicing is a key process required for the regulation of gene expression in normal development and physiology. It is regulated by splice factors whose activities are in turn regulated by splice factor kinases and phosphatases. The CDC-like protein kinases are a widespread family of splice factor kinases involved in normal physiology and in several diseases including cancer. In humans they include the CLK1, CLK2, CLK3 and CLK4 genes. The expression of CLK1 is regulated through alternative splicing producing both full-length catalytically active and truncated catalytically inactive isoforms, CLK

Topics: Alternative Splicing; Cell Line, Tumor; Exons; Gene Expression Regulation; Harmine; HL-60 Cells; Homeostasis; Hot Temperature; Humans; Introns; Neoplasms; Osmotic Pressure; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Stress, Physiological; Thiazoles

The breast cancer resistance protein (ABCG2) transports chemotherapeutic drugs out of cells, which makes it a major player in mediating multidrug resistance (MDR) of cancer cells. To overcome this mechanism, inhibitors of ABCG2 can be used. Only a few potent and selective ABCG2 inhibitors have been discovered, i.e., fumitremorgin C (FTC), Ko143, and the alkaloid harmine, which contain a tetrahydro-β-carboline or β-carboline backbone, respectively. However, toxicity and or instability prevent their use in vivo. Therefore, there is a need for further potent inhibitors. We synthesized and pharmacologically investigated 37 tetrahydro-β-carboline derivatives. The inhibitory activity of two compounds (51, 52) is comparable to that of Ko143, and they are selective for ABCG2 over ABCB1. Furthermore, they are able to reverse the ABCG2-mediated resistance toward SN-38 and inhibit the ATPase activity. The cytotoxicity data show that their inhibitory effect is substantially higher than their toxicity.

Topics: Adenosine Triphosphatases; Animals; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily G, Member 2; Camptothecin; Carbolines; Cell Line; Dogs; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Irinotecan; Neoplasm Proteins; Neoplasms

A series of novel harmine derivatives bearing a benzylindine substituent in position-1 of β-carboline ring were synthesized and evaluated as antitumor agents. The N2-benzylated β-carboline derivatives 3a-g represented the most interesting anticancer activities and compound 3c was found to be the most active agent to diverse cancer cell lines such as gastric carcinoma, melanoma and colorectal cancer. Notably, compound 3c showed low toxicity to normal cells. The treatment significantly induced cell apoptosis. Mechanistically, PI3K/AKT signaling pathway mediated compound 3c-induced apoptosis. Compound 3c inhibited phosphorylation of AKT and promoted the production of reactive oxygen species (ROS). The ROS scavenger, LNAC and GSH, could disturb the effect of compound 3c induced apoptosis and PI3K activity inhibitor LY294002 synergistically enhanced compound 3c efficacy. Moreover, the results from nude mice xenograft model showed that compound 3c treatment effectively inhibited tumor growth and decreased tumor weight. Collectively, our results demonstrated that compound 3c exerts apoptotic effect in cancer cells via suppression of phosphorylated AKT and evocation of ROS generation, which suggested that compound 3c might be served as a promising therapeutic agent for cancer treatment.

Topics: A549 Cells; Animals; Antineoplastic Agents; Chromones; Harmine; HeLa Cells; Hep G2 Cells; Humans; Mice; Mice, Nude; Morpholines; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Xenograft Model Antitumor Assays

A novel series of hybrids (7a-l, 8a-l) from β-carboline and salicylic acid (SA) were designed and synthesized, and their in vitro biological activities were evaluated. Most of the hybrids displayed potent antiproliferative activity against five cancer cell lines in vitro, showing potencies superior to 5-FU and harmine. In particular, compound 8h selectively inhibited proliferation of liver cancer SMMC-7721 cells but not normal liver LO2 cells, and displayed greater inhibitory selectivity than intermediate 5h and SA. 8h also induced cancer cell apoptosis in an Annexin V-FITC/propidium iodide flow cytometry assay, and triggered the mitochondrial/caspase apoptosis by decreasing mitochondrial membrane potential which was associated with up-regulation of Bax, down-regulation of Bcl-2 and activation levels of the caspase cascade in a concentration-dependent manner. Our findings suggest that the β-carboline/SA hybrids may hold greater promise as therapeutic agents for the intervention of human cancers.

Topics: Antineoplastic Agents; bcl-2-Associated X Protein; Carbolines; Caspase 9; Cell Line, Tumor; Cell Survival; Drug Design; Fluorouracil; Gene Expression Regulation, Neoplastic; Harmine; Humans; Membrane Potential, Mitochondrial; Molecular Structure; Neoplasms; Salicylic Acid

The interaction of small biologically active molecules in the nanocavity of supramolecular host is very interesting and thriving research area. In the presence of supramolecular host the absorption and emission properties of small biologically active molecules were modulated several folds compared to bulk solution. In this study we have investigated the supramolecular interaction of a cancer cell photosensitizer molecule harmane in the presence of cucurbit[7]uril (CB7) as host in aqueous buffer solution (pH∼7.2). We have used steady state absorption, emission and time resolved fluorescence spectroscopy techniques. The thermodynamics of the binding between harmane in the nanochannel of CB7 were studied by using isothermal titration calorimetry (ITC) method. The emission properties of harmane are modulated several fold in the presence of CB7. ITC study indicates that the complexation between harmane and CB7 are enthalpically favourable.

Topics: Bridged-Ring Compounds; Calorimetry; Harmine; Imidazoles; Nanostructures; Neoplasms; Photosensitizing Agents; Spectrometry, Fluorescence

Molecular iodine facilitated the reaction of 5,5-dimethyl-1,3-cyclohexanedione with aromatic aldehydes in iso-propanol affording a variety of 1,8-dioxo-octahydroxanthenes in high yields. Most of the compounds synthesized showed good anti-proliferative properties in vitro against three cancer cell lines and 9-(2-hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione possessing a 2-hydroxy phenyl group at C-9 position was found to be promising. Further structure elaboration of the same compound and the crystal structure analysis and hydrogen bonding patterns of another compound that is, 9-(4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione prepared by using this methodology is presented.

Topics: Aldehydes; Antineoplastic Agents; Catalysis; Cell Line, Tumor; Cell Survival; Crystallography, X-Ray; Cyclohexanes; Drug Screening Assays, Antitumor; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Iodine; Molecular Structure; Neoplasms; Xanthenes

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K(i) = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.

Topics: Animals; Antineoplastic Agents; Biological Availability; Cell Line; Drug Design; Enzyme Inhibitors; Humans; Immunologic Factors; Indoles; Kinetics; Mice; Neoplasms; Structure-Activity Relationship; Tryptophan Oxygenase

Blood concentrations of harmane, a tremor-producing neurotoxin, are elevated in essential tremor (ET). Harmane is also a comutagen. Using a case-control design, we compared the prevalence of cancer in ET cases vs. controls, and determined whether blood harmane concentrations are elevated among ET cases with cancer. 66/267 (24.7%) ET cases vs. 55/331 (16.6%) controls had cancer (adjusted OR 1.52, 95% CI 1.01-2.30, P = 0.04). Among specific cancer types, colon cancer was more prevalent in ET cases than controls (2.6% vs. 0.6%, P = 0.04). Log blood harmane concentration was higher in ET cases vs. controls (P = 0.02) and in participants with vs. without cancer (P = 0.02). Log blood harmane concentration was highest in ET cases with cancer when compared with other groups (P = 0.009). These links between cancer and ET and between high blood harmane and cancer in ET deserve further study.

Topics: Aged; Chi-Square Distribution; Essential Tremor; Female; Harmine; Humans; Male; Middle Aged; Neoplasms