17019-04-4

Upstream product

• 442-51-3 harmine 
• 100-39-0 benzyl bromide 
• 2016-04-8 N,N-dimethylformamide dibenzyl acetal 
• 486-93-1 tetrahydroharmine 
• 100-44-7 benzyl chloride 
• 3610-36-4 2-(6-methoxy-1H-indol-3-yl)ethanamine 

Downstream Products

• 103033-52-9 1-(9-benzyl-7-methoxy-9H-β-carbolin-1-ylmethyl)-2-methyl-cyclohexanol 

Relevant academic research and scientific papers

Structure-Based Design and Synthesis of Harmine Derivatives with Different Selectivity Profiles in Kinase versus Monoamine Oxidase Inhibition

Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome, in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases, could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand, harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design, we synthesized a collection of harmine analogues with tunable selectivity toward these two enzymes. Modifications at the 7-position typically decreased affinity for DYRK1A, whereas substitution at the 9-position had a similar effect on MAO-A inhibition but DYRK1A inhibition was maintained. The resulting collection of compounds can help to understand the biological role of DYRK1A and also to assess the interference in the biological effect originating in MAO-A inhibition.

Synthesis and biological evaluation of bivalent β-carbolines as potential anticancer agents

A series of novel bivalent β-carbolines were synthesized and evaluated for their anti-proliferative activities on a panel of cancer cell lines, apoptosis induction and cell cycle effects. The present study showed that bivalent β-carbolines possess stronger anti-proliferative effects than monomeric ones. Moreover, introduction of a methyl or benzyl group into the N9 position of the bivalent β-carbolines improved their anti-proliferative activities. Additionally, the most potent compounds 4c and 8a with IC50 values of 0.84 μM and 0.23 μM, respectively, were more potent than doxorubicin (IC50 = 2.48 μM) against A-549 cell lines. The most active compound 8a could induce cell apoptosis in a dose-dependent manner and cause cell cycle arrest in the S phase.

Synthesis and serum protein binding of novel ring-substituted harmine derivatives

A series of new derivatives of the natural β-carboline alkaloid harmine, introducing hydrophobic substituents into positions 7 and 9 were synthesized as potential anticancer agents. Their binding affinities for human serum albumin (HSA) and α1-acid glycoprotein (AAG) were investigated by affinity chromatography combined with fluorescence, circular dichroism (CD) and UV absorption spectroscopy. The weak binding of harmine to both proteins (Ka ～ 3 × 104 M-1) was highly increased by aromatic substitutions (Ka ～ 105-106 M-1). Derivatives having a substituted benzyl group in the N9-position of the β-carboline nucleus showed about tenfold and hundredfold affinity enhancement for HSA and AAG, respectively. Such a strong plasma protein interaction would be of pharmacokinetic relevance for these potential drug candidates. Induced CD spectra indicated the variant selective, dimeric binding of the 7-pyridylethoxy derivative to AAG. Absorbance and fluorescence spectra refer to the binding preference of the neutral form of the studied β-carbolines for both proteins.

Exploring kinase inhibition properties of 9hpyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives

We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β and DYRK1A). As a result, we have identified promising compounds targeting CK1δ/ε and DYRK1A and displaying micromolar and submicromolar IC50 values.

KINASE INHIBITOR COMPOUNDS AND COMPOSITIONS AND METHODS OF USE

Described herein are compounds having the following structure: formula (I) or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof. Also disclosed are compositions containing the compounds, methods of inhibiting activity of DYRKl A in a cell, methods of increasing cell proliferation in a population of pancreatic beta cells, methods of treating a subject for a condition associated with insufficient insulin secretion, and methods of treating a subject for a neurological disorder.

Synthesis and biological evaluation of N9-substituted harmine derivatives as potential anticancer agents

A series of N9-substituted harmine derivatives were synthesized and evaluated for their anticancer activity on a panel of cancer cell lines, their apoptosis induction and their cell cycle effects. The results showed that N9-substituted harmine derivatives had anticancer effects. In particular, N9-haloalkyl derivatives 9a–9c and N9-acyl harmine derivatives 11c and 11d, with IC50values less than 1?μM, were more potent than doxorubicin against A-549 and/or MCF-7 cell lines. Moreover, structure–activity relationships (SARs) indicated that introducing a haloalkyl or benzenesulfonyl group in the N9-position of harmine could significantly increase the anticancer activity. The most active compound (11d) caused cell cycle arrest in the G2/M phase, and induced cell apoptosis in a dose-dependent manner.

HARMINE DERIVATIVES, INTERMEDIATES USED IN THEIR PREPARATION, PREPARATION PROCESSES AND USE THEREOF

This invention relates to compounds of general formula (I), wherein R1, R2, R3, R4 and R5 are as defined specification; intermediates used in their preparation, preparation processes and use thereof. The present invention produce harmine derivatives with enhanced antihumour activity and lower nervous system toxicity by structurally modification parent structure of β-carboline of harmines at position 1, 2, 3, 7 and 9, The compounds of the present invention can be pre easily with high yield. They can be used in manufacture of a variety of antitumour medicines and medicines used in treatm tumour diseases in combination of light or radiation therapy.

Synthesis, acute toxicities, and antitumor effects of novel 9-substituted β-carboline derivatives

A series of novel 9-substituted β-carboline derivatives was synthesized from the starting material harmine and l-tryptophan, respectively. Cytotoxic activities, acute toxicities, and antitumor effects of these compounds were investigated. A series of nove