Potent Selective Inhibitor Research Articles

Safety and Efficacy of Venetoclax Combined with Rituximab, Ifosfamide, Carboplatin and Etoposide Chemoimmunotherapy (VICER) for Treatment of Relapsed Diffuse Large B Cell Lymphoma: Results from the Phase 1 Study

Safety and Efficacy of Venetoclax Combined with Rituximab, Ifosfamide, Carboplatin and Etoposide Chemoimmunotherapy (VICER) for Treatment of Relapsed Diffuse Large B Cell Lymphoma: Results from the Phase 1 Study

Efficacy of a New Small-Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) in Preclinical Models of B-Cell Lymphoma and Acute Myeloid Leukemia

Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibitors or drugs that target the other HDAC classes. In this regard, the compound ACY-1215 (Rocilinostat), the described selective HDAC6 inhibitors, is undergoing clinical trials for the treatment of multiple myeloma. Taking into account the previous information about HDAC6 inhibitor structures, the structural differences between HDAC6 and other HDAC isoforms and also the structural information of other developed HDAC inhibitors, we have previously designed and synthesized a new potential HDAC6 selective inhibitor, QTX125 with growth inhibitory effects in mantle cell lymphoma (MCL) cell lines, mouse models and ex vivo treatment of primary samples obtained from patients with MCL. Herein, we have extended these findings to show that the newly identified HDAC6 inhibitor QTX125 is also able to inhibit the growth of preclinical models of other B-cell lymphomas such as follicular lymphoma and Burkitt's cell lymphoma, but also of acute acute myeloid leukemia. In addition beyond a-tubulin, a well known HDAC6 target, we have developed a pharmacological and proteomic screening to identify other proteins modified by HDAC6 that can contribute to the described lymphoma and leukemia phenotypes. DisclosuresEneko:Quimatryx: Employment. Yosu:Quimatryx: Employment. Myriam:Oncomatryx: Employment. Cristina:Oncomatryx: Employment. González-Barca:Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Fernando:Quimatryx: Consultancy.

Multi-targeting aurones with monoamine oxidase and amyloid-beta inhibitory activities: Structure-activity relationship and translating multi-potency to neuroprotection

Previously, a series of aurones bearing amine and carbamate functionalities was synthesized and evaluated for their cholinesterase inhibitory activity and drug-like attributes. In the present study, these aurones were evaluated for their multi-targeting properties in two Alzheimer’s disease (AD)-related activities namely, monoamine oxidase (MAO) and amyloid-beta (Aβ) inhibition. Evaluation of the aurones for MAO inhibitory activity disclosed several potent selective inhibitors of MAO-B, particularly those with 6-methoxyl group attached at ring A. Of the different amine moieties attached as side chains, pyrrolidine-bearing aurones were prominent as represented by 2-2, the most potent inhibitor. Evaluation on the Aβ aggregation inhibition identified 4-3 as the best inhibitor with a percentage inhibition comparable to that of a known Aβ inhibitor curcumin. Examination on the neuroprotective ability of the more drug-like aurone 4-3 in two Caenorhabditis elegans neurodegeneration models showed 4-3 to protect the nematodes against both Aβ- and 6-hydroxydopamine-induced toxicities. These new activities further support 4-3 as a promising lead to develop the aurones as potential multipotent agents for neurodegenerative diseases.

Search and evaluation of pharmacodynamic and pharmacokinetic parameters of selective blocker of TRPA 1 ion channels from the group of substituted pyrazinopyrimidinones

Introduction. Doctors of almost all specialties have to deal with the problem of pain and its relief. According to the literature, almost 30 million people daily take analgesics from the group of non-opioid analgesics, but in more than half of them 4-6 hours after taking the medication, the severity of pain is unchanged.
 Objective. to search for the most active molecules potential selective inhibitors of the TRPA1 ion channel with further investigation of their pharmacodynamic effects, toxicological safety, pharmacokinetic parameters and organ distribution, as well as to assess their impact on the psychoemotional state, general locomotor activity levels and anxiety in laboratory animals.
 Materials and methods. According to the results of in vitro tests, the most active molecule under code ZC02-0012 was selected from the pool of candidates. Further its analgesic activity was evaluated using an acetic acid-induced writhing test and a hot plate test; its anti-inflammatory activity was studied in the acute exudative paw edema model; in the open field and elevated plus-maze tests the influence of ZC02-0012 on the general locomotor activity levels and the anxiety of the laboratory animals was studied. The pharmacokinetic parameters and organ distribution of the substance ZC02-0012 were studied using a liquid chromatograph with an operating pressure range of 0-60 mPa (Thermo Scientific Dionex UltiMate 3000).
 Results and discussion. According to the results of in vitro tests, it was found that IC50 of the TRPA1 selective inhibitor under laboratory code ZC02-0012 was 91.3 nmol. The preclinical studies showed that ZC02-0012 possessed pronounced analgesic and anti-inflammatory activities and absence of the influence on the behavior and anxiety of the laboratory animals. Absolute bioavailability of ZC02-0012 in rabbits was 47%, while ZC02-0012 was intensely distributed into organs and tissues with a high level of blood circulation. The highest content of ZC02-0012 is typical of liver, kidneys and lungs, the lowest – for muscle tissue. Most of the substance is undergone rapid biotransformation and excreted as metabolites.

Pharmacophore-based virtual screening for identification of potential selective inhibitors of human histone deacetylase 6

Histone deacetylase (HDAC) 6 plays a role in oncogenic transformation and cancer metastasis via tubulin deacetylation, making it a critical target for anticancer drug design. However, lack of selectivity shown by many of the current HDAC6 inhibitors in clinical use and trials prompts the continuous search for selective inhibitors. Here, 10 pharmacophore hypotheses were developed based on the 3D common features of training set of 20 HDAC inhibitors in clinical use and trials. The hypotheses were validated using a test set of another 20 HDAC inhibitors along with 400 inactive (decoys) molecules based on Güner-Henry pharmacophore scoring method. Hypothesis 1 consisting of 1 H-bond donor, 1 H-bond acceptor and 2 hydrophobic features, was used to screen “DruglikeDiverse” database using Biovia Discovery Studio 4.5. The top 10 hit compounds were selected based on the pharmacophore fit values (>3.00). Their binding affinity against HDAC6 compared to class I HDACs (1, 2, 3 & 8) and a class IIa member (HDAC7), was calculated by molecular docking using AutoDock4. The stability of binding modes of 2 potential HDAC6-selective inhibitors (ENA501965 and IBS399024) was examined by 30 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software. Both ligands showed potential stability in HDAC6 active site over time. Therefore, these may provide additional scaffolds for further optimization towards the design of safe, potent and selective HDAC6 inhibitors.

Computation-guided analysis of paroxetine binding to hSERT reveals functionally important structural elements and dynamics

The serotonin transporter (SERT) is one of the primary targets for medications to treat neuropsychiatric disorders and functions by exploiting pre-existing ion gradients of Na+, Cl−, and K+ to translocate serotonin from the synaptic cleft into the presynaptic neuron. Although recent hSERT crystal structures represent a milestone for structure-function analyses of mammalian neurotransmitter:sodium symporters, they are all derived from thermostabilized but transport-deficient constructs. Two of these structures are in complex with paroxetine, the most potent selective serotonin reuptake inhibitor known. In this study, by carrying out and analyzing the results of extensive and comparative molecular dynamics simulations while also re-evaluating the transport and binding properties of the thermostabilized constructs, we identified functionally important structural elements that are perturbed by these mutations, revealed unexpected dynamics in the central primary binding site of SERT, and uncovered a conceivable ambiguity in paroxetine's binding orientation. We propose that the favored entropy contribution plays a significant role in paroxetine's extraordinarily high affinity for SERT. Our findings lay the foundation for future mechanistic studies and rational design of high-affinity SERT inhibitors.This article is part of the issue entitled ‘Special Issue on Neurotransmitter Transporters’.

Determination of potential selective inhibitors for ROCKI and ROCKII isoforms with molecular modeling techniques: structure based docking, ADMET and molecular dynamics simulation

Rho-associated protein kinases (ROCKs) are a member of the serine/threonine protein kinase family and potential therapeutic target for various diseases. This enzyme has two isoforms, Rho-associated protein kinase I (ROCKI) and Rho-associated protein kinase II (ROCKII). They share an overall 65% homology in all amino acid sequence and 92% homology in kinase domains. Since, the kinase domains of ROCKI and ROCKII are highly conserved and similar, the discovery and design of isoform-selective inhibitors are more challenging. Thus, most currently available agents that is against ROCKs exhibit low selectivity and severe side effects. Therefore, this study aimed to elucidate the interaction of compounds that indicated high potential in experimental studies against ROCKI and ROCKII enzymes in the molecular level with molecular modeling techniques. Firstly, we determined the interaction property of catalytic sites of the ROCKs by analyzing with molecular docking. Based on these results, the best ligands (50 compounds) corresponding to experimental studies were selected, and then absorption, distribution, metabolism and excretion – toxicity (ADMET) analysis of these compounds were implemented. According to these study results, the compound 40 for ROCKI and the compound 50 for ROCKII were identified as selective and highly potent inhibitors. And finally, molecular dynamics (MD) simulations were performed for the stability of ROCKs with identified compounds. In the light of this study, it will be possible to treat diseases that ROCKs have a role by developing more effective and specific ROCK inhibitors.Communicated by Ramaswamy H. Sarma

Structural Basis for Isoform Selective Nitric Oxide Synthase Inhibition by Thiophene-2-carboximidamides.

The overproduction of nitric oxide in the brain by neuronal nitric oxide synthase (nNOS) is associated with a number of neurodegenerative diseases. Although inhibiting nNOS is an important therapeutic goal, it is important not to inhibit endothelial NOS (eNOS) because of the critical role played by eNOS in maintaining vascular tone. While it has been possible to develop nNOS selective aminopyridine inhibitors, many of the most potent and selective inhibitors exhibit poor bioavailability properties. Our group and others have turned to more biocompatible thiophene-2-carboximidamide (T2C) inhibitors as potential nNOS selective inhibitors. We have used crystallography and computational methods to better understand how and why two commercially developed T2C inhibitors exhibit selectivity for human nNOS over human eNOS. As with many of the aminopyridine inhibitors, a critical active site Asp residue in nNOS versus Asn in eNOS is largely responsible for controlling selectivity. We also present thermodynamic integration results to better understand the change in p Ka and thus the charge of inhibitors once bound to the active site. In addition, relative free energy calculations underscore the importance of enhanced electrostatic stabilization of inhibitors bound to the nNOS active site compared to eNOS.

Discovery of a Potent Grp94 Selective Inhibitor with Anti-Inflammatory Efficacy in a Mouse Model of Ulcerative Colitis.

As the endoplasmic reticulum paralogue of Hsp90, Grp94 chaperones a small set of client proteins associated with some diseases, including cancer, primary open-angle glaucoma, and inflammatory disorders. Grp94-selective inhibition has been a potential therapeutic strategy for these diseases. In this study, inspired by the conclusion that ligand-induced "Phe199 shift" effect is the structural basis of Grp94-selective inhibition, a series of novel Grp94 selective inhibitors incorporating "benzamide" moiety were developed, among which compound 54 manifested the most potent Grp94 inhibitory activity with an IC50 value of 2 nM and over 1000-fold selectivity to Grp94 against Hsp90α. In a DSS-induced mouse model of ulcerative colitis (UC), compound 54 exhibited significant anti-inflammatory efficacy. This work provides a potent Grp94 selective inhibitor as probe compound for the biological study of Grp94 and represents the first study that confirms the potential therapeutic efficacy of Grp94-selective inhibitors against UC.

Molecular simulation studies on the binding activity and selectivity of 3-amino-phenyl-5-chloro-pyrimidine-2, 4-diamine derivatives in complexes with kinases c-Met and ALK

ABSTRACTReceptor tyrosine kinases c-Met and ALK have been demonstrated to be important therapeutic targets for cancer therapy. However, selectivity and drug resistance could hinder the development of their corresponding inhibitors. In this study, three compounds with similar scaffold were examined to study activity and selectivity mechanism towards c-Met or ALK by utilising a combined approach of computational techniques, including flexible dock, molecular electrostatic potential (MESP) calculations, molecular dynamic (MD) simulation, and binding free-energy calculation. Molecular simulation provides us new chemical insights into steric and electronic complementarities of these inhibitors to target binding sites. The computed binding free energies were consistent with the changing trend of experimental affinities on c-Met and ALK. H-bond with Asp169 and hydrophobic interaction with Phe36 of c-Met, respectively, could be crucial for the binding affinity of an inhibitor binding to c-Met. Meanwhile, for inhibitor–ALK complex, both H-bond interactions with Arg28 and Met101 and hydrophobic interactions with Leu30, Val38, and Leu158 could enhance the bioactivity and selectivity. The present work may provide a structural understanding of molecular mechanism expected to be valuable for the guidelines of the development of new potent c-Met or ALK selective inhibitors.

Screening for the selective inhibitors of MMP-9 from natural products based on pharmacophore modeling and molecular docking in combination with bioassay experiment, hybrid QM/MM calculation, and MD simulation

Matrix metalloproteinase-9 (MMP-9) has been considered as an attractive target involving cancer therapy. In this study, the 3D QSAR pharmacophore model of MMP-9 inhibitors is built, and its reliability is subsequently validated based on different methods. The built pharmacophore model consists of the four chemical features, including two hydrogen bond acceptors (HBA), one hydrophobic (HY), and one ring aromatic (RA). Among them, both HY and RA are found to be especially important features because they involve the interactions of inhibitors with the S1′ pocket of MMP-9, which determines the selectivity of MMP-9 inhibitors. By combining pharmacophore model with molecular docking, the virtual screening is carried out to identify the selective MMP-9 inhibitors from natural products. The four potential selective MMP-9 inhibitors of natural products are found. One of them was used to carry out the bioassay experiment inhibiting MMP-9, and the estimated IC50 value of only 26.94 µM clearly shows its strongly inhibitory activity; besides, both the hybrid quantum mechanics/molecular mechanics (QM/MM) calculation and the molecular dynamics simulation are performed to examine the reliability regarding the binding mode of this inhibitor with MMP-9 active sites predicted by molecular docking. All the screened four natural products are found to well bind with the MMP-9 active sites by different kinds of interactions. Finally, the ADMET properties of screened four natural products are assessed. These screened MMP-9 inhibitors of natural products could be used as the lead compounds to perform structural modifications and optimizations in the future work.Communicated by Ramaswamy H. Sarma

Protection against UVB-Induced Wrinkle Formation in SKH-1 Hairless Mice: Efficacy of Tricin Isolated from Enzyme-Treated Zizania latifolia Extract.

Tricin, a flavone found mainly in rice bran and sugarcane, has various beneficial effects. It has proven to be a clinically safe and selective potent inhibitor of different cancer cell lines. In this study, we evaluated the efficacy of enzyme-treated Zizania latifolia (ETZL) and its major active compound tricin on skin photoaging in SKH-1 hairless mice. Tricin (0.3 mg/kg) and ETZL (50, 150, and 300 mg/kg) were orally administrated to mice for 14 weeks; no cytotoxicity was observed during the entire experimental period. After UVB exposure, we observed significant increases in keratinization, coarse wrinkles, loss of moisture, thickened epidermis, and collagen fiber degradation in the dorsal skin. These features of photoaging were significantly suppressed after oral administration of tricin or ETZL. In addition, the protein expression of collagen effectively increased in ETZL (150 and 300 mg/kg)-treated mice, while the increased metalloproteinase (MMP)-1 and MMP-3 expressions were reduced after exposure to tricin or ETZL, although the effects were not dose-dependent. These data indicate that ETZL may be effective for attenuation of UVB-induced skin damage and photoaging in hairless mice, possibly by inhibiting MMPs expression.

Design, synthesis, and biological evaluation of selective and potent Carbazole-based butyrylcholinesterase inhibitors

Alzheimer’s disease (AD) is the most common form of dementia. Inhibition of BChE might be a useful therapeutic target for AD. A new series of Carbazole-Benzyl Pyridine derivatives were designed synthesized and evaluated as butyrylcholinesterase (BChE) inhibitors. In vitro assay revealed that all of the derivatives had selective and potent anti- BChE activities. 3-((9H-Carbazol-9-yl)methyl)-1-(4-chlorobenzyl)pyridin-1-ium chloride (compound 8f) had the most potent anti-BChE activity (IC50 value = 0.073 μM), the highest BChE selectivity and mixed-type inhibition. Docking study revealed that 8f interacted with the peripheral site, the choline binding site, catalytic site and the acyl pocket of BChE. Physicochemical properties were accurate to Lipinski's rule. In addition, compound 8f demonstrated neuroprotective activity at 10 µM. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation at concentration of 100 µM and 10 µM respectively. The in-vivo study showed that compound 8f in 10 mg/kg increased the time spent in target quadrant in the probe day and decreased mean training period scape latency in rats. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.

Evaluation of WO2017018805: 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors

ABSTRACTIntroduction: There are great potential in the development of selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine diseases, and other diseases associated with HDAC6 activity.Areas covered: The application claims 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; disease of the musculoskeletal system and connective tissue; or congenital malformations, deformations and chromosomal abnormalities. Many of the exemplified compounds showed nanomole potency against HDAC6 and were more than 5000-fold selectivity for HDAC6 over HDAC1.Expert opinion: These 1,3,4-oxadiazole sulfamide derivatives have a unique zinc-binding group (ZBG) that provide good leads for the discovery of potent selective HDAC6 inhibitors for the treatment of a variety of diseases associated with HDAC6 activity.

Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib

Resistance to chemotherapy is a challenging problem for treatment of cancer patients and autophagy has been shown to mediate development of resistance. In this study we systematically screened a library of 306 known anti-cancer drugs for their ability to induce autophagy using a cell-based assay. 114 of the drugs were classified as autophagy inducers; for 16 drugs, the cytotoxicity was potentiated by siRNA-mediated knock-down of Atg7 and Vps34. These drugs were further evaluated in breast cancer cell lines for autophagy induction, and two tyrosine kinase inhibitors, Sunitinib and Erlotinib, were selected for further studies. For the pharmacological inhibition of autophagy, we have characterized here a novel highly potent selective inhibitor of Vps34, SB02024. SB02024 blocked autophagy in vitro and reduced xenograft growth of two breast cancer cell lines, MDA-MB-231 and MCF-7, in vivo. Vps34 inhibitor significantly potentiated cytotoxicity of Sunitinib and Erlotinib in MCF-7 and MDA-MB-231 in vitro in monolayer cultures and when grown as multicellular spheroids. Our data suggests that inhibition of autophagy significantly improves sensitivity to Sunitinib and Erlotinib and that Vps34 is a promising therapeutic target for combination strategies in breast cancer.

Febuxostat for the treatment of hyperuricaemia in gout

ABSTRACTIntroduction: Febuxostat is a potent non-purine selective xanthine oxidase inhibitor approved by the FDA in 2009 for management of hyperuricemia in people with gout.Areas covered: The authors summarize the pre-clinical studies and pivotal randomized controlled trials of febuxostat when used as a treatment for hyperuricaemia in goutExpert opinion: Febuxostat has clinical efficacy in serum urate lowering, and long-term use leads to improved outcomes such as gout flare frequency and tophus burden. Recently published post-approval placebo-controlled trials have demonstrated urate-lowering efficacy and safety of febuxostat in patients with chronic kidney disease, and reduced frequency of gout flares in people with early onset of gout. In November 2017, the FDA issued a drug safety communication based on the preliminary results of the CARES trial. This cardiovascular safety study of 6190 patients with gout and established cardiovascular disease comparing febuxostat and allopurinol showed no difference in the primary endpoint (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization), but did report higher all-cause mortality (hazard ratio 1.22) and cardiovascular mortality (hazard ratio 1.34) with febuxostat. Based on currently available data, it seems likely that allopurinol, rather than febuxostat, will remain first line urate-lowering therapy for people with gout.

Molecular modelling studies of tricyclic triazinone analogues as potential PKC-θ inhibitors through combined QSAR, molecular docking and molecular dynamics simulations techniques

Abstract Protein kinase C theta (PKC-θ), which can trigger dysregulation of the T cell pathway and consequently lead to immune diseases, is a highly promising target for immunosuppressive agents. To search for potential PKC-θ inhibitors with few side effects, the structure activity relationship (SAR) of 54 tricyclic triazinone analogues as PKC-θ inhibitors was systematically discussed and studied by combined QSAR, molecular docking and molecular dynamics (MD) simulation, and reliable CoMFA (q2 = 0.863, r2 = 0.988, rpred2 = 0.899) and CoMSIA (q2 = 0.824, r2 = 0.984, rpred2 = 0.835) models were established and assisted with the HQSAR and 2D-QSAR models. Several key resides, namely, Glu459, Val394, Leu511, Met458, Phe668 and Asp465 were identified by Surflex–dock. Based on contour maps analysis and the docking analysis, eight novel PKC-θ inhibitors (D1–D8) were designed. The 10-ns MD simulations of 54 and D8 revealed that the introduction of fluorine atoms or hydrophobic structures into the β strand domain under the glycine-rich loop favored the stabilization of the ligand binding with the receptor. The predictive non-toxic compound D7, which showed good activity, was selected by ADMET predictions. Additionally, to expand the molecular library of PKC-θ inhibitors, we screened the database from the ZINC library based on the pharmacophore and obtained four skeletons (G1–G4). These results provided strong guidance for the discovery and design of novel potential PKC-θ selective inhibitors.

Multi-target-directed ligands for treating Alzheimer's disease: Butyrylcholinesterase inhibitors displaying antioxidant and neuroprotective activities

The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki = 1.09 ± 0.12 nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu2+ ions in a Cu-ascorbate redox system. Compounds 8 and 11 decrease intracellular levels of reactive oxygen species, and are not substrates of the active efflux transport system, as determined in Caco2 cells. Compound 11 also protects neuroblastoma SH-SY5Y cells from toxic Aβ1–42 species. These data indicate that compounds 8 and 11 are promising multifunctional lead ligands for treatment of Alzheimer's disease.

Sinapic acid phenethyl ester as a potent selective 5-lipoxygenase inhibitor: Synthesis and structure-activity relationship.

Given the hepatotoxicity and an unfavorable pharmacokinetic profile of zileuton (Zyflo® ), currently the only approved and clinically used 5-Lipoxygenase (5-LO) inhibitor, the search for potent and safe 5-LO inhibitors is highly demanded. The action of several phenolic acid phenethyl esters as potential 5-Lipoxygenase (5-LO) inhibitors has been investigated. For this purpose, a series of 14 phenethyl esters was synthesized and their impact on 5-LO inhibition was evaluated. The effects of position and number of hydroxyl and methoxy groups on the phenolic acid were investigated. The shortening of the linker between the carbonyl and the catechol moiety as well as the presence of the α,β-unsaturated carbonyl group was also explored. The sinapic acid phenethyl ester (10), which can be named SAPE (10) by analogy to caffeic acid phenethyl ester (CAPE), inhibited 5-LO in a concentration-dependent manner and outperformed both zileuton (1) and CAPE (2). With an IC50 of 0.3μm, SAPE (10) was threefold more potent than CAPE (2) and 10-fold more potent than zileuton (1), the only 5-LO inhibitor approved for clinical use. Unlike CAPE (2), SAPE (10) had no effect on 12-lipoxygenase (12-LO) and less effect on cyclooxygenase 1 (COX-1) which makes it a more selective 5-LO inhibitor.

Vibrational (FT-IR and FT-Raman), electronic (UV–Vis), NMR (1H and 13C) spectra and molecular docking analyses of anticancer molecule 4-hydroxy-3-methoxycinnamaldehyde

The structure of 4-Hydroxy-3-methoxycinnamaldehyde (4H3MC) has been analyzed by spectroscopic and theoretical investigations. The vibrational spectral analysis of title compound was characterized by FT-IR and FT-Raman in the mid IR region. The 1H and 13C NMR chemical shifts of title compound were recorded at 300 K in DMSO solution. The HOMO-LUMO energy was calculated for the molecule. The Global reactivity descriptors and molecular electrostatic surface potential (MESP) were obtained to get better insight on charge density distribution. Thermodynamic parameters such as heat capacity (C), entropy (S), enthalpy changes (H) also determined for the title compound at different temperatures. NPA and MPA charge distribution was investigated with the help of quantum chemical calculations. The optimized bond lengths, bond angles, vibrational wave numbers, chemical shift and electronic transitions showed the best agreement with the experimental results. The biological activites were carried out using PASS online data base prediction and hence, these molecules could be potential selective inhibitors of JAK2 that can be experimentally validated and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for JAK2. Hence, the above docking study indicate that the binding affinity and hydrogen bond interactions of these molecule with respect to amino residues can be supportive evidence for the further studies in designing structure-based JAK2 kinase inhibitors may be of significant therapeutic importance.