2013年12月20日金曜日

マリアアザミ

2013年12月11日水曜日

Cu-Catalyzed Electerophilic Amination

Oxime Benzoate Can DoI t!

An efficient copper-catalyzed electrophilic amination of benzoxazoles with O-benzoyl hydroxylamines is described, employing CuCl catalyst, PPh₃ ligand, and LiO^tBu base.

This simple air-stable copper catalysis enables the preparation of various 2-aminobenzoxazole derivatives at room temperature in good yields.

Protonated DBU Can Catalyze Cyclization

Protonated 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) as a catalyst for cascade addition/cyclization of 2-alkynylaniline and carbon disulfide has been described.

This process provides a convenient route for synthesis of a variety of benzo[d][1,3]thiazine-2(4H)-thiones in high yields with high regio- and stereoselectivity at room temperature without metal.

Benzothiazole From Weinreb Amide

One pot synthesis of 2-substituted benzimidazoles/benzothiazoles through condensation is followed by cyclization of Weinreb amide with o-diaminoarene or o-aminothiophenol is reported.

In the presence of boron trifluoride etherate in 1,4-dioxane solvent, a high yield (75–94%) was achieved within 60 min.

Weinreb amide shows high selectivity in the reaction, even in presence of other active functional groups such as carboxyl, halogen, cyano, and methoxy.

2013年12月9日月曜日

N-(substituted benzothiazol-2-yl)amides as anticonvulsant and neuroprotective

Design, synthesis and evaluation of N-(substituted benzothiazol-2-yl)amides as anticonvulsant and neuroprotective

A series of N-(substituted benzothiazol-2-yl)amide derivatives 2a–h and 4a–h were synthesized by the EDC coupling reactions of substituted-benzothiazol-2-amine with 4-oxo-4-phenylbutanoic acid/2-benzoyl benzoic acid and evaluated for their anticonvulsant and neuroprotective effect.

N-(6-methoxybenzothiazol-2-yl)-4-oxo-4-phenylbutanamide (2f) emerged as the most effective anticonvulsant with median doses of 40.96 mg/kg (MES ED₅₀), 85.16 mg/kg (scPTZ ED₅₀) and 347.6 mg/kg (TD₅₀).

Furthermore, compound 2f displayed promising neuroprotective effect by lowering the levels of MDA and LDH; therefore, it represents a potential lead in search for safer and effective anticonvulsants having neuroprotective effects.

Indole-N-glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor

Abstract

Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia.

To explore the potential of new antihyperglycemic agents, we synthesized and determined the human SGLT2 (hSGLT2) inhibitory potential of novel substituted 3-benzylindole-N-glucosides 6.

Optimization of 6 resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside 6a-4 (TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice.

Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2.

Keywords:

Type 2 diabetes; sodium glucose cotransporter 2 inhibitor; urinary glucose excretion; indole-N-glucoside; TA-1887; antihyperglycemic effect

2013年12月8日日曜日

Rhodanine Class of Compounds as Inhibitors of Protein Reductase

Enoyl acyl carrier protein (ACP) reductase, one of the enzymes of the type II fatty acid biosynthesis pathway, has been established as a promising target for the development of new drugs for malaria.

Here we present the discovery of a rhodanine (2-thioxothiazolidin-4-one) class of compounds as inhibitors of this enzyme using a combined approach of rational selection of compounds for screening, analogue search, docking studies, and lead optimization.

The most potent inhibitor exhibits an IC₅₀ of 35.6 nM against Plasmodium falciparum enoyl ACP reductase (PfENR) and inhibits growth of the parasite in red blood cell cultures at an IC₅₀ value of 750 nM.

Many more compounds of this class were found to inhibit PfENR at low nanomolar to low micromolar concentrations, expanding the scope for developing new antimalarial drugs. The structure−activity relationship of these rhodanine compounds is discussed.

2013年12月7日土曜日

Aminothiazole Secretase Inhibitors

A new γ-secretase modulators with an Aminothiazole core starting from a HTS hit is disclosed . Also, synthesis and SAR of this series are discussed.

These novel compounds demonstrate moderate to good in vitro potency in inhibiting amyloid beta (Aβ) peptide production.

Overall γ-secretase is not inhibited but the formation of the aggregating, toxic Aβ42 peptide is shifted to smaller non-aggregating Aβ peptides. Compound 15 reduced brain Aβ42 in vivo in APPSwe transgenic mice at 30 mg/kg p.o.

Protein Phosphatase-Directed Therapeutics　２０１６

Approaches to Study Phosphatases

Sara Fahs^†, Pablo Lujan^†, and Maja Köhn^*^†

^† European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany

ACS Chem. Biol., 2016, 11 (11), pp 2944–2961

DOI: 10.1021/acschembio.6b00570

Publication Date (Web): October 4, 2016

*E-mail: koehn@embl.de.

ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract

Phosphatases play key roles in normal physiology and diseases. Studying phosphatases has been both essential and challenging, and the application of conventional genetic and biochemical methods has led to crucial but still limited understanding of their mechanisms, substrates, and exclusive functions within highly intricate networks. With the advances in technologies such as cellular imaging and molecular and chemical biology in terms of sensitive tools and methods, the phosphatase field has thrived in the past years and has set new insights for cell signaling studies and for therapeutic development. In this review, we give an overview of the existing interdisciplinary tools for phosphatases, give examples on how they have been applied to increase our understanding of these enzymes, and suggest how they—and other tools yet barely used in the phosphatase field—might be adapted to address future questions and challenges.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschembio.6b00570.

Abbreviations, Glossary, and Supporting Table 1 (PDF)

View: ACS ActiveView PDF | PDF | PDF w/ Links | Full Text HTML

Related Content

Protein phosphatases have both protective and promoting roles in the etiology of diseases. A prominent example is the existence of oncogenic as well as tumor-suppressing protein phosphatases.

A few protein phosphatase activity modulators are already applied in therapies. These were however not developed in target-directed approaches, and the recent discovery of phosphatase involvement followed their application in therapy.

Nevertheless, these examples demonstrate that small molecules can be generated that modulate the activity of protein phosphatases and are beneficial for the treatment of protein phosphorylation diseases.

We describe here strategies for the development of activators and inhibitors of protein phosphatases and clarify some long-standing misconceptions concerning the druggability of these enzymes.

Recent developments suggest that it is feasible to design potent and selective protein phosphatase modulators with a therapeutic potential.

http://pubs.acs.org/doi/abs/10.1021/cb300597g?prevSearch=%2528ERK%2Binhibitor%2529%2Band%2B%255BAbstract%253A%2Bsmall%255D&searchHistoryKey=

Live & Let Dye: ERK Phosphorilation Inhibitors

Both small molecules 22 and 23 inhibited the proliferation
of several cancer cell lines, including HeLa cells with
IC50 values of around 15–20 mm, and A549 lung carcinoma cells
with IC50 values of 25 and 15 mm, respectively.

Given the finding that compound 22 binds directly to ERK2, the authors investigated the possible binding mode to the protein. The computational
screening applied at the onset of this research predicted
that 22 fits into the polar grove located between the
CD and ED sites on the ERK2 protein.

More specifically, 22 appears to make contacts with several amino acid residues between
Asp316/Asp319 of the CD domain and Thr157/Thr158
of the ED domain. In particular, as well as a possible cation–p
interaction between Arg133 and the phenyl ring of 22, several
hydrogen bonds were observed between 22 and Asp316 and
Asp319.

It is likely that the amino group of 22 (protonated at
physiological pH) is engaged in salt bridges with Asp316 and
Asp319. Indeed, as well as taking advantage of its facile functionalization
towards structure optimization,

we are currently investigating the significance of the primary amine of 22 by introducing a variety of chemical modifications to reduce the
number of polar N H bonds and to alter the basicity of the nitrogen
atom; these results shall be reported in due course.

2013年12月6日金曜日

Dynamin GTPase Inhibitory Activity: Rhodadyns

From Rhodanine To Dynamin I GTPase Inhibitors

Abstract Image

Six focused rhodanine-based libraries, 60 compounds in total,
were synthesized and evaluated as potential dynamin I GTPase inhibitors.

Twenty-six were more potent than the lead compound with 13 returning IC₅₀ values ≤10 μM, making the Rhodadyn series among the most active dynamin inhibitors reported.

Two analogues were highly effective at blocking receptor-mediated endocytosis: C10 and D10 with IC_50(RME) = 7.0 ± 2.2 and 5.9 ± 1.0 μM, respectively.

These compounds are equipotent with the best reported in-cell dynamin inhibitors.

http://pubs.acs.org/doi/abs/10.1021/ml200284s

Dynamin is required for clathrin-mediated endocytosis (CME).

Its GTPase activity is stimulated by phospholipid binding to its PH domain, which induces helical oligomerization.

We have designed a series of novel pyrimidine-based “Pyrimidyn” compounds that inhibit the lipid-stimulated GTPase activity of full length dynamin I and II with similar potency.

The most potent analogue, Pyrimidyn 7, has an IC₅₀ of 1.1 μM for

dynamin I and 1.8 μM for dynamin II, making it among the most potent dynamin inhibitors identified to date.

We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin.
The compound competitively inhibits both GTP and phospholipid interactions with dynamin I. While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby to target two distinct domains of dynamin.

Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non-neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals.

Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation.
This dual mode of action provides an important new tool for molecular dissection of dynamin’s role in endocytosis.

2013年12月1日日曜日

Protein Misfolding Modulators

Aldose Reductase Inhibitor can Inhibit tau Aggregation.

Alzheimer's disease is often referred as protein misfolding disease through peptide plaque accumulation of abnormally folded amyloid such as beta amyloid (Aβ) and tau amyloid protein in the brain system. According to the precedent reviews, some aggregation inhibitors of tau protein as well as selected amyloids are becoming a cornerstone of the capable chemotherapy for Alzheimer disease and other neurodegenerative symptoms.

Among the emerging small molecule tau inhibitors, particular heterocyclic structural motifs such as rhodanines and cyanine dyes are highlighted as promising and privileged key pharmacophores. Guided by these precedent findings, we are interested in the behavior and inhibitory functions of some generic (classical) drugs with traditional pigment skeletons towards tau protein aggregation. Thus, described herein is our preliminary investigation on the modulating activity of the aldose reductase inhibitor eparlestat on the tau aggregation under the in vitro experiments.

Rhodanine derivatives are classical heterocyclic dye materials, which recently have been investigated intensively by the German researchers towards tau interactions. Their previous results as well as commentary summary indicated the similar potency of the generic drug eparlestat, in view of the pre-existing nontoxic drugs, although no experimental results available. Thus, in order to gain a precise knowledge and evaluate the exact pleiotropic effects of eparlestat on tau aggregation, we have been investigating of some existing generic drugs along these lines, as summarized below.

In our preliminary in vitro experiments, three generic drugs at hands are investigated towards tau aggregation inhibitory activity along with the known methylene blue as a positive standard.

2013年11月23日土曜日

Rhodanine can Visualize Neurofibrillary Tangles

There is a high demand for the development of an imaging agent for neurofibrillary tangles (NFTs) detection in Alzheimer’s diagnosis.

A series of rhodanine-3-acetic acids was synthesized and evaluated for fluorescence imaging of NFTs in brain tissues of AD patients. Five out of seven probes have shown excellent binding affinity to NFTs over amyloid plaques in the Thiazine red R displacement assay.

However, the selectivity in this in vitro assay is not confirmed by the histopathological evaluation, which indicates significant differences in the binding sites in the assays.

Probe 6 showed binding affinity (IC₅₀ = 19 nM) to tau aggregates which is the highest among this series. Probes 2, 3, 4 and 5 display IC₅₀ values of lower than 100 nM to tau aggregates to displace Thiazine red R.

Evaluation of the cytotoxicity of these five probes with human liver carcinoma cells revealed that these compounds excert negligible cytotoxicity.

The in vivo studies with zebrafish embryos confirmed negligible cytotoxicity at 24 and 72 h post fertilization.

2013年11月7日木曜日

Cyanine Dyes Can Modulate tau Aggregation.

A structure−activity relationship for symmetrical cyanine inhibitors of human tau aggregation was elaborated using a filter trap assay.

Antagonist activity depended on cyanine heterocycle, polymethine bridge length, and the nature of meso- and N-substituents. One potent member of the series, 3,3′-diethyl-9-methylthiacarbocyanine iodide (compound 11), retained submicromolar potency and had calculated physical properties consistent with blood−brain barrier and cell membrane penetration.

Exposure of organotypic slices prepared from JNPL3 transgenic mice (which express human tau harboring the aggregation prone P301L tauopathy mutation) to compound 11 for one week revealed a biphasic dose response relationship. Low nanomolar concentrations decreased insoluble tau aggregates to half those observed in slices treated with vehicle alone.

In contrast, high concentrations (≥300 nM) augmented tau aggregation and produced abnormalities in tissue tubulin levels. These data suggest that certain symmetrical carbocyanine dyes can modulate tau aggregation in the slice biological model at concentrations well below those associated with toxicity.

http://pubs.acs.org/doi/abs/10.1021/jm900116d?prevSearch=N744&searchHistoryKey=

2013年11月6日水曜日

Tranilast Binds to Aβ Monomers and Promotes Aβ Fibrillation

AD may be a potential complication for tranilast usage in elderly patients.

Abstract Image

The antiallergy and potential anticancer drug tranilast has been patented for treating Alzheimer’s disease (AD), in which amyloid β-protein (Aβ) plays a key pathogenic role.

We used solution NMR to determine that tranilast binds to Aβ40 monomers with

300 μM affinity.

Remarkably, tranilast increases Aβ40 fibrillation more than 20-fold in the thioflavin T assay at a 1:1 molar ratio, as well as significantly reducing the lag time.

Tranilast likely promotes fibrillation by shifting Aβ monomer conformations to those capable of seed formation and fibril elongation. Molecular docking results qualitatively agree with NMR chemical shift perturbation, which together indicate that hydrophobic interactions are the major driving force of the Aβ–tranilast interaction.

These data suggest that AD may be a potential complication for tranilast usage in elderly patients.

http://pubs.acs.org/doi/abs/10.1021/bi400426t?prevSearch=tranilast&searchHistoryKey=

2013年10月28日月曜日

Curcuminoids Block TGF-b Sibnaling in HBC

Effects of curcuminoids on breast cancer cell secretion of the bone-resorptive peptide parathyroid hormone-related protein (PTHrP) and on lytic breast cancer bone metastasis were evaluated.

In vitro, transforming growth factor (TGF)-β-stimulated PTHrP secretion was inhibited by curcuminoids (IC₅₀ = 24 μM) in MDA-MB-231 human breast cancer cells independent of effects on cell growth inhibition.

Effects on TGF-β signaling revealed decreases in phospho-Smad2/3 and Ets-1 protein levels with no effect on p-38 MAPK-mediated TGF-β signaling.

In vivo, mice were inoculated with MDA-MB-231 cells into the left cardiac ventricle and treated ip every other day with curcuminoids (25 or 50 mg/kg) for 21 days.

Osteolytic bone lesion area was reduced up to 51% (p < 0.01).

Consistent with specific effects on bone osteolysis, osteoclast number at the bone–tumor interface was reduced up to 53% (p < 0.05), while tumor area within bone was unaltered.

In a separate study, tumor mass in orthotopic mammary xenografts was also unaltered by treatment.

These data suggest that curcuminoids prevent TGF-β induction of PTHrP and reduce osteolytic bone destruction by blockade of Smad signaling in breast cancer cells.

2013年10月27日日曜日

Cancer Drug Clinical Candidate Tipifarnib for Anti-Chagas Disease Drug Discovery

We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14α-demethylase.

Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites.

This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe.

Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14α-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4).

Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.

N-Heteroarylation of Chiral α-Aminoesters by Means of Palladium-Catalyzed Buchwald–Hartwig Reaction

N-Heteroaryl-α-amino acid derivatives are valuable pharmacological agents as peptidomimetics.

Classical S_NAr methods using acid catalysis and elevated temperatures could not be extended to various α-amino acids and fairly electrophilic heterocyclic partners.

Here, we report a mild and versatile method of N-heteroarylation of chiral α-aminoesters without racemization, involving Buchwald–Hartwig conditions.

It could be extended to various α-amino acids and azines.

This efficient N-heteroarylation leads to (i) a chemical library of putative peptidomimetics combining diverse azaheterocycles with the chiral α-aminoesters and their corresponding derivatives (amides, alcohols, etc.) and (ii) arginine derivatives designed as NPFF receptor ligands.

http://pubs.acs.org/doi/pdfplus/10.1021/jo4011427

2013年10月26日土曜日

Setileuton, a Potent and Selective 5-Lipoxygenase Inhibitor

Versatile One-Pot Route to 2-Quinoline-3-carboxamides

2013年10月25日金曜日

Novel Inhibitors of TGF Signaling

Annulated 1,4-Dihydropyridines Cardiomyogenic Compounds

as Novel Inhibitors of TGFβ Signaling

A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor β (TGFβ)/Smad signaling by clearing the type II TGFβ receptor from the cell surface.

Because this is an unprecedented mechanism of action, we explored the series’ structure–activity relationship (SAR) based on TGFβ inhibition, and evaluated SAR aspects for cell-surface clearance of TGFβ receptor II (TGFBR2) and for biological activity in mESCs.

We determined a pharmacophore and generated 1,4-DHPs with IC₅₀s for TGFβ inhibition in the nanomolar range (e.g., compound 28, 170 nM).

Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGFβ inhibition for the (+)- than the (−) enantiomer.

This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells.

http://pubs.acs.org/doi/abs/10.1021/jm301144g?prevSearch=TGF%25CE%25B2%2BInhibitor&searchHistoryKey=

2013年10月24日木曜日

Cyanine Dye N744 Inhibits Tau Fibrillization

Cyanine Dye N744 Inhibits Tau Fibrillization by Blocking Filament Extension: Implications for the Treatment of Tauopathic Neurodegenerative Diseases

登録: 投稿 (Atom)

2013年12月20日金曜日

2013年12月11日水曜日

2013年12月9日月曜日

Design, synthesis and evaluation of N-(substituted benzothiazol-2-yl)amides as anticonvulsant and neuroprotective

Abstract

Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia.

To explore the potential of new antihyperglycemic agents, we synthesized and determined the human SGLT2 (hSGLT2) inhibitory potential of novel substituted 3-benzylindole-N-glucosides 6.

Optimization of 6 resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside 6a-4 (TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice.

Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2.

Keywords:

Type 2 diabetes; sodium glucose cotransporter 2 inhibitor; urinary glucose excretion; indole-N-glucoside; TA-1887; antihyperglycemic effect

2013年12月8日日曜日

2013年12月7日土曜日

Approaches to Study Phosphatases

Abstract

PDF

Other ACS content by these authors:

Related Content:

Metrics

Protein phosphatases have both protective and promoting roles in the etiology of diseases. A prominent example is the existence of oncogenic as well as tumor-suppressing protein phosphatases.

A few protein phosphatase activity modulators are already applied in therapies. These were however not developed in target-directed approaches, and the recent discovery of phosphatase involvement followed their application in therapy.

Nevertheless, these examples demonstrate that small molecules can be generated that modulate the activity of protein phosphatases and are beneficial for the treatment of protein phosphorylation diseases.

We describe here strategies for the development of activators and inhibitors of protein phosphatases and clarify some long-standing misconceptions concerning the druggability of these enzymes.

Recent developments suggest that it is feasible to design potent and selective protein phosphatase modulators with a therapeutic potential.

2013年12月6日金曜日

2013年12月1日日曜日

Aldose Reductase Inhibitor can Inhibit tau Aggregation.

In our preliminary in vitro experiments, three generic drugs at hands are investigated towards tau aggregation inhibitory activity along with the known methylene blue as a positive standard.

2013年11月23日土曜日

2013年11月7日木曜日

2013年11月6日水曜日

2013年10月28日月曜日

2013年10月27日日曜日

2013年10月26日土曜日

2013年10月25日金曜日

2013年10月24日木曜日