Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists

May 31, 2015, 2:30 am

≫ Next: Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques

≪ Previous: Perspective: Challenges and opportunities in TB drug discovery from phenotypic screening

Publication date: 1 January 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
Author(s): Matteo Gianella-Borradori , Ivy Christou , Carole J.R. Bataille , Rebecca L. Cross , Graham M. Wynne , David R. Greaves , Angela J. Russell

The cannabinoid receptor 2 (CB2R) has been linked with the regulation of inflammation, and selective receptor activation has been proposed as a target for the treatment of a range of inflammatory diseases such as atherosclerosis and arthritis. In order to identify selective CB2R agonists with appropriate physicochemical and ADME properties for future evaluation in vivo, we first performed a ligand-based virtual screen. Subsequent medicinal chemistry optimisation studies led to the identification of a new class of selective CB2R agonists. Several examples showed high levels of activity (EC50 <200nM) and binding affinity (K i <200nM) for the CB2R, and no detectable activity at the CB1R. The most promising example, DIAS2, also showed favourable in vitro metabolic stability and absorption properties along with a clean selectivity profile when evaluated against a panel of GPCRs and kinases.

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Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques

May 31, 2015, 2:30 am

≫ Next: A peptide affinity reagent for isolating an intact and catalytically active multi-protein complex from mammalian cells

≪ Previous: Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists

Publication date: 15 February 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 4
Author(s): Rafael J. Rojas , Dale E. Edmondson , Terri Almos , Roderick Scott , Mark E. Massari

Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson’s disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.

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A peptide affinity reagent for isolating an intact and catalytically active multi-protein complex from mammalian cells

May 31, 2015, 2:30 am

≫ Next: 18F-AmBF3-MJ9: A novel radiofluorinated bombesin derivative for prostate cancer imaging

≪ Previous: Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques

Publication date: 1 March 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
Author(s): Hinnerk Saathoff , Mattias Brofelth , Anne Trinh , Benjamin L. Parker , Daniel P. Ryan , Jason K.K. Low , Sarah R. Webb , Ana P.G. Silva , Joel P. Mackay , Nicholas E. Shepherd

We have developed an approach for directly isolating an intact multi-protein chromatin remodeling complex from mammalian cell extracts using synthetic peptide affinity reagent 4. FOG1(1–15), a short peptide sequence known to target subunits of the nucleosome remodeling and deacetylase (NuRD) complex, was joined via a 35-atom hydrophilic linker to the StreptagII peptide. Loading this peptide onto Streptactin beads enabled capture of the intact NuRD complex from MEL cell nuclear extract. Gentle biotin elution yielded the desired intact complex free of significant contaminants and in a form that was catalytically competent in a nucleosome remodeling assay. The efficiency of 4 in isolating the NuRD complex was comparable to other reported methods utilising recombinantly produced GST–FOG1(1–45).

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18F-AmBF3-MJ9: A novel radiofluorinated bombesin derivative for prostate cancer imaging

May 31, 2015, 2:30 am

≫ Next: Enhanced detection of type C botulinum neurotoxin by the Endopep-MS assay through optimization of peptide substrates

≪ Previous: A peptide affinity reagent for isolating an intact and catalytically active multi-protein complex from mammalian cells

Publication date: 1 April 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7
Author(s): Maral Pourghiasian , Zhibo Liu , Jinhe Pan , Zhengxing Zhang , Nadine Colpo , Kuo-Shyan Lin , David M. Perrin , François Bénard

A novel radiofluorinated derivative of bombesin, ¹⁸F-AmBF3-MJ9, was synthesized and evaluated for its potential to image prostate cancer by targeting the gastrin releasing peptide receptor (GRPR). AmBF3-MJ9 was prepared from an ammoniomethyl-trifluoroborate (AmBF3) conjugated alkyne 2 and azidoacetyl-MJ9 via a copper-catalyzed click reaction, and had good binding affinity for GRPR (K i =0.5±0.1nM). The ¹⁸F-labeling was performed via a facile one-step ¹⁸F–¹⁹F isotope exchange reaction, and ¹⁸F-AmBF3-MJ9 was obtained in 23±5% (n =3) radiochemical yield in 25min with >99% radiochemical purity and 100±32GBq/μmol specific activity. ¹⁸F-AmBF3-MJ9 was stable in mouse plasma, and was partially (22–30%) internalized after binding to GRPR. Positron emission tomography (PET) imaging and biodistribution studies in mice showed fast renal excretion and good uptake of ¹⁸F-AmBF3-MJ9 by GRPR-expressing pancreas and PC-3 prostate cancer xenografts. Tumor uptake was 1.37±0.25%ID/g at 1h, and 2.20±0.13%ID/g at 2h post-injection (p.i.) with low background uptake and excellent tumor visualization (tumor-to-muscle ratios of 75.4±5.5). These data suggest that ¹⁸F-AmBF3-MJ9 is a promising PET tracer for imaging GRPR-expressing prostate cancers.

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Enhanced detection of type C botulinum neurotoxin by the Endopep-MS assay through optimization of peptide substrates

May 31, 2015, 2:30 am

≫ Next: The relationship between target-class and the physicochemical properties of antibacterial drugs

≪ Previous: 18F-AmBF3-MJ9: A novel radiofluorinated bombesin derivative for prostate cancer imaging

Publication date: Available online 10 April 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Dongxia Wang , Joan Krilich , Jakub Baudys , John R. Barr , Suzanne R. Kalb

It is essential to have a simple, quick and sensitive method for the detection and quantification of botulinum neurotoxins, the most toxic substances and the causative agents of botulism. Type C botulinum neurotoxin (BoNT/C) represents one of the seven members of distinctive BoNT serotypes (A to G) that cause botulism in animals and avians. Here we report the development of optimized peptide substrates for improving the detection of BoNT/C and /CD mosaic toxins using an Endopep-MS assay, a mass spectrometry-based method that is able to rapidly and sensitively detect and differentiate all types of BoNTs by extracting the toxin with specific antibodies and detecting the unique cleavage products of peptide substrates. Based on the sequence of a short SNAP-25 peptide, we conducted optimization through a comprehensive process including length determination, terminal modification, single and multiple amino acid residue substitution, and incorporation of unnatural amino acid residues. Our data demonstrate that an optimal peptide provides a more than 200-fold improvement over the substrate currently used in the Endopep-MS assay for the detection of BoNT/C1 and /CD mosaic. Using the new substrate in a four-hour cleavage reaction, the limit of detection for the BoNT/C1 complex spiked in buffer, serum and milk samples was determined to be 0.5, 0.5 and 1mouseLD50/mL, respectively, representing a similar or higher sensitivity than that obtained by traditional mouse bioassay.

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The relationship between target-class and the physicochemical properties of antibacterial drugs

May 31, 2015, 2:30 am

≫ Next: N-mustard analogs of S-adenosyl-l-methionine as biochemical probes of protein arginine methylation

≪ Previous: Enhanced detection of type C botulinum neurotoxin by the Endopep-MS assay through optimization of peptide substrates

Publication date: Available online 28 April 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Grace Mugumbate , John P. Overington

The discovery of novel mechanism of action (MOA) antibacterials has been associated with the concept that antibacterial drugs occupy a differentiated region of physicochemical space compared to human-targeted drugs. With, in broad terms, antibacterials having higher molecular weight, lower log P and higher polar surface area (PSA). By analysing the physicochemical properties of about 1700 approved drugs listed in the ChEMBL database, we show, that antibacterials for whose targets are riboproteins (i.e., composed of a complex of RNA and protein) fall outside the conventional human ‘drug-like’ chemical space; whereas antibacterials that modulate bacterial protein targets, generally comply with the ‘rule-of-five’ guidelines for classical oral human drugs. Our analysis suggests a strong target-class association for antibacterials—either protein-targeted or riboprotein-targeted. There is much discussion in the literature on the failure of screening approaches to deliver novel antibacterial lead series, and linkage of this poor success rate for antibacterials with the chemical space properties of screening collections. Our analysis suggests that consideration of target-class may be an underappreciated factor in antibacterial lead discovery, and that in fact bacterial protein-targets may well have similar binding site characteristics to human protein targets, and questions the assumption that larger, more polar compounds are a key part of successful future antibacterial discovery.

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N-mustard analogs of S-adenosyl-l-methionine as biochemical probes of protein arginine methylation

May 31, 2015, 2:30 am

≫ Next: Structure–activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL)

≪ Previous: The relationship between target-class and the physicochemical properties of antibacterial drugs

Publication date: Available online 11 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Sarah J. Hymbaugh Bergman , Lindsay R. Comstock

Nucleosomes, the fundamental building blocks of eukaryotic chromatin, undergo post-synthetic modifications and play a major role in the regulation of transcriptional processes. Combinations of these modifications, including methylation, regulate chromatin structure, determining its different functional states and playing a central role in differentiation. The biological significance of cellular methylation, particularly on chromatin, is widely recognized, yet we know little about the mechanisms that link biological methylation events. To characterize and fully understand protein methylation, we describe here novel N-mustard analogs of S-adenosyl-l-methionine (SAM) as biochemical tools to better understand protein arginine methylation events using protein arginine methyltransferase 1 (PRMT1). Specifically, azide- and alkyne-functionalized N-mustard analogs serve as cofactor mimics of SAM and are enzymatically transferred to a model peptide substrate in a PRMT1-dependent fashion. Once incorporated, the resulting alkynes and azides can be modified through chemoselective ligations, including click chemistry and the Staudinger ligation. These results readily demonstrate the feasibility of utilizing N-mustard analogs as biochemical tools to site-specifically label substrates of PRMT1 and serve as an alternative approach to study protein methylation events.

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Structure–activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL)

May 31, 2015, 2:30 am

≫ Next: Towards the computational design of protein post-translational regulation

≪ Previous: N-mustard analogs of S-adenosyl-l-methionine as biochemical probes of protein arginine methylation

Publication date: 15 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12
Author(s): Nicole Mayer , Martina Schweiger , Michaela-Christina Melcher , Christian Fledelius , Rudolf Zechner , Robert Zimmermann , Rolf Breinbauer

Adipose triglyceride lipase (ATGL) catalyzes the degradation of cellular triacylglycerol stores and strongly determines the concentration of circulating fatty acids (FAs). High serum FA levels are causally linked to the development of insulin resistance and impaired glucose tolerance, which eventually progresses to overt type 2 diabetes. ATGL-specific inhibitors could be used to lower circulating FAs, which can counteract the development of insulin resistance. In this article, we report about structure–activity relationship (SAR) studies of small molecule inhibitors of ATGL based on a hydrazone chemotype. The SAR indicated that the binding pocket of ATGL requests rather linear compounds without bulky substituents. The best inhibitor showed an IC50 =10μM in an assay with COS7-cell lysate overexpressing murine ATGL.

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Towards the computational design of protein post-translational regulation

May 31, 2015, 2:30 am

≫ Next: A single-cell model of PIP3 dynamics using chemical dimerization

≪ Previous: Structure–activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL)

Publication date: 15 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12
Author(s): Marta Strumillo , Pedro Beltrao

Protein post-translational modifications (PTMs) are a fast and versatility mechanism used by the cell to regulate the function of proteins in response to changing conditions. PTMs can alter the activity of proteins by allosteric regulation or by controlling protein interactions, localization and abundance. Recent advances in proteomics have revealed the extent of regulation by PTMs and the different mechanisms used in nature to exert control over protein function via PTMs. These developments can serve as the foundation for the rational design of protein regulation. Here we review the advances in methods to determine the function of PTMs, protein allosteric control and examples of rational design of PTM regulation. These advances create an opportunity to move synthetic biology forward by making use of a level of regulation that is of yet unexplored.

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A single-cell model of PIP3 dynamics using chemical dimerization

May 31, 2015, 2:30 am

≫ Next: Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3

≪ Previous: Towards the computational design of protein post-translational regulation

Publication date: 15 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12
Author(s): Aidan MacNamara , Frank Stein , Suihan Feng , Carsten Schultz , Julio Saez-Rodriguez

Most cellular processes are driven by simple biochemical mechanisms such as protein and lipid phosphorylation, but the sum of all these conversions is exceedingly complex. Hence, intuition alone is not enough to discern the underlying mechanisms in the light of experimental data. Toward this end, mathematical models provide a conceptual and numerical framework to formally evaluate the plausibility of biochemical processes. To illustrate the use of these models, here we built a mechanistic computational model of PI3K (phosphatidylinositol 3-kinase) activity, to determine the kinetics of lipid metabolizing enzymes in single cells. The model is trained to data generated upon perturbation with a reversible small-molecule based chemical dimerization system that allows for the very rapid manipulation of the PIP3 (phosphatidylinositol 3,4,5-trisphosphate) signaling pathway, and monitored with live-cell microscopy. We find that the rapid relaxation system used in this work decreased the uncertainty of estimating kinetic parameters compared to methods based on in vitro assays. We also examined the use of Bayesian parameter inference and how the use of such a probabilistic method gives information on the kinetics of PI3K and PTEN activity.

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Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3

May 31, 2015, 12:22 pm

≫ Next: Discovery of a 1-Isopropyltetrahydroisoquinoline Derivative as an Orally Active N-type Calcium Channel Blocker for Neuropathic Pain

≪ Previous: A single-cell model of PIP3 dynamics using chemical dimerization

Publication date: Available online 27 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Yutaka Nakajima , Takayuki Inoue , Kazuo Nakai , Koichiro Mukoyoshi , Hisao Hamaguchi , Keiko Hatanaka , Hiroshi Sasaki , Akira Tanaka , Fumie Takahashi , Shigeki Kunikawa , Hiroyuki Usuda , Ayako Moritomo , Yasuyuki Higashi , Masamichi Inami , Shohei Shirakami

Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.

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Discovery of a 1-Isopropyltetrahydroisoquinoline Derivative as an Orally Active N-type Calcium Channel Blocker for Neuropathic Pain

May 31, 2015, 12:22 pm

≫ Next: Synthesis and Bioevaluation of Heterocyclic Derivatives of Cleistanthin-A

≪ Previous: Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3

Publication date: Available online 27 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Takashi Ogiyama , Koichi Yonezawa , Makoto Inoue , Toshihiro Watanabe , Yukihito Sugano , Takayasu Gotoh , Tetsuo Kiso , Akiko Koakutsu , Shuichiro Kakimoto , Jun-ichi Shishikura

N-type calcium channel blockade is a promising therapeutic approach for the treatment of neuropathic pain. Starting from lead compound (S)-1, we focused our optimization efforts on potency for N-type calcium channel inhibition and improvement of CYP inhibition profile. 2-{[(1-Hydroxycyclohexyl)methyl]amino}-(1R)-(1-isopropyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethanone oxalate ((R)-5r) was identified as a novel orally active small-molecule N-type calcium channel inhibitor with reduced CYP inhibition liability. Oral administration of (R)-5r improved mechanical allodynia in a spinal nerve ligation model of neuropathic pain in rats with an ED50 value of 2.5 mg/kg.

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Synthesis and Bioevaluation of Heterocyclic Derivatives of Cleistanthin-A

May 31, 2015, 12:22 pm

≫ Next: Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi

≪ Previous: Discovery of a 1-Isopropyltetrahydroisoquinoline Derivative as an Orally Active N-type Calcium Channel Blocker for Neuropathic Pain

Publication date: Available online 27 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Yu Zhao , Rui Zhang , Yapeng Lu , Jinlong Ma , Li Zhu

The vacuolar H⁺-ATPase (V-ATPase) was proposed as a key target for new strategies in cancer treatment recently. We have synthesized a novel class of derivatives of Cleistanthin-A bearing heterocyclic moieties. Most of these compounds displayed potent antiproliferative effects on four cancer cells at submicromolar concentration, and they have no cytotoxicity on normal WRL-68 cells at 200 nM. The most potent compound 3a has been shown to inhibit the activity of vacuolar H⁺-ATPase at submicromolar concentration, and it could also significantly decrease the cytosolic pH values in HepG2 cells. The current findings provide valuable insights for future development of novel V-ATPase inhibitors as anticancer agents.

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Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi

May 31, 2015, 12:22 pm

≫ Next: Synthesis and Antileukemic Activities of C1-C10-Modified Parthenolide Analogues

≪ Previous: Synthesis and Bioevaluation of Heterocyclic Derivatives of Cleistanthin-A

Publication date: Available online 30 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Guadalupe García Liñares , M. Antonela Zígolo , Leandro Simonetti , Silvia A. Longhi , Alicia Baldessari

Enzyme catalysis was applied to synthesize derivatives of three bile acids and their biological activity was evaluated as growth inhibitors of the protozoan Trypanosoma cruzi. Twelve mono-, diacetyl and ester derivatives of deoxycholic, chenodeoxycholic and lithocholic acid, seven of them new compounds, were obtained through lipase-catalyzed acetylation, esterification and alcoholysis reactions in very good to excellent yield and a highly regioselective way. Among them, acetylated ester products, in which the lipase catalyzed both reactions in one-pot, were obtained. The influence of various reaction parameters in the enzymatic reactions, such as enzyme source, acylating agent/substrate ratio, enzyme/substrate ratio, solvent and temperature, was studied. Some of the evaluated compounds showed a remarkable activity as Trypanosoma cruzi growth inhibitors, obtaining the best results with ethyl chenodeoxycholate 3-acetate and chenodeoxycholic acid 3,7-diacetate, which showed IC50: 8.6 μM and 22.8 μM respectively. In addition, in order to shed light to bile acids behavior in enzymatic reactions, molecular modeling was applied to some derivatives. The advantages showed by the enzymatic methodology, such as mild reaction conditions and low environmental impact, make the biocatalysis a convenient way to synthesize these bile acid derivatives with application as potential antiparasitic agents.

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Synthesis and Antileukemic Activities of C1-C10-Modified Parthenolide Analogues

May 31, 2015, 12:22 pm

≫ Next: Synthesis, β-hematin inhibition studies and antimalarial evaluation of dehydroxy Isotebuquine derivatives against Plasmodium berghei

≪ Previous: Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi

Publication date: Available online 30 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Aaron M. Kempema , John C. Widen , Joseph K. Hexum , Timothy E. Andrews , Dan Wang , Susan K. Rathe , Frederick A. Meece , Klara E. Noble , Zohar Sachs , David A. Largaespada , Daniel A. Harki

Parthenolide (PTL) is a sesquiterpene lactone natural product with anti-proliferative activity to cancer cells. Selective eradication of leukemic stem cells (LSCs) over healthy hematopoietic stem cells (HSCs) by PTL has been demonstrated in previous studies, which suggests PTL and related molecules may be useful for targeting LSCs. Eradication of LSCs is required for curative therapy. Chemical optimizations of PTL to improve potency and pharmacokinetic parameters have focused largely on the α-methylene-γ-butyrolactone, which is essential for activity. Conversely, we evaluated modifications to the C1-C10 olefin and benchmarked new inhibitors to PTL with respect to inhibitory potency across a panel of cancer cell lines, ability to target drug-resistant acute myeloid leukemia (AML) cells, efficacy for inhibiting clonal growth of AML cells, toxicity to healthy bone marrow cells, and efficiency for promoting intracellular reactive oxygen species (ROS) levels. Cyclopropane 4 was found to possess less toxicity to healthy bone marrow cells, enhanced potency for the induction of cellular ROS, and similar broad-spectrum anti-proliferative activity to cancer cells in comparison to PTL.

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Synthesis, β-hematin inhibition studies and antimalarial evaluation of dehydroxy Isotebuquine derivatives against Plasmodium berghei

May 31, 2015, 12:22 pm

≫ Next: Discovery of thieno[3,2-c]pyridin-4-amines as novel Bruton’s tyrosine kinase (BTK) inhibitors

≪ Previous: Synthesis and Antileukemic Activities of C1-C10-Modified Parthenolide Analogues

Publication date: Available online 31 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Angel H. Romero , María E. Acosta , Neira Gamboa , Jaime E. Charris , José Salazar , Simón E. López

Diverse dehydroxy-isotebuquine derivatives were prepared by using a five step synthetic sequence in good yields. All these new 4-aminoquinolines were evaluated as inhibitors of haemozoin formation, where most of them showed a significant inhibition value (% IHF >97). The best inhibitors were tested in vivo as potential antimalarials in mice infected with P.berghei ANKA chloroquine susceptible strain, three of them (11b, 11d and 11h) displayed an antilmalarial activity comparable to that of chloroquine.

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Discovery of thieno[3,2-c]pyridin-4-amines as novel Bruton’s tyrosine kinase (BTK) inhibitors

May 31, 2015, 12:22 pm

≫ Next: Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium

≪ Previous: Synthesis, β-hematin inhibition studies and antimalarial evaluation of dehydroxy Isotebuquine derivatives against Plasmodium berghei

Publication date: Available online 31 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Xinge Zhao , Minhang Xin , Yazhou Wang , Wei Huang , Qiu Jin , Feng Tang , Gang Wu , Yong Zhao , Hua Xiang

A novel series of BTK inhibitors bearing thieno[3,2-c]pyridin-4-amine framework as the core scaffold were designed, synthesized and well characterized. In this paper, twenty one compounds displayed variant inhibitory activities against BTK in vitro, and compound 14g showed the most potent inhibitory activity against BTK enzyme, with the IC50 value of 12.8nM. Moreover, compounds 14g displayed relatively good kinase selectivity and was subsequently evaluated in vivo for profiling its PK properties. This work identified the thieno[3,2-c]pyridin-4-amine derivatives as novel BTK inhibitors and verified the value of thieno[3,2-c]pyridin-4-amine scaffold in drug design.

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Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium

May 31, 2015, 12:22 pm

≫ Next: New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

≪ Previous: Discovery of thieno[3,2-c]pyridin-4-amines as novel Bruton’s tyrosine kinase (BTK) inhibitors

Publication date: Available online 31 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Utpal K. Karmakar , Naoki Ishikawa , Kazufumi Toume , Midori A. Arai , Samir K. Sadhu , Firoj Ahmed , Masami Ishibashi

The ability of TRAIL to selectively induce apoptosis in cancer cells while sparing normal cells makes it an attractive target for the development of new cancer therapy. In search of bioactive natural products for overcoming TRAIL-resistance from natural resources, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionations of the extract of Xanthium strumarium led to the isolation of five sesquiterpene compounds (1-5). 11α,13-dihydroxanthinin (2) and 11α,13-dihydroxanthuminol (3) were first isolated from natural resources and xanthinosin (1), desacetylxanthanol (4), and lasidiol p-methoxybenzoate (5) were known compounds. All compounds (1-5) showed potent TRAIL-resistance overcoming activity at 8, 20, 20, 16, and 16 μM respectively in TRAIL-resistant AGS cells. Compounds 1 and 5 enhanced the levels of apoptosis inducing proteins DR4, DR5, p53, CHOP, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant AGS cells in a dose-dependent manner. Compound 1 also enhanced the levels of DR4 and DR5 proteins in a time-dependent manner. Thus, compounds 1 and 5 were found to induce both extrinsic and intrinsic apoptotic cell death. Compound 1 also exhibit TRAIL-resistance overcoming activity in DLD1, DU146, HeLa, and MCF7 cells but did not decrease viability in non-cancer HEK293 cells upto 8 μM.

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New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

May 31, 2015, 12:22 pm

≫ Next: Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries

≪ Previous: Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium

Publication date: Available online 31 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Yu Zhang , Bin Liu , Xingyu Wu , Ridong Li , Xianling Ning , Yu Liu , Zhenming Liu , Zemei Ge , Runtao Li , Yuxin Yin

Pyruvate Kinase M2 (PKM2) is a key protein responsible for cancer’s Warburg effect. Activation of PKM2 may alter aberrant metabolism in cancer cells, which suggests PKM2 as a tumor selective therapeutic target. In this paper, the lead compound 8 was first discovered as a new kind of PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8 analogues were designed, synthesized and evaluated for their activation of PKM2 and anticancer activities. 7-Azaindole analogue 32 was identified as the most potent PKM2 activator. Compounds with potent enzyme activity also exhibited selective anti-proliferation activity on cancer cell lines HCT116, Hela and H1299 compared with non-tumor cell line BEAS-2B. The structure-activity relationships of these compounds were supported by molecular docking results. Preliminary pharmacological studies also showed that compound 32 arrests the cell cycle at the G2/M phase in HCT116 cell line.

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Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries

May 31, 2015, 12:22 pm

≫ Next: Seven-membered ring scaffolds for drug discovery: Access to functionalised azepanes and oxepanes through diazocarbonyl chemistry

≪ Previous: New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

Publication date: 1 June 2015
Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
Author(s): Ignacio Colomer , Ololade Adeniji , George M. Burslem , Philip Craven , Martin Ohsten Rasmussen , Anthony Willaume , Tuomo Kalliokoski , Richard Foster , Stephen P. Marsden , Adam Nelson

The application of [4+2] cycloadditions between alkenes and an N-benzoyl iminium species, generated in situ under acidic conditions, is described in the synthesis of diverse molecular scaffolds. The key reaction led to the formation of cyclic imidates in good yield and with high regioselectivity. It was demonstrated that the cyclic imidates may be readily converted into 1,3-amino alcohols. Incorporation of orthogonally-reactive functionality, such as aryl and alkyl bromides, into the cycloaddition substrates enabled the synthesis of additional scaffolds. For one scaffold, the synthesis of exemplar screening compounds was undertaken to demonstrate potential value in small molecule library production.

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