6-Phenoxy-2-phenylbenzoxazoles, novel inhibitors of receptor for advanced glycation end products (RAGE)

May 22, 2015, 2:14 am

≫ Next: Synthesis and in vitro kinetic evaluation of N-thiazolylacetamide monoquaternary pyridinium oximes as reactivators of sarin, O-ethylsarin and VX inhibited human acetylcholinesterase (hAChE)

≪ Previous: Synthesis of (2-amino)ethyl derivatives of quercetin 3-O-methyl ether and their antioxidant and neuroprotective effects

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Publication date: Available online 21 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Kwanghyun Choi , Kwang Su Lim , Juhee Shin , Seo Hee Kim , Young-Ger Suh , Hyun-Seok Hong , Hee Kim , Hee-Jin Ha , Young-Ho Kim , Jiyoun Lee , Jeewoo Lee
Receptor for advanced glycation end products (RAGE) is known to be involved in the transportation of amyloid β (Aβ) peptides and causes the accumulation of Aβ in the brain. Moreover, recent studies suggest that the interactions between RAGE and Aβ peptides may be the culprit behind Alzheimer’s disease (AD). Inhibitors of the RAGE-Aβ interactions would not only prevent the accumulation of toxic Aβ in the brain, and but also block the progress of AD, therefore, have the potential to provide a ‘disease-modifying therapy’. In this study, we have developed a series of 6-phenoxy-2-phenylbenzoxazole analogs as novel inhibitors of RAGE. Among these derivatives, we found several effective inhibitors that block the RAGE-Aβ interactions without causing significant cellular toxicity. Further testing showed that compound 48 suppressed Aβ induced toxicity in mouse hippocampal neuronal cells and reduced Aβ levels in the brains of a transgenic mouse model of AD after oral administration.

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Synthesis and in vitro kinetic evaluation of N-thiazolylacetamide monoquaternary pyridinium oximes as reactivators of sarin, O-ethylsarin and VX inhibited human acetylcholinesterase (hAChE)

May 23, 2015, 2:15 am

≫ Next: Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors

≪ Previous: 6-Phenoxy-2-phenylbenzoxazoles, novel inhibitors of receptor for advanced glycation end products (RAGE)

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Publication date: Available online 22 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Aditya Kapil Valiveti , Uma M. Bhalerao , Jyotiranjan Acharya , Hitendra N. Karade , Badrinarayan Acharya , G. Raviraju , Anand K. Halve , Mahabir Parshad Kaushik
Presently available medications for treatment of organophosphate poisoning are not sufficiently effective due to various pharmacological and toxicological reasons. In this regard, herein we report the synthesis of a series of N-thiazolylacetamide monoquaternary pyridinium oximes and its analogues (1a-1b to 6a-6b) with diversely substituted thiazole ring and evaluation of their in vitro reactivation efficacies against nerve agent (sarin, O-ethylsarin and VX) inhibited human erythrocyte acetylcholinesterase (hAChE). Reactivation kinetics was performed to determine dissociation constant (K D), reactivity rate constant (k r) and the second order rate constant (k r2) for all the compounds and compared their efficacies with commercial antidotes viz. 2-PAM and obidoxime. All the newly synthesized oximes were evaluated for their physicochemical parameters (pKa) and correlated with their respective reactivation efficacies to assess the capability of the oxime reactivator. Three of these novel compounds showed promising reactivation efficacies toward OP inhibited hAChE. Further molecular docking studies were performed in order to correlate the reactivation efficacies with their interactions in the active site of the AChE.

Graphical abstract

Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors

May 23, 2015, 2:15 am

≫ Next: Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase

≪ Previous: Synthesis and in vitro kinetic evaluation of N-thiazolylacetamide monoquaternary pyridinium oximes as reactivators of sarin, O-ethylsarin and VX inhibited human acetylcholinesterase (hAChE)

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Publication date: Available online 23 May 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Hiroaki Yamagishi , Shohei Shirakami , Yutaka Nakajima , Akira Tanaka , Fumie Takahashi , Hisao Hamaguchi , Keiko Hatanaka , Ayako Moritomo , Masamichi Inami , Yasuyuki Higashi , Takayuki Inoue
Because Janus kinases (JAKs) play a crucial role in cytokine-mediated signal transduction, JAKs are an attractive target for the treatment of organ transplant rejection and autoimmune diseases such as rheumatoid arthritis (RA). To identify JAK inhibitors, we focused on the 1H-pyrrolo[2,3-b]pyridine derivative 3, which exhibited moderate JAK3 and JAK1 inhibitory activities. Optimization of 3 identified the tricyclic imidazo-pyrrolopyridinone derivative 19, which exhibited potent JAK3 and JAK1 inhibitory activities (IC50 = 1.1 nM, 1.5 nM, respectively) with favorable metabolic stability.

Graphical abstract

Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase

May 31, 2015, 2:30 am

≫ Next: 20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs

≪ Previous: Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors

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Publication date: 15 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
Author(s): Oleg Sadovski , Justin W. Hicks , Jun Parkes , Roger Raymond , José Nobrega , Sylvain Houle , Mariateresa Cipriano , Christopher J. Fowler , Neil Vasdev , Alan A. Wilson
Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an ¹⁸F-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [¹⁸F]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17–22% (from [¹⁸F]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82nM after a preincubation of 60min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [¹⁸F]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [¹⁸F]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [¹⁸F]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.

Graphical abstract

20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs

May 31, 2015, 2:30 am

≫ Next: Microwave assisted solid phase synthesis of highly functionalized N-alkylated oligobenzamide α-helix mimetics

≪ Previous: Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase

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Publication date: 15 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
Author(s): Junhua Liu , Xu Wang , Peng Liu , Rongxin Deng , Min Lei , Wantao Chen , Lihong Hu
Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure–activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3–2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.

Graphical abstract

Microwave assisted solid phase synthesis of highly functionalized N-alkylated oligobenzamide α-helix mimetics

May 31, 2015, 2:30 am

≫ Next: Synthesis, biological evaluation, X-ray molecular structure and molecular docking studies of RGD mimetics containing 6-amino-2,3-dihydroisoindolin-1-one fragment as ligands of integrin αIIbβ3

≪ Previous: 20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs

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Publication date: 15 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
Author(s): Kérya Long , Thomas A. Edwards , Andrew J. Wilson
Protein–protein interactions (PPIs) mediate cellular pathways and are implicated in numerous aberrant conditions. α-Helix mimetics—small molecules that reproduce the spatial projection of key residues from an α-helix involved in a PPI—are attractive generic templates for development of screening libraries, however library syntheses of α-helix mimetics with diverse functionality are less established. This manuscript describes the automated, microwave assisted solid phase synthesis based on one such scaffold; an N-alkylated oligobenzamide.

Graphical abstract

Synthesis, biological evaluation, X-ray molecular structure and molecular docking studies of RGD mimetics containing 6-amino-2,3-dihydroisoindolin-1-one fragment as ligands of integrin αIIbβ3

May 31, 2015, 2:30 am

≫ Next: Chemically modified siRNAs and miRNAs bearing urea/thiourea-bridged aromatic compounds at their 3′-end for RNAi therapy

≪ Previous: Microwave assisted solid phase synthesis of highly functionalized N-alkylated oligobenzamide α-helix mimetics

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Publication date: 1 August 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 15
Author(s): Andrei A. Krysko , Georgiy V. Samoylenko , Pavel G. Polishchuk , Marina S. Fonari , Victor Ch. Kravtsov , Sergei A. Andronati , Tatyana A. Kabanova , Janusz Lipkowski , Tetiana M. Khristova , Victor E. Kuz’min , Vladimir M. Kabanov , Olga L. Krysko , Alexandre A. Varnek
A series of novel RGD mimetics containing phthalimidine fragment was designed and synthesized. Their antiaggregative activity determined by Born’s method was shown to be due to inhibition of fibrinogen binding to αIIbβ3. Molecular docking of RGD mimetics to αIIbβ3 receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores. The single crystal X-ray data were obtained for five mimetics.

Graphical abstract

Chemically modified siRNAs and miRNAs bearing urea/thiourea-bridged aromatic compounds at their 3′-end for RNAi therapy

May 31, 2015, 2:30 am

≫ Next: Control of the intracellular levels of prostaglandin E2 through inhibition of the 15-hydroxyprostaglandin dehydrogenase for wound healing

≪ Previous: Synthesis, biological evaluation, X-ray molecular structure and molecular docking studies of RGD mimetics containing 6-amino-2,3-dihydroisoindolin-1-one fragment as ligands of integrin αIIbβ3

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Publication date: 1 August 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 15
Author(s): Yoshiaki Kitamura , Yuki Masegi , Shunsuke Ogawa , Remi Nakashima , Yukihiro Akao , Yoshihito Ueno , Yukio Kitade
We have developed chemically modified siRNAs and miRNAs bearing urea/thiourea-bridged aromatic compounds at their 3′-end for RNAi therapy. Chemically modified RNAs possessing urea/thiourea-bridged aromatic compounds instead of naturally occurring dinucleotides at the 3′-overhang region were easily prepared in good yields and were more resistant to nucleolytic hydrolysis than unmodified RNA. siRNAs containing urea or thiourea derivatives showed the desired knockdown effect. Furthermore, modified miR-143 duplexes carrying the urea/thiourea compounds in the 3′-end of each strand were able to inhibit the growth of human bladder cancer T24 cells.

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Control of the intracellular levels of prostaglandin E2 through inhibition of the 15-hydroxyprostaglandin dehydrogenase for wound healing

May 31, 2015, 2:30 am

≫ Next: Multimerized CHR-derived peptides as HIV-1 fusion inhibitors

≪ Previous: Chemically modified siRNAs and miRNAs bearing urea/thiourea-bridged aromatic compounds at their 3′-end for RNAi therapy

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Publication date: 1 August 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 15
Author(s): Dubok Choi , Yu Lan Piao , Ying Wu , Hoon Cho
Excessive scar formation is an aberrant form of wound healing and is an indication of an exaggerated function of fibroblasts and excess accumulation of extracellular matrix during wound healing. Much experimental data suggests that prostaglandin E2 (PGE2) plays a role in the prevention of excessive scarring. However, it has a very short half-live in blood, its oxidization to 15-ketoprostaglandins is catalyzed by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Previously, we reported that 15-PGDH inhibitors significantly increased PGE2 levels in A549 cells. In our continuing attempts to develop highly potent 15-PGDH inhibitors, we newly synthesized various thiazolidine-2,4-dione derivatives. Compound 27, 28, 29, and 30 demonstrated IC50 values of 0.048, 0.020, 0.038 and 0.048μM, respectively. They also increased levels of PGE2 in A549 cells. Especially, compound 28 significantly increased level of PGE2 at 260pg/mL, which was approximately fivefold higher than that of control. Scratch wounds were analyzed in confluent monolayers of HaCaT cells. Cells exposed to compound 28 showed significantly improved wound healing with respect to control.

Graphical abstract

Multimerized CHR-derived peptides as HIV-1 fusion inhibitors

May 31, 2015, 2:30 am

≫ Next: A one-pot enzymatic approach to the O-fluoroglucoside of N-methylanthranilate

≪ Previous: Control of the intracellular levels of prostaglandin E2 through inhibition of the 15-hydroxyprostaglandin dehydrogenase for wound healing

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Publication date: 1 August 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 15
Author(s): Wataru Nomura , Chie Hashimoto , Takaharu Suzuki , Nami Ohashi , Masayuki Fujino , Tsutomu Murakami , Naoki Yamamoto , Hirokazu Tamamura
To date, several HIV-1 fusion inhibitors based on the carboxy-terminal leucine/isoleucine heptad repeat (CHR) region of an HIV-1 envelope protein gp41 have been discovered. We have shown that a synthetic peptide mimetic of a trimer form of the CHR-derived peptide C34 has potent inhibitory activity against the HIV-1 fusion mechanism, compared to a monomer C34 peptide. The present study revealed that a dimeric form of C34 is evidently structurally critical for fusion inhibitors, and that the activity of multimerized CHR-derived peptides in fusion inhibition is affected by the properties of the unit peptides C34, SC34EK, and T20. The fluorescence-based study suggested that the N36-interactive sites of the C34 trimer, including hydrophobic residues, are exposed outside the trimer and that trimerization of C34 caused a remarkable increase in fusion inhibitory activity. The present results could be useful in the design of fusion inhibitors against viral infections which proceed via membrane fusion with host cells.

Graphical abstract

A one-pot enzymatic approach to the O-fluoroglucoside of N-methylanthranilate

May 31, 2015, 2:30 am

≫ Next: Synthesis and α-glucosidase inhibitory activity evaluation of N-substituted aminomethyl-β-d-glucopyranosides

≪ Previous: Multimerized CHR-derived peptides as HIV-1 fusion inhibitors

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Publication date: 15 August 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 16
Author(s): Lorenzo Caputi , Martin Rejzek , Thomas Louveau , Ellis C. O’Neill , Lionel Hill , Anne Osbourn , Robert A. Field
In connection with prospective ¹⁸F-PET imaging studies, the potential for enzymatic synthesis of fluorine-labelled glycosides of small molecules was investigated. Approaches to the enzymatic synthesis of anomeric phosphates of d-gluco-configured fluorosugars proved ineffective. In contrast, starting in the d-galacto series and relying on the consecutive action of Escherichia coli galactokinase (GalK), galactose-1-phosphate uridylyltransferase (GalPUT), uridine-5′-diphosphogalactose 4-epimerase (GalE) and oat root glucosyltransferase (SAD10), a quick and effective synthesis of 6-deoxy-6-fluoro-d-glucosyl N-methylanthranilate ester was achieved.

Graphical abstract

Synthesis and α-glucosidase inhibitory activity evaluation of N-substituted aminomethyl-β-d-glucopyranosides

May 31, 2015, 2:30 am

≫ Next: Effect of single pyrrole replacement with β-alanine on DNA binding affinity and sequence specificity of hairpin pyrrole/imidazole polyamides targeting 5′-GCGC-3′

≪ Previous: A one-pot enzymatic approach to the O-fluoroglucoside of N-methylanthranilate

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Publication date: 1 September 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
Author(s): Xiaoli Bian , Xiangni Fan , Changhu Ke , Yajun Luan , Guilan Zhao , Aiguo Zeng
A series of N-substituted 1-aminomethyl-β-d-glucopyranoside derivatives was prepared. These novel synthetic compounds were assessed in vitro for inhibitory activity against yeast α-glucosidase and both rat intestinal α-glucosidases maltase and sucrase. Most of the compounds displayed α-glucosidase inhibitory activity, with IC50 values covering the wide range from 2.3μM to 2.0mM. Compounds 19a (IC50 =2.3μM) and 19b (IC50 =5.6μM) were identified as the most potent inhibitors for yeast α-glucosidase, while compounds 16 (IC50 =7.7 and 15.6μM) and 19e (IC50 =5.1 and 10.4μM) were the strongest inhibitors of rat intestinal maltase and sucrase. Analysis of the kinetics of enzyme inhibition indicated that 19e inhibited maltase and sucrase in a competitive manner. The results suggest that the aminomethyl-β-d-glucopyranoside moiety can mimic the substrates of α-glucosidase in the enzyme catalytic site, leading to competitive enzyme inhibition. Moreover, the nature of the N-substituent has considerable influence on inhibitory potency.

Graphical abstract

Effect of single pyrrole replacement with β-alanine on DNA binding affinity and sequence specificity of hairpin pyrrole/imidazole polyamides targeting 5′-GCGC-3′

May 31, 2015, 2:30 am

≫ Next: A sphingosine 1-phosphate receptor 2 selective allosteric agonist

≪ Previous: Synthesis and α-glucosidase inhibitory activity evaluation of N-substituted aminomethyl-β-d-glucopyranosides

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Publication date: 1 September 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
Author(s): Yong-Woon Han , Gengo Kashiwazaki , Hironobu Morinaga , Tomoko Matsumoto , Kaori Hashiya , Toshikazu Bando , Yoshie Harada , Hiroshi Sugiyama
N-Methylpyrrole (Py)–N-methylimidazole (Im) polyamides are small organic molecules that can recognize predetermined DNA sequences with high sequence specificity. As many eukaryotic promoter regions contain highly GC-rich sequences, it is valuable to synthesize and characterize Py–Im polyamides that recognize GC-rich motifs. In this study, we synthesized four hairpin Py–Im polyamides 1–4, which recognize 5′-GCGC-3′ and investigated their binding behavior with surface plasmon resonance assay. Py–Im polyamides 2–4 contain two, one, and one β-alanine units, replacing the Py units of 1, respectively. The binding affinities of 2–4 to the target DNA increased 430, 390, and 610-fold, respectively, over that of 1. The association and dissociation rates of 2 to the target DNA were improved by 11 and 37-fold, respectively, compared with those of 1. Interestingly, the association and dissociation rates of 3 and 4 were higher than those of 2, even though the binding affinities of 2, 3, and 4 to the target DNA were comparable to each other. The binding affinity of 2 to DNA with a 2bp mismatch was reduced by 29-fold, compared with that to the matched DNA. Moreover, the binding affinities of 3 and 4 to the same mismatched DNA were reduced by 270 and 110-fold, respectively, indicating that 3 and 4 have greater specificities than 2 and are suitable as DNA-binding modules for engineered epigenetic regulation.

Graphical abstract

A sphingosine 1-phosphate receptor 2 selective allosteric agonist

May 31, 2015, 2:30 am

≫ Next: Gene suppression via U1 small nuclear RNA interference (U1i) machinery using oligonucleotides containing 2′-modified-4′-thionucleosides

≪ Previous: Effect of single pyrrole replacement with β-alanine on DNA binding affinity and sequence specificity of hairpin pyrrole/imidazole polyamides targeting 5′-GCGC-3′

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Publication date: 1 September 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
Author(s): Hideo Satsu , Marie-Therese Schaeffer , Miguel Guerrero , Adrian Saldana , Christina Eberhart , Peter Hodder , Charmagne Cayanan , Stephan Schürer , Barun Bhhatarai , Ed Roberts , Hugh Rosen , Steven J. Brown
Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound.

Graphical abstract

Gene suppression via U1 small nuclear RNA interference (U1i) machinery using oligonucleotides containing 2′-modified-4′-thionucleosides

May 31, 2015, 2:30 am

≫ Next: Synthesis of novel isothiazolopyridines and their in vitro evaluation against Mycobacterium and Propionibacterium acnes

≪ Previous: A sphingosine 1-phosphate receptor 2 selective allosteric agonist

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Publication date: 1 September 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
Author(s): Yusaku Kikuchi , Naoshi Yamazaki , Noriko Tarashima , Kazuhiro Furukawa , Yoshiharu Takiguchi , Kohji Itoh , Noriaki Minakawa
Gene suppression via U1 small nuclear RNA interference (U1i) is considered to be one of the most attractive approaches, and takes the place of general antisense, RNA interference (RNAi), and anti-micro RNA machineries. Since the U1i can be induced by short oligonucleotides (ONs), namely U1 adaptors consisting of a ‘target domain’ and a ‘U1 domain’, we prepared adaptor ONs using 2′-modified-4′-thionucleosides developed by our group, and evaluated their U1i activity. As a result, the desired gene suppression via U1i was observed in ONs prepared as a combination of 2′-fluoro-4′-thionucleoside and 2′-fluoronucleoside units as well as only 2′-fluoronucleoside units, while those prepared as combination of 2′-OMe nucleoside/2′-OMe-4′-thionucleoside and 2′-fluoronucleoside units did not show significant activity. Measurement of T m values indicated that a higher hybridization ability of adaptor ONs with complementary RNA is one of the important factors to show potent U1i activity.

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Synthesis of novel isothiazolopyridines and their in vitro evaluation against Mycobacterium and Propionibacterium acnes

May 31, 2015, 2:30 am

≫ Next: Exploring pyrimidine-substituted curcumin analogues: Design, synthesis and effects on EGFR signaling

≪ Previous: Gene suppression via U1 small nuclear RNA interference (U1i) machinery using oligonucleotides containing 2′-modified-4′-thionucleosides

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Publication date: 1 September 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
Author(s): Wiesław Malinka , Piotr Świątek , Małgorzata Śliwińska , Bogumiła Szponar , Andrzej Gamian , Zbigniew Karczmarzyk , Andrzej Fruziński
In this paper we describe synthesis, structures and some physicochemical properties of 20 isothiazolopyridines 8–13 substituted differently into an isothiazole ring as well as their in vitro antibacterial assays against Mycobacterium tuberculosis H37Rv, Mycobacterium fortuitum PCM 672 and Propionibacterium acnes PCM 2400. Compound 13a was found to be the most active derivative against M. tuberculosis H37Rv, demonstrating 100% growth inhibition of microorganisms in the primary screen (minimum inhibitory concentration [MIC] 6.25μg/mL). Nineteen of the prepared compounds were evaluated against M. fortuitum PCM 672 and P. acnes PCM 2400 and only compounds 9 and 12d exhibited excellent activity against individual strains of microorganisms with MIC90 <1μg/mL. The inhibitory action of the remaining isothiazolopyridines towards the tested strains of the microorganism was low, absent, or a non-linear correlation prohibited accurate determination of MIC values. Unexpectedly, seven of the remaining isothiazolopyridines tested against M. fortuitum and P. acnes stimulated growth of the microorganisms in the range 10–50% or even more (10b) under experimental conditions.

Graphical abstract

Exploring pyrimidine-substituted curcumin analogues: Design, synthesis and effects on EGFR signaling

May 31, 2015, 2:30 am

≫ Next: Quantification of free ligand conformational preferences by NMR and their relationship to the bioactive conformation

≪ Previous: Synthesis of novel isothiazolopyridines and their in vitro evaluation against Mycobacterium and Propionibacterium acnes

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Publication date: 1 September 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
Author(s): Peiju Qiu , Lingling Xu , Lei Gao , Meng Zhang , Shixi Wang , Sheng Tong , Yue Sun , Lijuan Zhang , Tao Jiang
Epidermal growth factor receptor (EGFR) is an effective molecular target of anti-cancer therapies. Curcumin inhibits cancer cell growth in vitro by suppressing gene expression of EGFR and reduces tumor growth in various animal models. To overcome instable and insoluble properties of curcumin as therapeutics, we designed and synthesized six novel pyrimidine-substituted curcumin analogues with or without a hydroxyl group originally present in curcumin. The cell viability tests indicated that IC50 of the analogues containing hydroxyl group were 3 to 8-fold lower than those of the analogues without hydroxyl group in two colon cancer cell lines tested. Western blot analysis indicates the analogues containing hydroxyl group inhibited expression and tyrosine phosphorylation of EGFR. Further protein analyses showed that the analogues had anti-cellular proliferation, pro-apoptosis, and cell cycle arrest properties associated with suppressed EGFR expression. These results indicate that the hydroxyl groups in curcumin and the analogues were critical for observed biological activities.

Graphical abstract

Quantification of free ligand conformational preferences by NMR and their relationship to the bioactive conformation

May 31, 2015, 2:30 am

≫ Next: Investigation of acyclic uridine amide and 5′-amido nucleoside analogues as potential inhibitors of the Plasmodium falciparum dUTPase

≪ Previous: Exploring pyrimidine-substituted curcumin analogues: Design, synthesis and effects on EGFR signaling

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Publication date: 1 September 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
Author(s): Charles D. Blundell , Martin J. Packer , Andrew Almond
Accurate unbound solution 3D-structures of ligands provide unique opportunities for medicinal chemistry and, in particular, a context to understand binding thermodynamics and kinetics. Previous methods of deriving these 3D-structures have had neither the accuracy nor resolution needed for drug design and have not yet realized their potential. Here, we describe and apply a NMR methodology to the aminoglycoside streptomycin that can accurately quantify accessible 3D-space and rank the occupancy of observed conformers to a resolution that enables medicinal chemistry understanding and design. Importantly, it is based upon conventional small molecule NMR techniques and can be performed in physiologically-relevant solvents. The methodology uses multiple datasets, an order of magnitude more experimental data than previous NMR approaches and a dynamic model during refinement, is independent of computational chemistry and avoids the problem of virtual conformations. The refined set of solution 3D-shapes for streptomycin can be grouped into two major families, of which the most populated is almost identical to the 30S ribosomal subunit bioactive shape. We therefore propose that accurate unbound ligand solution conformations may, in some cases, provide a subsidiary route to bioactive shape without crystallography. This experimental technique opens up new opportunities for drug design and more so when complemented with protein co-crystal structures, SAR data and pharmacophore modeling.

Graphical abstract

Investigation of acyclic uridine amide and 5′-amido nucleoside analogues as potential inhibitors of the Plasmodium falciparum dUTPase

May 31, 2015, 2:30 am

≫ Next: Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases

≪ Previous: Quantification of free ligand conformational preferences by NMR and their relationship to the bioactive conformation

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Publication date: 15 September 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 18
Author(s): Shahienaz E. Hampton , Alessandro Schipani , Cristina Bosch-Navarrete , Eliseo Recio , Marcel Kaiser , Pia Kahnberg , Dolores González-Pacanowska , Nils Gunnar Johansson , Ian H. Gilbert
Previously we have shown that trityl and diphenyl deoxyuridine derivatives and their acyclic analogues can inhibit Plasmodium falciparum dUTPase (PfdUTPase). We report the synthesis of conformationally restrained amide derivatives as inhibitors PfdUTPase, including both acyclic and cyclic examples. Activity was dependent on the orientation and location of the amide constraining group. In the case of the acyclic series, we were able to obtain amide-constrained analogues which showed similar or greater potency than the unconstrained analogues. Unfortunately these compounds showed lower selectivity in cellular assays.

Graphical abstract

Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases

May 31, 2015, 2:30 am

≫ Next: Enantioselective binding of chiral 1,14-dimethyl[5]helicene–spermine ligands with B- and Z-DNA

≪ Previous: Investigation of acyclic uridine amide and 5′-amido nucleoside analogues as potential inhibitors of the Plasmodium falciparum dUTPase

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Publication date: 15 September 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 18
Author(s): Charlotte E. Allen , Chiau L. Chow , John J. Caldwell , Isaac M. Westwood , Rob L. M. van Montfort , Ian Collins
With the success of protein kinase inhibitors as drugs to target cancer, there is a continued need for new kinase inhibitor scaffolds. We have investigated the synthesis and kinase inhibition of new heteroaryl-substituted diazaspirocyclic compounds that mimic ATP. Versatile syntheses of substituted diazaspirocycles through ring-closing metathesis were demonstrated. Diazaspirocycles directly linked to heteroaromatic hinge binder groups provided ligand efficient inhibitors of multiple kinases, suitable as starting points for further optimization. The binding modes of representative diazaspirocyclic motifs were confirmed by protein crystallography. Selectivity profiles were influenced by the hinge binder group and the interactions of basic nitrogen atoms in the scaffold with acidic side-chains of residues in the ATP pocket. The introduction of more complex substitution to the diazaspirocycles increased potency and varied the selectivity profiles of these initial hits through engagement of the P-loop and changes to the spirocycle conformation, demonstrating the potential of these core scaffolds for future application to kinase inhibitor discovery.

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