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

May 31, 2015, 2:30 am

≫ Next: Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase–LEDGF/p75 interaction

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

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Publication date: 1 October 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 19
Author(s): Genichiro Tsuji , Kyoko Kawakami , Shigeki Sasaki
Duplex DNA adopts a right-handed B-DNA conformation under physiological conditions. Z-DNA, meanwhile, has a left-handed helical structure and is in equilibrium with right-handed B-DNA. We recently reported that the bisnaphthyl maleimide–spermine conjugate (1) induced a B- to Z-DNA transition with high efficiency at low salt concentrations. It was also found that the bisnaphthyl ligand (1) spontaneously transformed into the corresponding [5]helicene derivative (2). Because [5]helicene 2 can potentially be chiral and because the chiral discrimination of B- and Z-DNA is also of interest, we became interested in whether enatiomerically pure [5]helicene–spermine conjugates might discriminate the chirality of B- or Z-DNA. In this study, we have demonstrated an efficient synthesis of chiral DNA-binding ligands by the conjugation of a [5]helicene unit with a spermine unit. These chiral helicene ligands exhibited recognition of B- and Z-DNA, with (P)-3 displaying preference for B-DNA and (M)-3 for Z-DNA. The characteristic features of the helicene–spermine ligands developed in this study include two points: the cationic spermine portion produces electrostatic interactions along the phosphate backbone of the minor groove, and the helicene forms complexes in an end-stacking mode. Such binding modes, together with the thermodynamic parameters, account for the mode of chiral recognition of (P)- and (M)-3 for B- and Z-DNA.

Graphical abstract

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Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase–LEDGF/p75 interaction

May 31, 2015, 2:30 am

≫ Next: 5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2

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

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Publication date: 1 October 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 19
Author(s): Erik Serrao , Zhong-Liang Xu , Bikash Debnath , Frauke Christ , Zeger Debyser , Ya-Qiu Long , Nouri Neamati
Though much progress has been made in the inhibition of HIV-1 integrase catalysis, clinical resistance mutations have limited the promise of long-term drug prescription. Consequently, allosteric inhibition of integrase activity has emerged as a promising approach to antiretroviral discovery and development. Specifically, inhibitors of the interaction between HIV-1 integrase and cellular cofactor LEDGF/p75 have been validated to diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Here, we have contributed to the development of novel allosteric integrase inhibitors with a high-throughput AlphaScreen-based random screening approach, with which we have identified novel 5-carbonyl-1H-imidazole-4-carboxamides capable of inhibiting the HIV-1 integrase–LEDGF/p75 interaction in vitro. Following a structure–activity relationship analysis of the initial 1H-imidazole-4,5-dicarbonyl core, we optimized the compound’s structure through an industrial database search, and we went further to synthesize a selective and non-cytotoxic panel of inhibitors with enhanced potency.

Graphical abstract

5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2

May 31, 2015, 2:30 am

≫ Next: Exploring a potential palonosetron allosteric binding site in the 5-HT3 receptor

≪ Previous: Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase–LEDGF/p75 interaction

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Publication date: 15 November 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 22
Author(s): Michael P. Dickens , Patricia Roxburgh , Andreas Hock , Mokdad Mezna , Barrie Kellam , Karen H. Vousden , Peter M. Fischer
Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure–activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e.g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy.

Graphical abstract

Exploring a potential palonosetron allosteric binding site in the 5-HT3 receptor

May 31, 2015, 2:30 am

≫ Next: Discovery of a novel activator of 5-lipoxygenase from an anacardic acid derived compound collection

≪ Previous: 5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2

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Publication date: 1 December 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 23
Author(s): Marta Del Cadia , Francesca De Rienzo , David A. Weston , Andrew J. Thompson , Maria Cristina Menziani , Sarah C.R. Lummis
Palonosetron (Aloxi) is a potent second generation 5-HT3 receptor antagonist whose mechanism of action is not yet fully understood. Palonosetron acts at the 5-HT3 receptor binding site but recent computational studies indicated other possible sites of action in the extracellular domain. To test this hypothesis we mutated a series of residues in the 5-HT3A receptor subunit (Tyr⁷³, Phe¹³⁰, Ser¹⁶³, and Asp¹⁶⁵) and in the 5-HT3B receptor subunit (His⁷³, Phe¹³⁰, Glu¹⁷⁰, and Tyr¹⁴³) that were previously predicted by in silico docking studies to interact with palonosetron. Homomeric (5-HT3A) and heteromeric (5-HT3AB) receptors were then expressed in HEK293 cells to determine the potency of palonosetron using both fluorimetric and radioligand methods to test function and ligand binding, respectively. The data show that the substitutions have little or no effect on palonosetron inhibition of 5-HT-evoked responses or binding. In contrast, substitutions in the orthosteric binding site abolish palonosetron binding. Overall, the data support a binding site for palonosetron at the classic orthosteric binding pocket between two 5-HT3A receptor subunits but not at allosteric sites previously identified by in silico modelling and docking.

Graphical abstract

Discovery of a novel activator of 5-lipoxygenase from an anacardic acid derived compound collection

May 31, 2015, 2:30 am

≫ Next: Antioxidant action of propolis on mouse lungs exposed to short-term cigarette smoke

≪ Previous: Exploring a potential palonosetron allosteric binding site in the 5-HT3 receptor

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Publication date: 15 December 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 24
Author(s): Rosalina Wisastra , Petra A.M. Kok , Nikolaos Eleftheriadis , Matthew P. Baumgartner , Carlos J. Camacho , Hidde J. Haisma , Frank J. Dekker
Lipoxygenases (LOXs) and cyclooxygenases (COXs) metabolize poly-unsaturated fatty acids into inflammatory signaling molecules. Modulation of the activity of these enzymes may provide new approaches for therapy of inflammatory diseases. In this study, we screened novel anacardic acid derivatives as modulators of human 5-LOX and COX-2 activity. Interestingly, a novel salicylate derivative 23a was identified as a surprisingly potent activator of human 5-LOX. This compound showed both non-competitive activation towards the human 5-LOX activator adenosine triphosphate (ATP) and non-essential mixed type activation against the substrate linoleic acid, while having no effect on the conversion of the substrate arachidonic acid. The kinetic analysis demonstrated a non-essential activation of the linoleic acid conversion with a K A of 8.65μM, αK A of 0.38μM and a β value of 1.76. It is also of interest that a comparable derivative 23d showed a mixed type inhibition for linoleic acid conversion. These observations indicate the presence of an allosteric binding site in human 5-LOX distinct from the ATP binding site. The activatory and inhibitory behavior of 23a and 23d on the conversion of linoleic compared to arachidonic acid are rationalized by docking studies, which suggest that the activator 23a stabilizes linoleic acid binding, whereas the larger inhibitor 23d blocks the enzyme active site.

Graphical abstract

Antioxidant action of propolis on mouse lungs exposed to short-term cigarette smoke

May 31, 2015, 2:30 am

≫ Next: Differential response of orthologous l,l-diaminopimelate aminotransferases (DapL) to enzyme inhibitory antibiotic lead compounds

≪ Previous: Discovery of a novel activator of 5-lipoxygenase from an anacardic acid derived compound collection

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Publication date: 15 December 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 24
Author(s): Alan Aguiar Lopes , Thiago Santos Ferreira , Renata Tiscoski Nesi , Manuella Lanzetti , Karla Maria Pereira Pires , Ari Miranda Silva , Ricardo Moreira Borges , Antonio Jorge Ribeiro Silva , Samuel Santos Valença , Luís Cristóvão Porto
Propolis is a natural product with antioxidant properties. In this study, we tested the efficacy of propolis against acute lung inflammation (ALI) caused by cigarette smoke (CS). C57BL6 male mice were exposed to CS and treated with propolis (200mg/kg orally, CS+P) or only with propolis (P). A Control group treated with propolis was sham-smoked (Control+P). We collected the lungs for histological and biochemical analyses. We observed an increase in alveolar macrophages and neutrophils in the CS group compared with the Control+P. These counts reduced in the CS+P group compared to the CS group. The treatment with propolis normalized all biochemical parameters in the CS+P group compared with the CS group, including nitrite, myeloperoxidase level, antioxidant enzyme activities (superoxide dismutase, catalase and glutathione peroxidase), reduced glutathione/oxidized glutathione ratio and malondialdehyde. Additionally, TNF-α expression reduced in the CS+P group when compared with the CS group. These data imply a potential antioxidant and anti-inflammatory role for propolis with regard to ALI caused by CS in mice.

Graphical abstract

Differential response of orthologous l,l-diaminopimelate aminotransferases (DapL) to enzyme inhibitory antibiotic lead compounds

May 31, 2015, 2:30 am

≫ Next: Lipoic acid analogs with enhanced pharmacological activity

≪ Previous: Antioxidant action of propolis on mouse lungs exposed to short-term cigarette smoke

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Publication date: 1 January 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 1
Author(s): Shaun M.K. McKinnie , Eva M. Rodriguez-Lopez , John C. Vederas , Jennifer M. Crowther , Hironori Suzuki , Renwick C.J. Dobson , Thomas Leustek , Alexander J. Triassi , Matthew S. Wheatley , André O. Hudson
l,l-Diaminopimelate aminotransferase (DapL) is an enzyme required for the biosynthesis of meso-diaminopimelate (m-DAP) and l-lysine (Lys) in some bacteria and photosynthetic organisms. m-DAP and Lys are both involved in the synthesis of peptidoglycan (PG) and protein synthesis. DapL is found in specific eubacterial and archaeal lineages, in particular in several groups of pathogenic bacteria such as Leptospira interrogans (LiDapL), the soil/water bacterium Verrucomicrobium spinosum (VsDapL) and the alga Chlamydomonas reinhardtii (CrDapL). Here we present the first comprehensive inhibition study comparing the kinetic activity of DapL orthologs using previously active small molecule inhibitors formerly identified in a screen with the DapL of Arabidopsis thaliana (AtDapL), a flowering plant. Each inhibitor is derived from one of four classes with different central structural moieties: a hydrazide, a rhodanine, a barbiturate, or a thiobarbituate functionality. The results show that all five compounds tested were effective at inhibiting the DapL orthologs. LiDapL and AtDapL showed similar patterns of inhibition across the inhibitor series, whereas the VsDapL and CrDapL inhibition patterns were different from that of LiDapL and AtDapL. CrDapL was found to be insensitive to the hydrazide (IC50 >200μM). VsDapL was found to be the most sensitive to the barbiturate and thiobarbiturate containing inhibitors (IC50 ∼5μM). Taken together, the data shows that the homologs have differing sensitivities to the inhibitors with IC50 values ranging from 4.7 to 250μM. In an attempt to understand the basis for these differences the four enzymes were modeled based on the known structure of AtDapL. Overall, it was found that the enzyme active sites were conserved, although the second shell of residues close to the active site were not. We conclude from this that the altered binding patterns seen in the inhibition studies may be a consequence of the inhibitors forming additional interactions with residues proximal to the active site, or that the inhibitors may not act by binding to the active site. Compounds that are specific for DapL could be potential biocides (antibiotic, herbicide or algaecide) that are nontoxic to animals since animals do not contain the enzymes necessary for PG or Lys synthesis. This study provides important information to expand our current understanding of the structure/activity relationship of DapL and putative inhibitors that are potentially useful for the design and or discovery of novel biocides.

Graphical abstract

Lipoic acid analogs with enhanced pharmacological activity

May 31, 2015, 2:30 am

≫ Next: Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect

≪ Previous: Differential response of orthologous l,l-diaminopimelate aminotransferases (DapL) to enzyme inhibitory antibiotic lead compounds

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Publication date: 1 January 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 1
Author(s): Steven A. Kates , Ralph A. Casale , Alexander Baguisi , Reinier Beeuwkes III
Lipoic acid (1,2-dithiolane-3-pentanoic acid) is a pharmacophore with unique antioxidant and cytoprotective properties. We synthesized a library based upon the condensation of natural and unnatural amino acids with the carboxylic acid moiety of lipoic acid. SAR studies were conducted using a cardiac ischemia-reperfusion animal model. Cytoprotective efficacy was associated with the R-enantiomer of the dithiolane. Potency of library compounds was dictated by the acidic strength of the adduct. α-N-[(R)-1,2-dithiolane-3-pentanoyl]-l-glutamyl-l-alanine, designated CMX-2043, was chosen for further pharmacologic evaluation.

Graphical abstract

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Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect

May 31, 2015, 2:30 am

≫ Next: Inhibitory effects of novel synthetic methimazole derivatives on mushroom tyrosinase and melanogenesis

≪ Previous: Lipoic acid analogs with enhanced pharmacological activity

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Publication date: 1 April 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 7
Author(s): Zuzana Gaziova , Volker Baumann , Anna-Maria Winkler , Johannes Winkler
The therapeutic application of siRNA suffers from poor bioavailability caused by rapid degradation and elimination. The covalent attachment of PEG is a universal concept to increase molecular size and enhance the pharmacokinetic properties of biomacromolecules. We devised a facile approach for attachment of PEG molecules with a defined molecular weight, and successful purification of the resulting conjugates. We directly conjugated structurally defined PEG chains with twelve ethylene glycol units to the 3′-terminal hydroxyl group of both sense and antisense strands via an aminoalkyl linker. The conjugates were easily purified by HPLC and successful PEGylation and molecule integrity were confirmed by ESI-MS. The evaluation of in vitro gene knockdown of two different targets in MCF-7 breast cancer cells showed stable pharmacologic activity when combined with a standard transfection reagent. Sense strand PEGylation even increased the silencing potency of a CRCX4-siRNA which had modest activity in its wild-type form. The results indicate that PEG chains at the 3′-terminus of both strands of siRNA are well tolerated by the RNAi effector. The attachment of short, chemically defined PEG chains is a feasible approach to improve the pharmacokinetic properties of siRNA, and can be combined with other targeted and untargeted delivery vehicles.

Graphical abstract

Inhibitory effects of novel synthetic methimazole derivatives on mushroom tyrosinase and melanogenesis

May 31, 2015, 2:30 am

≫ Next: Inhibition by active site directed covalent modification of human glyoxalase I

≪ Previous: Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect

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Publication date: 1 May 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 9
Author(s): Chin-Feng Chan , Shih-Ting Lai , Yi-Cin Guo , Ming-Jen Chen
In this study, we synthesized 4 methimazole (2-mercapto-1-methylimidazole, MMI) derivatives. The kinetics of inhibition on mushroom tyrosinase by methimazole and its derivatives were investigated. The results indicated that tert-butyl 3-methyl-2-sulfanylidene-2,3-dihydro-1H-imidazole-1-carboxylate (compound 3; 3), 2-mercaptoimidazole (MI; compound 1; 1) and MMI (compound 2; 2) significantly inhibited tyrosinase activity in a dose-dependent manner, exhibiting an IC50 value of 1.50mM, 4.11mM, and 1.43mM. However, compound 4 (4), compound 5 (5), and compound 6 (6) exerted no inhibitory effect on mushroom tyrosinase activity. Kinetic analysis indicated that 3 was a noncompetitive tyrosinase inhibitor, whereas both 1 and 2 were exhibited as mixed-type tyrosinase inhibitors. Furthermore, 3 exerted a potent inhibitory effect on intracellular melanin formation in the B16/F10 murine melanoma cells and did not cause cytotoxicity, as 1 and 2 did.

Graphical abstract

Inhibition by active site directed covalent modification of human glyoxalase I

May 31, 2015, 2:30 am

≫ Next: An azido-oxazolidinone antibiotic for live bacterial cell imaging and generation of antibiotic variants

≪ Previous: Inhibitory effects of novel synthetic methimazole derivatives on mushroom tyrosinase and melanogenesis

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Publication date: 1 July 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
Author(s): Ronald J. Holewinski , Donald J. Creighton
The glyoxalase pathway is responsible for conversion of cytotoxic methylglyoxal (MG) to d-lactate. MG toxicity arises from its ability to form advanced glycation end products (AGEs) on proteins, lipids and DNA. Studies have shown that inhibitors of glyoxalase I (GLO1), the first enzyme of this pathway, have chemotherapeutic effects both in vitro and in vivo, presumably by increasing intracellular MG concentrations leading to apoptosis and cell death. Here, we present the first molecular inhibitor, 4-bromoacetoxy-1-(S-glutathionyl)-acetoxy butane (4BAB), able to covalently bind to the free sulfhydryl group of Cys60 in the hydrophobic binding pocket adjacent to the enzyme active site and partially inactivate the enzyme. Our data suggests that partial inactivation of homodimeric GLO1 is due to the modification at only one of the enzymatic active sites. Although this molecule may have limited use pharmacologically, it may serve as an important template for the development of new GLO1 inhibitors that may combine this strategy with ones already reported for high affinity GLO1 inhibitors, potentially improving potency and specificity.

Graphical abstract

An azido-oxazolidinone antibiotic for live bacterial cell imaging and generation of antibiotic variants

May 31, 2015, 2:30 am

≫ Next: A C-14 labeled Py–Im polyamide localizes to a subcutaneous prostate cancer tumor

≪ Previous: Inhibition by active site directed covalent modification of human glyoxalase I

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Publication date: 15 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 16
Author(s): Wanida Phetsang , Mark A.T. Blaskovich , Mark S. Butler , Johnny X. Huang , Johannes Zuegg , Sreeman K. Mamidyala , Soumya Ramu , Angela M. Kavanagh , Matthew A. Cooper
An azide-functionalised analogue of the oxazolidinone antibiotic linezolid was synthesised and shown to retain antimicrobial activity. Using facile ‘click’ chemistry, this versatile intermediate can be further functionalised to explore antimicrobial structure–activity relationships or conjugated to fluorophores to generate fluorescent probes. Such probes can report bacteria and their location in a sample in real time. Modelling of the structures bound to the cognate 50S ribosome target demonstrates binding to the same site as linezolid is possible. The fluorescent probes were successfully used to image Gram-positive bacteria using confocal microscopy.

Graphical abstract

A C-14 labeled Py–Im polyamide localizes to a subcutaneous prostate cancer tumor

May 31, 2015, 2:30 am

≫ Next: Design, synthesis and SAR exploration of tri-substituted 1,2,4-triazoles as inhibitors of the annexin A2–S100A10 protein interaction

≪ Previous: An azido-oxazolidinone antibiotic for live bacterial cell imaging and generation of antibiotic variants

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Publication date: 15 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 16
Author(s): Jevgenij A. Raskatov , James W. Puckett , Peter B. Dervan
In an effort to quantitate Py–Im polyamide concentrations in vivo, we synthesized the C-14 radioactively labeled compounds 1–3, and investigated their tumor localization in a subcutaneous xenograft model of prostate cancer (LNCaP). Tumor concentrations were compared with representative host tissues, and exhibited a certain degree of preferential localization to the xenograft. Compound accumulation upon repeated administration was measured. Py–Im polyamide 1 was found to accumulate in LNCaP tumors at concentrations similar to the IC50 value for this compound in cell culture experiments.

Graphical abstract

Design, synthesis and SAR exploration of tri-substituted 1,2,4-triazoles as inhibitors of the annexin A2–S100A10 protein interaction

May 31, 2015, 2:30 am

≫ Next: Neuraminidase inhibitory activities of quaternary isoquinoline alkaloids from Corydalis turtschaninovii rhizome

≪ Previous: A C-14 labeled Py–Im polyamide localizes to a subcutaneous prostate cancer tumor

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Publication date: 1 October 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
Author(s): Tummala R.K. Reddy , Chan Li , Xiaoxia Guo , Peter M. Fischer , Lodewijk V. Dekker
Recent target validation studies have shown that inhibition of the protein interaction between annexin A2 and the S100A10 protein may have potential therapeutic benefits in cancer. Virtual screening identified certain 3,4,5-trisubstituted 4H-1,2,4-triazoles as moderately potent inhibitors of this interaction. A series of analogues were synthesized based on the 1,2,4-triazole scaffold and were evaluated for inhibition of the annexin A2–S100A10 protein interaction in competitive binding assays. 2-[(5-{[(4,6-Dimethylpyrimidin-2-yl)sulfanyl]methyl}-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)sulfanyl]-N-[4-(propan-2-yl)phenyl]acetamide (36) showed improved potency and was shown to disrupt the native complex between annexin A2 and S100A10.

Graphical abstract

Neuraminidase inhibitory activities of quaternary isoquinoline alkaloids from Corydalis turtschaninovii rhizome

May 31, 2015, 2:30 am

≫ Next: 2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion

≪ Previous: Design, synthesis and SAR exploration of tri-substituted 1,2,4-triazoles as inhibitors of the annexin A2–S100A10 protein interaction

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Publication date: 1 November 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 21
Author(s): Jang Hoon Kim , Young Bae Ryu , Woo Song Lee , Young Ho Kim
Clostridium perfringens is a Gram-positive spore-forming bacterium that causes food poisoning. The neuraminidase (NA) protein of C. perfringens plays a pivotal role in bacterial proliferation and is considered a novel antibacterial drug target. Based on screens for novel NA inhibitors, a 95% EtOH extract of Corydalis turtschaninovii rhizome showed NA inhibitory activity (68% at 30μg/ml), which resulted in the isolation of 10 isoquinoline alkaloids; namely, palmatine (1), berberine (2), coptisine (3), pseudodehydrocorydaline (4), jatrorrhizine (5), dehydrocorybulbine (6), pseudocoptisine (7), glaucine (8), corydaline (9) and tetrahydrocoptisine (10). Interestingly, seven quaternary isoquinoline alkaloids 1–7 (IC50 =12.8±1.5 to 65.2±4.5μM) showed stronger NA inhibitory activity than the tertiary alkaloids 8–10. In addition, highly active compounds 1 and 2 showed reversible non-competitive behavior based on a kinetic study. Molecular docking simulations using the Autodock 4.2 software increased our understanding of receptor–ligand binding of these compounds. In addition, we demonstrated that compounds 1 and 2 suppressed bacterial growth.

Graphical abstract

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2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion

May 31, 2015, 2:30 am

≫ Next: Computational identification of a phospholipidosis toxicophore using 13C and 15N NMR-distance based fingerprints

≪ Previous: Neuraminidase inhibitory activities of quaternary isoquinoline alkaloids from Corydalis turtschaninovii rhizome

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Publication date: 15 November 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 22
Author(s): James R. Sayer , Karin Walldén , Thomas Pesnot , Frederick Campbell , Paul J. Gane , Michela Simone , Hans Koss , Floris Buelens , Timothy P. Boyle , David L. Selwood , Gabriel Waksman , Alethea B. Tabor
A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyrazines has been used to probe the structure–activity relationships of these inhibitors, which show potential as antibacterial agents.

Graphical abstract

Computational identification of a phospholipidosis toxicophore using 13C and 15N NMR-distance based fingerprints

May 31, 2015, 2:30 am

≫ Next: Synthesis of aminoacylated N6,N6-dimethyladenosine solid support for efficient access to hydrolysis-resistant 3′-charged tRNA mimics

≪ Previous: 2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion

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Publication date: 1 December 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 23
Author(s): Svetoslav H. Slavov , Jon G. Wilkes , Dan A. Buzatu , Naomi L. Kruhlak , James M. Willard , Joseph P. Hanig , Richard D. Beger
Modified 3D-SDAR fingerprints combining ¹³C and ¹⁵N NMR chemical shifts augmented with inter-atomic distances were used to model the potential of chemicals to induce phospholipidosis (PLD). A curated dataset of 328 compounds (some of which were cationic amphiphilic drugs) was used to generate 3D-QSDAR models based on tessellations of the 3D-SDAR space with grids of different density. Composite PLS models averaging the aggregated predictions from 100 fully randomized individual models were generated. On each of the 100 runs, the activities of an external blind test set comprised of 294 proprietary chemicals were predicted and averaged to provide composite estimates of their PLD-inducing potentials (PLD+ if PLD is observed, otherwise PLD−). The best performing 3D-QSDAR model utilized a grid with a density of 8ppm×8ppm in the C–C region, 8ppm×20ppm in the C–N region and 20ppm×20ppm in the N–N region. The classification predictive performance parameters of this model evaluated on the basis of the external test set were as follows: accuracy=0.70, sensitivity=0.73 and specificity=0.66. A projection of the most frequently occurring bins on the standard coordinate space suggested a toxicophore composed of an aromatic ring with a centroid 3.5–7.5Å distant from an amino-group. The presence of a second aromatic ring separated by a 4–5Å spacer from the first ring and at a distance of between 5.5Å and 7Å from the amino-group was also associated with a PLD+ effect. These models provide comparable predictive performance to previously reported models for PLD with the added benefit of being based entirely on non-confidential, publicly available training data and with good predictive performance when tested in a rigorous, external validation exercise.

Graphical abstract

Synthesis of aminoacylated N6,N6-dimethyladenosine solid support for efficient access to hydrolysis-resistant 3′-charged tRNA mimics

May 31, 2015, 2:30 am

≫ Next: Synthesis and evaluation of the 2,4-diaminoquinazoline series as anti-tubercular agents

≪ Previous: Computational identification of a phospholipidosis toxicophore using 13C and 15N NMR-distance based fingerprints

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Publication date: 15 December 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 24
Author(s): Sandro Neuner , Ronald Micura
RNA-amino acid and RNA-peptide conjugates that mimic charged tRNA 3′-ends are valuable substrates for structural and functional investigations of ribosomal complexes. To obtain such conjugates, most synthetic approaches that are found in the literature make use of puromycin. This well available aminonucleoside antibiotic contains a dimethylamino group at the nucleobase and a methylated tyrosine that is connected via an amide linkage to the ribose moiety. To increase structural diversity, we present the synthesis of a N ⁶,N ⁶-dimethylated 3′-azido-3′-deoxyadenosine precursor that can be coupled to any amino acid. Further derivatization results in the solid support that is eligible for the preparation of stable 3′-aminoacyl- or 3′-peptidyl-tRNA termini with an amide instead of the natural ester linkage. The present work expands our previously established route that delivered a broad range of peptidyl-tRNA mimics to the corresponding counterparts with N ⁶,N ⁶-dimethylation pattern of the terminal adenosine (A76). This aspect is of significance to modulate the binding preferences of the mimics for ribosomal A- versus P-site.

Graphical abstract

Synthesis and evaluation of the 2,4-diaminoquinazoline series as anti-tubercular agents

May 31, 2015, 2:30 am

≫ Next: Perspective: Challenges and opportunities in TB drug discovery from phenotypic screening

≪ Previous: Synthesis of aminoacylated N6,N6-dimethyladenosine solid support for efficient access to hydrolysis-resistant 3′-charged tRNA mimics

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Publication date: 15 December 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 24
Author(s): Joshua Odingo , Theresa O’Malley , Edward A. Kesicki , Torey Alling , Mai Ann Bailey , Julie Early , Juliane Ollinger , Suryakanta Dalai , Naresh Kumar , Ravindra Vikram Singh , Philip A. Hipskind , Jeffrey W. Cramer , Thomas Ioerger , James Sacchettini , Richard Vickers , Tanya Parish
The 2,4-diaminoquinazoline class of compounds has previously been identified as an effective inhibitor of Mycobacterium tuberculosis growth. We conducted an extensive evaluation of the series for its potential as a lead candidate for tuberculosis drug discovery. Three segments of the representative molecule N-(4-fluorobenzyl)-2-(piperidin-1-yl)quinazolin-4-amine were examined systematically to explore structure–activity relationships influencing potency. We determined that the benzylic amine at the 4-position, the piperidine at 2-position and the N-1 (but not N-3) are key activity determinants. The 3-deaza analog retained similar activity to the parent molecule. Biological activity was not dependent on iron or carbon source availability. We demonstrated through pharmacokinetic studies in rats that good in vivo compound exposure is achievable. A representative compound demonstrated bactericidal activity against both replicating and non-replicating M. tuberculosis. We isolated and sequenced M. tuberculosis mutants resistant to this compound and observed mutations in Rv3161c, a gene predicted to encode a dioxygenase, suggesting that the compound may act as a pro-drug.

Graphical abstract

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

May 31, 2015, 2:30 am

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Publication date: Available online 24 December 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Ujjini H. Manjunatha , Paul W. Smith
Tuberculosis poses a major global health problem and multi-drug resistant strains are increasingly prevalent. Hence there is an urgent need to discover new TB drugs. Cell based phenotypic screening represents a powerful approach to identify anti-mycobacterial compounds and elucidate novel targets. Three high throughput phenotypic screens were performed at NITD against mycobacterium. Hits were identified and chemical series selected for optimisation. This produced compounds with good in vitro anti-mycobacterial activity and pharmacokinetic properties. Some compounds displayed oral activity in mouse efficacy models of TB. Herein, we review the TB discovery efforts at NITD and share experiences in optimisation of phenotypic hits, describing challenges encountered and lessons learned. We also offer perspectives to facilitate future selection and advancement of phenotypic hits.

Graphical abstract