Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8
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Graphical contents list ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8
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β-Sheet interfering molecules acting against β-amyloid aggregation and fibrillogenesis ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Antonio Francioso , Pasqualina Punzi , Alberto Boffi , Clorinda Lori , Sara Martire , Cesare Giordano , Maria D’Erme , Luciana Mosca β-Sheet aggregates and amyloid fibrils rising from conformational changes of proteins are observed in several pathological human conditions. These structures are organized in β-strands that can reciprocally interact by hydrophobic and π–π interactions. The amyloid aggregates can give rise to pathological conditions through complex biochemical mechanisms whose physico-chemical nature has been understood in recent times. This review focuses on the various classes of natural and synthetic small molecules able to act against β-amyloid fibrillogenesis and toxicity that may represent new pharmacological tools in Alzheimer’s diseases. Some peptides, named ‘β-sheet breaker peptides’, are able to hamper amyloid aggregation and fibrillogenesis by interfering with and destabilizing the non native β-sheet structures. Other natural compounds, like polyphenols or indolic molecules such as melatonin, can interfere with β-amyloid peptide pathogenicity by inhibiting aggregation and counteracting oxidative stress that is a key hallmark in Alzheimer’s disease. Graphical abstract image
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Synthesis, optical properties and preliminary in vitro photodynamic effect of pyridyl and quinoxalyl substituted chlorins ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Jiazhu Li , Xin Zhang , Yang Liu , Il Yoon , Dong-Kyoo Kim , Jun-Gang Yin , Jin-Jun Wang , Young Key Shim A series of chlorophyll a-based chlorins conjugated with pyridyl or quinoxalyl group at different positions were synthesized, characterized and evaluated for their photodynamic effect in vitro. It was found that all the pyridyl and quinoxalyl chlorins showed promising photocytotoxicities but nontoxic without irradiation in HeLa cells, and the substituted types and positions had a significant influence on the photocytotoxicities of the chlorophyll a-based chlorins. All the chlorins with a pyridyl group at the C–D ring end exhibited relatively high photocytotoxicity as compared to those with 32-pyridyl. Among them, compound 12 conjugated with a pyridyl group at its C12 position showed the best photodynamic effect in HeLa cells with an IC50 value of 0.033μM. These facts, associated with the relative high long wavelength absorptions of those chlorins may provide valuable ways to design and prepare promising photosensitizers for application in photodynamic therapy. Graphical abstract image
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Triazine–benzimidazole hybrids: Anticancer activity, DNA interaction and dihydrofolate reductase inhibitors ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Prinka Singla , Vijay Luxami , Kamaldeep Paul A new series of triazine–benzimidazole hybrids has been synthesized with different substitution of primary and secondary amines at one of the position of triazine in moderate to good yields. These compounds were evaluated for their inhibitory activities over 60 human tumor cell lines at one dose and five dose concentrations. Compounds 6b, 8 and 9 showed broad spectrum of antitumor activities with GI50 values of 9.79, 2.58 and 3.81μM, respectively. DNA binding studies also indicated strong interaction properties of these compounds. These synthesized compounds also showed inhibition of mammalian dihydrofolate reductase (DHFR). Compound 6b was depicted as the most active member of DHFR inhibitor with IC50 value of 1.05μM. Molecular modelling studies were used to identify the stabilized interactions of Compound 6b within the active site of enzyme for DHFR. Graphical abstract image
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Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Yunyun Yuan , Saheem A. Zaidi , David L. Stevens , Krista L. Scoggins , Philip D. Mosier , Glen E. Kellogg , William L. Dewey , Dana E. Selley , Yan Zhang A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure–activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1′- and/or 4′-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6′- and/or 7′-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6′-nitro group varied significantly in the different ‘address’ domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. Graphical abstract image
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In vitro radical scavenging and cytotoxic activities of novel hybrid selenocarbamates ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Beatriz Romano , Daniel Plano , Ignacio Encío , Juan Antonio Palop , Carmen Sanmartín Novel selenocyanate and diselenide derivatives containing a carbamate moiety were synthesised and evaluated in vitro to determine their cytotoxic and radical scavenging properties. Cytotoxic activity was tested against a panel of human cell lines including CCRF-CEM (lymphoblastic leukaemia), HT-29 (colon carcinoma), HTB-54 (lung carcinoma), PC-3 (prostate carcinoma), MCF-7 (breast adenocarcinoma), 184B5 (non-malignant, mammary gland derived) and BEAS-2B (non-malignant, derived from bronchial epithelium). Most of the compounds displayed high antiproliferative activity with GI50 values below 10μM in MCF-7, CCRF-CEM and PC-3 cells. Radical scavenging properties of the new selenocompounds were confirmed testing their ability to scavenge DPPH and ABTS radicals. Based on the activity of selenium-based glutathione peroxidases (GPxs), compounds 1a, 2e and 2h were further screened for their capacity to reduce hydrogen peroxide under thiol presence. Results suggest that compound 1a mimics GPxs activity. Cytotoxic parameters, radical scavenging activity and ADME profile point to 1a as promising drug candidate. Graphical abstract image
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Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic cyanobacterium Nostoc commune ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Daniela Vullo , Viviana De Luca , Sonia Del Prete , Vincenzo Carginale , Andrea Scozzafava , Clemente Capasso , Claudiu T. Supuran A carbonic anhydrase (CA, EC 4.2.1.1) belonging to the γ-class has been cloned, purified and characterized from the Antarctic cyanobacterium Nostoc commune. The enzyme showed a good catalytic activity for the physiologic reaction (hydration of carbon dioxide to bicarbonate and a proton) with the following kinetic parameters, k cat of 9.5×105 s−1 and k cat/K M of 8.3×107 M−1 s−1, being the γ-CA with the highest catalytic activity described so far. A range of aromatic/heterocyclic sulfonamides and one sulfamate were investigated as inhibitors of the new enzyme, denominated here NcoCA. The best NcoCA inhibitors were some sulfonylated sulfanilamide derivatives possessing elongated molecules, aminobenzolamide, acetazolamide, benzolamide, dorzolamide, brinzolamide and topiramate, which showed inhibition constants in the range of 40.3–92.3nM. As 1,5-bisphosphate carboxylase/oxygenase (RubisCO) and γ-CAs are closely associated in carboxysomes of cyanobacteria for enhancing the affinity of RubisCO for CO2 and the efficiency of photosynthesis, investigation of this new enzyme and its affinity for modulators of its activity may bring new insights in these crucial processes. Graphical abstract image
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Design and synthesis of new potassium channel activators derived from the ring opening of diazoxide: Study of their vasodilatory effect, stimulation of elastin synthesis and inhibitory effect on insulin release ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Nafila Bouider , Wassim Fhayli , Zeinab Ghandour , Marjorie Boyer , Kamel Harrouche , Xavier Florence , Bernard Pirotte , Philippe Lebrun , Gilles Faury , Smail Khelili Benzenesulfonylureas and benzenesulfonylthioureas, as well as benzenecarbonylureas and benzenecarbonylthioureas, were prepared and evaluated as myorelaxants on 30mMKCl-precontracted rat aortic rings. The most active compounds were further examined as stimulators of elastin synthesis by vascular smooth muscle cells and as inhibitors of insulin release from pancreaticβ-cells. The drugs were also characterized for their effects on glycaemia in rats. Benzenesulfonylureas and benzenesulfonylthioureas did not display any myorelaxant activity on precontracted rat aortic rings. Such an effect could be attributed to their ionization at physiological pH. By contrast, almost all benzenecarbonylureas and benzenecarbonylthioureas displayed a myorelaxant activity, in particular the benzenecarbonylureas with an oxybenzyl group linked to the ortho position of the phenyl ring. The vasodilatory activity of the most active compounds was reduced when measured in the presence of 80mMKCl or in the presence of 30mM KCl and 10μM glibenclamide. Such results suggested the involvement, at least in part, of KATP channels. Preservation of a vasodilatory activity in rat aortic rings without endothelium indicated that the site of action of such molecules was located on the vascular smooth muscle cells and not on the endothelial cells. Some of the most active compounds also stimulated elastin synthesis by vascular smooth muscle cells. Lastly, most of the active vasorelaxant drugs, except 15k and 15t at high concentrations, did not exhibit marked inhibitory effects on the insulin releasing process and on glycaemia, suggesting a relative tissue selectivity of some of these compounds for the vascular smooth muscle. Graphical abstract image
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A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Nicolas Levoin , Duc Duy Vo , Fabien Gautier , Sophie Barillé-Nion , Philippe Juin , Olivier Tasseau , René Grée Inhibition of Bcl-2 family protein–protein interactions (PPI) is a very promising direction in cancer chemotherapy. Hence over the last decade, many medicinal chemistry studies endeavoured to discover drug candidates, and a wealth of chemical scaffolds with striking chemical diversity was reported as Bcl-xL inhibitors. This raises the question of whether all these molecules could occupy a unique binding site, or rather discrete pockets of the protein surface. To test if small and chemically diverse Bcl-xL inhibitors are likely to bind a single pocket, and to identify which pocket, we used a battery of computational and modeling approaches. We first checked that the large dataset of Bcl-xL inhibitors we built can actually fit to a universal pharmacophore. Then we defined the probable binding hot spots of interaction through comparison of crystal structures, as well as virtual fragment screening. Finally, new analogues of small polyphenol derivatives were synthesized to precisely probe a hydrogen bond suggested by docking experiments. Bcl-xL inhibition potency of these products confirmed the predicted binding mode. This combination of X-ray structure exploration, molecular modeling studies and medicinal chemistry supports that all these small Bcl-xL inhibitors occupy the same hot spot of interaction. The identification of this binding site should help the design and optimization of small PPI Bcl-xL inhibitors. Graphical abstract image
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Molecular design of Cy3 derivative for highly sensitive in-stem molecular beacon and its application to the wash-free FISH ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Hiromu Kashida , Takuya Osawa , Kazuhiro Morimoto , Yukiko Kamiya , Hiroyuki Asanuma We herein describe a novel in-stem molecular beacon (ISMB) containing multiple Cy3-quencher pairs on d-threoninol scaffolds in the stem region. The designed Cy3 derivative was not significantly quenched by the adjacent nucleobases, self-quenching of the fluorophore was minimal, and the fluorophore did not severely destabilize the duplex. Using newly designed Cy3, we synthesized ISMBs containing two Cy3 moieties. The signal to background ratio of the ISMB containing two Cy3 moieties was above 100, whereas that with one Cy3 was 30. A Cy3-derivative containing ISMB used in a fluorescence in situ hybridization (FISH) detected endogenous β-actin mRNA in fixed cells without need for washing procedures. Graphical abstract image
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Synthesis and biological activity of novel mono-indole and mono-benzofuran inhibitors of bacterial transcription initiation complex formation ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Marcin Mielczarek , Ruth V. Thomas , Cong Ma , Hakan Kandemir , Xiao Yang , Mohan Bhadbhade , David StC. Black , Renate Griffith , Peter J. Lewis , Naresh Kumar Our ongoing research focused on targeting transcription initiation in bacteria has resulted in synthesis of several classes of mono-indole and mono-benzofuran inhibitors that targeted the essential protein–protein interaction between RNA polymerase core and σ 70/σ A factors in bacteria. In this study, the reaction of indole-2-, indole-3-, indole-7- and benzofuran-2-glyoxyloyl chlorides with amines and hydrazines afforded a variety of glyoxyloylamides and glyoxyloylhydrazides. Similarly, condensation of 2- and 7-trichloroacetylindoles with amines and hydrazines delivered amides and hydrazides. The novel molecules were found to inhibit the RNA polymerase–σ 70/σ A interaction as measured by ELISA, and also inhibited the growth of both Gram-positive and Gram-negative bacteria in culture. Structure–activity relationship (SAR) studies of the mono-indole and mono-benzofuran inhibitors suggested that the hydrophilic–hydrophobic balance is an important determinant of biological activity. Graphical abstract image
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Design, synthesis, and structure–activity relationships of 1-ethylpyrazole-3-carboxamide compounds as novel hypoxia-inducible factor (HIF)-1 inhibitors ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Yorinobu Yasuda , Takeaki Arakawa , Yumi Nawata , Sayaka Shimada , Shinya Oishi , Nobutaka Fujii , Shinichi Nishimura , Akira Hattori , Hideaki Kakeya Hypoxia-inducible factor (HIF)-1 is well known as a promising target for cancer chemotherapy. By screening an in-house chemical library using a hypoxia-responsive luciferase reporter gene assay, we identified CLB-016 (1) containing 1-ethylpyrazole-3-carboxamide as a HIF-1 inhibitor (IC50 =19.1μM). In a subsequent extensive structure-activity relationship (SAR) study, we developed compound 11Ae with an IC50 value of 8.1μM against HIF-1-driven luciferase activity. Compounds 1 and 11Ae were shown to significantly suppress the HIF-1-mediated hypoxia response, including carbonic anhydrase IX (CAIX) gene expression and migration of human sarcoma HT1080 cells. These results revealed 1-ethylpyrazole-3-carboxamide as a novel scaffold to develop promising anti-cancer drugs targeting the HIF-1 signaling pathway. Graphical abstract image
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Synthesis, structure–activity relationships, and anticonvulsant activities of 2-amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives as orally active AMPA receptor antagonists ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Hiroshi Inami , Jun-ichi Shishikura , Tomoyuki Yasunaga , Kazushige Ohno , Hiroshi Yamashita , Kota Kato , Shuichi Sakamoto As part of a program aimed at discovering orally active 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonists, we screened our compound library and identified 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (7) as a lead compound that inhibited kainate-induced neurotoxicity mediated by AMPA receptors in rat hippocampal cultures. Structure–activity relationship studies of a series of 2-amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives revealed that substituents on the phenyl ring attached to the 2-amino group and the 4H-pyrido[3,2-e][1,3]thiazin-4-one ring system play an important role in inhibitory activity against kainate-induced neurotoxicity. Several analogs bearing a phenyl group with a 4-substituent or five- or six-membered ring fused at the 3,4-positions exhibited potent inhibitory activity against kainate-induced neurotoxicity. Further, some of these compounds exhibited significant suppression of maximal electroshock seizure in mice following oral administration. Of these compounds, 2-[(4-chlorophenyl)(methyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (16i) (YM928) demonstrated the most potent inhibitory effect with an ED50 value of 7.4mg/kg. Graphical abstract image
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Synthesis and biological evaluation of benzimidazole acridine derivatives as potential DNA-binding and apoptosis-inducing agents ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Chunmei Gao , Bin Li , Bin Zhang , Qinsheng Sun , Lulu Li , Xi Li , Changjun Chen , Chunyan Tan , Hongxia Liu , Yuyang Jiang The discovery of new effective DNA-targeted antitumor agent is needed because of their clinical significance. As acridines can intercalate into DNA and benzimidazoles have the ability to bind in the DNA minor groove, a series of novel benzimidazole acridine derivatives were designed and synthesized to be new DNA-targeted compounds. MTT assay indicated that most of the synthesized compounds displayed good antiproliferative activity, among which compound 8l demonstrated the highest activity against both K562 and HepG-2 cells. Further experiments showed that 8l displayed good DNA-binding capability and inhibited topoisomerase I activity. Moreover, compound 8l could induce apoptosis in K562 cell lines through mitochondrial pathway. These data suggested that compound 8l might be potential as new DNA-binding and apoptosis-inducing antitumor agents. Graphical abstract image
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Discovery and structure–activity relationships of pyrazolodiazepine derivatives as the first small molecule agonists of the Drosophila sex peptide receptor ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Joeng-hyun Kim , Pyeong-hwa Jeong , Ju-Yeon Lee , Jae-hyuk Lee , Young-Joon Kim , Yong-Chul Kim In behavioral research, the sex peptide receptor in Drosophila melanogaster (DrmSPR) is the most interesting G protein-coupled receptor (GPCR) and is involved in post-mating responses such as increased egg-laying and decreased receptivity of the female; during these responses, the receptors are activated by a specific natural peptide agonist (sex peptide, SP). To discover small molecule agonists for DrmSPR, a compound library based on a pyrazolodiazepine scaffold, which was previously reported as a potential privileged structure, was screened. Structure–activity relationship (SAR) studies of the hit compounds, which exhibited weak agonistic effects (69–72% activation at 100μM), were explored through the synthesis of various analogs with substituents at the R1, R2, R3 and R4 positions of the pyrazolodiazepine skeleton. As a result, compounds 21 and 31 of the 6-benzyl pyrazolodiazepine derivative series were found to be small molecule agonists for DrmSPR with EC50 values of 3–4μM. Graphical abstract image
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Design, synthesis and biological evaluation of functionalized phthalimides: A new class of antimalarials and inhibitors of falcipain-2, a major hemoglobinase of malaria parasite ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Anil K. Singh , Vinoth Rajendran , Akansha Pant , Prahlad C. Ghosh , Neelu Singh , N. Latha , Sandeep Garg , Kailash C. Pandey , Brajendra K. Singh , Brijesh Rathi Phthalimides functionalized with cyclic amines were synthesized, characterized and screened for their in vitro antimalarial efficacy against Plasmodium falciparum (Pf3D7). Of all the listed phthalimides evaluated, 14 and 24 were identified as potent antimalarial agents as advocated by assessment of their ability to inhibit [3H] hypoxanthine incorporation in the nucleic acid of parasites. In addition, phthalimides 14 and 24 were incubated for 60 and 90h and an enhanced antimalarial effect was noticed with increase in time to great extent. A reduction in IC50 values was observed with increase in exposure time of the parasite to the compounds. A symmetric phthalimide, 24 possessing piperazine as linker unit was identified as the most potent antimalarial agent with IC50 values of 5.97±0.78, 2.0±1.09 and 1.1±0.75μM on incubation period of 42, 60 and 90h, respectively. The abnormal morphologies such as delay in developmental stages, growth arrest and condensed nuclei of parasite were observed with the aid of microscopic studies upon exposure with 14 and 24. The evaluation of 14 and 24 against chloroquine resistant strain, (Pf7GB) of P. falciparum afforded IC50 values, 13.29±1.20 and 7.21±0.98μM, respectively. The combination of 24 with artemisinin (ART) showed enhanced killing of parasite against Pf3D7. Further, all phthalimides were evaluated for their activity against falcipain-2 (FP2), a major hemoglobinase of malarial parasite. The enzymatic assay afforded 6 as most active member against FP2. To the best of our knowledge this is the initial study represents phthalimide protected amino acids functionalized with cyclic amines as potent antimalarial agents. Graphical abstract image
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A class of sulfonamide carbonic anhydrase inhibitors with neuropathic pain modulating effects ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Fabrizio Carta , Lorenzo Di Cesare Mannelli , Melissa Pinard , Carla Ghelardini , Andrea Scozzafava , Robert McKenna , Claudiu T. Supuran A series of benzene sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors which incorporate lipophilic 4-alkoxy- and 4-aryloxy moieties, together with several derivatives of ethoxzolamide and sulfanilamide are reported. These derivatives were investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) of which multiple isoforms are known, and some appear to be involved in pain. These sulfonamides showed modest inhibition against the cytosolic isoform CA I, but were generally effective, low nanomolar CA II, VII, IX and XII inhibitors. X-ray crystallographic data for the adduct of several such sulfonamides with CA II allowed us to rationalize the good inhibition data. In a mice model of neuropathic pain induced by oxaliplatin, one of the strong CA II/VII inhibitors reported here induced a long lasting pain relieving effect, a fact never observed earlier. This is the first report of rationally designed sulfonamide CA inhibitors with pain effective modulating effects. Graphical abstract image
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Development of a time-resolved fluorescence probe for evaluation of competitive binding to the cholecystokinin 2 receptor ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): N.G.R. Dayan Elshan , Thanuja Jayasundera , Craig S. Weber , Ronald M. Lynch , Eugene A. Mash The synthesis, characterization, and use of Eu-DTPA-PEGO-Trp-Nle-Asp-Phe-NH2 (Eu-DTPA-PEGO-CCK4), a luminescent probe targeted to cholecystokinin 2 receptor (CCK2R, aka CCKBR), are described. The probe was prepared by solid phase synthesis. A K d value of 17±2nM was determined by means of saturation binding assays using HEK-293 cells that overexpress CCK2R. The probe was then used in competitive binding assays against Ac-CCK4 and three new trivalent CCK4 compounds. Repeatable and reproducible binding assay results were obtained. Given its ease of synthesis, purification, receptor binding properties, and utility in competitive binding assays, Eu-DTPA-PEGO-CCK4 could become a standard tool for high-throughput screening of compounds in development targeted to cholecystokinin receptors. Graphical abstract image
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Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: Insight into functional group effects and biological activity ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Robert J. Sharpe , Justin T. Malinowski , Federico Sorana , J. Christopher Luft , Charles J. Bowerman , Joseph M. DeSimone , Jeffrey S. Johnson The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin’s biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation. Graphical abstract image
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Identification of novel inhibitors of Aurora A with a 3-(pyrrolopyridin-2-yl)indazole scaffold ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Pinrao Song , Ming Chen , Xiaodong Ma , Lei Xu , Tao Liu , Yubo Zhou , Yongzhou Hu A novel series of 3-(pyrrolopyridin-2-yl)indazole derivatives were synthesized and biologically evaluated for their anti-proliferative effects on five human cancer cell lines. As a result, all of them exhibited vigorous potency against HL60 cell line with IC50 values ranging from singe digital nanomolar to micromolar level. Besides, a majority of them displayed modest to good antiproliferative activities against the other four cell lines, including KB, SMMC-7721, HCT116, and A549. Particularly, compound 2y, as the most distinguished one in this series, demonstrated IC50 values of 8.3nM and 1.3nM against HL60 and HCT116 cell lines, respectively. Afterwards, for exploring the molecular target, compounds2d, 2g and 2y were further selected to evaluate the inhibitory activities against a panel of kinases. Finally, they were identified to be targeting Aurora A kinase with significant selectivity over other kinases, such as CHK1, CDK2, MEK1, GSK3β, BRAF, IKKβ and PKC. Graphical abstract image
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Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Kayla M. Borland , Safnas F. AbdulSalam , Morwena J. Solivio , Matthew P. Burke , Patrick R. Wolfkiel , Sean M. Lawson , Courtney A. Stockman , Joel M. Andersen , Skyler Smith , Julia N. Tolstolutskaya , Purujit N. Gurjar , Aron P. Bercz , Edward J. Merino , Vladislav A. Litosh Current FDA-approved chemotherapeutic antimetabolites elicit severe side effects that warrant their improvement; therefore, we designed compounds with mechanisms of action focusing on inhibiting DNA replication rather than targeting multiple pathways. We previously discovered that 5-(α-substituted-2-nitrobenzyloxy)methyluridine-5′-triphosphates were exquisite DNA synthesis terminators; therefore, we synthesized a library of 35 thymidine analogs and evaluated their activity using an MTT cell viability assay of MCF7 breast cancer cells chosen for their vulnerability to these nucleoside derivatives. Compound 3a, having an α-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy group, showed an IC50 of 9±1μM. The compound is more selective for cancer cells than for fibroblast cells compared with 5-fluorouracil. Treatment of MCF7 cells with 3a elicits the DNA damage response as indicated by phosphorylation of γ-H2A. A primer extension assay of the 5′-triphosphate of 3a revealed that 3aTP is more likely to inhibit DNA polymerase than to lead to termination events upon incorporation into the DNA replication fork. Graphical abstract image
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Editorial board ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7
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Graphical contents list ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7
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Cannabidiol (CBD) and its analogs: a review of their effects on inflammation ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Sumner Burstein First isolated from Cannabis in 1940 by Roger Adams, the structure of CBD was not completely elucidated until 1963. Subsequent studies resulted in the pronouncement that THC was the ‘active’ principle of Cannabis and research then focused primarily on it to the virtual exclusion of CBD. This was no doubt due to the belief that activity meant psychoactivity that was shown by THC and not by CBD. In retrospect this must be seen as unfortunate since a number of actions of CBD with potential therapeutic benefit were downplayed for many years. In this review, attention will be focused on the effects of CBD in the broad area of inflammation where such benefits seem likely to be developed. Topics covered in this review are; the medicinal chemistry of CBD, CBD receptor binding involved in controlling Inflammation, signaling events generated by CBD, downstream events affected by CBD (gene expression and transcription), functional effects reported for CBD and combined THC plus CBD treatment. Graphical abstract image
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Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Marcian E. Van Dort , Stefanie Galbán , Hanxiao Wang , Judith Sebolt-Leopold , Christopher Whitehead , Hao Hong , Alnawaz Rehemtulla , Brian D. Ross The MAP kinase (Ras/MEK/ERK) and PI3K/Akt/mTOR oncogenic signaling pathways are central regulators of KRAS-mediated transformation. Molecular reciprocity between the Ras/MEK/ERK and PI3K/Akt/mTOR pathways provides cancer cells with the ability to evade treatment when targeting only one pathway with monotherapy. Multi-kinase targeting was explored through the development of a single bivalent chemical entity by covalent linking of high-affinity MEK and PI3K inhibitors. A prototype dual-acting agent (compound 8) designed using the PI3K inhibitor ZSTK474 and the Raf/MEK inhibitor RO5126766 as scaffolds displayed high in vitro inhibition of both PI3K (IC50 =172nM) and MEK1 (IC50 =473nM). Additionally, compound 8 demonstrated significant modulation of MEK and PI3K signaling pathway activity in human A549 human lung adenocarcinoma cells and pancreatic cancer cells (PANC-1) and also decreased cellular viability in these two cell lines. Graphical abstract image
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Synthesis and antifungal activity of 5-iodo-1,4-disubstituted-1,2,3-triazole derivatives as pyruvate dehydrogenase complex E1 inhibitors ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Jun-Bo He , Hai-Feng He , Lu-Lu Zhao , Li Zhang , Ge-Yun You , Ling-Ling Feng , Jian Wan , Hong-Wu He To identify new antifungal lead compound based on inhibitors of pyruvate dehydrogenase complex E1, a series of 5-iodo-1,4-disubstituted-1,2,3-triazole derivatives 3 were prepared and evaluated for their Escherichia coli PDHc-E1 inhibitory activity and antifungal activity. The in vitro bioassay for the PDHc-E1 inhibition indicated all the compounds exhibited significant inhibition against E. coli PDHc-E1 (IC50 <21μM), special compound 3g showed the most potent inhibitory activity (IC50 =4.21±0.11μM) and was demonstrated to act as a competitive inhibitor of PDHc-E1. Meanwhile, inhibitor 3g exhibited very good enzyme-selective inhibition of PDHc-E1 between pig heart and E. coli. The assay of antifungal activity showed compounds 3e, 3g, and 3n exhibited fair to good activity against Rhizoctonia solani and Botrytis cinerea even at 12.5μg/mL. Especially compound 3n (EC50 =5.4μg/mL; EC90 =21.1μg/mL) exhibited almost 5.50 times inhibitory potency against B. cinerea than that of pyrimethanil (EC50 =29.6μg/mL; EC90 =113.4μg/mL). Therefore, in this study, compound 3n was found to be a novel lead compound for further optimization to find more potent antifungal compounds as microbial PDHc-E1 inhibitors. Graphical abstract image
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Development of 2-amino-5-phenylthiophene-3-carboxamide derivatives as novel inhibitors of Mycobacterium tuberculosis DNA GyrB domain ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Shalini Saxena , Ganesh Samala , Janupally Renuka , Jonnalagadda Padma Sridevi , Perumal Yogeeswari , Dharmarajan Sriram DNA gyrase is the only type II topoisomerase in Mycobacterium tuberculosis (Mtb), unlike other bacteria and its absence in human being makes it a clinically validated target for developing anti-tubercular leads against Mtb. In the present study, our effort was to optimize and synthesize a series of compounds by a combination of molecular docking, and synthetic chemistry approach for better activity. A series of twenty eight substituted 2-amino-5-phenylthiophene-3-carboxamide derivatives were designed based on our earlier reported Mtb GyrB inhibitor lead. Hit expansion of the previously identified lead by chemical synthesis led to improved inhibitor with an IC50 value of 0.86±0.81μM against Mtb DNA gyrase supercoiling and Mycobacterium smegmatis GyrB IC50 of 1.35±0.58μM. Further a biophysical investigation using differential scanning fluorimetry experiments re-ascertained the affinity of these molecules towards the GyrB domain. Graphical abstract image
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Aminobenzoic acid incorporated octapeptides for cation transport ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Bahiru P. Benke , Nandita Madhavan Robust oligopeptides that mimic natural ion channels are attractive for use as molecular switches or model systems to study ion transport. Herein, we report octapeptides derived from aminobenzoic acid and l/d amino acids. Two of the alanine containing peptides were found to be most active and the peptide containing p-aminobenzoic acid was found to be most active (2.4 times its m-analog). Experimental studies indicate the peptides do not transport halides and transport alkali metal ions. Graphical abstract image
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New approaches to the synthesis of sildenafil analogues and their enzyme inhibitory activity ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Mariusz Mojzych , Zbigniew Karczmarzyk , Waldemar Wysocki , Mariangela Ceruso , Claudiu T. Supuran , Vladimir Kryštof , Zofia Urbańczyk-Lipkowska , Przemysław Kalicki In the search for new biologically active chemotypes, several sildenafil analogs were prepared and characterized. The presence of the pyrazolo[4,3-e][1,2,4]triazine core is thought to be of interest for the enzyme inhibitory activity of these compounds. The designed derivatives incorporating the sildenafil scaffold were assayed as carbonic anhydrase inhibitors, and for their cytotoxic activity against MCF-7 and K562 cell lines. The X-ray analysis of one of these model compounds was performed and its crystal structure is described/compared to that of sildenafil. Graphical abstract image
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Synthesis of 6-aryl-substituted sulfocoumarins and investigation of their carbonic anhydrase inhibitory action ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Aiga Grandane , Muhammet Tanc , Raivis Žalubovskis , Claudiu T. Supuran A series of 6-aryl-substituted 1,2-benzoxathiine 2,2-dioxides was obtained by reacting 6-iodo-sulfocoumarin with arylboronic acids in Suzuki cross-coupling conditions. The new sulfocoumarins incorporating various substituted phenyl moieties in position 6 of the heterocyclic ring were investigated for the inhibition of four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms with medicinal chemistry applications, the cytosolic hCA I and II, and the transmembrane, tumor-associated hCA IX and XII. The aryl-substituted sulfocoumarins did not inhibit the ubiquitous, off-target cytosolic isoforms hCA I and II (K Is>10μM) but showed effective inhibition against the two transmembrane CAs, with K Is ranging from 9.0 to 95.3nM against hCA IX, and between 3.5 and 14.2nM against hCA XII. As hCA IX and XII are validated anti-tumor targets, such sulfocoumarin, isoform-selective inhibitors may be useful for identifying suitable drug candidates for further clinical trials of this class of pharmacologic agents. Graphical abstract image
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Synthesis and antitumor activity of novel per-butyrylated glycosides of podophyllotoxin and its derivatives ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Cheng-Ting Zi , Dan Yang , Fa-Wu Dong , Gen-Tao Li , Yan Li , Zhong-Tao Ding , Jun Zhou , Zi-Hua Jiang , Jiang-Miao Hu A series of perbutyrylated glycosides of podophyllotoxin and its derivatives were synthesized and evaluated for their antitumor activity in vitro. Most of them exhibit cytotoxic activity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using MTT assays. Among the synthesized compounds, epipodophyllotoxin α-d-galactopyranoside 8b, epipodophyllotoxin α-d-arabinopyranoside 8e, and podophyllotoxin β-d-glucopyranoside 11a show the highest potency of anticancer activity with their IC50 values ranging from 0.14 to 1.69μM. Structure activity relationship analysis indicates that the type of glycosidic linkage, the configuration at C-4 of the podophyllotoxin scaffold, and the substitution at 4′-position (OH vs OCH3) can all have significant effect on the potency of their anticancer activity. Several compounds are more active than the control drugs Etoposide and Cisplatin, suggesting their potential as anticancer agents for further development. Graphical abstract image
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Identification of anti-HIV agents with a novel benzo[4,5]isothiazolo[2,3-a]pyrimidine scaffold ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Shiho Okazaki , Tsukasa Mizuhara , Kazuya Shimura , Hiroto Murayama , Hiroaki Ohno , Shinya Oishi , Masao Matsuoka , Nobutaka Fujii 3,4-Dihydro-2H-benzo[4,5]isothiazolo[2,3-a]pyrimidine is a newly identified antiviral agent against human immunodeficiency virus type 1 (HIV-1) infection, derived from 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182). The introduction of the hydrophobic 8-aryl substituent on the benzene substructure improved its anti-HIV activity, resulting in the identification of 6-fold more potent analogs. In addition, it was demonstrated that these isothiazolopyrimidine derivatives exert anti-HIV effects at an early stage of viral infection. Graphical abstract image
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Pheophorbide-a conjugates with cancer-targeting moieties for targeted photodynamic cancer therapy ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Hyun You , Hyo-Eun Yoon , Pyeong-Hwa Jeong , Hyojin Ko , Jung-Hoon Yoon , Yong-Chul Kim Pheophorbide-a, a non-selective photosensitizer, was conjugated with cancer-targeting moieties, such as folic acid, the CRGDLASLC peptide, the cRGDfK peptide and leuprorelin, for the purpose of targeted photodynamic cancer therapy. The cellular uptake of pheophorbide-a conjugates in cancer cells overexpressing the corresponding receptors of the targeting moieties was largely enhanced compared with that in the receptor-negative cells. In the study of in vitro photodynamic activity and selectivity of pheophorbide-a conjugates in the receptor-positive and receptor-negative cells, a pheophorbide-a conjugate, (14) with an αvβ6 ligand (CRGDLASLC) exhibited the highest selectivity in the positive FaDu cells. Targeted PDT with 14 induced cell death through apoptosis and morphological apoptosis-like characteristics. These results suggest that pheophorbide-a conjugate 14 could be utilized in selective photodynamic therapy for oral cancers primarily expressing the αvβ6 receptor. Graphical abstract image
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Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Zong-Wen Wu , Shu-Yong Song , Li Li , He-Lin Lu , Brian Lieberman , Yun-Sheng Huang , Robert H. Mach A series of tetrahydroindazole derivatives were synthesized and evaluated for their affinities for both sigma-1 and sigma-2 receptors. These compounds are hybrid structures of a tetrahydroindazole substituted benzamide and a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety or a 9-azabicyclo[3.3.1]nonan-3-yl-amine moiety. These newly synthesized hybrid analogs showed various affinities for sigma-2 receptor without any significant affinities for sigma-1 receptor. In particular, compounds 12, 15b, 15c, and 15d, demonstrated moderate affinity and excellent selectivity for sigma-2 receptor. It is interesting to note that 3–5 carbon units between the tetrahydroindazole substituted benzamide and the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety are appropriate for sigma-2 receptor binding. No substitution on the 9-aza nitrogen is proper for sigma-2 affinity in the 2-(9-azabicyclo[3.3.1]nonan-3-yl-amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide analogs. Graphical abstract image
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The short way to chiral compounds with hexahydrofluoreno[9,1-bc]furan framework: Synthesis and cytotoxic activity ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Svetlana Yu. Kurbakova , Irina V. Il‘ina , Oksana S. Mikhalchenko , Mikhail A. Pokrovsky , Dina V. Korchagina , Konstantin P. Volcho , Andrey G. Pokrovsky , Nariman F. Salakhutdinov A simple and efficient method for synthesizing chiral heterocyclic compounds with the hexahydrofluoreno[9,1-bc]furan framework via interaction between trans-4-hydroxymethyl-2-carene and aromatic aldehydes containing methoxy and hydroxyl moieties in the presence of montmorillonite clay was found. One of the synthesized compounds exhibited a high cytotoxic activity against lymphoblastoid cell line MT-4 (CTD50 0.9μM), which was higher than that of the comparative drug Doxorubicin. Death of cancer cells in this case substantially occurs via induction of apoptosis. Graphical abstract image
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Synthesis and biological evaluation of fluconazole analogs with triazole-modified scaffold as potent antifungal agents ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Seyedeh Mahdieh Hashemi , Hamid Badali , Hamid Irannejad , Mohammad Shokrzadeh , Saeed Emami In order to find new azole antifungals, we have recently designed a series of triazole alcohols in which one of the 1,2,4-triazol-1-yl group in fluconazole structure has been replaced with 4-amino-5-aryl-3-mercapto-1,2,4-triazole motif. In this paper, we focused on the structural refinement of the primary lead, by removing the amino group from the structure to achieve 5-aryl-3-mercapto-1,2,4-triazole derivatives 10a–i and 11a–i. The in vitro antifungal susceptibility testing of title compounds demonstrated that most compounds had potent inhibitory activity against Candida species. Among them, 5-(2,4-dichlorophenyl)triazole analogs 10h and 11h with MIC values of <0.01 to 0.5μg/mL were 4–256 times more potent than fluconazole against Candida species. Graphical abstract image
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Identification of Bacillus anthracis PurE inhibitors with antimicrobial activity ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Anna Kim , Nina M. Wolf , Tian Zhu , Michael E. Johnson , Jiangping Deng , James L. Cook , Leslie W.-M. Fung N5-carboxy-amino-imidazole ribonucleotide (N5-CAIR) mutase (PurE), a bacterial enzyme in the de novo purine biosynthetic pathway, has been suggested to be a target for antimicrobial agent development. We have optimized a thermal shift method for high-throughput screening of compounds binding to Bacillus anthracis PurE. We used a low ionic strength buffer condition to accentuate the thermal shift stabilization induced by compound binding to Bacillus anthracis PurE. The compounds identified were then subjected to computational docking to the active site to further select compounds likely to be inhibitors. A UV-based enzymatic activity assay was then used to select inhibitory compounds. Minimum inhibitory concentration (MIC) values were subsequently obtained for the inhibitory compounds against Bacillus anthracis (ΔANR strain), Escherichia coli (BW25113 strain, wild-type and ΔTolC), Francisella tularensis, Staphylococcus aureus (both methicillin susceptible and methicillin-resistant strains) and Yersinia pestis. Several compounds exhibited excellent (0.05–0.15μg/mL) MIC values against Bacillus anthracis. A common core structure was identified for the compounds exhibiting low MIC values. The difference in concentrations for inhibition and MIC suggest that another enzyme(s) is also targeted by the compounds that we identified. Graphical abstract image
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18F-AmBF3-MJ9: A novel radiofluorinated bombesin derivative for prostate cancer imaging ()
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. Graphical abstract image
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Novel curcumin analogs to overcome EGFR–TKI lung adenocarcinoma drug resistance and reduce EGFR–TKI-induced GI adverse effects ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Koji Wada , Jen-Yi Lee , Hsin-Yi Hung , Qian Shi , Li Lin , Yu Zhao , Masuo Goto , Pan-Chyr Yang , Sheng-Chu Kuo , Hui-Wen Chen , Kuo-Hsiung Lee Curcumin (1) down-regulates the expression as well as phosphorylation of epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells expressing gefitinib-resistant EGFR. Thirty-seven newly synthesized curcumin analogues including dimethoxycurcumin (2, DMC) were evaluated for their effects on EGFR expression as well as phosphorylation in two gefitinib-resistant lung adenocarcinoma cell lines, CL1-5 (EGFRwt) and H1975 (EGFRL858R+T790M). Based on the identified structure–activity relationships, methoxy substitution at C-3′, C-4′, or both positions favored inhibitory activity (compounds 1, 2, 5, 8–15, 17, 36), while compounds with more polar substituents were generally less active in both cell lines. Compound 36 with a fluorine substituent at C-6′ and its protonated counterpart 2 did not lose activity, suggesting halogen tolerance. In addition, a conjugated linker was essential for activity. Among all evaluated curcumin derivatives, compound 2 showed the best inhibitory effects on both wild-type and mutant EGFR by efficiently inducing gefitinib-insensitive EGFR degradation. Compound 23 also reduced gefitinib-induced gastrointestinal damage in the non-transformed intestinal epithelial cell line IEC-18. Graphical abstract image
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Structure activity studies of nociceptin/orphanin FQ(1–13)-NH2 derivatives modified in position 5 ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Remo Guerrini , Erika Marzola , Claudio Trapella , Salvatore Pacifico , Maria Camilla Cerlesi , Davide Malfacini , Federica Ferrari , Mark Francis Bird , David George Lambert , Severo Salvadori , Girolamo Calo Nociceptin/orphanin FQ (N/OFQ) is a heptadecapeptide acting as the endogenous ligand of the N/OFQ peptide receptor (NOP). N/OFQ(1–13)-NH2 is the shortest N/OFQ sequence maintaining the same potency and efficacy as the natural peptide. Thus N/OFQ(1–13)-NH2 was used as chemical template for investigating the structure activity relationship of threonine in position 5. 28 [X5]N/OFQ(1–13)-NH2 derivatives, in which Thr was substituted with natural and unnatural residues, were synthesized and characterized pharmacologically for their effects at the human NOP receptor. Two different functional assays were used: agonist stimulated [35S]GTPγS binding in cell membranes and calcium mobilization in whole cells co-expressing chimeric G proteins. All [X5]N/OFQ(1–13)-NH2 derivatives behaved as full NOP agonists showing large differences in their potency. There was an excellent correlation between the results obtained in the two assays. The results of this study suggest that: position 5 does not play a pivotal role in receptor activation; the secondary alcoholic function of Thr is not important for receptor binding; side chain size, lipo/hydrophilic balance as well as hydrogen bond capability are also not crucial for receptor binding; an aliphatic amino function positively charged with at least 3 carbon atom distance from the peptide backbone has a huge disrupting effect on receptor binding. In conclusion this study demonstrates that a simple ethyl side chain as in compound 23 is sufficient in N/OFQ position 5 for maintaining bioactivity. Graphical abstract image
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Anti-trypanosomal cadinanes synthesized by transannular cyclization of the natural sesquiterpene lactone nobilin ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Maria De Mieri , Marcel Kaiser , Reto Brun , Ursula Thormann , Georgios Imanidis , Matthias Hamburger Acid-catalyzed transannular cyclization of the germacrene-type sesquiterpene lactone nobilin 1 was investigated with the aim of obtaining new anti-trypanosomal cadinane derivatives. The reaction was regiospecific in all tested reaction conditions. Compounds were fully characterized by spectroscopic and computational methods, and the anti-trypanosomal activity was evaluated and compared to nobilin (IC50 3.19±1.69μM). The tricyclic derivative 11 showed most potent in vitro activity against Trypanosoma brucei rhodesiense bloodstream forms (IC50 0.46±0.01μM). Acid-catalyzed transannular cyclization of natural cyclodecadienes is an efficient strategy to generate new natural product derivatives with anti-protozoal activity. Graphical abstract image
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N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: Design, synthesis and antiplasmodial activity ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Marta Figueiras , Lis Coelho , Kathryn J. Wicht , Sofia A. Santos , João Lavrado , Jiri Gut , Philip J. Rosenthal , Fátima Nogueira , Timothy J. Egan , Rui Moreira , Alexandra Paulo We recently reported that potent N10,O11-bis-alkylamine indolo[3,2-b]quinoline antimalarials act as hemozoin (Hz) growth inhibitors. To improve access and binding to the target we have now designed novel N10,N11-di-alkylamine bioisosteres. 3-Chloro derivatives (10a–f) showed selectivity for malaria parasite compared to human cells, high activity against Plasmodium falciparum chloroquine (CQ)-resistant strain W2 (IC50s between 20 and 158nM), good correlation with β-hematin inhibition and improved vacuolar accumulation ratios, thus suggesting inhibition of Hz growth as one possible mechanism of action for these compounds. Moreover, our studies show that Hz is a valid target for the development of new antimalarials able to overcome CQ resistance. Graphical abstract image
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Molecular features and toxicological properties of four common pesticides, acetamiprid, deltamethrin, chlorpyriphos and fipronil ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Emiliane Taillebois , Zakaria Alamiddine , Christine Brazier , Jérôme Graton , Adèle D. Laurent , Steeve H. Thany , Jean-Yves Le Questel Structural features and selected physicochemical properties of four common pesticides: acetamiprid (neonicotinoid), chlorpyriphos (organophosphate insecticide), deltamethrin (pyrethroid) and fipronil (phenylpyrazole) have been investigated by Density Functional Theory quantum chemical calculations. The high flexible character of these insecticides is revealed by the numerous conformers obtained, located within a 20kJmol−1 range in the gas phase. In line with this trend, a redistribution of the energetic minima is observed in water medium. Molecular electrostatic potential calculations provide a ranking of the potential interaction sites of the four insecticides. The theoretical studies reported in the present work are completed by comparative toxicological assays against three aphid strains. Thus, the same toxicity order for the two susceptible strains Myzus persicae 4106A and Acyrthosiphon pisum LSR1: acetamiprid>fipronil>deltamethrin>chlorpyriphos is revealed. In the resistant strain M. persicae 1300145, the toxicity order is modified: acetamiprid>fipronil>chlorpyriphos>deltamethrin. Interestingly, the strain 1300145 which is known to be resistant to neonicotinoids, is also less sensitive to deltamethrin, chlorpyriphos and fipronil. Graphical abstract image
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2-Benzisothiazolylimino-5-benzylidene-4-thiazolidinones as protective agents against cartilage destruction ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Lucia Crascì , Paola Vicini , Matteo Incerti , Venera Cardile , Sergio Avondo , Annamaria Panico We report the synthesis, the antioxidant and the inhibitory activity (IC50) on metalloproteinases (MMPs) 3 and 13 of 2-benzo[d]isothiazolylimino-5-benzylidene-4-thiazolidinones. Their potential as protective agents in osteoarthritis (OA) was evaluated by biological assays on chondrocytes cultures, stimulated by IL-1β. The chondroprotective capability, related both to antioxidant activity and to inhibition of MMPs, was studied in vitro, by determining nitric oxide production and glycosaminoglycans release. Moreover, selected derivatives 1h and 1g was studied for nuclear factor kappaB (NF-κB) inhibition by Western Blot analysis and for MMP-3 protein release using ELISA test. The structure–activity relationship of tested compounds demonstrates a favorable effect of the para substitution on the 5-benzilydene ring. Compound 1g shows a potent and selective activity on MMP-3 versus MMP-13. Accordingly, 1g possesses high antioxidant effect, NO lowering and GAGs restoring capability and also reduces the production of MMPs and NF-κB expression. Thus 1g can be considered as new potential chondroprotective agents. Graphical abstract image
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Synthesis, structural analysis and antitumor activity of novel 17α-picolyl and 17(E)-picolinylidene A-modified androstane derivatives ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Jovana J. Ajduković , Katarina M. Penov Gaši , Dimitar S. Jakimov , Olivera R. Klisurić , Suzana S. Jovanović-Šanta , Marija N. Sakač , Lidija D. Aleksić , Evgenija A. Djurendić The heterocyclic ring at C-17 position of the androstane compounds plays an important role in biological activity. The aim of the present study was to synthesize and evaluate potential antitumor activity of different A-modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives. In several synthetic steps, novel derivatives bearing the hydroximino, nitrile or lactame functions in A-ring were synthesized and characterized according to the spectral data, by mass analysis as well as XRD analysis (compounds 6, 13 and 15). The structurally most promising compounds 6, 11–17 were investigated as antitumor agents. The in vitro antiproliferative activity was evaluated against six human cancer cell lines: estrogen receptor negative (ER−) breast adenocarcinoma (MDA-MB-231); estrogen receptor positive (ER+) breast adenocarcinoma (MCF-7); prostate cancer (PC-3); human cervical carcinoma (HeLa); lung adenocarcinoma (A549) and colon adenocarcinoma (HT-29) using MTT assay. The results of the 48h incubation time in vitro tests showed that compound 15 was the most effective against PC-3 (IC50 6.6μM), compound 17 against MCF-7 (IC50 7.9μM) cells, while compound 16 exhibited strong antiproliferative effect against both, MCF-7 (IC50 1.7μM) and PC-3 (IC50 8.7μM) cancer cells. It was also found that compounds 16 and 17 induced apoptosis in MCF-7 cells (dicyano derivative 17 stronger then dioxime 16 and reference formestane), with no distinct changes in the cell cycle of MCF-7 cells. Graphical abstract image
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Discovery of anthranilamides as a novel class of inhibitors of neurotropic alphavirus replication ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Scott J. Barraza , Philip C. Delekta , Janice A. Sindac , Craig J. Dobry , Jianming Xiang , Richard F. Keep , David J. Miller , Scott D. Larsen Neurotropic alphaviruses are debilitating pathogens that infect the central nervous system (CNS) and are transmitted to humans via mosquitoes. There exist no effective human vaccines against these viruses, underlining the need for effective antivirals, but no antiviral drugs are available for treating infection once the viruses have invaded the CNS. Previously, we reported the development of novel indole-2-carboxamide-based inhibitors of alphavirus replication that demonstrate significant reduction of viral titer and achieve measurable brain permeation in a pharmacokinetic mouse model. Herein we report our continued efforts to improve physicochemical properties predictive of in vivo blood–brain barrier (BBB) permeability through reduction of overall molecular weight, replacing the indole core with a variety of aromatic and non-aromatic monocyclics. These studies culminated in the identification of simple anthranilamides that retain excellent potency with improved metabolic stability and significantly greater aqueous solubility. Furthermore, in a live virus study, we showed that two new compounds were capable of reducing viral titer by two orders of magnitude and that these compounds likely exert their effects through a mechanism similar to that of our indole-2-carboxamide inhibitors. Graphical abstract image
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Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Rajeev Sakhuja , Krishnakanth Kondabolu , Tania Córdova-Sintjago , Sean Travers , Adam S. Vincek , Myong Sang Kim , Khalil A. Abboud , Lijuan Fang , Zhuming Sun , Clinton E. Canal , Raymond G. Booth Syntheses were undertaken of derivatives of (2S,4R)-(−)-trans-4-phenyl-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (4-phenyl-2-dimethylaminotetralin, PAT), a stereospecific agonist at the serotonin 5-HT2C G protein-coupled receptor (GPCR), with inverse agonist activity at 5-HT2A and 5-HT2B GPCRs. Molecular changes were made at the PAT C(4)-position, while preserving N,N-dimethyl substitution at the 2-position as well as trans-stereochemistry, structural features previously shown to be optimal for 5-HT2 binding. Affinities of analogs were determined at recombinant human 5-HT2 GPCRs in comparison to the phylogenetically closely-related histamine H1 GPCR, and in silico ligand docking studies were conducted at receptor molecular models to help interpret pharmacological results and guide future ligand design. In most cases, C(4)-substituted PAT analogs exhibited the same stereoselectivity ([−]-trans >[+]-trans) as the parent PAT across 5-HT2 and H1 GPCRs, albeit, with variable receptor selectivity. 4-(4′-substituted)-PAT analogs, however, demonstrated reversed stereoselectivity ([2S,4R]-[+]-trans >[2S,4R]-[−]-trans), with absolute configuration confirmed by single X-ray crystallographic data for the 4-(4′-Cl)-PAT analog. Pharmacological affinity results and computational results herein support further PAT drug development studies and provide a basis for predicting and interpreting translational results, including, for (+)-trans-4-(4′-Cl)-PAT and (−)-trans-4-(3′-Br)-PAT that were previously shown to be more potent and efficacious than their corresponding enantiomers in rodent models of psychoses, psychostimulant-induced behaviors, and compulsive feeding (‘binge-eating’). Graphical abstract image
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Structure–activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Shannon L. Nowotarski , Boobalan Pachaiyappan , Steven L. Holshouser , Craig J. Kutz , Youxuan Li , Yi Huang , Shiv K. Sharma , Robert A. Casero Jr. , Patrick M. Woster Methylation at specific histone lysine residues is a critical post-translational modification that alters chromatin architecture, and dysregulated lysine methylation/demethylation is associated with the silencing of tumor suppressor genes. The enzyme lysine-specific demethylase 1 (LSD1) complexed to specific transcription factors catalyzes the oxidative demethylation of mono- and dimethyllysine 4 of histone H3 (H3K4me and H3K4me2, respectively). We have previously reported potent (bis)urea and (bis)thiourea LSD1 inhibitors that increase cellular levels of H3K4me and H3K4me2, promote the re-expression of silenced tumor suppressor genes and suppress tumor growth in vitro. Here we report the design additional (bis)urea and (bis)thiourea LSD1 inhibitors that feature 3-5-3 or 3-6-3 carbon backbone architectures. Three of these compounds displayed single-digit IC50 values in a recombinant LSD1 assay. In addition, compound 6d exhibited an IC50 of 4.2μM against the Calu-6 human lung adenocarcinoma line, and 4.8μM against the MCF7 breast tumor cell line, in an MTS cell viability assay. Following treatment with 6b–6d, Calu-6 cells exhibited a significant increase in the mRNA expression for the silenced tumor suppressor genes SFRP2, HCAD and p16, and modest increases in GATA4 message. The compounds described in this paper represent the most potent epigenetic modulators in this series, and have potential for use as antitumor agents. Graphical abstract image
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Stereoselective synthesis, biological evaluation, and modeling of novel bile acid-derived G-protein coupled Bile acid receptor 1 (GP-BAR1, TGR5) agonists ()
Publication date: 1 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7 Author(s): Donna D. Yu , Kyle M. Sousa , Daniell L. Mattern , Jeffrey Wagner , Xianghui Fu , Nagarajan Vaidehi , Barry M. Forman , Wendong Huang GP-BAR1 (also known as TGR5), a novel G-protein coupled receptor regulating various non-genomic functions via bile acid signaling, has emerged as a promising target for metabolic disorders, including obesity and type II diabetes. However, given that many bile acids (BAs) are poorly tolerated for systemic therapeutic use, there is significant need to develop GP-BAR1 agonists with improved potency and specificity and there also is significant impetus to develop a stereoselective synthetic methodology for GP-BAR1 agonists. Here, we report the development of highly stereo-controlled strategies to investigate a series of naturally occurring bile acid derivatives with markedly enhanced GP-BAR1 activity. These novel GP-BAR1 agonists are evaluated in vitro using luciferase-based reporter and cAMP assays to elucidate their biological properties. In vivo studies revealed that the GP-BAR1 agonist 23(S)-m-LCA increased intestinal GLP-1 transcripts by 26-fold. Additionally, computational modeling studies of selected ligands that exhibit enhanced potency and specificity for GP-BAR1 provide information on potential binding sites for these ligands in GP-BAR1. Graphical abstract image
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