Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23
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Organic synthesis in flow for medicinal chemistry ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Thomas Wirth
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The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Péter Bana, Róbert Örkényi, Klára Lövei, Ágnes Lakó, György István Túrós, János Éles, Ferenc Faigl, István Greiner Recent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps. In this review, we summarize innovative solutions for these challenges, in order to benefit chemists aiming to exploit flow chemistry systems for the synthesis of biologically active molecules. Graphical abstract image
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Improving the throughput of batch photochemical reactions using flow: Dual photoredox and nickel catalysis in flow for C(sp2)C(sp3) cross-coupling ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Irini Abdiaj, Jesús Alcázar We report herein the transfer of dual photoredox and nickel catalysis for C(sp 2) C(sp 3) cross coupling form batch to flow. This new procedure clearly improves the scalability of the previous batch reaction by the reactor’s size and operating time reduction, and allows the preparation of interesting compounds for drug discovery in multigram amounts. Graphical abstract image
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A photochemical flow reactor for large scale syntheses of aglain and rocaglate natural product analogues ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Han Yueh, Qiwen Gao, John A. Porco, Aaron B. Beeler Herein, we report the development of continuous flow photoreactors for large scale ESIPT-mediated [3+2]-photocycloaddition of 2-(p-methoxyphenyl)-3-hydroxyflavone and cinnamate-derived dipolarophiles. These reactors can be efficiently numbered up to increase throughput two orders of magnitude greater than the corresponding batch reactions. Graphical abstract image
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High throughput photo-oxidations in a packed bed reactor system ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Caleb J. Kong, Daniel Fisher, Bimbisar K. Desai, Yuan Yang, Saeed Ahmad, Katherine Belecki, B. Frank Gupton The efficiency gains produced by continuous-flow systems in conducting photochemical transformations have been extensively demonstrated. Recently, these systems have been used in developing safe and efficient methods for photo-oxidations using singlet oxygen generated by photosensitizers. Much of the previous work has focused on the use of homogeneous photocatalysts. The development of a unique, packed-bed photoreactor system using immobilized rose bengal expands these capabilities as this robust photocatalyst allows access to and elaboration from these highly useful building blocks without the need for further purification. With this platform we were able to demonstrate a wide scope of singlet oxygen ene, [4+2] cycloadditions and heteroatom oxidations. Furthermore, we applied this method as a strategic element in the synthesis of the high-volume antimalarial artemisinin. Graphical abstract image
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Reagent-free continuous thermal tert-butyl ester deprotection ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Kevin P. Cole, Sarah J. Ryan, Jennifer McClary Groh, Richard D. Miller Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemist’s toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120–240°C and 15–40min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation. The method was then expanded to encompass a variety of more challenging substrates to test selectivity and racemization potential. The acid products were generally isolated as crystalline solids by simple solvent exchange after the deprotection reaction in good to high yield and purity. Graphical abstract image
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A continuous flow synthesis and derivatization of 1,2,4-thiadiazoles ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Marcus Baumann, Ian R. Baxendale A continuous flow process is presented that enables the efficient synthesis and derivatization of 1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile yet hazardous trichloromethane sulfenylchloride reagent including its in-line quenching in order to eliminate malodourous and corrosive by-products. Based on this flow method gram quantities of 5-chloro-3-phenyl-1,2,4-thiadiazole were safely prepared allowing for further elaboration of this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based nucleophiles. This synthetic approach was subsequently applied to generate a series of bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural diversification on this important heterocyclic scaffold. Graphical abstract image
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Generation of hazardous methyl azide and its application to synthesis of a key-intermediate of picarbutrazox, a new potent pesticide in flow ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Daisuke Ichinari, Aiichiro Nagaki, Jun-ichi Yoshida Generation and reactions of methyl azide (MeN3) were successfully performed by using a flow reactor system, demonstrating that the flow method serves as a safe method for handling hazardous explosive methyl azide. The reaction of NaN3 and Me2SO4 in a flow reactor gave a MeN3 solution, which was used for Huisgen reaction with benzoyl cyanide in a flow reactor after minimal washing. The resulting 1-methyl-5-benzoyltetrazole serves as a key intermediate of picarbutrazox (IX), a new potent pesticide. Graphical abstract image
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Continuous-flow synthesis using a column reactor packed with heterogeneous catalysts: A convenient production of nitroolefins by using amino-functionalized silicagel ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Haruro Ishitani, Yuichi Furiya, Shū Kobayashi A continuous-flow synthesis of β-nitroolefins by using heterogeneous base catalysts has been developed. Although the use of an excess amount of nitro-donor such as nitromethane is required in conventional methods, nearly equimolar amounts of nitro-donors and carbonyl compounds are sufficient for high-yielding production of nitroolefins. Catalysts for this flow protocol are inexpensive and abundant, and high durability and high productivity were also realized by using an appropriate second support. Graphical abstract image
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Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Anne-Catherine Bédard, Ashley R. Longstreet, Joshua Britton, Yuran Wang, Hideki Moriguchi, Robert W. Hicklin, William H. Green, Timothy F. Jamison Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9. Graphical abstract image
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A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Davide Brenna, Margherita Pirola, Laura Raimondi, Anthony J. Burke, Maurizio Benaglia The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds. Graphical abstract image
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An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors ()
Publication date: 1 December 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 23 Author(s): Nicholas Pagano, Peter Teriete, Margrith E. Mattmann, Li Yang, Beth A. Snyder, Zhaohui Cai, Marintha L. Heil, Nicholas D.P. Cosford Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP). Mechanism of action (MOA) studies using cellular and biochemical assays coupled with 3D fingerprinting and in silico modeling demonstrated that these drug-like probe compounds exert their effects by inhibiting the viral reverse transcriptase polymerase (RT). This led to the design and synthesis of the novel DHPM 1at that inhibits the replication of drug resistant strains of HIV. Our work demonstrates that combining flow chemistry-driven analogue refinement with phenotypic assays, in silico modeling and MOA studies is a highly effective strategy for hit-to-lead optimization applicable to the discovery of future therapeutic agents. Graphical abstract image
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Podophyllotoxin derivatives as an excellent anticancer aspirant for future chemotherapy: A key current imminent needs ()
Publication date: Available online 16 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Xu Zhang, K.P. Rakesh, C.S. Shantharam, H.M. Manukumar, A.M. Asiri, H.M. Marwani, Hua-Li Qin Cancer is one of the leading groups of threatened caused by abnormal state cell growth and second leading diseases involved in the major global death. To treat this, research looking for promising anticancer drugs from natural resource, or synthesized novel molecules by diverse group of scientists worldwide. Currently, drugs get into clinical practices and showing side effects with target actions which in turn leading to multidrug resistance unknowingly. Podophyllotoxin, a naturally occurring lignan and its hybrids have become one of the most attractive subjects due to their broad spectrum of pharmacological activities. Podophyllotoxin derivatives have been the centre of attention of extensive chemical amendment and pharmacological investigation in modern decades. Mainly, the innovation of the semi-synthetic anticancer drugs etoposide and teniposide has stimulated prolonged research interest in this structural phenotype. The present review focuses mainly onnew anticancer drugs from podophyllotoxin analogs, mechanism of action and their structure-activity relationships (SAR) as potential anticancer candidates for future discovery of suitable drug candidates. Graphical abstract image
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Editorial board ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
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Bioactive natural products ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22 Author(s): Mathias Christmann
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Natural products and morphogenic activity of γ-Proteobacteria associated with the marine hydroid polyp Hydractinia echinata ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22 Author(s): Huijuan Guo, Maja Rischer, Martin Sperfeld, Christiane Weigel, Klaus Dieter Menzel, Jon Clardy, Christine Beemelmanns Illumina 16S rRNA gene sequencing was used to profile the associated bacterial community of the marine hydroid Hydractinia echinata, a long-standing model system in developmental biology. 56 associated bacteria were isolated and evaluated for their antimicrobial activity. Three strains were selected for further in-depth chemical analysis leading to the identification of 17 natural products. Several γ-Proteobacteria were found to induce settlement of the motile larvae, but only six isolates induced the metamorphosis to the primary polyp stage within 24h. Our study paves the way to better understand how bacterial partners contribute to protection, homeostasis and propagation of the hydroid polyp. Graphical abstract image
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Synthesis of novel C-9 carbon substituted derivatives of artemisinin ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22 Author(s): Daniel Meyer, Toni Smeilus, Dimanthi Pliatsika, Farnoush Mousavizadeh, Athanassios Giannis Several artemisinin derivatives carrying several groups (alkyl, hydroxyalkyl, allyl or azide) at position 9 have been synthesized starting from artemisinin via enolate formation and subsequent reaction with appropriate electrophiles. Graphical abstract image
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Biological evaluation of pyridone alkaloids on the endocannabinoid system ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22 Author(s): Andrea Chicca, Regina Berg, Henning J. Jessen, Nicolas Marck, Fabian Schmid, Patrick Burch, Jürg Gertsch, Karl Gademann Naturally occurring pyridone alkaloids as well as synthetic derivatives were previously shown to induce neurite outgrowth. However, the molecular basis for this biological effect remains poorly understood. In this work, we have prepared new pyridones, and tested the effect of thirteen 4-hydroxy-2-pyridone derivatives on the components of the endocannabinoid system. Investigation of binding affinities towards CB1 and CB2 receptors led to the identification of a compound binding selectively to CB1 (12). Compound 12 and a closely related derivative (11) also inhibited anandamide (AEA) hydrolysis by fatty acid amide hydrolase. Interestingly, none of the compounds tested showed any effect on 2-AG hydrolysis by monoacylglycerol lipase at 10μM. Assessment of AEA uptake did, however, lead to the identification of four inhibitors with IC50 values in the submicromolar range and high selectivity over the other components of the endocannabinoid system. Graphical abstract image
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Synthesis and cytotoxic activities of goniothalamins and derivatives ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22 Author(s): Anja Weber, Katja Döhl, Julia Sachs, Anja C.M. Nordschild, Dennis Schröder, Andrea Kulik, Thomas Fischer, Lutz Schmitt, Nicole Teusch, Jörg Pietruszka Substituted goniothalamins containing cyclopropane-groups were efficiently prepared in high yields and good selectivity. Antiproliferative activity was measured on three human cancer cell lines (A549, MCF-7, HBL-100), to show which of the structural elements of goniothalamins is mandatory for cytotoxicity. We found that the configuration of the stereogenic centre of the δ-lactone plays an important role for cytotoxicity. In our studies only (R)-configured goniothalamins showed antiproliferative activity, whereby (R)-configuration accords to natural goniothalamin (R)-1. Additionally, the δ-lactone needs to be unsaturated whereas our results show that the vinylic double bond is not mandatory for cytotoxicity. Furthermore, with a two-fold in vitro and in vivo strategy, we determined the inhibitory effect of the compounds to the yeast protein Pdr5. Here, we clearly demonstrate that the configuration seems to be of minor influence, only, while the nature of the substituent of the phenyl ring is of prime importance. Graphical abstract image
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Simplifying nature: Towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22 Author(s): Eoin R. Gould, Elizabeth F.B. King, Stefanie K. Menzies, Andrew L. Fraser, Lindsay B. Tulloch, Marija K. Zacharova, Terry K. Smith, Gordon J. Florence The need for new treatments for the neglected tropical diseases African sleeping sickness, Chagas disease and Leishmaniasis remains urgent with the diseases widespread in tropical regions, affecting the world’s very poorest. We have previously reported bis-tetrahydropyran 1,4-triazole analogues designed as mimics of the annonaceous acetogenin natural product chamuvarinin, which maintained trypanocidal activity. Building upon these studies, we here report related triazole compounds with pendant heterocycles, mimicking the original butenolide of the natural product. Analogues were active against T. brucei, with a nitrofuran compound displaying nanomolar trypanocidal activity. Several analogues also showed strong activity against T. cruzi and L. major. Importantly, select compounds gave excellent selectivity over mammalian cells with a furan-based analogue highly selective while remaining active against all three cell lines, thus representing a potential lead for a new broad spectrum kinetoplastid inhibitor. Graphical abstract image
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Synthesis and biological evaluation of a D-ring-contracted analogue of lamellarin D ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22 Author(s): Vanessa Colligs, Steven Peter Hansen, Dennis Imbri, Ean-Jeong Seo, Onat Kadioglu, Thomas Efferth, Till Opatz A D-ring contracted analogue of the strongly cytotoxic marine pyrrole alkaloid lamellarin D was synthesized and investigated for its antiproliferative action towards a wild type and a multidrug resistant (MDR) cancer cell line. The compound was found to inhibit tumor cell growth at submicromolar concentrations and showed a lower relative resistance in the MDR cell line than the antitumor drug camptothecin to which lamellarin D shows cross resistance and with which lamellarin D shares the same binding site. Graphical abstract image
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Recent developments in the isolation, biological function, biosynthesis, and synthesis of phenazine natural products ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22 Author(s): Nikolaus Guttenberger, Wulf Blankenfeldt, Rolf Breinbauer Phenazines are natural products which are produced by bacteria or by archaeal Methanosarcina species. The tricyclic ring system enables redox processes, which producing organisms use for oxidation of NADH or for the generation of reactive oxygen species (ROS), giving them advantages over other microorganisms. In this review we summarize the progress in the field since 2005 regarding the isolation of new phenazine natural products, new insights in their biological function, and particularly the now almost completely understood biosynthesis. The review is complemented by a description of new synthetic methods and total syntheses of phenazines. Graphical abstract image
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Anti-tuberculosis activity and structure–activity relationships of oxygenated tricyclic carbazole alkaloids and synthetic derivatives ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22 Author(s): Carsten Börger, Christian Brütting, Konstanze K. Julich-Gruner, Ronny Hesse, V. Pavan Kumar, Sebastian K. Kutz, Marika Rönnefahrt, Claudia Thomas, Baojie Wan, Scott G. Franzblau, Hans-Joachim Knölker A series of 49 oxygenated tricyclic carbazole derivatives has been tested for inhibition of the growth of Mycobacterium tuberculosis and a mammalian cell line (vero cells). From this series, twelve carbazoles showed a significant anti-TB activity. The four most active compounds were the naturally occurring carbazole alkaloids clauszoline-M (45), murrayaline-C (41), carbalexin-C (27), and the synthetic carbazole derivative 22 with MIC90 values ranging from 1.5 to 3.7μM. The active compounds were virtually nontoxic for the mammalian cell line in the concentration range up to 50μM. Graphical abstract image
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A conceptually novel construction of the 6a-hydroxypterocarpan skeleton – Synthesis of (±)-variabilin ()
Publication date: 15 November 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22 Author(s): Philipp Ciesielski, Peter Metz A new access to the 6a-hydroxypterocarpan variabilin was established. Key step of this concise total synthesis is a challenging cyclization of a haloketone via halogen–metal exchange and subsequent intramolecular addition to the carbonyl function. Graphical abstract image
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Mitochondria-targeted cationic porphyrin-triphenylamine hybrids for enhanced two-photon photodynamic therapy ()
Publication date: Available online 15 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Fabien Hammerer, Florent Poyer, Laura Fourmois, Su Chen, Guillaume Garcia, Marie-Paule Teulade-Fichou, Philippe Maillard, Florence Mahuteau-Betzer The proof of concept for two-photon activated photodynamic therapy has already been achieved for cancer treatment but the efficiency of this approach still heavily relies on the availability of photosensitizers combining high two-photon absorption and biocompatibility. In this line we recently reported on a series of porphyrin-triphenylamine hybrids which exhibit high singlet oxygen production quantum yield as well as high two-photon absorption cross-sections but with a very poor cellular internalization. We present herein new photosensitizers of the same porphyrin-triphenylamine hybrid series but bearing cationic charges which led to strongly enhanced water solubility and thus cellular penetration. In addition the new compounds have been found localized in mitochondria that are preferential target organelles for photodynamic therapy. Altogether the strongly improved properties of the new series combined with their specific mitochondrial localization lead to a significantly enhanced two-photon activated photodynamic therapy efficiency. Graphical abstract image
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Discovery of novel purine nucleoside derivatives as phosphodiesterase 2 (PDE2) inhibitors: structure-based virtual screening, optimization and biological evaluation ()
Publication date: Available online 14 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Xiaoxia Qiu, Yiyou Huang, Deyan Wu, Fei Mao, Jin Zhu, Wenzhong Yan, Hai-Bin Luo, Jian Li Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC50 = 3.12 ± 0.67 μM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC50 = 0.32 ± 0.04 μM). Further molecular docking and molecular dynamic (MD) simulations studies revealed that 5’-benzyl group of 14e could interact with the unique hydrophobic pocket of PDE2 by forming extra van der Waals interactions with hydrophobic residues such as Leu770, Thr768, Thr805 and Leu809, which might contribute to its enhancement of PDE2 inhibition. These potential compounds reported in this article and the valuable structure-activity relationships (SARs) might bring significant instruction for further development of potent PDE2 inhibitors. Graphical abstract image
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Bioluminescence Probe for γ-Glutamyl Transpeptidase Detection in vivo ()
Publication date: Available online 14 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Yuxing Lin, Yuqi Gao, Zhao Ma, Tianyu Jiang, Xin Zhou, Zhenzhen Li, Xiaojun Qin, Yun Huang, Lupei Du, Minyong Li To detect γ-Glutamyl Transpeptidase (GGT) activity in vitro and in vivo, a bioluminescence probe with high sensitivity and specificity was well designed and synthesized. This probe can be recognized by GGT and release strong bioluminescence with its further reaction with luciferase. The performance of this probe was demonstrated in vitro and in cells. Finally, we applied the probe for detection of GGT activity in xenograft model. Graphical abstract image
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Design and synthesis of highly selective pyruvate dehydrogenase complex E1 inhibitors as bactericides ()
Publication date: Available online 13 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Yuan Zhou, Shasha Zhang, Hongwu He, Wen Jiang, Leifeng Hou, Dan Xie, Meng Cai, Hao Peng, Lingling Feng In order to obtain PDHc-E1 inhibitors with high selectivity and efficacy, four series (7, 12, 15, and 19) of 35 novel 4-aminopyrimidine derivatives were rationally designed and synthesized based on the binding site of ThDP in E. coli PDHc-E1. 12, 15, and 19 were confirmed to be potent inhibitors against E. coli PDHc-E1. Selected compounds 12g, 12i, 15f, and 19a showed negligible inhibition against porcine PDHc-E1. To understand their selectivity, the interaction of inhibitor and E. coli PDHc-E1 or porcine PDHc-E1 was studied by molecular docking. The newly introduced acylhydrazone and N-phenylbenzamide moieties could form stronger interaction by hydrogen bond at the active site of E. coli PDHc-E1 compared with that of porcine PDHc-E1. A part of title compounds as potent PDHc-E1 inhibitors also exhibited notable antibacterial activity. In particular, 12e, 12f, 12g, 12o, and 19a exhibited 72-92% inhibition against Xanthomonas oryzae pv. Oryzae and Ralstonia solanacearum at 100 μg/mL, which was better than thiodiazole-copper (34 and 29%, respectively) and bismerthiazol (56 and 55%, respectively). The results proved that we could obtain effective bactericidal compounds as highly selective PDHc inhibitors by rational molecular design utilizing the binding model of active site of E. coli PDHc-E1. Graphical abstract image
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N-Arylsulfonylsubstituted-1H indole derivatives as small molecule dual inhibitors of signal transducer and activator of transcription 3 (STAT3) and tubulin ()
Publication date: Available online 13 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Qiang Zhou, Jinjin Zhu, Jinglei Chen, Peng Ji, Chunhua Qiao Signal transducer and activator of transcription (STAT3) is a proposed therapeutictarget for the development of anti-cancer agents. In this report, a series of N-arylsulfonylsubstituted-1H indole derivatives were designed and synthesized as STAT3 inhibitors, their anti-proliferative activities were evaluated against a number of tumor cells, some potent compounds exhibited IC50 values less than 10 μM. The most potent compound 4a was further confirmed to inhibit STAT3 phosphorylation at Tyr705. It was further revealed that 4a arrested the cell cycle at the G2/M phase and inhibited tubulin polymerization. This study describes a series of N-arylsulfonylsubstituted-1H indole derivatives as potent anti-cancer agents targeting both STAT3 and tubulin. Graphical abstract image
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TLR8 activation and inhibition by guanosine analogs in RNA: importance of functional groups and chain length ()
Publication date: Available online 11 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Tiannan Hu, Scott R. Suter, Madeline M. Mumbleau, Peter A. Beal Toll-like receptor 8 (TLR8) is an important component of the human innate immune system that recognizes single stranded RNA (ssRNA). Recent x-ray crystal structures of TLR8 bound to ssRNA revealed a previously unrecognized binding site for a 5’-UpG-3’ dinucleotide. Here we use an atomic mutagenesis strategy coupled with a cellular TLR8 activation assay to probe the importance of specific functional groups present on the guanine base in RNA-mediated receptor agonism and antagonism. Results from RNA analogs containing 7-deazaguanosine, 2-aminopurine and inosine confirm the importance of guanine N7, O6 and N2, respectively, in TLR8 activation. Nevertheless, these RNAs each retained TLR8 antagonism activity. RNA containing 7-deaza-8-azainosine (7d8aI) was prepared from a novel phosphoramidite and found to be a weaker TLR8 activator than guanosine-containing RNA. However, 7d8aI-containing RNA also retained TLR8 antagonism activity indicating that removal of multiple TLR8 H-bonding sites on guanine is insufficient for blocking TLR8 antagonism by guanine-containing RNA. We also identified an oligoribonucleotide length dependence on both TLR8 activation and antagonism. These studies extend our understanding of the effects of nucleobase modification on immune stimulation and will inform the design of novel RNA-based therapeutics. Graphical abstract image
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A Novel Series of Enoyl Reductase Inhibitors Targeting the ESKAPE Pathogens, Staphylococcus aureus and Acinetobacter baumannii ()
Publication date: Available online 11 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Jieun Kwon, Tina Mistry, Jinhong Ren, Michael E. Johnson, Shahila Mehboob S. aureus and A. baumannii are among the ESKAPE pathogens that are increasingly difficult to treat due to the rise in the number of drug resistant strains. Novel therapeutics targeting these pathogens are much needed. The bacterial enoyl reductase (FabI) is as potentially significant drug target for developing pathogen-specific antibiotics due to the presence of alternate FabI isoforms in many other bacterial species. We report the identification and development of a novel N-carboxy pyrrolidine scaffold targeting FabI in S. aureus and A. baumannii, two pathogens for which FabI essentiality has been established. This scaffold is unrelated to other known antibiotic families, and FabI is not targeted by any currently approved antibiotic. Our data shows that this scaffold displays promising enzyme inhibitory activity against FabI from both S. aureus and A. baumannii, as well as encouraging antibacterial activity in S. aureus. Compounds also display excellent synergy when combined with colistin and tested against A. baumannii. In this combination the MIC of colistin is reduced by 10 fold. Our first generation compound displays promising enzyme inhibition, targets FabI in S. aureus with a favorable selectivity index (ratio of cytotoxicity to MIC), and has excellent synergy with colistin against A. baumannii, including a multidrug resistant strain. Graphical abstract image
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Design and synthesis of aminoester heterodimers containing flavone or chromone moieties as modulators of P-glycoprotein-based multidrug resistance (MDR) ()
Publication date: Available online 10 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Silvia Dei, Maria Novella Romanelli, Dina Manetti, Niccolò Chiaramonte, Marcella Coronnello, Milena Salerno, Elisabetta Teodori In this study, a new series of heterodimers was synthesized. These derivatives are N,N -bis(alkanol)amine aryl esters or N,N -bis(ethoxyethanol)amine aryl esters carrying a methoxylated aryl residue combined with a flavone or chromone moiety. The new compounds were studied to evaluate their P-gp modulating activity on a multidrug-resistant leukemia cell line. Some of the new compounds show a good MDR reversing activity; interestingly this new series of compounds does not comply with the structure-activity relationships (SAR) outlined by previously synthesized analogs carrying different aromatic moieties. In the case of the compounds described in this paper, activity is linked to different features, in particular the characteristics of the spacer, which seem to be critical for the interaction with the pump. This fact indicates that the presence of a flavone or chromone residue influences the SAR of these series of products, and that flexible molecules can find different productive binding modes with the P-gp recognition site. These results support the synthesis of new compounds that might be useful leads for the development of drugs to control P-gp-dependent MDR. Graphical abstract image
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Anticancer activities of emetine prodrugs that are proteolytically activated by the prostate specific antigen (PSA) and evaluation of in vivo toxicity of emetine derivatives ()
Publication date: Available online 10 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Emmanuel S. Akinboye, Marc D. Rosen, Oladapo Bakare, Samuel R. Denmeade Emetine is a small molecule protein synthesis inhibitor that is toxic to all cell types and therefore suitable for complete killing of all types of heterogeneous cancer cells within a tumor. It becomes significantly inactive (non-toxic) when derivatized at its N-2′ secondary amine. This provides a strategy for targeting emetine to cancerous tumor without killing normal cells. In this report, PSA activatable peptide prodrugs of emetine were synthesized. To overcome steric hindrances and enhance protease specific cleavage, a 2-stage prodrug activation process was needed to release emetine in cancer cells. In this 2-stage process, emetine prodrug intermediates are coupled to PSA peptide substrate (Ac-His-Ser-Ser-Lys-Leu-Gln) to obtain the full prodrug. Both prodrug intermediates 10 (Ala-Pro-PABC-Emetine) and 14 (Ser-Leu-PABC-Emetine) were evaluated for kinetics of hydrolysis to emetine and potency [Where PABC = p-aminobenzyloxycarbonyl]. While both intermediates quantitatively liberate emetine when incubated under appropriate conditions, upon coupling of PSA substrate to give the full prodrugs, only prodrug 16, the prodrug obtained from 14 was hydrolyzable by PSA. Cytotoxicity studies in PSA producing LNCaP and CWR22Rv1 confirm the activation of the prodrug by PSA with an IC50 of 75 nM and 59 nM respectively. The cytotoxicity of 16 is significantly reduced in cell lines that do not produce PSA. Further, in vivo toxicity studies are done on these prodrugs and other derivatives of emetine. The results show the significance of conformational modulation in obtaining safe emetine prodrugs. Graphical abstract image
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Organoselenium compounds from purines: Synthesis of 6-arylselanylpurines with antioxidant and anticholinesterase activities and memory improvement effect ()
Publication date: Available online 10 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Luis Fernando B. Duarte, Renata L. Oliveira, Karline C. Rodrigues, Guilherme T. Voss, Benhur Godoi, Ricardo F. Schumacher, Gelson Perin, Ethel A. Wilhelm, Cristiane Luchese, Diego Alves We describe here a simple method for the synthesis of 6-arylselanylpurines with antioxidant and anticholinesterase activities, and memory improvement effect. This class of compounds was synthesized in good yields by a reaction of 6-chloropurine with diaryl diselenides using NaBH4 as reducing agent and PEG-400 as solvent. Furthermore, the synthesized compounds were evaluated for their in vitro antioxidant and acetylcholinesterase (AChE) inhibitor activities. The best AChE inhibitor was assessed on the in vivo memory improvement. Our results demonstrated that the 6-((4-chlorophenyl)selanyl)-9H-purine and 6-(p-tolylselanyl)-9H-purine presented in vitro antioxidant effect. In addition, 6-((4-fluorophenyl)selanyl)-9H-purine inhibited the AChE activity and improved memory, being a promising therapeutic agent for the treatment of Alzheimer’s disease. Graphical abstract image
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Unique arginine array improves cytosolic localization of hydrocarbon-stapled peptides ()
Publication date: Available online 7 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Kim Quach, Jonathan LaRochelle, Xiao-Han Li, Elizabeth Rhoades, Alanna Schepartz We have previously reported that miniature proteins containing a distinct array of 5 arginine residues on a folded α-helix – a penta-arg motif – traffic with high efficiency from endosomes into the cytosol and nucleus of mammalian cells. Here we evaluate whether a penta-arg motif can improve the intracellular trafficking of an otherwise impermeant hydrocarbon-stapled peptide, SAH-p53-4Rho. We prepared a panel of SAH-p53-4Rho variants containing penta-arg sequences with different spacings and axial arrangement and evaluated their overall uptake (as judged by flow cytometry) and their intracellular access (as determined by fluorescence correlation spectroscopy, FCS). One member of this panel reached the cytosol extremely well, matching the level achieved by SAH-p53-8Rho, a previously reported and highly permeant hydrocarbon-stapled peptide. Notably, we found no relationship between cellular uptake as judged by flow cytometry and cytosolic access as determined by FCS. This result reiterates that overall uptake and endosomal release represent fundamentally different biological processes. To determine cytosolic and/or nuclear access, one must measure concentration directly using a quantitative and non-amplified tool such as FCS. As has been observed for highly cell permeant miniature proteins such as ZF5.3, optimal penetration of hydrocarbon-stapled peptides into the cell cytosol results when the penta-arg motif is located within more (as opposed to less) structured regions. Graphical abstract image
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UVA irradiation of BrU-substituted DNA in the presence of Hoechst 33258 ()
Publication date: Available online 6 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Abhijit Saha, Seiichiro Kizaki, Ji Hoon Han, Zutao Yu, Hiroshi Sugiyama Given that our knowledge of DNA repair is limited because of the complexity of the DNA system, a technique called UVA micro-irradiation has been developed that can be used to visualize the recruitment of DNA repair proteins at double-strand break (DSB) sites. Interestingly, Hoechst 33258 was used under micro-irradiation to sensitize 5-bromouracil (BrU)-labelled DNA, causing efficient DSBs. However, the molecular basis of DSB formation under UVA micro-irradiation remains unknown. Herein, we investigated the mechanism of DSB formation under UVA micro-irradiation conditions. Our results suggest that the generation of a uracil-5-yl radical through electron transfer from Hoechst 33258 to BrU caused DNA cleavage preferentially at self-complementary 5’-AABrUBrU-3’ sequences to induce DSB. We also investigated the DNA cleavage in the context of the nucleosome to gain a better understanding of UVA micro-irradiation in a cell-like model. We found that DNA cleavage occurred in both core and linker DNA regions although its efficiency reduced in core DNA. Graphical abstract image
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Discovery of imidazo[1,2-a]pyridine-based anthelmintic targeting cholinergic receptors of Haemonchus contortus ()
Publication date: Available online 6 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Jean-Paul Déto Ursul N'Guessan, Pierre-Olivier Delaye, Mélanie Pénichon, Claude L. Charvet, Cédric Neveu, Mahama Ouattara, Cécile Enguehard-Gueiffier, Alain Gueiffier, Hassan Allouchi We report the synthesis of a series of imidazo[1,2-a]pyridine-based molecules as anthelmintic against the livestock parasite Haemonchus contortus. The molecules were tested by using Larval Paralysis Test (LPT), in order to target ionic channels, as most of the prominent marketed anthelminthics present such mechanism of action. The most active compound (5e) displayed paralysis on H. contortus stage 3 larvae until 31.25 µM. Effect of 5e on H. contortus cholinergic receptors (L-AChR1 and 2) was characterized via electrophysiological measurement and a rare antagonist mode of action was unveiled. Graphical abstract image
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Bimodal fluorescence/129Xe NMR probe for molecular imaging and biological inhibition of EGFR in Non-Small Cell Lung Cancer ()
Publication date: Available online 6 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Gaëlle Milanole, Bo Gao, Audrey Paoletti, Grégory Pieters, Christophe Dugave, Eric Deutsch, Sofia Rivera, Frédéric Law, Jean-Luc Perfettini, Emilie Mari, Estelle Léonce, Céline Boutin, Patrick Berthault, Hervé Volland, François Fenaille, Thierry Brotin, Bernard Rousseau Although Non-Small Cell Lung Cancer (NSCLC) is one of the main causes of cancer death, very little improvement has been made in the last decades regarding diagnosis and outcomes. In this study, a bimodal fluorescence/129Xe NMR probe containing a xenon host, a fluorescent moiety and a therapeutic antibody has been designed to target the Epidermal Growth Factor Receptors (EGFR) overexpressed in cancer cells. This biosensor shows high selectivity for the EGFR, and a biological activity similar to that of the antibody. It is detected with high specificity and high sensitivity (sub-nanomolar range) through hyperpolarized 129Xe NMR. This promising system should find important applications for theranostic use. Graphical abstract image
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Discovery and in vivo effects of novel human natriuretic peptide receptor A (NPR-A) agonists with improved activity for rat NPR-A ()
Publication date: Available online 6 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Takehiko Iwaki, Taisaku Tanaka, Kazuo Miyazaki, Yamato Suzuki, Yoshihiko Okamura, Akira Yamaki, Makoto Iwanami, Naomi Morozumi, Mayumi Furuya, Yoshiaki Oyama Natriuretic peptide receptor A (NPR-A) agonists were evaluated in vivo by optimizing the structure of quinazoline derivatives to improve agonistic activity for rat NPR-A. A 1,4-Cis-aminocyclohexylurea moiety at 4-position and hydroxy group of d-alaninol at 2-position on the quinazoline ring were found to be important factors in improving rat NPR-A activity. We identified potent quinazoline and pyrido[2,3-d]pyrimidine derivatives against rat NPR-A, with double-digit nanomolar EC50 values. The in vivo results showed that compound 56b administered at 1.0 mg/kg/min significantly increased plasma cGMP concentration and urine volume in rats. We discovered novel potent NPR-A agonists that showed agonistic effects similar to those of atrial natriuretic peptide. Graphical abstract image
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Synthesis and biological evaluation of isobutyrophenone analogs as potential inhibitors of class-II fructose-1,6-bisphosphate aldolase ()
Publication date: Available online 4 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Ding Li, Tuong Thi Mai Luong, Wen-Jia Dan, Yanliang Ren, Hoang Xuan Nien, An-Ling Zhang, Jin-Ming Gao Several recently identified antifungal compounds share the backbone structure of acetophenones. The aim of the present study was to develop new isobutyrophenone analogs as new antifungal agents. A series of new 2,4-dihydroxy-5-methyl isobutyrophenone derivatives were prepared and characterized by 1H, 13C NMR and MS spectroscopic data. These products were evaluated for in vitro antifungal activities against seven plant fungal pathogens by the mycelial growth inhibitory rate assay. Compounds 3, 4a, 5a, 5b, 5e, 5f and 5g showed a broad-spectrum high antifungal activity. On the other hand, for the first time, these compounds were also assayed as potential inhibitors against Class II fructose-1,6-bisphosphate aldolase (Fba) from the rice blast fungus, Magnaporthe grisea. Compounds 5e and 5g were found to exhibit the inhibition constants (Ki) for 15.12 and 14.27 μM, respectively, as the strongest competitive inhibitors against Fba activity. The possible binding-modes of compounds 5e and 5g were further analyzed by molecular docking algorithms. The results strongly suggested that compound 5g could be a promising lead for the discovery of new fungicides via targeting Class II Fba. Graphical abstract image
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Peptide Therapeutics for the Treatment of Gastrointestinal Disorders ()
Publication date: Available online 4 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Angelika Fretzen Graphical abstract image
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Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors ()
Publication date: Available online 4 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): William R. Shadrick, Peter J. Slavish, Sergio C. Chai, Brett Waddell, Michele Connelly, Jonathan A. Low, Cynthia Tallant, Brandon M. Young, Nagakumar Bharatham, Stefan Knapp, Vincent A. Boyd, Marie Morfouace, Martine F. Roussel, Taosheng Chen, Richard E. Lee, R. Kiplin Guy, Anang A. Shelat, Philip M. Potter Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC50 values comparable to BET inhibitor (BETi) clinical candidates. Graphical abstract image
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Design, synthesis and biological mechanisms research on 1,2,3-triazole derivatives of Jiyuan Oridonin A ()
Publication date: Available online 4 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Yu Ke, Wang Wang, Long-Fei Zhao, Jian-Jia Liang, Ying Liu, Xiao Zhang, Kai Feng, Hong-Min Liu Two series of derivatives with 1,2,3-triazole as heterocyclic moiety of Jiyuan Oridonin A, a new ent-kaurene diterpenoid which was isolated from genus Isodon rubescens, were synthesized and biologically evaluated. All the derivatives possessed good anti-proliferative activities. Among them, compound 8g was found to significantly induce cell apoptosis and cell cycle arrest in MGC-803 via a series of signals activated by the increased intracellular ROS levels. Graphical abstract image
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Nose-to-brain peptide delivery – the potential of nanotechnology ()
Publication date: Available online 4 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Eleni Samaridou, María José Alonso Nose-to-Brain (N-to-B) delivery offers to protein and peptide drugs the possibility to reach the brain in a non-invasive way. This article is a comprehensive review of the state-of-the-art of this emerging peptide delivery route, as well as of the challenges associated to it. Emphasis is given on the potential of nanosized drug delivery carriers to enhance the direct N-to-B transport of protein or peptide drugs. In particular, polymer- and lipid- based nanocarriers are comparatively analyzed in terms of the influence of their physicochemical characteristics and composition on their in vivo fate and efficacy. The use of biorecognitive ligands and permeation enhancers in order to enhance their brain targeting efficiency is also discussed. The article concludes highlighting the early stage of this research field and its still unveiled potential. The final message is that more explicatory PK/PD studies are required in order to achieve the translation from preclinical to the clinical development phase. Graphical abstract image
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Identification of cytotoxic, glutathione-reactive moieties inducing accumulation of reactive oxygen species via glutathione depletion ()
Publication date: Available online 4 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Julian Wilke, Tatsuro Kawamura, Nobumoto Watanabe, Hiroyuki Osada, Slava Ziegler, Herbert Waldmann Reactive oxygen species (ROS) play an essential role in the survival and progression of cancer. Moderate oxidative stress drives proliferation, whereas high levels of ROS induce cytotoxicity. Compared to cancer cells, healthy cells often exhibit lower levels of oxidative stress. Elevation of cellular ROS levels by small molecules could therefore induce cancer-specific cytotoxicity. We have employed high-throughput phenotypic screening to identify inducers of ROS accumulation. We found 4,5-dihalo-2-methylpyridazin-3-one (DHMP) and 2,3,4,5(6)-tetrachloro-6(5)-methylpyridine (TCMP) moieties to strongly deplete GSH, to cause ROS accumulation and to induce cell death.. Small molecules containing these fragments will most likely share the same properties and should therefore be carefully considered in the development of bioactive molecules. Graphical abstract image
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Design, synthesis and evaluation of 3-arylidene azetidin-2-ones as potential antifungal agents against Alternaria solani Sorauer ()
Publication date: Available online 4 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Wang Delong, Wu Yongling, Wang Lanying, Feng Juntao, Zhang Xing A new concise and facile method was explored to synthesize a collection of new 3-arylidene azetidin-2-ones, which could be regarded as the derivatives of the hybrid scaffold of bioactive natural cinnamamide and heterocycle azetidi-2-one. The structures of the synthesized compounds were characterized by 1H, 13C NMR, and MS; and their antifungal activity were evaluated against Alternaria solani Sorauer. These antifungal data were subjected to a quantitative structure–activity relationship (QSAR) analysis using Codessa software on the basis of the results from B3LYP/6-31G(d,p) quantum calculations. The best regressive model revealed that potentially more active compounds should have low dipole moments and QC-min (minimal net atomic charge for a C atom), and high QO-max (maximal net atomic charge for an O atom) and QN-min (minimal net atomic charge for an N atom). The most potent compound 7k could lead to intracellular accumulation of reactive oxygen species, dissipation of mitochondrial transmembrane potential, and an autophagy-like cell death process in A. solani Sorauer. Taken together, these results laid the foundation for further design of improved crop-protection agents based on this hybrid scaffold. Graphical abstract image
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Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors ()
Publication date: Available online 4 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Jieming Li, Weijie Gu, Xinzhou Bi, Huilan Li, Chen Liao, Chunxia Liu, Wenlong Huang, Hai Qian Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential. Graphical abstract image
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An opportunistic route to success: Towards a change of paradigm to fully exploit the potential of cell-penetrating peptides ()
Publication date: Available online 4 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Estel Collado Camps, Roland Brock About 25years ago it was demonstrated that certain peptides possess the ability to cross the plasma membrane. This led to the development of cell-penetrating peptides (CPPs) as vectors to mediate the cellular entry of (macro-)molecules that do not show cell entry by themselves. Nonetheless, in spite of an early bloom of promising pre-clinical studies, not a single CPP-based drug has been approved, yet. It is a paradigm in CPP research that the peptides are taken up by virtually all cells. In exploratory research and early preclinical development, this assumption guides the choice of the therapeutic target. However, while this indiscriminatory uptake may be the case for tissue culture experiments, in an organism this is clearly not the case. Biodistribution analyses demonstrate that CPPs only target a very limited number of cells and many tissues are hardly reached at all. Here, we review biodistribution analyses of CPPs and CPP-based drug delivery systems. Based on this analysis we propose a paradigm change towards a more opportunistic approach in CPP research. The application of CPPs should focus on those pathophysiologies for which the relevant target cells have been shown to be reached in vivo. Graphical abstract image
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Optimization of peptide-based polyagonists for treatment of diabetes and obesity ()
Publication date: Available online 2 November 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Patrick J. Knerr, Brian Finan, Vasily Gelfanov, Diego Perez-Tilve, Matthias H. Tschöp, Richard D. DiMarchi Graphical abstract image
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