- Photochemical regulation of an artificial hydrolase by a backbone incorporated tertiary structure switch
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A stilbene chromophore has been incorporated into the turn region of a 42 amino acid peptide, linking two helical peptide sections. Spatial proximity between these sections, as well as aggregation into dimers, is required to facilitate the catalytic function of this artificial hydrolase. Photomodulation of the hydrolase activity results in an increase of the activity of 42% upon switching from the trans to the cis isomer of the chromophore. This is rationalized by a change in the aggregation state of the peptidomimetic, which is supported by diffusion coefficients obtained from PFG-NMR experiments. The results show that incorporation of a small, relatively flexible chromophore into a large peptide is capable of inducing a considerable change in tertiary structure and thus, functionality.
- Lindgren, N. Johan V.,Varedian, Miranda,Gogoll, Adolf
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Read Online
- Design, Synthesis, and Anticancer Activity of Cinnamoylated Barbituric Acid Derivatives
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This work deals with the design and synthesis of 18 barbituric acid derivatives bearing 1,3-dimethylbarbituric acid and cinnamic acid scaffolds to find potent anticancer agents. The target molecules were obtained through Knoevenagel condensation and acylation reaction. The cytotoxicity was assessed by the MTT assay. Flowcytometry was performed to determine the cell cycle arrest, apoptosis, ROS levels and the loss of MMP. The ratios of GSH/GSSG and the MDA levels were determined by using UV spectrophotometry. The results revealed that introducing substitutions (CF3, OCF3, F) on the meta- of the benzyl ring of barbituric acid derivatives led to a considerable increase in the antiproliferative activities compared with that of corresponding ortho- and para-substituted barbituric acid derivatives. Mechanism investigation implied that the 1c could increase the ROS and MDA level, decrease the ratio of GSH/GSSG and MMP, and lead to cell cycle arrest. Further research is needed for structural optimization to enhance hydrophilicity, thereby improve the biological activity of these compounds.
- Liu, Yue,Li, Peng-Xiao,Mu, Wen-Wen,Sun, Ya-Lei,Liu, Ren-Min,Yang, Jie,Liu, Guo-Yun
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- Iron-catalyzed domino decarboxylation-oxidation of α,β-unsaturated carboxylic acids enabled aldehyde C-H methylation
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A practical and general iron-catalyzed domino decarboxylation-oxidation of α,β-unsaturated carboxylic acids enabling aldehyde C-H methylation for the synthesis of methyl ketones has been developed. This mild, operationally simple method uses ambient air as the sole oxidant and tolerates sensitive functional groups for the late-stage functionalization of complex natural-product-derived and polyfunctionalized molecules.
- Gong, Pei-Xue,Xu, Fangning,Cheng, Lu,Gong, Xu,Zhang, Jie,Gu, Wei-Jin,Han, Wei
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supporting information
p. 5905 - 5908
(2021/06/18)
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- Dual Nickel/Ruthenium Strategy for Photoinduced Decarboxylative Cross-Coupling of α,β-Unsaturated Carboxylic Acids with Cycloketone Oxime Esters
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Herein, a dual nickel/ruthenium strategy is developed for photoinduced decarboxylative cross-coupling between α,β-unsaturated carboxylic acids and cycloketone oxime esters. The reaction mechanism is distinct from previous photoinduced decarboxylation of α,β-unsaturated carboxylic acids. This reaction might proceed through a nickelacyclopropane intermediate. The C(sp2)-C(sp3) bond constructed by the aforementioned reaction provides an efficient approach to obtaining various cyanoalkyl alkenes, which are synthetically valuable organic skeletons in organic and medicinal chemistry, under mild reaction conditions. The protocol tolerates many critical functional groups and provides a route for the modification of complex organic molecules.
- Gao, Ang,Jiang, Run-Chuang,Liu, Chuang-Chuang,Liu, Qi-Le,Lu, Xiao-Yu,Xia, Ze-Jie
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supporting information
p. 8829 - 8842
(2021/06/30)
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- Metal-Free Hydropyridylation of Thioester-Activated Alkenes via Electroreductive Radical Coupling
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An electrochemical hydropyridylation of thioester-activated alkenes with 4-cyanopyridines has been developed. The reactions experience a tandem electroreduction of both substrates on the cathode surface, protonation, and radical cross-coupling process, resulting in a variety of valuable pyridine variants, which contain a tertiary and even a quaternary carbon at the α-position of pyridines, in high yields. The employment of thioesters to the conjugated alkenes enables no requirement of catalyst and high temperature, representing a highly sustainable synthetic method.
- Xu, Hehuan,Liu, Jiayu,Nie, Feiyun,Zhao, Xiaowei,Jiang, Zhiyong
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p. 16204 - 16212
(2021/10/25)
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- Toward a Scalable Synthesis and Process for EMA401, Part II: Development and Scale-Up of a Pyridine- A nd Piperidine-Free Knoevenagel-Doebner Condensation
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During route scouting for EMA401 (1), an angiotensin II type 2 antagonist, we identified the synthesis of key amino acid intermediate 2 via its cinnamic acid derivative 3 as a streamlined option. In general, cinnamic acids can be synthesized from the corresponding aldehydes by a Knoevenagel-Doebner condensation in pyridine with piperidine as an organocatalyst. We aimed to replace both of these reagents and found novel conditions involving toluene as the solvent and morpholine as the organocatalyst. Scale-up of the process allowed the production of 25 kg of cinnamic acid 3 that was of the quality required for process development of the subsequent phenylalanine ammonia lyase-catalyzed step. The modified conditions were found to be widely applicable to alternative aldehydes and thus are of relevance to practitioners of chemical scale-up.
- Hardegger, Leo A.,Humair, Roger,Sidler, Eric
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p. 1756 - 1762
(2020/10/26)
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- Tandem IBX-Promoted Primary Alcohol Oxidation/Opening of Intermediate β,γ-Diolcarbonate Aldehydes to (E)-γ-Hydroxy-α,β-enals
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A tandem IBX-promoted oxidation of primary alcohol to aldehyde and opening of intermediate β,γ-diolcarbonate aldehyde to (E)-γ-hydroxy-α,β-enal has been developed. Remarkably, the carbonate opening delivered exclusively (E)-olefin and no over-oxidation of γ-hydroxy was observed. The method developed has been extended to complete the stereoselective total synthesis of both (S)- and (R)-coriolides and d-xylo- and d-arabino-C-20 guggultetrols.
- Kumari, Anupama,Gholap, Sachin P.,Fernandes, Rodney A.
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p. 2278 - 2290
(2019/06/17)
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- Design, synthesis and biological evaluation of (E)-5-styryl-1,2,4-oxadiazoles as anti-tubercular agents
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Cinnamic acid and its derivatives are known for anti-tubercular activity. The present study reports the synthesis of cinnamic acid derivatives via bioisosteric replacement of terminal carboxylic acid with “oxadiazole”. A series of cinnamic acid derivatives (styryl oxadiazoles) were designed and synthesized in good yields by reaction of substituted cinnamic acids (2, 15a-15s) with amidoximes. The synthesized styryl oxadiazoles were evaluated in vitro for anti-tubercular activity against Mycobacterium tuberculosis (Mtb) H37Ra strain. The structure-activity relationship (SAR) study has identified several compounds with mixed anti-tubercular profiles. The compound 32 displayed potent anti-tubercular activity (IC50 = 0.045 μg/mL). Molecular docking studies on mycobacterial enoyl-ACP reductase enzyme corroborated well with the experimental findings providing a platform for structure based hit-to-lead development.
- Atmaram Upare, Abhay,Gadekar, Pradip K.,Sivaramakrishnan,Naik, Nishigandha,Khedkar, Vijay M.,Sarkar, Dhiman,Choudhari, Amit,Mohana Roopan
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supporting information
p. 507 - 512
(2019/02/19)
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- Iodine-Catalyzed Facile Approach to Sulfones Employing TosMIC as a Sulfonylating Agent
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A novel iodine-catalyzed functionalization of a variety of olefins and alkynes and direct decarboxylative functionalization of cinnamic and propiolic acids with TosMIC to provide access to various vinyl, allyl, and β-iodo vinylsulfones is described. This simple, efficient, and environmentally benign approach employing inexpensive molecular iodine as a catalyst demonstrates a versatile protocol for the synthesis of highly valuable sulfones, rendering it attractive to both synthetic and medicinal chemistry.
- Kadari, Lingaswamy,Palakodety, Radha Krishna,Yallapragada, Lakshmi Prapurna
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supporting information
p. 2580 - 2583
(2017/05/24)
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- Kinetic Resolution of Aromatic β-Amino Acids Using a Combination of Phenylalanine Ammonia Lyase and Aminomutase Biocatalysts
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An enzymatic strategy for the preparation of (R)-β-arylalanines employing phenylalanine aminomutase and ammonia lyase (PAM and PAL) enzymes has been demonstrated. Candidate PAMs with the desired (S)-selectivity from Streptomyces maritimus (EncP) and Bacillus sp. (PabH) were identified via sequence analysis using a well-studied template sequence. The newly discovered PabH could be linked to the first ever proposed biosynthesis of pyloricidin-like secondary metabolites and was shown to display better β-lyase activity in many cases. In spite of this, a method combining the higher conversion of EncP with a strict α-lyase from Anabaena variabilis (AvPAL) was found to be more amenable, allowing kinetic resolution of five racemic substrates and a preparative-scale reaction with >98% (R) enantiomeric excess. This work represents an improved and enantiocomplementary method to existing biocatalytic strategies, allowing simple product separation and modular telescopic combination with a preceding chemical step using an achiral aldehyde as starting material. (Figure presented.).
- Weise, Nicholas J.,Ahmed, Syed T.,Parmeggiani, Fabio,Turner, Nicholas J.
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supporting information
p. 1570 - 1576
(2017/05/05)
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- Chiral phosphoric acid catalyzed enantioselective annulation of acyclic enecarbamates to: In situ -generated ortho -quinone methides
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The first organocatalytic asymmetric reaction of acyclic enecarbamates with o-quinone methides is disclosed. BINOL-based phosphoric acid catalysts were found to be suitable for the annulation reaction. With 10 mol% of the TRIP catalyst, high yields as well as excellent diastereo- and enantioselectivities are achieved for a variety of 2,3,4-trisubstituted chroman products.
- Gharui, Chandan,Singh, Shreya,Pan, Subhas Chandra
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supporting information
p. 7272 - 7276
(2017/09/25)
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- Enantioselective Synthesis of N?H-Free 1,5-Benzothiazepines
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An enantioselective sulfa-Michael-cyclization reaction was developed for the synthesis of 1,5-benzothiazepines with versatile pharmacological activities. The reaction between 2-aminothiophenol and α,β-unsaturated pyrazoleamides gave direct access to N?H-free 1,5-benzothiazepines in the presence of a chiral N,N′-dioxide/Yb(OTf)3complex. Excellent enantioselectivities (up to 96 % ee) and high yields (up to 99 %) were obtained for a broad range of substrates under mild reaction conditions. This method provided a facile approach to the antidepressant drug (R)-(?)-Thiazesim.
- Wang, Guojin,Tang, Yu,Zhang, Yu,Liu, Xiaohua,Lin, Lili,Feng, Xiaoming
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supporting information
p. 554 - 557
(2017/01/18)
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- Engineering of phenylalanine ammonia lyase from Rhodotorula graminis for the enhanced synthesis of unnatural L-amino acids
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Phenylalanine ammonia lyase (PAL) catalyses the reversible non-oxidative deamination of phenylalanine to trans-cinnamic acid and ammonia. Analogues of L-phenylalanine are incorporated as pharmacophores in several peptidomimetic drug molecules and are therefore of particular interest to the fine chemical industry. PAL from Rhodotorula graminis (RgrPAL) has shown an ability to accept analogues of L-phenylalanine. Our aim was to increase enzymatic activity with directed evolution towards a specific non-natural substrate through the cloning and over-production of PAL in Escherichia coli. The identified variants of RgrPAL with significantly showed more catalytic efficient compared to the wild-type enzyme. These variants were used in a preparative scale biotransformation resulting in a 94% conversion to L-4-Br-phenylalanine (>99% ee).
- Rowles, Ian,Groenendaal, Bas,Binay, Baris,Malone, Kirk J.,Willies, Simon C.,Turner, Nicholas J.
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p. 7343 - 7347
(2016/10/30)
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- Synthesis and characterization of two novel biological-based nano organo solid acids with urea moiety and their catalytic applications in the synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol), coumarin-3-carboxylic acid and cinnamic acid derivatives under mild and green conditions
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2-Carbamoylhydrazine-1-sulfonic acid and carbamoylsulfamic acid as novel, mild and biological-based nano organocatalysts with urea moiety were designed, synthesized and fully characterized by FT-IR, 1H NMR, 13C NMR, mass spectrometry, elemental analysis, thermal gravimetric, derivative thermal gravimetric, X-ray diffraction patterns, scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, atomic force microscopy and UV/Vis analysis. The catalytic applications of 2-carbamoylhydrazine-1-sulfonic acid and carbamoylsulfamic acid were studied in the synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol), coumarin-3-carboxylic acid and cinnamic acid derivatives via the condensation reaction between several aromatic aldehydes and 1-phenyl-3-methylpyrazol-5-one (synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols)), the Knoevenagel condensation of Meldrum's acid with salicylaldehyde derivatives (synthesis of coumarin-3-carboxylic acids) and the condensation of Meldrum's acid with aromatic aldehydes (synthesis of cinnamic acids) under mild and solvent-free conditions. In the presented studies, some products were formed and reported for the first time. The described nano organo solid acids have potential in industry.
- Zolfigol, Mohammad Ali,Ayazi-Nasrabadi, Roya,Baghery, Saeed
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p. 71942 - 71954
(2015/09/08)
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- Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery
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Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors' biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.
- Devine, William,Woodring, Jennifer L.,Swaminathan, Uma,Amata, Emanuele,Patel, Gautam,Erath, Jessey,Roncal, Norma E.,Lee, Patricia J.,Leed, Susan E.,Rodriguez, Ana,Mensa-Wilmot, Kojo,Sciotti, Richard J.,Pollastri, Michael P.
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supporting information
p. 5522 - 5537
(2015/08/03)
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- Phototriggerable peptidomimetics for the inhibition of Mycobacterium tuberculosis ribonucleotide reductase by targeting protein-protein binding
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Incorporation of an artificial amino acid 2 with a stilbene chromophore into peptidomimetics with three to nine amino acids yields phototriggerable candidates for inhibition of the binding between the R1 and R2 subunits of the M. tuberculosis ribonucleotide reductase (RNR). Interstrand hydrogen bond probability was used as a guideline for predicting conformational preferences of the photoisomers. Binding of these inhibitors has been rationalized by docking studies with the R1 unit. Significant differences in binding of the photoisomers were observed. For the shorter peptidomimetics, stronger binding of the Z isomer might indicate hydrophobic interactions between the stilbene chromophore and the binding site. This journal is
- Karlsson, Christoffer,Blom, Magnus,Johansson, Miranda,Jansson, Anna M.,Scifo, Enzo,Karln, Anders,Govender, Thavendran,Gogoll, Adolf
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supporting information
p. 2612 - 2621
(2015/05/27)
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- Multifunctional novel Diallyl disulfide (DADS) derivatives with β-amyloid-reducing, cholinergic, antioxidant and metal chelating properties for the treatment of Alzheimer's disease
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A series of novel Diallyl disulfide (DADS) derivatives were designed, synthesized and evaluated as chemical agents, which target and modulate multiple facets of Alzheimer's disease (AD). The results showed that the target compounds 5a-l and 7e-m exhibited significant anti-Aβ aggregation activity, considerable acetylcholinesterase (AChE) inhibition, high selectivity towards AChE over butyrylcholinesterase (BuChE), potential antioxidant and metal chelating activities. Specifically, compounds 7k and 7l exhibited highest potency towards self-induced Aβ aggregation (74% and 71.4%, 25 μM) and metal chelating ability. Furthermore, compounds 7k and 7l disaggregated Aβ fibrils generated by Cu2+-induced Aβ aggregation by 80.9% and 78.5%, later confirmed by transmission electron microscope (TEM) analysis. Besides, 7k and 7l had the strongest AChE inhibitory activity with IC50 values of 0.056 μM and 0.121 μM, respectively. Furthermore, molecular modelling studies showed that these compounds were capable of binding simultaneously to catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. All the target compounds displayed moderate to excellent antioxidant activity with ORAC-FL values in the range 0.546-5.86 Trolox equivalents. In addition, absorption, distribution, metabolism and excretion (ADME) profile and toxicity prediction (TOPKAT) of best compounds 7k and 7l revealed that they have drug like properties and possess very low toxic effects. Collectively, the results strongly support our assertion that these compounds could provide good templates for developing new multifunctional agents for AD treatment.
- Manral, Apra,Saini, Vikas,Meena, Poonam,Tiwari, Manisha
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p. 6389 - 6403
(2015/10/05)
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- Aromatic diacylhydrazine derivatives as a new class of polo-like kinase 1 (PLK1) inhibitors
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A novel class of aromatic diacylhydrazine derivatives was designed as PLK1 inhibitors. All the 19 new synthesized compounds were assayed for antitumor activity against the respective cervical cancer cells. In which, nine compounds with better antitumor activities were further tested for their PLK1 inhibitory activity. Last, we have successfully found that compound 7k showed both the promising antitumor activity with IC50 of 0.17 μM against the cervical cancer cells, and also processed the most potent PLK1 inhibitory activity with IC50 of 0.03 μM. In addition, docking simulation also carried out in this study to give a potent prediction binding mode between the small molecule and PKL1 (PDB code: 1umw) protein.
- Sun, Juan,Lv, Peng-Cheng,Guo, Feng-Jiao,Wang, Xin-Yi,Han, Xiao-,Zhang, Yang,Sheng, Gui-Hua,Qian, Shao-Song,Zhu, Hai-Liang
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p. 420 - 426
(2014/06/09)
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- Synthesis and sar study of diarylpentanoid analogues as new anti-inflammatory agents
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A series of ninety-seven diarylpentanoid derivatives were synthesized and evaluated for their anti-inflammatory activity through NO suppression assay using interferone gamma (IFN-γ)/lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Twelve compounds (9, 25, 28, 43, 63, 64, 81, 83, 84, 86, 88 and 97) exhibited greater or similar NO inhibitory activity in comparison with curcumin (14.7 ± 0.2 μM), notably compounds 88 and 97, which demonstrated the most significant NO suppression activity with IC50 values of 4.9 ± 0.3 μM and 9.6 ± 0.5 μM, respectively. A structure-activity relationship (SAR) study revealed that the presence of a hydroxyl group in both aromatic rings is critical for bioactivity of these molecules. With the exception of the polyphenolic derivatives, low electron density in ring-A and high electron density in ring-B are important for enhancing NO inhibition. Meanwhile, pharmacophore mapping showed that hydroxyl substituents at both meta- and para-positions of ring-B could be the marker for highly active diarylpentanoid derivatives.
- Leong, Sze Wei,Mohd Faudzi, Siti Munirah,Abas, Faridah,Mohd Aluwi, Mohd Fadhlizil Fasihi,Rullah, Kamal,Wai, Lam Kok,Abdul Bahari, Mohd Nazri,Ahmad, Syahida,Tham, Chau Ling,Shaari, Khozirah,Lajis, Nordin H.
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p. 16058 - 16081
(2015/01/08)
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- Design, synthesis and biological evaluation of cinnamic acyl shikonin derivatives
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Inducing apoptosis is an important and promising therapeutic approach to overcome cancer. Here, we described a series of novel synthesized compounds, cinnamic acyl shikonin derivatives (1b-19b), which were synthesized starting from shikonin and cinnamic acids, which exhibit anticancer activity via inducing apoptosis in vitro. Our flow cytometry results showed that compound 8b((E)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent -3-enyl-3-(3-(trifluoromethyl) phenyl)acrylate) (IC50=0.69, 0.65, 1.62 μm for human SW872-s, A875 and A549 cell lines, respectively) exhibited conspicuous anticancer activities and has low cell toxicity in vitro. Therefore, we considered that compound 8b is potentially to be a candidate of anticancer agent. The proliferation inhibitory effect of compound 8b was associated with its apoptosis-inducing effect by activating caspase-3, caspase-7, caspase-9, and PARP. When the level of cleaved caspase-3, cleaved caspase-7, cleaved caspase-9, and cleaved PARP are rise, apoptosis of cancer cells will be induced.
- Lin, Hong-Yan,Chen, Wei,Shi, Jing,Kong, Wen-Yao,Qi, Jin-Liang,Wang, Xiao-Ming,Yang, Yong-Hua
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p. 275 - 283
(2013/03/13)
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- Titanium-catalyzed intermolecular hydroaminoalkylation of conjugated dienes
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Ti me kangaroo down: Conjugated dienes undergo intermolecular hydroaminoalkylation in the presence of Ti catalyst [Ind2TiMe 2] (Ind=η5-indenyl). This new reaction offers a highly atom-efficient approach to homoallylic amines from 1,3-butadienes. Copyright
- Preuss, Till,Saak, Wolfgang,Doye, Sven
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supporting information
p. 3833 - 3837
(2013/04/24)
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- Synthesis and antitumor activity of 1,3,4-oxadiazole possessing 1,4-benzodioxan moiety as a novel class of potent methionine aminopeptidase type II inhibitors
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A series of 1,3,4-oxadiazole derivatives containing 1,4-benzodioxan moiety (7a-7q) have been designed, synthesized and evaluated for their antitumor activity. Most of the synthesized compounds were proved to have potent antitumor activity and low toxicity. Among them, compound 7a showed the most potent biological activity against Human Umbilical Vein Endothelial cells, which was comparable to the positive control. The results of apoptosis and flow cytometry (FCM) demonstrated that compound 7a induce cell apoptosis by the inhibition of MetAP2 pathway. Molecular docking was performed to position compound 7a into MetAP2 binding site in order to explore the potential target.
- Sun, Juan,Li, Ming-Hui,Qian, Shao-Song,Guo, Feng-Jiao,Dang, Xiao-Fang,Wang, Xiao-Ming,Xue, Ya-Rong,Zhu, Hai-Liang
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supporting information
p. 2876 - 2879
(2013/06/26)
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- Synthesis and anticancer activity of 13-membered cyclic enediynes
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We herein describe the synthesis of 15 novel 13-membered cyclic enediyne derivatives using simple and straightforward approach. Representative examples were screened for their anticancer activities on 60 different human tumor cell lines representing various histologies viz. leukemia, melanoma, and cancers of lung, colon, kidney, ovary, breast, prostate, and central nervous system. The enediyne derivatives with halogen substitutions, especially fluorides were found to be active against most of the cell lines. The initial results indicates marginal to good inhibition for the growth of tumor cells for several cell lines, which shows the potential of these class of compound towards anticancer application. 15 novel 13-membered cyclic enediyne derivatives using a simple and straightforward approach are synthesized. The initial results show the potential of this class of compounds towards anticancer application. Copyright
- Sharma, Mukul,Joshi, Mukesh C,Kumar, Vineet,Malhotra, Sanjay V.,Rawat, Diwan S.
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scheme or table
p. 567 - 571
(2012/06/30)
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- Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors
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Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
- Ray, Peter,Wright, Jane,Adam, Julia,Bennett, Johnathan,Boucharens, Sylviane,Black, Darcey,Cook, Andrew,Brown, Angus R.,Epemolu, Ola,Fletcher, Dan,Haunso, Anders,Huggett, Margaret,Jones, Phil,Laats, Steven,Lyons, Amanda,Mestres, Jordi,De Man, Jos,Morphy, Richard,Rankovic, Zoran,Sherborne, Brad,Sherry, Lorcan,Van Straten, Nicole,Westwood, Paul,Zaman, Guido Z.R.
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supporting information; scheme or table
p. 97 - 101
(2011/02/28)
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- Synthesis, molecular modeling and biological evaluation of β-ketoacyl-acyl carrier protein synthase III (FabH) as novel antibacterial agents
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A series of novel cinnamic acid secnidazole ester derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of FabH. These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. Compounds with potent antibacterial activities were tested for their E. coli FabH inhibitory activity. Compound 3n showed the most potent antibacterial activity with MIC of 1.56-6.25 μg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 2.5 μM. Docking simulation was performed to position compound 3n into the E. coli FabH active site to determine the probable binding conformation.
- Zhang, Hong-Jia,Zhu, Di-Di,Li, Zi-Lin,Sun, Juan,Zhu, Hai-Liang
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experimental part
p. 4513 - 4519
(2011/09/12)
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- Phenylalanine aminomutase-catalyzed addition of ammonia to substituted cinnamic acids: A route to enantiopure α- and β-amino acids
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(Chemical Equation Presented) An approach is described for the synthesis of aromatic α- and β-amino acids that uses phenylalanine aminomutase to catalyze a highly enantioselective addition of ammonia to substituted cinnamic acids. The reaction has a broad scope and yields substituted α- and β-phenylalanines with excellent enantiomeric excess. The regioselectivity of the conversion is determined by substituents present at the aromatic ring. A box model for the enzyme active site is proposed, derived from the influence of the hydrophobicity of substituents on the enzyme affinity toward various substrates.
- Szymanski, Wiktor,Wu, Bian,Weiner, Barbara,De Wildeman, Stefaan,Feringa, Ben L.,Janssen, Dick B.
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supporting information; experimental part
p. 9152 - 9157
(2010/03/01)
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- Chemistry and folding of photomodulable peptides - Stilbene and thioaurone-type candidates for conformational switches
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Optimized synthetic strategies for the preparation of photoswitchable molecular scaffolds based on stilbene or on thioaurone chromophores and their conformationally directing properties, as studied by computations and by NMR spectroscopy, are addressed. For the stilbene peptidomimetics 1, 2 and 3, the length of connecting linkers between the chromophore and the peptide strands was varied, resulting in photochromic dipeptidomimetics with various flexibility. Building blocks of higher rigidity, based on para-substituted thioaurone (4 and 6) and meta-substituted thioaurone chromophores (5 and 7) are shown to have a stronger conformationally directing effect. Design, synthesis, theoretical and experimental conformational analyses are presented.
- Erdelyi, Mate,Varedian, Miranda,Skoeld, Christian,Niklasson, Ida B.,Nurbo, Johanna,Persson, Asa,Bergquist, Jonas,Gogoll, Adolf
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scheme or table
p. 4356 - 4373
(2009/02/07)
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- A new tool in peptide engineering: A photoswitchable stilbene-type β-hairpin mimetic
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Peptide secondary structure mimetics are important tools in medicinal chemistry, as they provide analogues of endogenous peptides with new physicochemical and pharmacological properties. The development, synthesis, photochemical investigation, and conformational analysis of a stil-bene-type β-hairpin mimetic capable of light-triggered conformational changes have been achieved. In addition to standard spectroscopic techniques (nuclear Overhauser effects, amide temperature coefficients, circular dichroism spectroscopy), the applicability of self-diffusion measurements (longitudinal eddy current delay pulsed-field gradient spin echo (LED-PGSE) NMR technique) in conformational studies of oligopeptides is demonstrated. The title compound shows photoisomerization of the stilbene chromophore, resulting in a change in solution conformation between an unfolded structure and a folded β-hairpin.
- Erdelyi, Mate,Karlen, Anders,Gogoll, Adolf
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p. 403 - 412
(2008/09/19)
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- Competitive formation of β-amino acids, propenoic, and ylidenemalonic acids by the Rodionov reaction from malonic acid, aldehydes, and ammonium acetate in alcoholic medium
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The Rodionov reaction of 49 available aliphatic and aromatic aldehydes with malonic acid and ammonium acetate in alcoholic medium, resulting in formation of β-amino acids, propenoic, and ylidenemalonic acids, was studied. Certain regioselectivity regularities of the reaction were revealed. Among the variety of ketones studied, cyclohexanone is the only whose reaction yields a β-amino acid. Unusual dehydrofluorination of 6-chloro-2-fluorocinnamic acid under the Rodionov reaction was discovered. 2005 Pleiades Publishing, Inc.
- Lebedev,Lebedeva,Sheludyakov,Kovaleva,Ustinova,Kozhevnikov
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p. 1113 - 1124
(2007/10/03)
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- Synthesis of trans-cinnamic acids from aryl aldehydes and aryl aldehyde bisulfite adducts with malonic acid using piperazine
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Piperazine as a new reagent for the condensation of aryl aldehydes and their bisulfite adducts with malonic acid are described which afford the corresponding cinnamic acids in excellent yields and short reaction times in the absence of solvents under microwave irradiation.
- Khosropour, Ahmad Reza,Khodaei, Mohammad Mehdi,Moghanian, Hassan
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p. 364 - 365
(2007/10/03)
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- PHARMACEUTICALLY ACTIVE BENZOXAZOLE, BENZTHIAZOLE AND BENZIMIDAZOLE ACID DERIVATIVES
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Compounds of formula (I): wherein R1, R2 and R3 are independently, hydrogen, halogen, CF3, OR6, NR7R8, NR8COR10, NR8SO2R10 or C1-6 alkyl optionally substituted by hydroxy, C1-6 alkoxy or NR7R8; R4 is NR8CONR8R9, NR8COR9, NR8SO2R9, or W-CONR8R9, where W is a bond, C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene; and R5 is Formula (A) methods for their synthesis, pharmaceutical compositions comprising them and their use in medicine, in particular for the treatment of cancer.
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- Synthesis, and biological evaluation of new 1,3,4-thiadiazolium-2-phenylamine derivatives against Leishmania amazonensis promastigotes and amastigotes
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1,3,4-Thiadiazolium-2-aminide, which is a class of mesoionic compounds, were tested against promastigote and amastigote forms of Leishmania amazonensis. Parasites were assayed with or without the drugs in axenic media, using pentamidine isethionate as a reference drug. The very promising results showed us the most active compounds were the 4′- and 3′-methoxy derivatives against promastigote forms, while the highest activity against the amastigote forms was obtained with the 4′-fluor and 3′-bromo derivatives.
- Da Silva, Edson F.,Canto-Cavalheiro, Marilene M.,Braz, Viviane R.,Cysne-Finkelstein, Lea,Leon, Leonor L.,Echevarria, Aurea
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p. 979 - 984
(2007/10/03)
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- Substituted sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds
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The compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, which are for treating a patient suffering from, or subject to, physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.
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- SUBSTITUTED SULFONIC ACID N-[(AMINOIMINOMETHYL)PHENYLALKYL]-AZAHETEROCYCLAMIDE COMPOUNDS
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The compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, which are for treating a patient suffering from, or subject to, physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.
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- Process for preparing N-benzyl indoles
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A process for producing a compound of the formu5la STR1 comprising the step of reacting a compound of the formula STR2 with a compound of the formula STR3 to form a compound of the formula STR4 wherein R2a is selected from the groups recited ab
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