- Synthesis of cyclic peptides through ring-closing metathesis of photolabile protecting groups
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The new photolabile protecting groups 4-allyl-5-methoxy-3-nitrobenzyl (AMNB) and 4-allyl-5-methoxy-3-nitrobenzyloxycarbonyl (AMNBOC) with an allylic side chain can easily be obtained from vanillin. These protecting groups can be introduced on the C- as well as on the N-terminus of peptides, and subsequent ring-closing metatheses provides a straightforward protocol for the synthesis of cyclic peptides. The protecting groups can be removed under UVA irradiation (365 nm).
- Hoffmann, Judith,Kazmaier, Uli
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- Efficacious anticancer drug delivery mediated by a pH-sensitive self-assembly of a conserved tripeptide derived from tyrosine kinase NGF receptor
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We present herein a short tripeptide sequence (Lys-Phe-Gly or KFG) that is situated in the juxtamembrane region of the tyrosine kinase nerve growth factor (Trk NGF) receptors. KFG self-assembles in water and shows a reversible and concentration-dependent switching of nanostructures from nanospheres (vesicles) to nanotubes, as evidenced by dynamic light scattering, transmission electron microscopy, and atomic force microscopy. The morphology change was associated with a transition in the secondary structure. The tripeptide vesicles have inner aqueous compartments and are stable at pH 7.4 but rupture rapidly at pH≈6. The pH-sensitive response of the vesicles was exploited for the delivery of a chemotherapeutic anticancer drug, doxorubicin, which resulted in enhanced cytotoxicity for both drug-sensitive and drug-resistant cells. Efficient intracellular release of the drug was confirmed by fluorescence-activated cell sorting analysis, fluorescence microscopy, and confocal microscopy. Package for special delivery: A biologically active tripeptide self-assembles to produce nanovesicles at lower concentrations and nanotubes at higher concentrations (see scheme). The nanovesicles rupture at pH≈6 and are highly efficient in doxorubicin delivery to both drug-sensitive and drug-resistant cancer cells. This system is highly promising as a stimulus-responsive biocompatible nanovehicle. Copyright
- Moitra, Parikshit,Kumar, Krishan,Kondaiah, Paturu,Bhattacharya, Santanu
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- Reusable resin plug-bound palladium catalysts for organic synthesis
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Resin plugs, a unique and conveniently handled form of resin, prepared by sintering high-density polyethylene (HDPE) with pre-functionalised resins, were derivatised and loaded with palladium(0). These 'plugs' were used in the preparation of a Suzuki reaction based library and the removal of allyl ester protecting groups. The 'plugs of catalyst' were easily separated from the reaction mixture and were re-used multiple times with minimal loss of activity.
- Atrash, Butrus,Reader, John,Bradley, Mark
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- Synthesis and Reversible Hydration of a Pseudoprotein, a Fully Organic Polymeric Desiccant by Multiple Single-Crystal-to-Single-Crystal Transformations
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A diphenylalanine derivative, N3-Phe-Phe-NHCH2CCH, was designed for topochemical azide–alkyne cycloaddition (TAAC) polymerization. This dipeptide adopted β-sheet arrangement as designed, in its crystals, but the azide and alkyne were not fitly aligned for
- Mohanrao, Raja,Sureshan, Kana M.
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- β-Sheet to Helical-Sheet Evolution Induced by Topochemical Polymerization: Cross-α-Amyloid-like Packing in a Pseudoprotein with Gly-Phe-Gly Repeats
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Protein-mimics are of great interest for their structure, stability, and properties. We are interested in the synthesis of protein-mimics containing triazole linkages as peptide-bond surrogate by topochemical azide-alkyne cycloaddition (TAAC) polymerization of azide- and alkyne-modified peptides. The rationally designed dipeptide N3-CH2CO-Phe-NHCH2CCH (1) crystallized in a parallel β-sheet arrangement and are head-to-tail aligned in a direction perpendicular to the β-sheet-direction. Upon heating, crystals of 1 underwent single-crystal-to-single-crystal polymerization forming a triazole-linked pseudoprotein with Gly-Phe-Gly repeats. During TAAC polymerization, the pseudoprotein evolved as helical chains. These helical chains are laterally assembled by backbone hydrogen bonding in a direction perpendicular to the helical axis to form helical sheets. This interesting helical-sheet orientation in the crystal resembles the cross-α-amyloids, where α-helices are arranged laterally as sheets.
- Hema, Kuntrapakam,Sureshan, Kana M.
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- Massive Parallel Catalyst Screening: Toward Asymmetric MCRs
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(Equation presented) Hundreds of Lewis acid/ligand combinations have been screened for stereochemical induction in the Passerini multicomponent reaction. The combination of titan tetraisopropylate and (4S,5S)-4,5- bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane was found to give enantiomeric excesses between 32% and 42% in several examples. The absolute stereo induction of one example was determined chemically and by means of X-ray crystallography. This comprises the first asymmetric Passerini reaction and the first example of a stereochemical induction in an isocyanide based multicomponent reaction by a chiral Lewis acid.
- Kusebauch, Ulrike,Beck, Barbara,Messer, Kim,Herdtweck, Eberhardt,Doemling, Alexander
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- Chiral secondary phosphine oxide pre-ligand and application thereof
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The invention discloses a chiral secondary phosphine oxide pre-ligand and application thereof. The structure of the ligand is as shown in Formula I, where R. 1 . R2 , R3 And R4 Hydrogen, benzyl, substituted alkyl, substituted or unsubstituted aryl. The more preferred structural formula comprises 4 structural general formulas shown in the general formula I in the following formula: I-d, and the formula is shown in the general formula. Based on the designed asymmetric catalytic reaction system, the stability and the easy preparation of the comprehensive test ligand under the hydrocarbon activation condition are synthesized, and finally the chiral secondary oxidation phosphorus precursor with the double functional groups in the oxidation and heating environment is selected. The catalyst formed by the front ligand and the active metal compound has high activity and high selectivity in the reaction of constructing a chiral center, and has the stability.
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Paragraph 0040-0043
(2021/10/20)
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- Topochemical Ene–Azide Cycloaddition Reaction
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Topochemical reactions, high-yielding solid-state reactions arising from the proximal alignment of reacting partners in the crystal lattice, do not require solvents, catalysts, and additives, are of high demand in the context of green processes and enviro
- Khazeber, Ravichandran,Sureshan, Kana M.
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supporting information
p. 24875 - 24881
(2021/09/22)
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- CONJUGATE OF FLUORESCENT DYE FOR THE VISUALIZATION OF PSMA EXPRESSING CELLS
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The invention relates to the field of organic and medicinal chemistry, as well as molecular biology, and concerns a new class of compounds for imaging PSMA expressing cells and tissues, such as prostate cancer cells. New diagnostic conjugates for the visu
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Page/Page column 10; 15
(2021/01/23)
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- Crystallization method of Boc-amino acid
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The invention belongs to the technical field of medicinal chemistry, and particularly relates to a crystallization method of Boc amino acid. The preparation method comprises the following steps: (1) reacting free amino acid with di-tert-butyl dicarbonate, carrying out post-treatment to obtain a Boc-protected amino acid reaction solution, and carrying out reduced pressure distillation to remove a solvent until the solvent is dry, thereby obtaining a colorless or light yellow transparent oily substance; (2) adding a seed crystal into the obtained oily substance, standing for a period of time at normal temperature, curing the oily substance to be white, and then adding a weak polar solvent for pulping; (3) pulping for a period of time, filtering, washing, and drying under reduced pressure to obtain the product. According to the method, crystallized Boc amino acid cannot be separated out and crystallized by a conventional method, so that the purity of the product is improved, and meanwhile, the product has certain stability and can be stored for a long time without being decomposed.
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Paragraph 0045-0052
(2021/04/17)
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- Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them
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Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is a suitable target for specific delivery of antitumor drugs and diagnostic agents due to its overexpression in prostate cancer cells. In the current work, we describe the design, synthesis, and biological evaluation of novel low-molecular PSMA ligands and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7. In vitro evaluation of synthesized PSMA ligands on the activity of PSMA shows that the addition of aromatic amino acids into a linker structure leads to a significant increase in inhibition. The conjugates of the most potent ligand with FAM-5 as well as SulfoCy5 demonstrated high affinities to PSMA-expressing tumor cells in vitro. In vivo biodistribution in 22Rv1 xenografts in Balb/c nude mice of PSMA-SulfoCy5 and PSMA-SulfoCy7 conjugates with a novel PSMA ligand demonstrated good visualization of PSMA-expressing tumors. Also, the conjugate PSMA-SulfoCy7 demonstrated the absence of any explicit toxicity up to 87.9 mg/kg.
- Machulkin, Aleksei E.,Shafikov, Radik R.,Uspenskaya, Anastasia A.,Petrov, Stanislav A.,Ber, Anton P.,Skvortsov, Dmitry A.,Nimenko, Ekaterina A.,Zyk, Nikolay U.,Smirnova, Galina B.,Pokrovsky, Vadim S.,Abakumov, Maxim A.,Saltykova, Irina V.,Akhmirov, Rauf T.,Garanina, Anastasiia S.,Polshakov, Vladimir I.,Saveliev, Oleg Y.,Ivanenkov, Yan A.,Aladinskaya, Anastasiya V.,Finko, Alexander V.,Yamansarov, Emil U.,Krasnovskaya, Olga O.,Erofeev, Alexander S.,Gorelkin, Petr V.,Dontsova, Olga A.,Beloglazkina, Elena K.,Zyk, Nikolay V.,Khazanova, Elena S.,Majouga, Alexander G.
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supporting information
p. 4532 - 4552
(2021/05/06)
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- CONJUGATE MONOMETHYL AURISTATIN E TO OBTAIN A COMPOSITION FOR TREATMENT OF PROSTATE CANCER
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?This invention is the conjugate of formula (I) for treatment of tumors expressing PSMA, including PSMA-ligand with linker and antineoplastic agent MMAE, the composition for lyophilizate preparation based on it, the dosage form for therapy and obtained by
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- Direct 3-Acylation of Indolizines by Carboxylic Acids for the Practical Synthesis of Red Light-Releasable Caged Carboxylic Acids
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To enhance the practicality of photouncaging system using 3-acyl-2-methoxyindolizines, direct acylation of indolizines with carboxylic acids was developed using condensation reagents, generally used for peptide coupling. This method allowed for caging a broad range of carboxylic acids with indolizines. The method enabled a facile synthesis of water-soluble caged bioactive carboxylic acids having an intramolecular photosensitizer. The efficient release of carboxylic acids from the synthesized caged compounds upon red light irradiation was confirmed in neutral buffered solutions.
- Watanabe, Kenji,Terao, Nodoka,Niwa, Takashi,Hosoya, Takamitsu
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p. 11822 - 11834
(2021/07/31)
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- Highly Stable Zr(IV)-Based Metal-Organic Frameworks for Chiral Separation in Reversed-Phase Liquid Chromatography
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Separation of racemic mixtures is of great importance and interest in chemistry and pharmacology. Porous materials including metal-organic frameworks (MOFs) have been widely explored as chiral stationary phases (CSPs) in chiral resolution. However, it remains a challenge to develop new CSPs for reversed-phase high-performance liquid chromatography (RP-HPLC), which is the most popular chromatographic mode and accounts for over 90% of all separations. Here we demonstrated for the first time that highly stable Zr-based MOFs can be efficient CSPs for RP-HPLC. By elaborately designing and synthesizing three tetracarboxylate ligands of enantiopure 1,1′-biphenyl-20-crown-6, we prepared three chiral porous Zr(IV)-MOFs with the framework formula [Zr6O4(OH)8(H2O)4(L)2]. They share the same flu topological structure but channels of different sizes and display excellent tolerance to water, acid, and base. Chiral crown ether moieties are periodically aligned within the framework channels, allowing for stereoselective recognition of guest molecules via supramolecular interactions. Under acidic aqueous eluent conditions, the Zr-MOF-packed HPLC columns provide high resolution, selectivity, and durability for the separation of a variety of model racemates, including unprotected and protected amino acids and N-containing drugs, which are comparable to or even superior to several commercial chiral columns for HPLC separation. DFT calculations suggest that the Zr-MOF provides a confined microenvironment for chiral crown ethers that dictates the separation selectivity.
- Jiang, Hong,Yang, Kuiwei,Zhao, Xiangxiang,Zhang, Wenqiang,Liu, Yan,Jiang, Jianwen,Cui, Yong
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supporting information
p. 390 - 398
(2021/01/13)
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- PHOTOLYTIC COMPOUNDS AND TRIPLET-TRIPLET ANNIHILATION MEDIATED PHOTOLYSIS
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The invention provides novel photolytic compounds and prodrugs, nanoparticles and compositions thereof, and methods of conducting photolysis mediated by triplet-triplet annihilation.
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Paragraph 0026; 00203
(2021/04/17)
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- A Simple Nickel Catalyst Enabling an E-Selective Alkyne Semihydrogenation
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Stereoselective alkyne semihydrogenations are attractive approaches to alkenes, which are key building blocks for synthesis. With regards to the most atom-economic reducing agent dihydrogen (H2), only few catalysts for the challenging E-selective alkyne semihydrogenation have been disclosed, each with a unique substrate scope profile. Here, we show that a commercially available nickel catalyst facilitates the E-selective alkyne semihydrogenation of a wide variety of substituted internal alkynes. This results in a simple and broadly applicable overall protocol to stereoselectively access E-alkenes employing H2, which could serve as a general method for synthesis.
- Thiel, Niklas O.,Kaewmee, Benyapa,Tran Ngoc, Trung,Teichert, Johannes F.
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supporting information
p. 1597 - 1603
(2020/02/05)
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- Carbon dots as photocatalysts for organic synthesis: Metal-free methylene-oxygen-bond photocleavage
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We report for the first time that irradiation of four different citric acid-derived carbon dots (CDs), in the absence of any other redox mediators, promotes an organic reaction. In this proof-of-concept study methylene-oxygen bond reductive photocleavage in N-methyl-4-picolinium esters is demonstrated. Cyclic voltammetry and UV-Vis spectra of the CDs and of the esters indicate that photocleavage reactivity correlates with the redox properties and the relative energies expressed in the Fermi scale. A photo-fragmentation mechanism is proposed. This study offers a new possibility to employ inexpensive and readily available CDs to promote photo-organic reactions.
- Cailotto, Simone,Negrato, Matteo,Daniele, Salvatore,Luque, Rafael,Selva, Maurizio,Amadio, Emanuele,Perosa, Alvise
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supporting information
p. 1145 - 1149
(2020/03/11)
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- Design and preparation of a novel prolinamide-based organocatalyst for the solvent-free asymmetric aldol reaction
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The preparation of four novel organocatalysts as highly diastereo and enantioselective catalysts for the solvent-free asymmetric aldol reaction was described. These organocatalysts were synthesized in eight steps applying simple and commercially available starting materials. The best results were obtained for the proline-derived catalyst, providing access to the desired adducts in up to 95% yield, 1:19 syn/anti and 98% e.e. Moreover, even sterically bulky aldehydes and substituted cyclohexanones were well tolerated. DFT calculations and control experiments indicated that several hydrogen bonding interactions between the aldehyde and the enamine intermediate are responsible for the stereoselective chiral induction process and that the trifluoroacetate counter-anion is crucial for the attainment of higher stereoselectivities.
- Martins, Rafaela de S.,Pereira, Mathias P.,de Castro, Pedro P.,Bombonato, Fernanda I.
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- A process for the preparation method of the sulfuric acid [...] intermediates
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The invention discloses a method for preparing sulfuric acid [...] intermediate (2 R, 3 S) - 1, 2 - epoxy - 3 - tert-butoxycarbonyl amino - 4 - phenyl butane of the method, the method cheap L - phenylalanine as the starting material, by with the di-T-n-butyl reaction for protecting amino group, with acetic anhydride condensation, with hydrochloric acid after the occurrence of the chloro in the chiral catalyst under the effects of the asymmetric hydrogenation reduction, finally cyclization under basic conditions to obtain the target product. The present invention provides of sulfuric acid is an important intermediate [...] (2 R, 3 S) - 1, 2 - epoxy - 3 - tert-butoxycarbonyl amino - 4 - phenyl butane preparation method of the raw material is cheap, mild reaction conditions, the synthesis efficiency is high, it is suitable for industrial production, in order to prepare sulfuric acid [...] and intermediate provides a highly efficient way.
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Paragraph 0023; 0024
(2019/07/08)
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- Engineered Substrate for Cyclooxygenase-2: A Pentapeptide Isoconformational to Arachidonic Acid for Managing Inflammation
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Beyond the conventional mode of working of anti-inflammatory agents through enzyme inhibition, herein, COX-2 was provided with an alternate substrate. A proline-centered pentapeptide isoconformational to arachidonic acid, which exhibited appreciable selectivity for COX-2, overcoming acetic acid- and formalin-induced pain in rats to almost 80%, was treated as a substrate by the enzyme. Remarkably, COX-2 metabolized the pentapeptide into small fragments consisting mainly of di- and tripeptides that ensured the safe breakdown of the peptide under in vivo conditions. The kinetic parameter Kcat/Km for COX-2-mediated metabolism of the peptide (6.3 × 105 M-1 s-1) was quite similar to 9.5 × 105 M-1 s-1 for arachidonic acid. Evidenced by the molecular dynamic studies and the use of Y385F COX-2, it was observed that the breakage of the pentapeptide has probably been taken place through H-bond activation of the peptide bond by the side chains of Y385 and S530.
- Kaur, Baljit,Kaur, Manpreet,Kaur, Navjot,Garg, Saweta,Bhatti, Rajbir,Singh, Palwinder
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p. 6363 - 6376
(2019/07/08)
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- Catalytic Transfer Hydrodebenzylation with Low Palladium Loading
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A highly-efficient catalytic system for hydrodebenzylation reaction is described. The cleavage of O-benzyl and N-benzyl protecting groups was performed using an uncommonly low palladium loading (0.02–0.3 mol%; TON up to 5000) in a relatively short reaction time. The approach was used for a variety of substrates including pharmaceutically important precursors, and gram-scale deprotection reaction was shown. Transfer conditions together with easy-to-make Pd/C catalyst are the key features of this debenzylation scheme. (Figure presented.).
- Yakukhnov, Sergey A.,Ananikov, Valentine P.
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supporting information
p. 4781 - 4789
(2019/09/16)
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- PENICILLIN-BINDING PROTEIN INHIBITORS
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Described herein are certain boron-containing compounds, compositions, preparations and their use as modulators of the transpeptidase function of bacterial penicillin-binding proteins and as antibacterial agents. In some embodiments, the compounds described herein inhibit penicillin-binding proteins. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
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Paragraph 00302
(2018/12/13)
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- Synthetic method of intermediate N-BOC-L-phenylalanine
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The invention discloses a synthetic method of intermediate N-BOC-L-phenylalanine. The method comprises the steps that L-phenylalanine, sodium hydroxide, di-tert-butyl dicarbonate ester, cobalt nitrate, sodium carbonate and cobalt oxide are taken as main r
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Paragraph 0008; 0010-0026
(2018/09/28)
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- Synthesis of Main-Chain Ionic Polymers of Chiral Imidazolidinone Organocatalysts and Their Application to Asymmetric Diels–Alder Reactions
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Main-chain ionic polymers incorporating chiral imidazolidinone moieties in the polymer main chain were successfully synthesized by the polyaddition reaction of a chiral imidazolidinone dimer with a disulfonic acid. The organocatalytic activities of these polymers were investigated in the asymmetric Diels–Alder reaction between trans-cinnamaldehyde and 1,3-cyclopentadiene. The catalytic performance of the polymers was found to be sensitive to the chemical structure of the disulfonate units and the imidazolidinone dimer. With the use of these heterogeneous polymeric chiral organocatalysts, enantioselectivities of up to 99% for the endo isomer were obtained. This result was higher than those obtained with corresponding monomeric and dimeric counterparts in a homogeneous solution. The polymeric chiral organocatalyst was recovered and reused several times, maintaining its high enantioselectivity. (Figure presented.).
- Haraguchi, Naoki,Takenaka, Nagisa,Najwa, Aisyah,Takahara, Yuta,Mun, Mah Kar,Itsuno, Shinichi
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supporting information
p. 112 - 123
(2017/12/26)
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- Tertiary-butoxycarbonyl (Boc) – A strategic group for N-protection/deprotection in the synthesis of various natural/unnatural N-unprotected aminoacid cyanomethyl esters
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A number of cyanomethyl esters of natural/unnatural aminoacids with un-protected amino functionality were synthesized because of their synthetic and medicinal importance. Critical N-Boc deprotection methods in the presence of labile (hydrolytic sensitivity) cyanomethyl functionality were screened thoroughly and it was found that readily available 4M HCl in 1,4-dioxane solution (2–4 equiv); acetonitrile, 0 °C, 2–4 h was a suitable condition. This condition was generalized and successfully applied to a variety of alkyl, alkynyl, aryl, heteroaryl, benzyl, azido, spiro amino acid cyanomethylesters irrespective of the nature of the amine (primary or secondary) and the distance between the amine and ester group to achieve final deprotected amino esters with high yield, and purity compared to other commonly known N-protecting groups (Cbz, Fmoc, Ac, Bn, Bz etc.). It was also demonstrated that N-Boc protected aminoacid cyanomethylesters are stable enough to carry out further functionalization compared to N-unprotected counterparts.
- Karmakar, Ananta,Basha, Mushkin,Venkatesh Babu,Botlagunta, Murali,Malik, Noormohamed Abdul,Rampulla, Richard,Mathur, Arvind,Gupta, Arun Kumar
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supporting information
p. 4267 - 4271
(2018/11/03)
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- Synthesis and bioactivities study of new antibacterial peptide mimics: The dialkyl cationic amphiphiles
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The emergence of infectious diseases caused by pathogenic bacteria is widespread. Therefore, it is urgently required to enhance the development of novel antimicrobial agents with high antibacterial activity and low cytotoxicity. A series of novel dialkyl cationic amphiphiles bearing two identical length lipophilic alkyl chains and one non-peptidic amide bond were synthesized and tested for antimicrobial activities against both Gram-positive and Gram-negative bacteria. Particular compounds synthesized showed excellent antibacterial activity toward drug-sensitive bacteria such as S. aureus, E. faecalis, E. coli and S. enterica, and clinical isolates of drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC-producing and NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MIC values of the best compound 4g ranged from 0.5 to 2 μg/mL against all these strains. Moreover, these small molecules acted rapidly as bactericidal agents, and functioned primarily by permeabilization and depolarization of bacterial membranes. Importantly, these compounds were difficult to induce bacterial resistance and can potentially combat drug-resistant bacteria. Thus, these compounds can be developed into a new class of antibacterial peptide mimics against Gram-positive and Gram-negative bacteria, including drug-resistant bacterial strains.
- Zhang, En,Bai, Peng-Yan,Cui, De-Yun,Chu, Wen-Chao,Hua, Yong-Gang,Liu, Qin,Yin, Hai-Yang,Zhang, Yong-Jie,Qin, Shangshang,Liu, Hong-Min
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p. 1489 - 1509
(2017/11/13)
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- Synthesis of Peptide Disulfide-Bond Mimics by Using Fully Orthogonally Protected Diaminodiacids
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A new strategy was developed for the synthesis of peptide disulfide-bond mimics using fully orthogonally protected diaminodiacids. This method overcomes the previous problems of heavy-metal contamination and poor compatibility with Fmoc chemistry and provides a practical avenue for the efficient preparation of peptide disulfide-bond mimics.
- Wang, Tao,Fan, Jian,Chen, Xiao-Xu,Zhao, Rui,Xu, Yang,Bierer, Donald,Liu, Lei,Li, Yi-Ming,Shi, Jing,Fang, Ge-Min
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supporting information
p. 6074 - 6078
(2018/09/27)
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- Synthesis and evaluation of chirally defined side chain variants of 7-chloro-4-aminoquinoline to overcome drug resistance in malaria chemotherapy
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A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methyl-piperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.
- Dola, Vasantha Rao,Soni, Awakash,Agarwal, Pooja,Ahmad, Hafsa,Raju, Kanumuri Siva Rama,Rashid, Mamunur,Wahajuddin, Muhammad,Srivastava, Kumkum,Haq,Dwivedi,Puri,Katti
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- D-amino acid position influences the anticancer activity of galaxamide analogs: An apoptotic mechanism study
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Galaxamide, an extract from Galaxaura filamentosa, is a cyclic pentapeptide containing five L-leucines. Due to the particular cyclic structure and the excellent anticancer activity, synthesis of Galaxamide and its analogs and their subsequent bio-applications have attracted great attention. In the present work, we synthesized six Galaxamide analogs by replacing one of the L-leucines with phenylalanine and varying the D-amino acid position. The anticancer effect of the synthesized Galaxamide analogs was tested against four in vitro human cancer cell lines, human hepatocellular cells (HepG2), human breast cancer cell (MCF-7), human breast adenocarcinoma cells (MDA-MB-435) and a human cervical carcinoma cell line (Hela). Results showed that Galaxamide analogs with differentD-amino acid positions displayed distinct anticancer potential. The Galaxamide analog containing D-amino acid at position 5 (Analog-6) presented the strongest anticancer activity. The mechanism study revealed that Analog-6 could cause the early apoptosis of HepG2 cells by inhibiting their growth in the sub-G1 stage of the cell cycle and induce the chromatin condensation and fragmentation, which can be seen as 68% of HepG2 cells inhibited in the sub-G1 stage. Moreover, a mitochondria-mediated pathway was found to be involved in the apoptotic process of Analog-6 on HepG2 cells.
- Bai, Defa,Yu, Siming,Zhong, Shenghui,Zhao, Bingxin,Qiu, Shaoling,Chen, Jianwei,Lunagariya, Jignesh,Liao, Xiaojian,Xu, Shihai
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- New reagent for the introduction of Boc protecting group to amines: Boc-OASUD
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A new reagent, tert-butyl (2,4-dioxo-3-azaspiro [5,5] undecan-3-yl) carbonate (Boc-OASUD) for the preparation of N-Boc-amino acids is described. The Boc-OASUD reacts with amino acids and their esters at room temperature in the presence of a base and gives N-Boc-amino acids and their esters in good yields and purity. Introduction of the Boc group takes place without racemization. The Boc-OASUD, being a solid and more stable, is a better alternative to di-tert-butyl dicarbonate which is low melting and has to be dispensed in plastic containers than glass because of its poor stability.
- Maheswara Rao, B. Leela,Nowshuddin, Shaik,Jha, Anjali,Divi, Murali K.,Rao
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p. 2127 - 2132
(2017/10/31)
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- Decarboxylative Giese-Type Reaction of Carboxylic Acids Promoted by Visible Light: A Sustainable and Photoredox-Neutral Protocol
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We describe herein a transition-metal-free method for the decarboxylative generation of radicals from carboxylic acids and their 1,4-addition to Michael acceptors. The Fukuzumi catalyst (9-mesitylene-10-methylacridinium perchlorate, [Acr-Mes]ClO4) enabled this transformation under visible-light irradiation at room temperature with CO2 as the only byproduct. The scope and limitations of this protocol were examined by using a range of Michael acceptors (15 examples) and carboxylic acids (18 examples). The use of 3-hydroxypivalic acid in this protocol allowed the straightforward formation of a diastereomerically pure δ-lactone. Moreover, when a homoallylic acid was used, a radical cascade reaction took place with the formation of three C–C bonds.
- Ramirez, Nieves P.,Gonzalez-Gomez, Jose C.
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supporting information
p. 2154 - 2163
(2017/04/24)
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- Synthesis and structural investigation of 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid containing a peptide analogue of the amyloidogenic AS(6-7) sequence: Inhibition of fibril formation
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The incorporation of a single β-amino acid moiety in a highly amyloidogenic peptide sequence resulted in the complete inhibition of amyloid fibril formation. The Boc-l-Phe-l-Leu-OMe sequence 1, which has sequence identity with the N-terminal AS(6-7) of th
- Paikar, Arpita,Debnath, Mintu,Podder, Debasish,Sasmal, Supriya,Haldar, Debasish
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supporting information
p. 4218 - 4225
(2017/07/10)
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- Enantioselective Synthesis of Quaternary Δ4- and Δ5-Dehydroprolines Based on a Two-Step Formal [3+2] Cycloaddition of α-Aryl and α-Alkyl Isocyano(thio)acetates with Vinyl Ketones
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A divergent synthesis of optically active quaternary Δ4- and Δ5-dehydro prolines is developed based on the first catalytic enantioselective conjugate addition of α-substituted isocyano(thio)acetates to vinyl ketones that is general for both α-aryl and α-alkyl isocyano(thio)acetates. The new tetrasubstituted C?N stereocenter is formed without the need of any metal salt due to a bifunctional tertiary amine/squaramide catalyst, featuring a bulky polyaryl sidearm and an unusually short squaramide diamide H???H interatomic distance in the solid state.
- Odriozola, Amaiur,Oiarbide, Mikel,Palomo, Claudio
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supporting information
p. 12758 - 12762
(2017/09/25)
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- Synthetic method for chiral epoxy compound of anti-HIV drug intermediate
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The invention belongs to the field of chemical synthesis and particularly relates to a preparation method for a chiral epoxy compound of an anti-HIV drug intermediate. The method provided by the invention synthesizes the chiral epoxy compound by using a special ligand according to a route represented by the formula. L-phenylalanine used for synthesizing the anti-HIV drug intermediate is low in price and is easily available. The synthetic method is simple and feasible, the yield of the chiral epoxy compound is high, and the synthetic cost of the chiral epoxy compound is obviously lowered compared with that in an existing process.
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Paragraph 0022; 0023; 0024; 0025
(2016/10/10)
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- Peptide based hydrogels for cancer drug release: Modulation of stiffness, drug release and proteolytic stability of hydrogels by incorporating d-amino acid residue(s)
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Synthetic tripeptide based noncytotoxic hydrogelators have been discovered for releasing an anticancer drug at physiological pH and temparature. Interestingly, gel stiffness, drug release capacity and proteolytic stability of these hydrogels have been suc
- Basu, Kingshuk,Baral, Abhishek,Basak, Shibaji,Dehsorkhi, Ashkan,Nanda, Jayanta,Bhunia, Debmalya,Ghosh, Surajit,Castelletto, Valeria,Hamley, Ian W.,Banerjee, Arindam
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supporting information
p. 5045 - 5048
(2016/04/19)
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- Carbon-Nanotube-Mediated Electrochemical Transition in a Redox-Active Supramolecular Hydrogel Derived from Viologen and an l -Alanine-Based Amphiphile
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A two-component hydrogelator (16-A)2-V2+, comprising an l-alanine-based amphiphile (16-A) and a redox-active viologen based partner (V2+), is reported. The formation the hydrogel depended, not only on the acid-to-amine stoichiometric ratio, but on the choice of the l-amino acid group and also on the hydrocarbon chain length of the amphiphilic component. The redox responsive property and the electrochemical behavior of this two-component system were further examined by step-wise chemical and electrochemical reduction of the viologen nucleus (V2+/V+ and V+/V0). The half-wave reduction potentials (E1/2) associated with the viologen ring shifted to more negative values with increasing amine component. This indicates that higher extent of salt formation hinders reduction of the viologen moiety. Interestingly, the incorporation of single-walled carbon nanotubes in the electrochemically irreversible hydrogel (16-A)2-V2+ transformed it into a quasi-reversible electrochemical system.
- Datta, Sougata,Bhattacharya, Santanu
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supporting information
p. 7524 - 7532
(2016/05/24)
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- Aggregation propensity of amyloidogenic and elastomeric dipeptides constituents
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This study demonstrates the self-assembly of N- and C-terminal protected dipeptides Phe–Gly and Pro–Gly which were derived from amyloidogenic and elastomeric peptide sequences. These constituents afforded nanostructured supramolecular ensembles through va
- Kumar, Vikas,Krishna, K. Vijaya,Khanna, Shruti,Joshi, Khashti Ballabh
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supporting information
p. 5369 - 5376
(2016/08/05)
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- Design, synthesis, and in vitro antiplasmodial activity of 4-aminoquinolines containing modified amino acid conjugates
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Abstract: A new series of side chain-modified 4-aminoquinolines were synthesized and screened for in vitro antiplasmodial activity against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Among the series, compounds 30 and 31 showed significant inhibition of parasite growth against K1 strain of P. falciparum with IC50 values 0.28 and 0.31?μM, respectively, whereas compounds 34, 35, and 38 exhibited superior activity against K1 strain with IC50 values 0.18, 0.22, and 0.17?μM, respectively, as compared to 0.255?μM for chloroquine (CQ). All the compounds displayed good resistance factor between 1.54 and >34.48 as against 51.0 for CQ. All these analogues were found to form strong complex with hematin and inhibited the β-hematin formation in vitro, suggesting that this class of compounds act on a heme polymerization target. Overall results suggest that present series of compounds appear to be promising for further lead optimization to obtain compounds active against drug-resistant parasites. Graphical Abstract: [Figure not available: see fulltext.]
- Srinivasarao, Kondaparla,Agarwal, Pooja,Srivastava, Kumkum,Haq,Puri, Sunil K.,Katti
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p. 1148 - 1162
(2016/07/06)
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- Preparation method of phosphonate derivative containing amino acid fragments and antineoplastic application
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The invention discloses a preparation method of a phosphonate derivative (I) containing amino acid fragments and antineoplastic application thereof, and belongs to the field of anticancer drug research. By adopting a drug discovery method based on fragmen
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Paragraph 0012
(2016/10/10)
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- Synthesis of Met-enkephalin by solution-phase peptide synthesis methodology utilizing para-toluene sulfonic acid as N-terminal masking of l-methionine amino acid
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The Met-enkephalin, Tyr-Gly-Gly-Phe-Met, was synthesized by the solution-phase synthesis (SPS) methodology employing -OBzl group as carboxyls' protection, while the t-Boc groups were employed for the N-terminal α-amines' protection for the majority of the amino acids of the pentapeptide sequence. The l-methionine (l-Met) amino acid was used as PTSA.Met-OBzl obtained from the simultaneous protection of the α-amino, and carboxyl group with para-toluene sulfonic acid (PTSA) and as-OBzl ester, respectively in a C-terminal start of the 2?+?2?+?1 fragments condensation convergent synthetic approach. The protection strategy provided a short, single-step, simultaneous, orthogonal, nearly quantitative, robust, and stable process to carry through the protected l-methionine and l-phenylalanine coupling without any structural deformities during coupling and workups. The structurally confirmed final pentapeptide product was feasibly obtained in good yields through the current approach.
- Khan, Riaz A.
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p. 884 - 888
(2016/11/11)
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- Synthesis and antimalarial activity of new 4-aminoquinolines active against drug resistant strains
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In the present study we have synthesized a new class of 4-aminoquinoline derivatives via replacement of the diethylamine functionality of chloroquine (CQ) with acyclic and/or cyclic amine groups containing basic tertiary terminal nitrogen and bioevaluated them for antimalarial activity against Plasmodium falciparum in vitro (CQ-sensitive strain-3D7 & CQ-resistant strain-K1) and Plasmodium yoelii in vivo (N-67 strain). Among the series, thirteen compounds showed superior antimalarial activity against K1 strain as compared to CQ. In addition, all these analogs showed 100% suppression of parasitaemia on day 4 in the in vivo mouse model against N-67 strain when administered orally. Further, biophysical studies suggest that these compounds act on the heme polymerization target.
- Kondaparla, Srinivasarao,Soni, Awakash,Manhas, Ashan,Srivastava, Kumkum,Puri, Sunil K.,Katti
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p. 105676 - 105689
(2016/11/18)
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- Carbohydrates as efficient catalysts for the hydration of α-amino nitriles
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Directed hydration of α-amino nitriles was achieved under mild conditions using simple carbohydrates as catalysts exploiting temporary intramolecularity. A broadly applicable procedure using both formaldehyde and NaOH as catalysts efficiently hydrated a variety of primary and secondary susbtrates, and allowed the hydration of enantiopure substrates to proceed without racemization. This work also provides a rare comparison of the catalytic activity of carbohydrates, and shows that the simple aldehydes at the basis of chemical evolution are efficient organocatalysts mimicking the function of hydratase enzymes. Optimal catalytic efficiency was observed with destabilized aldehydes, and with difficult substrates only simple carbohydrates such as formaldehyde and glycolaldehyde proved reliable.
- Chitale, Sampada,Derasp, Joshua S.,Hussain, Bashir,Tanveer, Kashif,Beauchemin, André M.
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supporting information
p. 13147 - 13150
(2016/11/09)
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- Study of the Paternò–Büchi type photolabile protecting group and application to various acids
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An efficient photolabile protecting group, thiochromone S,S-dioxides with the diazomethyl group for phosphate derivatives, amino acids and sulfonic acids was developed. Protection and photodeprotection reactions proceeded smoothly under mild conditions without any catalyst.1H NMR and HPLC spectra studies demonstrated the photolysis properties of the photolabile protecting group and gave an exact quantification of the released substrates. Specially, the photoproduct derived from the thiochromone derivatives following Paternò–Büchi type photo-cycloaddition showed high fluorescence intensity. This fluorescent characteristic demonstrated the photodeprotection progress also can be monitored by fluorescence spectra.
- Zhang, Youlai,Zhang, Huan,Ma, Chi,Li, Junru,Nishiyama, Yasuhiro,Tanimoto, Hiroki,Morimoto, Tsumoru,Kakiuchi, Kiyomi
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supporting information
p. 5179 - 5184
(2016/11/13)
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- Amidase activity of phosphonate analogue imprinted chymotrypsin mimics in shape-selective, substrate-specific and enantioselective amidolysis of l-phenylalanine-p-nitroanilides
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Focusing on chymotrypsin mimics, highly crosslinked enzyme mimics are synthesized by molecular imprinting technique for the amidolysis of p-nitroanilide of phenylalanine, using phenyl-1-(N-benzyloxycarbonylamino)-2-(phenyl)ethyl phosphonate - the transition state analog of amidolysis - as the template, N-methacryloyl-l-histidine, N-methacryloyl-l-aspartic acid, and N-methacryloyl-l-serine as the functional monomers and EGDMA as the crosslinking agent. The amidase activity of the enzyme mimics follows pseudo first order kinetics. The transition state analog provides a tetrahedral geometry complementary to the transition state intermediate, which is responsible for the catalytic activity of the imprinted enzyme mimics. The enzyme mimics show stereospecificity and substrate selectivity in the amidolysis of phenylalanine p-nitroanilide. The proper orientation of the reactive functionalities in the super crosslinked macroporous polymer matrix for selective binding of the substrate through H-bonding is responsible for the high imprinting efficiency and substrate specificity of the imprinted polymer catalysts. Low cost, ease of preparation, high thermal stability, reusability and higher shelf life make the polymer catalysts better chymotrypsin mimics.
- Mathew, Divya,Thomas, Benny,Devaky
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- Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation
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Novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation were developed; some of them possess Ki values in the micromolar range. We studied the structure-activity relationship of these derivatives and we performed docking studies, which allowed us to find out the key interactions established by the inhibitors with the target enzyme. Biological results indicate that the nature of the P2 and P3 substituents and their binding to the S2/S3 pockets is strictly interdependent.
- Ettari, Roberta,Pinto, Andrea,Previti, Santo,Tamborini, Lucia,Angelo, Ilenia C.,La Pietra, Valeria,Marinelli, Luciana,Novellino, Ettore,Schirmeister, Tanja,Zappalà, Maria,Grasso, Silvana,De Micheli, Carlo,Conti, Paola
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p. 7053 - 7060
(2015/11/11)
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- Aqueous MW eco-friendly protocol for amino group protection
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In this paper a new catalyst-free and on-water method for protection of amines and amino acids with di-tert-butyl dicarbonate, 9-fluorenylmethoxycarbonyl chloride, acetyl chloride and tosyl chloride is presented. The protection can be realized in a few minutes under microwave-assistance. The reaction proved to be chemoselective in presence of ambident nucleophiles and water solution of di-tert-butyl carboxylic acid or chloride acid are the only wastes produced.
- Nardi,Cano, N. Herrera,Costanzo,Oliverio,Sindona,Procopio
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p. 18751 - 18760
(2015/06/15)
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- Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; Synthesis of 5F203 hydrogels for local delivery
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Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts' generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles' activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R2 > 0.7). Time-dependent appearance of γ-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs' hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs' activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines.
- Stone, Erica L.,Citossi, Francesca,Singh, Rajinder,Kaur, Balvinder,Gaskell, Margaret,Farmer, Peter B.,Monks, Anne,Hose, Curtis,Stevens, Malcolm F.G.,Leong, Chee-Onn,Stocks, Michael,Kellam, Barrie,Marlow, Maria,Bradshaw, Tracey D.
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supporting information
p. 6891 - 6899
(2015/11/11)
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- Safe Removal of the Allyl Protecting Groups of Allyl Esters using a Recyclable, Low-Leaching and Ligand-Free Palladium Nanoparticle Catalyst
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A safe, facile and low-leaching (up to 0.04ppm) method has been developed for the removal of allyl, prenyl and benzyl protecting groups from the corresponding esters, using a sulfur-modified gold-supported palladium (SAPd) nanoparticle catalyst, which is known to be non-flammable. The catalyst itself was found to be recyclable and the reaction appeared to proceed on the surface of the SAPd.
- Takagi, Koji,Fukuda, Hayato,Shuto, Satoshi,Otaka, Akira,Arisawa, Mitsuhiro
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supporting information
p. 2119 - 2124
(2015/06/23)
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- Synthesis of d,l-amino acid derivatives bearing a thiol at the β-position and their enzymatic optical resolution
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Amino acids bearing a thiol group at the β-position are useful for native chemical ligation. Phenylalanine and tyrosine derivatives bearing a thiol group at the β-position were synthesized. Racemic phenylalanine and tyrosine were selected as starting materials and were introduced a bromo atom at the β-position by photoreaction. Subsequent substitution reaction of the bromo atom with p-methoxybenzylmercaptan yielded the corresponding amino acids bearing a thiol group at the β-position. Enzymatic optical resolution using l-aminoacylase and subsequent chemical conversion gave the corresponding optically pure l- and d-phenylalanine and tyrosine derivatives bearing a thiol group at the β-position.
- Morishita, Yasuhito,Kaino, Tomoka,Okamoto, Ryo,Izumi, Masayuki,Kajihara, Yasuhiro
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p. 6565 - 6568
(2015/11/09)
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- Chiral perylene diimides: Building blocks for ionic self-assembly
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A chiral perylene diimide building block has been prepared based on an amine derivative of the amino acid L-phenylalanine. Detailed studies were carried out into the self-assembly behaviour of the material in solution and the solid state using UV/Vis, circular dichroism (CD) and fluorescence spectroscopy. For the charged building block BTPPP, the molecular chirality of the side chains is translated into the chiral supramolecular structure in the form of right-handed helical aggregates in aqueous solution. Temperature-dependent UV/Vis studies of BTPPP in aqueous solution showed that the self-assembly behaviour of this dye can be well described by an isodesmic model in which aggregation occurs to generate short stacks in a reversible manner. Wide-angle X-ray diffraction studies (WXRD) revealed that this material self-organises into aggregates with π-π stacking distances typical for π-conjugated materials. TEM investigations revealed the formation of self-assembled structures of low order and with no expression of chirality evident. Differential scanning calorimetry (DSC) and polarised optical microscopy (POM) were used to investigate the mesophase properties. Optical textures representative of columnar liquid-crystalline phases were observed for solvent-annealed samples of BTPPP. The high solubility, tunable self-assembly and chiral ordering of these materials demonstrate their potential as new molecular building blocks for use in the construction of chiro-optical structures and devices.
- Echue, Geraldine,Lloyd-Jones, Guy C.,Faul, Charl F. J.
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supporting information
p. 5118 - 5128
(2015/03/30)
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- Deprotection/reprotection of the amino group in α-amino acids and peptides. A one-pot procedure in [Bmim][BF4] ionic liquid
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This paper presents an efficient one-pot protocol for the sequential deprotection/reprotection of the α-amino group in α-amino acid and dipeptide methyl esters. [Bmim][BF4] is used as the solvent in the entire process. In particular, the use of the ionic liquid allows for rapid and clean removal of the 4-nitrobenzenesulfonyl (nosyl) group and for facile subsequent tert-butyloxycarbonylation of the free α-amino function under very mild conditions. N-Boc-α-amino acid as well as peptide derivatives are isolated in excellent yields, and do not require any further purification. Absolute configurations of the precursors are totally preserved during the process.
- Di Gioia,Barattucci,Bonaccorsi,Leggio,Minuti,Romio,Temperini,Siciliano
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p. 2678 - 2686
(2014/01/06)
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- Soluble non-cross-linked poly(norbornene) supports for peptide synthesis with minimal reagents
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Solid-phase peptide synthesis has been an attractive method for synthesizing peptides because it is quick and can be automated. The heterogeneous reaction medium in solid-phase peptide synthesis necessitates the use of large equivalents of reagents to drive the reactions to completion. Peptide synthesis using soluble, yet isolable, supports is an attractive alternative to solid-phase peptide synthesis. Reported herein is a soluble poly(norbornene)-derived support containing multiple attachment sites for high loading capacities and solubilizing oligoether/alkyl groups. The Ala-attached support has been used to synthesize tri- to octapeptides in 28 to 97% yields using only 1.2 equiv of amino acids and coupling reagents. The acyclic hexapeptide precursor to natural product segatalin A was synthesized in 41% yield on the support using one-eighth of the equivalents of coupling reagents compared to that in reported procedures. The support could be recovered in up to 98% yield after peptide synthesis, and the recovered support was utilized to synthesize tri- and tetrapeptides that contain amino acids other than Ala at the C-terminus in ca. 80% yields.
- Naganna, Nimmashetti,Madhavan, Nandita
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p. 11549 - 11557
(2015/02/19)
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- PEPTIDYLARGININE DEIMINASES (PAD) INHIBITORS
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The present invention relates to compounds of the formula (I): as inhibitors of peptidylarginine deiminases (PADs). It also concerns their use in therapy, particularly in the prophylaxis or treatment of neural injury, and other conditions including cancer, multiple sclerosis, glaucoma, arthritis, rheumatoid arthritis lupus, Alzheimer's disease, and ulcerative colitis.
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(2014/12/12)
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