- Remarkable effects of donor esters on the α-chymotrypsin-catalyzed couplings of inherently poor amino acid substrates
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The extremely low efficiency during the α-chymotrypsin-catalyzed coupling of an inherently poor amino acid substrate, e.g., alanine, using the methyl ester as an acyl donor was significantly improved using esters such as the 2,2,2-trifluoroethyl or carbamoylmethyl ester. The ameliorating effect of the latter ester was especially significant.
- Miyazawa, Toshifumi,Tanaka, Kayoko,Ensatsu, Eiichi,Yanagihara, Ryoji,Yamada, Takashi
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- The reaction between C- and/or N-terminal protected α-aminoacid and sodium hydrogen telluride
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Sodium hydrogen telluride selectively removed C-terminal alkyl group of C- and/or N-terminal protected α-aminoacids with yields ranging from 70% to 95%.
- Li,Zhou,Ma
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- Photoinduced release of neurotransmitter amino acids from coumarin-fused julolidine ester cages
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The photoinduced release of several neurotransmitter amino acids (glycine, alanine, glutamic acid, β-alanine and γ-aminobutyric acid) was accomplished from ester cages based on a new photoremovable protecting group consisting of a coumarin built on the julolidine nucleus, namely a (11-oxo-2,3,5,6,7,11-hexahydro-1H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-9-yl) methyl group. Photolysis and steady-state sensitization studies revealed that release of the active molecule occurred in short irradiation times at long wavelengths, with a very promising performance at 419 nm. Given the interest in the development of novel protecting groups that are cleavable with UV A or even visible radiation, it was found that a structural modification in the coumarin ring by assembly of a fused julolidine leads to a promising photolabile protecting group for organic synthesis and also for bioapplications. Photolysis and steady-state sensitization studies of several neurotransmitter amino acids from ester cages based on a new photoremovable protecting group consisting of a coumarin-fused julolidine nucleus, revealed that the release of the active molecule occurred in short irradiation times at long wavelengths, especially at 419 nm. Copyright
- Piloto, Ana M.,Hungerford, Graham,Costa, Susana P. G.,Goncalves, M. Sameiro T.
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- A novel immobilized chloroperoxidase biocatalyst with improved stability for the oxidation of amino alcohols to amino aldehydes
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Chloroperoxidase from Caldariomyces fumago (CPO, EC 1.11.1.10) is one of the most promising of the heme peroxidase enzymes for synthetic applications. Since the synthetic use of CPO suffers severely from its rapid deactivation in the presence of peroxides, the immobilization of this enzyme was studied as a possibility for stability improvement. Three methods of immobilization were considered using monoaminoethyl-N-aminoethyl (MANA) agarose gels: ionic adsorption, covalent attachment via carbodiimide coupled activation and covalent attachment of oxidized CPO. The most successful results led to almost complete immobilization with retained activities of around 51% for the two methods of covalent attachment and 77% for the ionic adsorption of CPO on MANA. Besides, all of the immobilized enzyme systems showed drastically improved stability toward presence of peroxide; CPO immobilized on MANA through carbodiimide coupled method resulted to be the most stable one with an increase in apparent half-life time of more than 500-fold that of the soluble enzyme. CPO immobilized by this method was compared to the soluble enzyme as catalyst for Cbz-ethanolamine oxidation to Cbz-glycinal using tert-butyl hydroperoxide (t-BuOOH) as an oxidant. Despite the lower reaction rate, the reaction catalyzed by immobilized CPO reached higher Cbz-glycinal yield with almost three-fold lower activity loss.
- Pesic, Milja,Lopez, Carmen,Alvaro, Gregorio,Lopez-Santin, Josep
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- ACTION ON PEPTIDES BY WHEAT CARBOXYPEPTIDASE
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A kinetic analysis has been performed with purified wheat carboxypeptidase by the use of N-acyl dipeptides, Z-Gly-Pro-Leu-Gly (Z=benzyloxycarbonyl), angiotensin II and bradykinin.The values of kcat were dramatically influenced by amino acid residues occupying the penultimate position from the carbonyl terminus of substrates.The structure of the substrate did not appreciably affect the Km values. Key Word Index - Triticum aestivum; Gramineae; wheat; carboxypeptidase; peptides; kinetic parameters.
- Umetsu, H.,Ichishima, E.
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- Scandium(III) triflate-promoted serine/threonine-selective peptide bond cleavage
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The site-selective cleavage of peptide bonds is an important chemical modification that is useful not only for the structural determination of peptides, but also as an artificial modulator of peptide/protein function and properties. Here we report site-selective hydrolysis of peptide bonds at the Ser and Thr positions with a high conversion yield. This chemical cleavage relies on Sc(iii)-promoted N,O-acyl rearrangement and subsequent hydrolysis. The method is applicable to a broad scope of polypeptides with various functional groups, including a post-translationally modified peptide that is unsuitable for enzymatic hydrolysis. The system was further extended to site-selective cleavage of a native protein, Aβ1-42, which is closely related to the onset of Alzheimer's disease.
- Ni, Jizhi,Sohma, Youhei,Kanai, Motomu
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- 15N NMR Spectroscopy; 24-Chemical Shifts and Coupling Constants of α-Amino Acid N-Carboxyanhydrides and Related Heterocycles
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The chemical shifts of amino acid N-carboxyanhydrides (NCAs) and cyclic or linear urethanes are less sensitive to solvent effects than those of amides and lactams.The values of the one-bond 15N-1H coupling constants depend on the solvent and are 5-8 Hz larger than those of ureas and amides.The 15N-13C coupling constant of the N-CO group is also unusually high, while that of the N-CH group lies within the range known for N-acetylated aliphatic amines.The one-bond 15N-13C coupling constant was found to be insensitive to conformational changes.
- Kricheldorf, Hans R.
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- Synthesis, characterization, and DGAT1 inhibition of new 5-piperazinethiazole and 5-piperidinethiazole analogs
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In this study, a novel series of 5-piperazinethiazole 2,2-dimethylbutanoic acid and 5-piperidinethiazole 2,2-dimethylbutanoic acid derivatives have been synthesized. Structures of the newly synthesized compounds have been elucidated using 1H-NMR, 13C-NMR, high-resolution mass spectroscopy, and high-performance liquid chromatographic analysis. The synthesized derivatives have been evaluated in vitro for their ability to inhibit the enzyme diacylglycerol acyltransferase 1 responsible for triglyceride biosynthesis.
- Kadam, Kishorkumar S.,Gandhi, Thirumanavelan,Reddy, M. Maheshkumar,Gupte, Amol,Sharma, Rajiv
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- First examples of bispidine-ferrocene cyclophanes
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Two approaches for the syntheses of bispidine-ferrocene cyclophanes were reported. Both include the acylation of 1,5-dimethylbispidin-9-one (H2Bp) or its pendant amino-armed derivative by 1,1’-ferrocenoyl (Fc(CO)2) dichloride. The first approach allowed to isolate di-, tri- and pentameric cyclic oligomers of composition (BpFc(CO)2)n. The second one included the preliminary functionalization of H2Bp by N-protected glycine followed by deprotection and cyclization with Fc(COCl)2. The crystal structure of two new bispidine-ferrocene cyclophanes was established by single-crystal X-ray study. This study revealed the anti-conformation of amido-groups attached to the bispidine nitrogen atoms for both molecules. Various NMR techniques were applied to study the solution behavior of the macrocycles; the predominant anti-conformation in solution was also proved. The acyclic model compound Bp(FcCO)2 also showed only anti-conformer as revealed by VT-NMR and X-ray studies. Cyclic voltammetry study showed the difference in oxidation potentials of the Fc moiety within the row Bp(FcCO)2 – (BpFc(CO)2)2 – (BpFc(CO)2)3 with splitting of the oxidation curve in two later cases. The results obtained in this work will find an application in design and study of novel bispidine-ferrocene cyclophanes for the purposes of supramolecular sensing and catalysis.
- Churakov, A. V.,Gaisen, S. V.,Krut'ko, D. P.,Lemenovsky, D. A.,Medved'ko, A. V.,Minyaev, M. E.,Moiseeva, A. A.,Vatsadze, S. Z.,Wang, L.,Yu, H.
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- Enzyme-Specific Activation versus Leaving Group Ability
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Enzyme-specific activation and the substrate mimetics strategy are effective ways to circumvent the limited substrate recognition often encountered in protease-catalyzed peptide synthesis. A key structural element in both approaches is the guanidinophenyl (OGp) ester, which enables important interactions for affinity and recognition by the enzyme-at least, this is usually the explanation given for its successful application. In this study we show that leaving group ability is of equal or even greater importance. To this end we used both experimental and computational methods: 1) synthesis of close analogues of OGp, and their evaluation in a dipeptide synthesis assay with trypsin, 2) molecular docking studies to provide insights into the binding mode, and 3) ab initio calculations to evaluate their electronic properties.
- de Beer, Roseri J.A.C.,Boegels, Berry,Schaftenaar, Gijs,Zarzycka, Barbara,Quaedflieg, Peter J.L.M.,van Delft, Floris L.,Nabuurs, Sander B.,Rutjes, Floris P.J.T.
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- Preparation method of water-soluble amino acid phytosterol ester hydrochloride
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The invention discloses a preparation method of high-quality water-soluble amino acid phytosterol ester hydrochloride. According to the method, after N-Cbz-amino acid, phytosterol and a catalyst completely react in a solvent, benzyloxycarbonyl protection is removed through an inorganic acid to obtain a crude product, the crude product is separated through a silica gel column, an elution solvent isremoved through evaporation, an obtained solid is dried, and the product amino acid phytosterol ester hydrochloride is obtained. The preparation method is simple to operate, high in purity, good in quality and suitable for large-scale industrial production in the industries of medicines, foods and the like.
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Paragraph 0027-0028
(2020/07/21)
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- Synthesis and In Vitro Neuroprotective Activity of Glycine Analogs of Gk-2 Dimeric Dipeptide Mimetic of Nerve Growth Factor 4th Loop
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A dimeric dipeptide mimetic of nerve growth factor (NGF), bis-(N-monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), was previously developed at V. V. Zakusov State Institute of Pharmacology, activated specific TrkA receptors, and exhibited neuroprotective activity in vitro (10–5 – 10–9 M) and in vivo (0.1 – 10 mg/kg i.p. and p.o.). GK-2 was designed based on the beta-turn (-Asp94-Glu95-Lys96-Gln97-) of the NGF 4th loop and preserved the central dipeptide fragment (-Glu95-Lys96-). The Asp94 residue was replaced by its monosuccinyl bioisostere. The dimeric structure of NGF was reproduced using a bivalent hexamethylenediamine spacer. The structure—activity (neuroprotective) relationship for GK-2 was studied in the present work using a glycine scan, i.e., successive replacement of the peptide side groups by H. The bis-(N-acetyl-L-glutamyl-L-lysine) (GK-2Ac), bis-(N-monosuccinylglycyl-L-lysine) (GK-2-Gly1), and bis-(N-monosuccinyl-L-glutamylglycine) hexamethylenediamides (GK-2-Gly2) were less active with neuroprotective activity in vitro under oxidative stress for HT22 cells at concentrations 10 – 100 times greater than GK-2. The conclusion was drawn that each side radical of GK-2 was important for manifestation of the full neuroprotective activity of dimeric dipeptide GK-2, a mimetic of the NGF 4th loop. However, removal of any of the side radicals would probably not change the active structure of the beta-turn so that the two remaining side radicals should retain the ability to bind to their TrkA subsites. This could explain the retention of neuroprotective activity in the GK-2 glycine analogs.
- Antipov, P. I.,Antipova, T. A.,Firsova, Yu. N.,Gudasheva, T. A.,Nikolaev, S. V.,Rebeko, A. G.,Sazonova, N. M.,Tarasyuk, A. V.,Zvyagintsev, A. A.
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- Thiourea Modified Doxorubicin: A Perspective pH-Sensitive Prodrug
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A novel approach to the synthesis of pH-sensitive prodrugs has been proposed: thiourea drug modification. Resulting prodrugs can release the cytotoxic agent and the biologically active 2-thiohydantoin in the acidic environment of tumor cells. The concept of acid-catalyzed cyclization of thioureas to 2-thiohydantoins has been proven using a FRET model. Dual prodrugs of model azidothymidine, cytotoxic doxorubicin, and 2-thiohydantoin albutoin were obtained, which release the corresponding drugs in the acidic environment. The resulting doxorubicin prodrug was tested on prostate cancer cells and showed that the thiourea-modified prodrug is less cytotoxic (average IC50 ranging from 0.5584 to 0.9885 μM) than doxorubicin (IC50 ranging from 0.01258 to 0.02559 μM) in neutral pH 7.6 and has similar toxicity (average IC50 ranging from 0.4970 to 0.7994 μM) to doxorubicin (IC50 ranging from 0.2303 to 0.8110 μM) under mildly acidic conditions of cancer cells. Cellular and nuclear accumulation in PC3 tumor cells of Dox prodrug is much higher than accumulation of free doxorubicin.
- Krasnovskaya, Olga O.,Malinnikov, Vladislav M.,Dashkova, Natalia S.,Gerasimov, Vasily M.,Grishina, Irina V.,Kireev, Igor I.,Lavrushkina, Svetlana V.,Panchenko, Pavel A.,Zakharko, Marina A.,Ignatov, Pavel A.,Fedorova, Olga A.,Jonusauskas, Gediminas,Skvortsov, Dmitry A.,Kovalev, Sergey S.,Beloglazkina, Elena K.,Zyk, Nikolay V.,Majouga, Alexander G.
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p. 741 - 750
(2019/03/02)
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- Pd(II)-Catalyzed [4 + 2] Heterocyclization Sequence for Polyheterocycle Generation
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A new Pd(II)-catalyzed cascade sequence for the formation of polyheterocycles, from simple starting materials, is reported. The sequence is applicable to both indole and pyrrole substrates, and a range of substituents are tolerated. The reaction is thought to proceed by a Pd(II)-catalyzed C-H activated Heck reaction followed by a second Pd(II)-catalyzed aza-Wacker reaction with two Cu(II)-mediated Pd(0) turnovers per sequence. The sequence can be considered a formal [4 + 2] heterocyclization.
- Glaisyer, Elizabeth L.,Watt, Michael S.,Booker-Milburn, Kevin I.
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supporting information
p. 5877 - 5880
(2018/09/25)
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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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- NOVEL SUBSTITUTED AMIDES OF TRITERPENE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to compounds of novel substituted amides of triteripene derivatives of formula (I); or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, prodrugs, compositions or combination thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, Y, Z1, Z2, Z3 and formula (II) are as defined herein. The present invention also relates to,, and pharmaceutical compositions comprising compounds of formula (I) useful for the treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 32
(2017/02/28)
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- Environmentally Benign CO2-Based Copolymers: Degradable Polycarbonates Derived from Dihydroxybutyric Acid and Their Platinum-Polymer Conjugates
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(S)-3,4-Dihydroxybutyric acid ((S)-3,4-DHBA), an endogenous straight chain fatty acid, is a normal human urinary metabolite and can be obtained as a valuable chiral biomass for synthesizing statin-class drugs. Hence, its epoxide derivatives should serve as promising monomers for producing biocompatible polymers via alternating copolymerization with carbon dioxide. In this report, we demonstrate the production of poly(tert-butyl 3,4-dihydroxybutanoate carbonate) from racemic-tert-butyl 3,4-epoxybutanoate (rac-tBu 3,4-EB) and CO2 using bifunctional cobalt(III) salen catalysts. The copolymer exhibited greater than 99% carbonate linkages, 100% head-to-tail regioselectivity, and a glass-transition temperature (Tg) of 37 °C. By way of comparison, the similarly derived polycarbonate from the sterically less congested monomer, methyl 3,4-epoxybutanoate, displayed 91.8% head-to-tail content and a lower Tg of 18 °C. The tert-butyl protecting group of the pendant carboxylate group was removed using trifluoroacetic acid to afford poly(3,4-dihydroxybutyric acid carbonate). Depolymerization of poly(tert-butyl 3,4-dihydroxybutanoate carbonate) in the presence of strong base results in a stepwise unzipping of the polymer chain to yield the corresponding cyclic carbonate. Furthermore, the full degradation of the acetyl-capped poly(potassium 3,4-dihydroxybutyrate carbonate) resulted in formation of the biomasses, β-hydroxy-γ-butyrolacetone and 3,4-dihydroxybutyrate, in water (pH = 8) at 37 °C. In addition, water-soluble platinum-polymer conjugates were synthesized with platinum loading of 21.3-29.5%, suggesting poly(3,4-dihydroxybutyric acid carbonate) and related derivatives may serve as platinum drug delivery carriers.
- Tsai, Fu-Te,Wang, Yanyan,Darensbourg, Donald J.
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supporting information
p. 4626 - 4633
(2016/05/19)
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- Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent
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Among the small peptides 2-31, (H)Gly-Gly-Phe-Leu(OMe) (30) reduced prostaglandin production of COX-2 with an IC50 of 60 nM relative to 6000 nM for COX-1. The 5 mg kg-1 dose of compound 30 rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound 30 for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and veratrine, respectively, as biomarkers. The interactions of 30 with COX-2 were supported by isothermal calorimetry experiments showing a Ka of 6.10 ± 1.10 × 104 M-1 and ΔG of -100.3 kJ mol-1 in comparison to a Ka 0.41 × 103 ± 0.09 M-1 and ΔG of -19.2 ± 0.06 kJ mol-1 for COX-1. Moreover, compound 30 did not show toxicity up to a 2000 mg kg-1 dose. Hence, we suggest peptide 30 as a highly potent and promising candidate for further development into an anti-inflammatory drug.
- Singh, Palwinder,Kaur, Sukhmeet,Kaur, Jagroop,Singh, Gurjit,Bhatti, Rajbir
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p. 3920 - 3934
(2016/05/24)
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- Structural verification via convergent total synthesis of dipeptide–lipids isolated from Porphyromonas gingivalis
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A periodontal pathogen, Porphyromonas gingivalis, produces two serine dipeptide lipid classes that we labeled lipid 654 and lipid 430, and both contain L-serine as the terminal amino acid. The lipid 654 and lipid 430 classes are each comprised of three species with differing fatty acid substitutions, but the most abundant species demonstrate unit masses of either 654 or 430, respectively. Recently we observed that the lipid 654 can be hydrolyzed by specific lipases to lipid 430. However, a substantial percentage of the naturally occurring lipid 654 cannot be enzymatically hydrolyzed to lipid 430. The observed partial hydrolysis could be due to the presence of a mixture of stereoisomers. Testing this theory requires structural verification of our so-called 654 and 430 by total synthesis. We present herein details of the convergent synthesis of lipids 430 and 654, which confirm the proposed structure of P. gingivalis lipid 654 to be (3R and 3S)-L-serine-2. The bis(fatty acid) (3R)-L-serine-2 was prepared as well as the synthetic precursor, serine dipeptide mono-fatty acid (3R)-L-serine-1, which is the structure of lipid 430. We also synthesized the (3S)-L-serine-2 diastereomer as well as (3S)-L-serine-1. Using these synthetic standards, we confirmed that PLA2-mediated hydrolysis of lipid 654 is enantioselective in that only the (3R)-L-serine-2, but not (3S)-L-serine 2 is enzymatically hydrolyzed.
- Dietz, Christopher,Hart, Theresa K.,Nemati, Reza,Yao, Xudong,Nichols, Frank C.,Smith, Michael B.
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p. 7557 - 7569
(2016/11/11)
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- A kind of amino acid tanshinone phenolic derivative and its preparation method
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The invention relates to amino acid tanshinone phenolic ester derivatives and a preparation method thereof. The derivatives are obtained by reducing tanshinone compounds and performing esterified modification on the reduced tanshinone compounds and an amino acid into prodrugs, wherein the tanshinone compounds are phenanthrenequinone compounds which exist in salvia miltiorrhiza and have an o-quinone structure; the esterified amino acid is alpha-amino acid. The amino acid tanshinone phenolic ester derivatives are compounds having a structure of a general formula (I) or medicinal salts thereof, wherein R1 and R2 represent H or acyl alpha-amino acid and a salt thereof, and R1 and R2 are not H at the same time. The amino acid tanshinone phenolic ester derivatives have the beneficial effects that firstly, the new tanshinone derivatives are provided and the new substances have potential treatment effect on some serious diseases such as tumors, and secondly, amino acid tanshinone phenolic ester derivatives have excellent water solubility and thus can be prepared into injections conveniently in addition to various oral preparations, and therefore, the amino acid tanshinone phenolic ester derivatives are capable of quickly taking effect in disease treatment. As important prodrugs, the amino acid tanshinone phenolic ester derivatives have important application value.
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Paragraph 0035; 0175; 0186
(2016/10/09)
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- Compound with anti-tumor activity and application of compound
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The invention discloses an amino-acid-oriented steroid small peptide compound with anti-tumor activity.The structure of the compound is shown in the general formula I.Corresponding hydrazone and oxime are synthesized with dehydroepiandrosterone (DHEA), DHEA and an amino acid derivative are then condensed, and the compound is obtained.The compound has a remarkable inhibiting effect on growth of tumor cells especially human hepatoma cells, human lung cancer cells and human melanoma cells, and can serve as an active ingredient for anti-tumor medicine to be applied to prevention and treatment of cancer.
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Paragraph 0027; 0028; 0029
(2016/10/10)
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- Synthesis and applications in Henry reactions of novel chiral thiazoline tridentate ligands
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Several novel chiral tridentate ligands containing thiazoline were efficiently synthesized from commercially available l=cysteine in high yield. These ligands were subsequently applied to the asymmetric Henry reaction of nitromethane and various aldehydes. It was found that the structures of the thiazoline ligands had a significant influence on the enantioselectivity. It was shown that the optimal catalyst for this reaction was a ligand complexed with CuCl, which was formed from chiral thiazoline with chiral aminoalcohol. At -20°C, with 10 mol% of this ligand, a product with (S)-configuration was isolated in 93% yield and 98% enantiomeric excess.
- Shi, Ye,Li, Yang,Sun, Jingbo,Lai, Qi,Wei, Chiyu,Gong, Zhiyong,Gu, Qiang,Song, Zhiguang
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p. 661 - 667
(2015/09/28)
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- Autotandem catalysis: Synthesis of pyrroles by gold-catalyzed cascade reaction
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A novel synthesis of substituted pyrroles by a gold(I)-catalyzed cascade reaction has been developed. The reaction proceeded with an autotandem catalysis consisting of an initial addition of gold-acetylide to an acetal moiety and was followed by gold-catalyzed 5-endo-dig cyclization and aromatization. Gold catalysts play a dual role in activating nucleophilicity or electrophilicity of terminal acetylenes by forming gold-acetylides or by π-coordination. The formal (3 + 2) annulation of two components provided a variety of substituted pyrroles in a modular fashion.
- Ueda, Hirofumi,Yamaguchi, Minami,Kameya, Hiroshi,Sugimoto, Kenji,Tokuyama, Hidetoshi
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supporting information
p. 4948 - 4951
(2015/04/27)
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- Total synthesis of PDE-I and -II by copper-mediated double aryl amination This paper is dedicated to Professor Teruaki Mukaiyama in celebration of the 40th anniversary of the Mukaiyama aldol reaction
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A concise total synthesis of PDE-I and -II featuring copper-mediated double aryl amination with the combination of CuI, CsOAc, and Cs2CO 3 is described. The highly substituted pyrroloindole skeleton was constructed by a one-pot five-step sequence including double aryl amination, β-elimination, deprotection of a Cbz group, and unexpected formation of an indole via removal of an Ns group followed by rearomatization. The undesired elimination of the protecting group (Ns group) was hampered by using the Boc group as a protecting group in the second-generation synthesis, which excluded the reduction of the indole required in the first-generation synthesis.
- Okano, Kentaro,Mitsuhashi, Nakako,Tokuyama, Hidetoshi
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p. 10946 - 10954
(2014/01/06)
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- An approach to nanobioparticles - Synthesis and characterization of fulleropeptides
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Two sets of new peptides incorporating fulleropyrrolidine units - Fp-GABAn-Glym-OtBu - have been designed, synthesized and completely characterized. In the first series the chain contained only GABA (γ-aminobutyric) residues, whereas in the second one glycine moieties were also inserted as well as GABA. Most of the target compounds were prepared by DCC/DMAP-assisted coupling of previously synthesized GABA-containing fulleropyrrolidinic acid and corresponding C-protected small peptides, although for two fulleropeptides [3+2] cycloadditions of azomethine ylides to C 60 were employed. All new compounds were characterized by standard spectroscopic methods. Complete assignments of peptide spin systems were achieved by extensive NMR analysis (1H, 13C, H,H-COSY, HSQC, HMBC and TOCSY). Copyright
- Bjelakovic, Mira,Todorovic, Nina,Milic, Dragana
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supporting information
p. 5291 - 5300
(2012/10/29)
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- In situ aldehyde generation for aldol addition reactions catalyzed by d-fructose-6-phosphate aldolase
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In situ coupling of aldehyde generation, by a mild alcohol oxidation, with an enzymatic aldol addition reaction, mediated by d-fructose-6-phosphate aldolase (FSA) has been investigated as an approach to improve the performance of the process. Four sustainable oxidation methods compatible with the activity and stability of the enzymatic aldol addition have been assayed. Among them, the laccase/O2/2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and alcohol oxidase gave the best results for the N-Cbz-aminoethanol to N-Cbz-glycinal (53%) and furfuryl alcohol to furfural (89%), respectively, followed by the aldol addition with hydroxyacetone catalyzed by FSA A129S mutant.
- Mifsud, Maria,Szekrenyi, Anna,Joglar, Jesus,Clapes, Pere
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p. 102 - 107
(2012/10/30)
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- Papain-Specific Activating Esters in Aqueous Dipeptide Synthesis
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Enzymatic peptide synthesis has the potential to be a viable alternative for chemical peptide synthesis. Because of the increasing commercial interest in peptides, new and improved enzymatic synthesis methods are desirable. In recently developed enzymatic strategies such as substrate mimetic approaches and enzyme-specific activation, use of the guanidinophenyl ester (OGp) group has been shown to suffer from some drawbacks. OGp esters are sensitive to spontaneous chemical hydrolysis and the group is expensive to synthesize and therefore not suitable for large-scale applications. On the basis of earlier computational studies, we hypothesized that OGp might be replaceable by simpler ester groups to make the enzyme-specific activation approach to peptide bond formation more accessible. To this end, a set of potential activating esters (Z-Gly-Act) was designed, synthesized, and evaluated. Both the benzyl (OBn) and the dimethylaminophenyl (ODmap) esters gave promising results. For these esters, the scope of a model dipeptide synthesis reaction under aqueous conditions was investigated by varying the amino acid donor. The results were compared with those obtained from a previous study of Z-XAA-OGp esters. Computational docking analysis of the set of esters was performed in order to provide insight into the differences in the reactivities of all the potential activating esters. Finally, selected ODmap- and OBn-activated amino acids were applied in the synthesis of two biologically active dipeptides on preparative scales.
- de Beer, Roseri J.A.C.,Zarzycka, Barbara,Mariman, Michiel,Amatdjais-Groenen, Helene I.V.,Mulders, Marc J.,Quaedflieg, Peter J.L.M.,van Delft, Floris L.,Nabuurs, Sander B.,Rutjes, Floris P.J.T.
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experimental part
p. 1319 - 1326
(2012/08/28)
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- A mild method for the cleavage of the 4-picolyloxy group with magnesium under neutral conditions
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A mild and efficient method for the selective hydrolysis of 4-picolyl esters with magnesium in methanol or water in the presence of other esters and sensitive protecting groups is described. 4-Picolyl aryl ethers and thioethers are also smoothly deprotected to give the corresponding phenols and thiophenols. Georg Thieme Verlag Stuttgart. New York.
- Zhu, Jianwei,Miao, Wenjun,Bao, Lingling,Ji, Tao,Tang, Guo,Xu, Pengxiang,Zhao, Yufen
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supporting information; experimental part
p. 142 - 144
(2012/02/04)
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- Papain-catalyzed peptide bond formation: Enzyme-specific activation with guanidinophenyl esters
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The substrate mimetics approach is a versatile method for small-scale enzymatic peptide-bond synthesis in aqueous systems. The protease-recognized amino acid side chain is incorporated in an ester leaving group, the substrate mimetic. This shift of the specific moiety enables the acceptance of amino acids and peptide sequences that are normally not recognized by the enzyme. The guanidinophenyl group (OGp), a known substrate mimetic for the serine proteases trypsin and chymotrypsin, has now been applied for the first time in combination with papain, a cheap and commercially available cysteine protease. To provide insight in the binding mode of various Z-XAA-OGp esters, computational docking studies were performed. The results strongly point at enzyme-specific activation of the OGp esters in papain through a novel mode of action, rather than their functioning as mimetics. Furthermore, the scope of a model dipeptide synthesis was investigated with respect to both the amino acid donor and the nucleophile. Molecular dynamics simulations were carried out to prioritize 22 natural and unnatural amino acid donors for synthesis. Experimental results correlate well with the predicted ranking and show that nearly all amino acids are accepted by papain.
- de Beer, Roseri J.A.C.,Zarzycka, Barbara,Amatdjais-Groenen, Helene I.V.,Jans, Sander C.B.,Nuijens, Timo,Quaedflieg, Peter J.L.M.,van Delft, Floris L.,Nabuurs, Sander B.,Rutjes, Floris P.J.T.
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experimental part
p. 2201 - 2207
(2012/05/05)
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- Total synthesis of PDE-II by copper-mediated double amination
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A concise total synthesis of PDE-II featuring copper-mediated double aryl amination with the combination of CuI, CsOAc, and Cs2CO3 is described. The highly substituted pyrroloindole skeleton was constructed by a one-pot five-step sequence including double aryl amination, β-elimination, deprotection of a Cbz group, and removal of an Ns group followed by rearomatization.
- Okano, Kentaro,Mitsuhashi, Nakako,Tokuyama, Hidetoshi
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supporting information; experimental part
p. 2641 - 2643
(2010/07/09)
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- 2-Oxo-2H-benzo[h]benzopyran as a new light sensitive protecting group for neurotransmitter amino acids
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Aiming at the development of new benzopyran-based photocleavable protecting groups, novel chloromethylated and hydroxymethylated 2-oxo-2H-benzo[h] benzopyran derivatives bearing a methoxy substituent were designed and used in the synthesis of a series of fluorescent bioconjugates, by linking through an ester or urethane bond to several model neurotransmitter amino acids (glycine, alanine, β-alanine and γ-aminobutyric acid, GABA). The resulting fluorescent bioconjugates with emission in the visible range and high fluorescent quantum yields, were subjected to photocleavage reaction in methanol/HEPES buffer (80:20) solution at different wavelengths of irradiation (250, 300, 350 and 419 nm) and photocleavage kinetic data were obtained.
- Soares, Ana M. S.,Costa, Susana P. G.,Goncalves, M. Sameiro T.
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experimental part
p. 121 - 133
(2010/09/07)
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- Inhibitors interacting with the magnesium binding site of reverse transcriptase: Synthesis and biological activity studies of 3′-(Ω- amino-acyl) amino-3′-deoxy-thymidine
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Active site of reverse transcriptase contains carboxylate groups involved in the magnesium binding. We prepared some nucleoside analogs which could bind to these carboxylates preventing the binding of nucleotides. To the 3′-amino-3′-deoxy-thymidine, different N-protected ω-amino-acids were bound, the protection removed to give the 3′-(ω-amino-acyl-) amino-3′-deoxy-thymidines in good yield. Some showed moderate to low activity in HIV 1 replication test. Copyright Taylor & Francis Group, LLC.
- Goud, Thirumani Venkateshwar,Aubertin, Anne-Marie,Biellmann, Jean-Francois
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p. 495 - 505
(2008/09/21)
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- Synthesis and self-association properties of flexible guanidiniocarbonylpyrrole-carboxylate zwitterions in DMSO: Intra- versus intermolecular ion pairing
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(Chemical Equation Presented) We have synthesized a new class of flexible zwitterions 6a-e, in which a carboxylate is linked via an alkyl chain with variable length (one to five methylene groups) to a guanidiniocarbonylpyrrole cation. The self-association properties of these zwitterions were determined by NMR dilution studies in DMSO and by ESI-MS experiments. The stability and hence also the size of the aggregates formed via self-assembly is critically dependent on the length and therefore flexibility of the spacer. Whereas the smallest zwitterion 6a forms large aggregates already at low concentrations, the more flexible zwitterions only form small oligomers (6b) or dimers (6c-e) at much larger concentrations. The differences between the five zwitterions can be explained based on the different extent of intramolecular ion pairing within the monomers. Any intramolecular ion pairing, which becomes possible with increasing linker length, stabilizes the monomer and therefore destabilizes any oligomer.
- Schmuck, Carsten,Rehm, Thomas,Geiger, Lars,Schaefer, Mathias
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p. 6162 - 6170
(2008/02/10)
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- N-(3-(4-Hydroxyphenyl)-propenoyl)-amino acid tryptamides as SIRT2 inhibitors
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A series of N-(3-(4-hydroxyphenyl)-propenoyl)-amino acid tryptamides was based on a previously reported new SIRT2 inhibitor from our group, and it was designed to study if the molecular size of the compound could be reduced. The most potent compounds, N-(3-(4-hydroxyphenyl)-propenoyl)-2-aminoisobutyric acid tryptamide and N-(3-(4-hydroxyphenyl)-propenoyl)-l-alanine tryptamide, were equipotent, 30% smaller in molecular weight, and slightly more selective (SIRT2/SIRT1) than the parent compound.
- Kiviranta, Paeivi H.,Leppaenen, Jukka,Rinne, Valtteri M.,Suuronen, Tiina,Kyrylenko, Olga,Kyrylenko, Sergiy,Kuusisto, Erkki,Tervo, Anu J.,Jaervinen, Tomi,Salminen, Antero,Poso, Antti,Wallen, Erik A.A.
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p. 2448 - 2451
(2008/02/03)
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- Aqueous phase mono-protection of amines and amino acids as N-benzyloxycarbonyl derivatives in the presence of β-cyclodextrin
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A simple and selective protection of amines/amino acids with Cbz-Cl has been achieved in aqueous phase with catalytic amounts of β-cyclodextrin in high yields at room temperature. This reaction proceeds without the formation of any by-products and has advantages over existing methods.
- Pavan Kumar,Somi Reddy,Narender,Surendra,Nageswar,Rama Rao
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p. 6393 - 6396
(2007/10/03)
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- Diastereoselective cationic tandem cyclizations to N-heterocyclic scaffolds: Total synthesis of (-)-dysibetaine PP
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Herein, we report a short and diastereoselective synthesis of the natural product (-)-dysibetaine PP. The key step in the synthetic sequence is a novel highly diastereoselective tandem-cyclization reaction of an enantiomerically pure dipeptide. This cyclization methodology is applied in the synthesis of a broader range of N-heterocyclic scaffolds.
- IJzendoorn, Denis R.,Botman, Peter N. M.,Blaauw, Richard H.
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p. 239 - 242
(2007/10/03)
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- Novel inhibitor compounds specific of secreted non-pancreatic human a2phospholipase of group II
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The present invention relates to a compound of the following formula (I) and pharmaceutical compositions containing the compound of formula (I): wherein D, Y, A, B, p, q, W and R have the same meanings as defined in the specification.
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Page/Page column 10
(2010/02/11)
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- Photorelease of carboxylic acids, amino acids, and phosphates from N-alkylpicolinium esters using photosensitization by high wavelength laser dyes
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Visible light (>450 nm) is used to efficiently cleave carboxylic acids, amino acids, and phosphates from their N-methyl picolinium esters. Photolysis using pyrromethene dyes PM 546 and PM 597 and also coumarin 6 as photosensitizers effects release of carboxylic acids, N-protected amino acids, and phosphates in quantitative yields. The effective rate of photorelease by the dyes, Φε, was found to be as high as 4500 M-1 cm-1. The photorelease proceeds through photoinduced electron transfer from the dye sensitizers to the N-methyl picolinium group. Fluorescence quenching and laser flash photolysis experiments support the photoinduced electron-transfer mechanism. Copyright
- Sundararajan, Chitra,Falvey, Daniel E.
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p. 8000 - 8001
(2007/10/03)
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- Synthesis of proline-modified analogues of the neuroprotective agent glycyl-L-prolyl-glutamic acid (GPE)
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The synthesis of ten proline-modified analogues of the neuroprotective tripeptide GPE is described. Five of the analogues incorporate a proline residue with a hydrophobic group at C-2 and two further analogues have this side chain locked into a spirolactam ring system. The pyrrolidine ring was also modified by replacing the γ-CH2 group with sulfur and/or incorporation of two methyl groups at C-5.
- Harris, Paul W.R.,Brimble, Margaret A.,Muir, Victoria J.,Lai, Michelle Y.H.,Trotter, Nicholas S.,Callis, David J.
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p. 10018 - 10035
(2007/10/03)
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- Preparation and Characterization of [5-13C]-(2S,4R)-Leucine and [4-13C]-(2S,3S)-Valine - Establishing Synthetic Schemes to Prepare Any Site-Directed Isotopomer of L-Leucine, L-Isoleucine and L-Valine
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In this paper a chemo-enzymatic method has been developed that gives access to any isotopomer of the essential amino acids isoleucine and valine. The method gives the correct introduction of the second chiral center in (2S,3S)-isoleucine and allows for discrimination between the two prochiral methyl groups in valine as shown by the preparation of (2S,3S)-[4- 13C] valine. For the preparation of (2S)-leucine in any isotopomeric form, the O'Donnell method to prepare optically active amino acids has been used. The protected glycine scaffold used in this method has been prepared by a strategy that allows access to any isotopomeric form. The preparation of [5-13C]-(2S,4R)-leucine shows that the O'Donnell method in combination with the Evans method to obtain chiral 2-methylpropyl iodide leads to a good discrimination between the two prochiral methyl groups. The O'Donnell strategy for the preparation of α-amino acids is preferred over other methods since the reaction conditions are mild, the chiral auxiliary can be easily recovered and the optically active product can be easily separated. For the preparation of isotopically enriched valine and isoleucine the O'Donnell method is not suitable, because the alkyl substituents involved have a secondary halide substituent which is sterically too hindered to give an effective reaction with the protected glycine. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Siebum, Arjan H. G.,Woo, Wei Sein,Lugtenburg, Johan
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p. 4664 - 4678
(2007/10/03)
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- Trichloroisocyanuric/TEMPO oxidation of alcohols under mild conditions: A close investigation
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Efficient oxidation of primary alcohols to the corresponding carboxylic acids can be carried out at room temperature and in acetone/water, using trichloroisocyanuric acid (TCCA) in the presence of catalytic TEMPO. The mild conditions of this procedure and the total absence of any transition metal make this reaction suitable for safe laboratory use. A possible mechanism is presented and discussed.
- De Luca, Lidia,Giacomelli, Giampaolo,Masala, Simonetta,Porcheddu, Andrea
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p. 4999 - 5001
(2007/10/03)
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- A simple, mild and efficient procedure for selective cleavage of prenyl esters using silica-supported sodium hydrogen sulphate as a heterogenous catalyst
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Prenyl esters were selectively and efficiently cleaved under slightly acidic reaction conditions using silica-supported sodium hydrogen sulfate as a heterogenous catalyst at room temperature to regenerate the parent carboxylic acids in very high yields.
- Ramesh,Mahender,Ravindranath,Das, Biswanath
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p. 1465 - 1467
(2007/10/03)
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- Phenylhydrazide as an enzyme-labile protecting group in peptide synthesis
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The enzymatic cleavage of amino acid phenylhydrazides with the enzyme tyrosinase (EC 1.14.18.1) offers a new, mild, and selective method for C-terminal deprotection of peptides. The advantages of the described methodology are the very mild oxidative removal of the protecting group at room temperature and pH 7, a high chemo- and regioselectivity, and the availability of the biocatalyst. Even in oxygen-saturated solution, the oxidation of sensitive methionine residues was not observed. These features make the methodology suitable for the synthesis of sensitive peptide conjugates. Mechanistic data suggest that the hydrolysis of the oxidized adducts proceeds by a free-radical mechanism.
- Voelkert, Martin,Koul, Surrinder,Mueller, Gernot H.,Lehnig, Manfred,Waldmann, Herbert
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p. 6902 - 6910
(2007/10/03)
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- Highly selective deprotection of tert-butyl esters using ytterbium triflate as a catalyst under mild conditions
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Ytterbium triflate catalyses the deprotection of tert-butyl esters selectively in the presence of other esters under mild conditions in almost quantitative yields. The reactions are carried out in nitromethane (45°-50°C) using 5 mole percent of the catalyst.
- Sridhar, P. Ramu,Sinha, Surajit,Chandrasekaran
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p. 157 - 160
(2007/10/03)
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- The use of cellulose (chromatography paper) as a cheap, versatile and non-covalent support for organic molecules during multi-step synthesis
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Cellulose chromatography paper provides a novel non-covalent support for synthesis and in-situ purification of multi-dimensional arrays.
- Shanahan, Stephen E.,Byrne, Douglas D.,Inglis, Graham G. A.,Alam, Mahbub,Macdonald, Simon J. F.
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p. 2554 - 2555
(2007/10/03)
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- Benzyl 4,6-dimethoxy-1,3,5-triazinyl carbonate as N-protecting reagent
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A new active carbonate ester, benzyl 4,6-dimethoxy-1,3,5-triazinyl carbonate (Z-DMT), was prepared, and found to be a useful reagent for the introduction of benzyloxycarbonyl group into amines. Since Z-DMT is neither unstable nor irritating, it is practically useful.
- Hioki, Kazuhito,Fujiwara, Miho,Tani, Shohei,Kunishima, Munetaka
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- A facile and selective cleavage of prenyl esters catalyzed by CeCl3·7 H2O-NaI
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A highly selective cleavage of prenyl esters has been achieved in high yields using CeCl3·7 H2O-NaI in refluxing acetonitrile under neutral conditions. This method is mild and compatible with a wide variety of functional groups such
- Yadav,Subba Reddy,Venkateshwara Rao,Chand,Prasad
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p. 137 - 139
(2007/10/03)
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- A novel concept in combinatorial chemistry in solution with the advantages of solid-phase synthesis: Formation of N-betaines by multicomponent domino reactions
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Advantages of solid-phase and liquid-phase synthesis are combined in a new concept of combinatorial chemistry: a domino sequence comprising Knoevenagel and hetero-Diels-Alder reactions, with subsequent hydrogenation starting from protected aminoaldehydes, 1.3-dicarbonyl compounds, and enol ethers leads to N-heterocycles of high diversity with a betaine structure, which are isolated in highly pure form by precipitation with diethyl ether (see scheme), Cbz = benzylocycarbonyl, Bn = benzyl.
- Tietze, Lutz F.
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p. 903 - 905
(2007/10/03)
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- Phase-transfer catalysis in alkaline hydrolysis of N-benzyloxycarbonylglycine 4-nitrophenyl ester in the two-phase system 1-butanol-borate buffer
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The kinetics of alkaline hydrolysis of N-benzyloxycarbonylglycine 4-nitrophenyl ester were studied in the two-phase system 1-butanol-borate buffer (pH 8.3 and 10) at a phase volume ratio of 1:1 in the presence and in the absence of quaternary ammonium sal
- Baranova,Kosmynin,Savelova,Popov,Vakhitova
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p. 1301 - 1311
(2007/10/03)
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- The phenyl hydrazide as an enzyme-labile protecting group - Oxidative cleavage with mushroom tyrosinase
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Amino acid and peptide phenyl hydrazides are selectively cleaved by oxidation to acyl diazenes with mushroom tyrosinase and their subsequent hydrolysis.
- Mueller, Gernot H.,Waldmann, Herbert
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p. 3549 - 3552
(2007/10/03)
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- New facile alkoxycarbonylating agent, alkyl pyrazole-1-carboxylates. The preparation and the utilities
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Alkyl pyrazole-1-carboxylates (2), which were readily prepared from alkyl chloroformate or carbazate in good yields, were provided as the new facile alkoxycarbonylating agents toward the Grignard reagents for the synthesis of one carbon higher carboxylic esters. Also amines were alkoxycarbonylated by 2 to produce the corresponding urethanes even in an aqueous medium. Benzyl 3,5-dimethylpyrazole-1-carboxylate (2d) could be utilized for the Cbz-protection of amino acids and esters in good yield without any racemization.
- Kashima, Choji,Tsuruoka, Shiro,Mizuhara, Saori
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p. 14679 - 14688
(2007/10/03)
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- Conformational analysis of β-turn structure in tetrapeptides containing proline or proline analogs
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In order to evaluate the influence of cyclic secondary amino acids on the stability of β-turn structure, we have prepared Ac-Gly-L-Xxx-L-Leu-Gly-N(CH3)2 (Xxx = Aze, 4-membered ring: 1, Xxx = Pro, 5-membered ring: 2, Xxx = Pip, 6-membered ring: 3). The NOE cross peaks that support β-turn structure were observed in 1-3. The NOE cross peak between both terminals of the synthetic peptides, however, was observed only in the NOESY spectra of 2. This result indicates that 5-membered ring side chain in proline plays a very important role in the formation of β-hairpin structure.
- Hayashi, Takashi,Asai, Tomohito,Ogoshi, Hisanobu
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p. 3039 - 3042
(2007/10/03)
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