- Fast Cyclization of a Proline-Derived Self-Immolative Spacer Improves the Efficacy of Carbamate Prodrugs
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Self-immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)-2-(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease-sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.
- Belvisi, Laura,Borlandelli, Valentina,Corno, Cristina,Dal Corso, Alberto,Gennari, Cesare,Perego, Paola,Pignataro, Luca
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p. 4176 - 4181
(2020/02/05)
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- Mechanistic Insight Facilitates Discovery of a Mild and Efficient Copper-Catalyzed Dehydration of Primary Amides to Nitriles Using Hydrosilanes
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Metal-catalyzed silylative dehydration of primary amides is an economical approach to the synthesis of nitriles. We report a copper-hydride(CuH)-catalyzed process that avoids a typically challenging 1,2-siloxane elimination step, thereby dramatically increasing the rate of the overall transformation relative to alternative metal-catalyzed systems. This new reaction proceeds at ambient temperature, tolerates a variety of metal-, acid-, or base-sensitive functional groups, and can be performed using a simple ligand, inexpensive siloxanes, and low catalyst loading.
- Liu, Richard Y.,Bae, Minwoo,Buchwald, Stephen L.
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supporting information
p. 1627 - 1631
(2018/02/17)
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- One-pot synthesis of orthogonally protected dipeptide selenazoles employing Nα-amino selenocarboxamides and α-bromomethyl ketones
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A simple and efficient protocol for the synthesis of selenazole containing dipeptidomimetics using Nα-amino selenocarboxamides and α-bromomethyl ketones is described. All the compounds made were isolated in good yields and fully characterized.
- Madhu, Chilakapati,Panguluri, Nageswara Rao,Narendra,Panduranga,Sureshbabu, Vommina V.
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supporting information
p. 6831 - 6835
(2015/01/09)
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- Glycosylation mediated - BAIL in aqueous solution
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The use of Br?nsted acid ionic liquid (BAIL) as a catalyst for the activation of unreactive and unprotected glycosyl donors has been demonstrated for the first time in aqueous solution.
- Delacroix, Sébastien,Bonnet, Jean-Pierre,Courty, Matthieu,Postel, Denis,Van Nhien, Albert Nguyen
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- Enantioselective total synthesis of (S)-(+)-lennoxamine through asymmetric hydrogenation mediated by l-proline-tetrazole ruthenium catalyst
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A novel asymmetric synthetic strategy to prepare isoindolobenzazepine based lennoxamine alkaloid has been achieved in high ee% starting from 2-(benzo[d][1,3]dioxol-5-yl)ethanamine and 1-(chloromethyl)-2,3-dimethoxybenzene in 5 steps and with a 34% overall yield. The potentiality of this route involved the Bischler-Napieralsky cyclization that leads to tetracyclic indolinium skeleton, generation of chiral center through asymmetric hydrogen-transfer reaction employing l-proline-tetrazole as chiral ligand with Ru/Ir/Rh, and anodic oxidation as the key steps in the synthesis.
- Mirabal-Gallardo, Yaneris,Piérola, Johanna,Shankaraiah, Nagula,Santos, Leonardo S.
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scheme or table
p. 3672 - 3675
(2012/10/07)
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- Pyrrolidine amides of pyrazolodihydropyrimidines as potent and selective KV1.5 blockers
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Design and synthesis of pyrazolodihydropyrimidines as KV1.5 blockers led to the discovery of 7d as a potent and selective antagonist. This compound showed atrial selective prolongation of effective refractory period in rabbits and was selected for clinical development.
- Lloyd, John,Finlay, Heather J.,Vacarro, Wayne,Hyunh, Tram,Kover, Alexander,Bhandaru, Rao,Yan, Lin,Atwal, Karnail,Conder, Mary Lee,Jenkins-West, Tonya,Shi, Hong,Huang, Christine,Li, Danshi,Sun, Huabin,Levesque, Paul
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scheme or table
p. 1436 - 1439
(2010/07/02)
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- Synthesis of substituted 5-(pyrrolidin-2-yl)tetrazoles and their application in the asymmetric Biginelli reaction
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A series of chiral substituted 5-(pyrrolidin-2-yl)tetrazoles have been synthesized and evaluated as organocatalysts for the asymmetric Biginelli reaction. The relationship between catalytic activity and the different catalyst structures is briefly discussed. By using the optimized catalyst C10 (10 mol-%), a series of 3,4-dihydropyrimidin-2(1H)-one (DHPM) derivatives have been obtained in 63-88% yields and 68-81 % ee values within 24 h at room temperature.
- Wu, Yong-Yong,Chai, Zhuo,Liu, Xin-Yuan,Zhao, Gang,Wang, Shao-Wu
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experimental part
p. 904 - 911
(2009/07/19)
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- N-urethane-protected amino alkyl isothiocyanates: Synthesis, isolation, characterization, and application to the synthesis of thioureidopeptides
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(Chemical Equation Presented) Synthetically useful N-Fmoc amino-alkyl isothiocyanates have been described, starting from protected amino acids. These compounds have been synthesized in excellent yields by thiocarbonylation of the monoprotected 1,2-diamines with CS2/TEA/p-TsCl, isolated as stable solids, and completely characterized. The procedure has been extended to the synthesis of amino alkyl isothiocyanates from Boc- and Z-protected amino acids as well. The utility of these isothiocyanates for peptidomimetics synthesis has been demonstrated by employing them in the preparation of a series of dithioureidopeptide esters. Boc-Gly-OH and Boc-Phe-OH derived isothiocyanates 9a and 9c have been obtained as single crystals and their structures solved through X-ray diffraction. They belong to the orthorhombic crystal system, and have a single molecule in the asymmetric unit (Z′ = 1). 9a crystallizes in the centrosymmetric space group Pbca, while 9c crystallizes in the noncentrosymmetric space group P212121.
- Sureshbabu, Vommina V.,Naik, Shankar A.,Hemantha,Narendra,Das, Ushati,Guru Row, Tayur N.
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supporting information; experimental part
p. 5260 - 5266
(2009/12/06)
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- Peptide deformylase inhibitors of Mycobacterium tuberculosis: Synthesis, structural investigations, and biological results
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Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.
- Pichota, Arkadius,Duraiswamy, Jeyaraj,Yin, Zheng,Keller, Thomas H.,Alam, Jenefer,Liung, Sarah,Lee, Gladys,Ding, Mei,Wang, Gang,Chan, Wai Ling,Schreiber, Mark,Ma, Ida,Beer, David,Ngew, Xinyi,Mukherjee, Kakoli,Nanjundappa, Mahesh,Teo, Jeanette W.P.,Thayalan, Pamela,Yap, Amelia,Dick, Thomas,Meng, Wuyi,Xu, Mei,Koehn, James,Pan, Shi-Hao,Clark, Kirk,Xie, Xiaoling,Shoen, Carolyn,Cynamon, Michael
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scheme or table
p. 6568 - 6572
(2009/09/30)
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- Modular syntheses of oxazolinylamine ligands and characterization of group 10 metal complexes
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The syntheses of aminoalkyloxazoline and pyrrolidinyloxazoline ligands, each of which bear a pair of chiral centres, by both known and new routes are reported. Variable temperature NMR studies show that the known stepwise syntheses of the pyrrolidinyl compounds are not complicated by epimerization; however, coordination of one of the aminoalkyl derivatives to Pt(II) under conditions of prolonged heating to 80°C does give mixtures of diastereomeric N,N′-chelated complexes that result from inversion of the chiral centre associated with the aminoalkyl fragment. A new synthesis of pyrrolidinyloxazoline ligands that involves the Zn-catalyzed cyclization of Cbz-protected 2-cyanopyrrolidine and β-amino alcohols is also reported. This procedure offers the advantages of economy, shorter time, and fewer purification steps over the previously reported synthesis. In addition, the crystal structure of an enantiopure Pd(II) complex of an N.N′-chelated pyrrolidinyloxazoline is disclosed. This compound has a pseudo-C2 axis of symmetry, which may make it suitable for asymmetric catalytic applications.
- Caputo, Christine A.,Carneiro, Florentino D S.,Jennings, Michael C.,Jones, Nathan D.
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- PDF INHIBITORS
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The invention relates to novel compounds that are inhibitors of peptidyl deformylase (PDF). The compounds are useful as antimicrobials and antibiotics. The compounds of the invention display selective inhibition of peptidyl deformylase versus other metalloproteinases such as MMPs. Methods of preparation and uses of the compounds are also disclosed.
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Page/Page column 32
(2010/11/28)
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- PEPTIDE DEFORMYLASE INHIBITORS
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Novel PDF inhibitors of formulas (I) and (II), pharmaceutical compositions thereof and methods for their use in the treatment of bacterial infections are described.
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Page/Page column 14; 24
(2010/11/27)
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- Microwave-assisted one-pot tandem reactions for direct conversion of primary alcohols and aldehydes to triazines and tetrazoles in aqueous media
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(Chemical Equation Presented) A series of primary alcohols and aldehydes were treated with iodine in ammonia water under microwave irradiation to give the intermediate nitriles, which without isolation underwent [2 + 3] cycloadditions with dicyandiamide and sodium azide to afford high yields of the corresponding triazines and tetrazoles, including the α-amino- and dipeptidyl tetrazoles in high optical purity.
- Shie, Jiun-Jie,Fang, Jim-Min
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p. 3141 - 3144
(2008/02/13)
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- Practical synthesis of (S)-pyrrolidin-2-yl-1H-tetrazole, incorporating efficient protecting group removal by flow-reactor hydrogenolysis
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A practical, safe, high-yielding and efficient synthesis of (S)-pyrrolidin-2-yl-1H-tetrazole has been developed, which avoids the generation of ammonium azide in the cyclisation step and the use of a 9:1 acetic acid-water mixture as the solvent in the hydrogenation. The previously extended hydrogenolysis reaction time (three days) is now reduced to hours through the use of an H-Cube (a continuous-flow reactor employing a mixed hydrogen-liquid flow stream). Georg Thieme Verlag Stuttgart.
- Franckevi?ius, Vilius,Knudsen, Kristian Rahbek,Ladlow, Mark,Longbottom, Deborah A.,Ley, Steven V.
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p. 889 - 892
(2007/10/03)
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- VLA-4 INHIBITOR
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A compound which selectively inhibits bonding between a ligand and α4β1 integrin (VLA-4); a process for producing the compound; and a medicine containing the compound. The compound is one represented by, e.g., the formula (I) or a salt thereof. Also provided is a preventive and/or therapeutic agent which contains the compound or salt as a major component and is effective against diseases attributable to cell adhesion, such as, e.g., inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal obstruction, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory intestinal disease, and rejection reaction in transplantation. (In the formula, Y1 represents arylene, etc.; V1 represents aryl, etc.; and R11 to R14 each represents H, OH, halogeno, etc.)
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Page/Page column 241-242
(2010/02/15)
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- 5-(Pyrrolidine-2-yl)tetrazole: Rationale for the increased reactivity of the tetrazole analogue of proline in organocatalyzed aldol reactions
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5-[(2S)-Pyrrolidine-2-yl]-1H-tetrazole (1), i.e. the tetrazolic acid analogue of proline, has been found to be significant more reactive than L-proline (2) in various organocatalyzed reactions. In the organocatalyzed direct asymmetric aldol reaction, acetone was reacted with aromatic and aliphatic aldehydes to afford the resulting β-hydroxy ketones in good yields and moderate to high enantiomeric excesses. The increased reactivity of 1, as compared to 2, has been rationalized through a combined computational and NMR spectroscopic study. It was found that catalyst 2 was almost completely engaged in oxazolidinone formation with the aldehyde whereas 1 did not take part in such parasitic equilibrium. This finding, together with the improved solubility of the tetrazole analogue, is proposed to account for the observed reactivity. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.
- Hartikka, Antti,Arvidsson, Per I.
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p. 4287 - 4295
(2007/10/03)
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- Organocatalysis with proline derivatives: Improved catalysts for the asymmetric Mannich, nitro-Michael and aldol reactions
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Tetrazole and acylsulfonamide organocatalysts derived from proline have been synthesised and applied to the asymmetric Mannich, nitro-Michael and aldol reactions to give results that are superior to the proline-catalysed counterpart.
- Cobb, Alexander J. A.,Shaw, David M.,Longbottom, Deborah A.,Gold, Johan B.,Ley, Steven V.
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- Rational design of asymmetric organocatalysts - Increased reactivity and solvent scope with a tetrazolic acid
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Replacement of the carboxylic acid functionality in the widely used organocatalyst proline with a tetrazolic acid leads to a catalyst with increased reactivity and solvent scope, as demonstrated in the direct catalytic asymmetric aldol reaction.
- Hartikka, Antti,Arvidsson, Per I.
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p. 1831 - 1834
(2007/10/03)
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- 5-Pyrrolidin-2-yltetrazole: A New, Catalytic, More Soluble Alternative to Proline in an Organocatalytic Asymmetric Mannich-type Reaction
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A Mannich-type addition of ketones to N-PMP protected α-imino ethyl glyoxalate is catalyzed by a new proline analogue, 5-pyrrolidin-2-yltetrazole 1. The new organocatalyst has significant advantage over its parent in that it can be used in non-polar solvents without loss of enantioselectivity.
- Cobb, Alexander J. A.,Shaw, David M.,Ley, Steven V.
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p. 558 - 560
(2007/10/03)
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- Synthesis and biological activity of carboxylic acid replacement analogues of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline
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The carboxylic acid group on the proline of the ketomethylene analog of the tripeptide Bz-Phe-Gly-Pro 1 was replaced by a phosphoric acid, a hydroxamic acid, and a tetrazole to give compounds 2-4, respectively. Testing of 2-4 as angiotensin converting enz
- Almquist,Chao,Jennings-White
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p. 1067 - 1071
(2007/10/02)
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