- Synthesis, molecular modeling and functional evaluation of a GnRH antagonist
-
In the present study, a series of novel Trp-Pro-Val containing peptides were prepared via solid-phase synthesis, and their structures were cyclized by a disulfide bridge, or modified by adding heterocycles of pyrazine, pyroglutamic acid, and 1,3,4-oxadiaz
- Asghari, S. Mohsen,Balalaie, Saeed,Fathi Vavsari, Vaezeh,Ghassempour, Alireza,Golmohammadi, Farhad,Panahi Kokhdan, Esmaeel,Shakeri, Pegah
-
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- Design, Synthesis, and Cytotoxic Activity of New Tubulysin Analogues
-
Synthesis of tubulysin analogues, containing an N-methyl substituent on tubuvaline-amide together with the replacement of either the hydrophobic N-terminal N-methyl pipecolic acid (Mep) or at both N- and C- terminal peptides with available heteroaromatic
- Le, Hai Van,Tran, Loc Van,Tran, Anh Tuan,Tran, Thao Thi Phuong,Tran, Sung Van,Tran, Chien Van
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supporting information
p. 187 - 195
(2021/12/03)
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- Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts
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A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.
- Le Manach, Claire,Dam, Jean,Woodland, John G.,Kaur, Gurminder,Khonde, Lutete P.,Brunschwig, Christel,Njoroge, Mathew,Wicht, Kathryn J.,Horatscheck, André,Paquet, Tanya,Boyle, Grant A.,Gibhard, Liezl,Taylor, Dale,Lawrence, Nina,Yeo, Tomas,Mok, Sachel,Eastman, Richard T.,Dorjsuren, Dorjbal,Talley, Daniel C.,Guo, Hui,Simeonov, Anton,Reader, Janette,Van Der Watt, Mari?tte,Erlank, Erica,Venter, Nelius,Zawada, Jacek W.,Aswat, Ayesha,Nardini, Luisa,Coetzer, Theresa L.,Lauterbach, Sonja B.,Bezuidenhout, Belinda C.,Theron, Anjo,Mancama, Dalu,Koekemoer, Lizette L.,Birkholtz, Lyn-Marie,Wittlin, Sergio,Delves, Michael,Ottilie, Sabine,Winzeler, Elizabeth A.,Smith, Dennis,Fidock, David A.,Street, Leslie J.,Basarab, Gregory S.,Duffy, James,Chibale, Kelly
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supporting information
p. 2291 - 2309
(2021/03/01)
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- Synthesis of Isotopically Labeled, Spin-Isolated Tyrosine and Phenylalanine for Protein NMR Applications
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Isotopically labeled amino acids are widely used to study the structure and dynamics of proteins by NMR. Herein we describe a facile, gram-scale synthesis of compounds 1b and 2b under standard laboratory conditions from the common intermediate 7. 2b is ob
- Cui, Yixin,Das, Jitendra,Kalodimos, Charalampos G.,Rankovic, Zoran,Rossi, Paolo,Slavish, P. Jake,Sowaileh, Munia,Young, Brandon M.
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supporting information
p. 6288 - 6292
(2021/09/02)
-
- Ultrasound promoted environmentally benign, highly efficient, and chemoselective N-tert-butyloxycarbonylation of amines by reusable sulfated polyborate
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The sulfated polyborate catalyzed an efficient and chemoselective N-tert-butyloxycarbonylation of amines under ultrasonic irradiation is developed. A broad substrate scope has been demonstrated for N-Boc protection of various primary/secondary amines. It allows converting several aliphatic/aryl/heteroaryl amines, amino alcohol, aminoester, and chiral amines to their N-Boc-protected derivatives under solvent-free conditions with excellent yields. The protocol has several advantages such as easy catalyst, and product isolation, short reaction time, excellent yields, outstanding chemoselectivity, and catalyst recyclability, among others. This makes the process practicable, economical, and environmentally benign.
- Pise, Ashok S.,Ingale, Ajit P.,Dalvi, Navnath R.
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supporting information
p. 3768 - 3780
(2021/10/26)
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- Nanoceria as an efficient and green catalyst for the chemoselective N-tert-butyloxycarbonylation of amines under the solvent-free conditions
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Nanocerium oxide mediated an efficient and green protocol has been described for the chemoselective N-tert-butyloxycarbonylation of amines under the solvent-free conditions at ambient temperature. Various aliphatic, aromatic and heteroaromatic amines were protected using developed protocol and several functional groups such as alcohol, phenol and ester were well tolerated under these conditions. The rapid reaction rate, mild conditions, very good functional group tolerance, excellent yield, solvent-free, easy recovery products and excellent catalyst recyclability are the advantages of this protocol. This makes the protocol feasible, economical and environmentally benign.
- Garad, Dnyaneshwar N.,Ingale, Ajit P.,Shinde, Sandeep V.,Ukale, Dattatraya
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supporting information
p. 1656 - 1668
(2021/04/05)
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- Sulfated tungstate: A highly efficient, recyclable and ecofriendly catalyst for chemoselective N-tert butyloxycarbonylation of amines under the solvent-free conditions
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Sulfated tungstate catalyzed an efficient and ecofriendly protocol has been described for the chemoselective N-tert-butyloxycarbonylation of amines under the solvent-free conditions at room temperature. The variety of functionalized aliphatic, aromatic and heteroaromatic amines efficiently undergoes the N-tert-butyloxycarbonylation under the developed protocol. The aminoalcohol, aminophenol, aminoester as well as various chiral amines underwent the chemoselective N-Boc protection under the optimized reaction condition. The rapid reaction rate, mild conditions, very good functional group tolerance, excellent yield, solvent-free, easy recovery products and excellent catalyst recyclability are the advantages of this protocol. This makes the protocol feasible, economical and environmentally benign.
- Ingale, Ajit P.,Shinde, Sandeep V.,Thorat, Nitin M.
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supporting information
p. 2528 - 2543
(2021/07/02)
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- Identification of inhibitors of UDP-galactopyranose mutaseviacombinatorialin situscreening
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Anin situscreening assay for UDP-galactopyranose mutase (UGM, an essential enzyme ofM. tuberculosiscell wall biosynthesis) has been developed to discover novel UGM inhibitors. The approach is based on the amide-forming reaction of an amino acid core with various cinnamic acids, followed by a direct fluorescence polarization assay to identify the best UGM binders without isolation and purification of the screened ligands. This assay allows us to perform one-pot high-throughput synthesis and screening of enzyme inhibitors in a 384-well plate format. UGM ligands were successfully identified by this technology and their inhibition levels were established from pure synthetic compoundsin vitroand in a whole cell antibacterial assay. This study provides a blueprint for designing enamide structures as new UGM inhibitors and anti-mycobacterial agents.
- Fu, Jian,Fu, Huixiao,Xia, Yufen,N'Go, Inès,Cao, Jun,Pan, Weidong,Vincent, Stéphane P.
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p. 1818 - 1826
(2021/03/14)
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- Asymmetric Reduction of Aromatic α-Dehydroamino Acid Esters with Water as Hydrogen Source
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The asymmetric reduction of aromatic α-dehydroamino acid esters with water as the hydrogen source was developed by a Rh/Cu co-catalytic system. The reaction tolerates various functional groups, providing a valuable synthetic tool to access chiral α-amino acid esters readily. Moreover, the present methodology also was applied in the cost-effective and easy to handle preparation of chiral deuterated α-amino esters by using D2O.
- Dai, Yuze,Chen, Jingchao,Wang, Zheting,Wang, Ting,Wang, Lin,Yang, Yong,Qiao, Xingfang,Fan, Baomin
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supporting information
p. 7141 - 7147
(2021/05/29)
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- Synthesis and photophysics of benzazole based triazoles with amino acid-derived pendant units. Multiparametric optical sensors for BSA and CT-DNA in solution
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Herein we report the synthesis of a series of amino acid-derived triazoles by an organocatalytic cycloaddition reaction between azides and carbonyl compounds, catalyzed by a simple amine. These compounds present absorption maxima located in the UV-B ascribed to fully spin and symmetry allowed electronic transitions and a main fluorescence emission in the UV-A (~380 nm) with a relatively large Stokes shift (5700 cm?1). No significant solvatochromism was observed in both ground and excited states. Unexpectedly, the benzoxazole derivatives presented much higher fluorescence quantum yield values (40–80%) of compared to the sulfur analogues (3–6%). In addition, the DNA binding assays indicated that these compounds presented strong interaction with CT-DNA, which could be attributed to π-stacking and intermolecular hydrogen-bonding. The interaction of the benzazoles with bovine serum albumin (BSA) was also investigated, where a suppression mechanism was observed. In each case, docking was performed to better understand the observed interactions.
- Debia, Natalí P.,Rodríguez, Juan J.P.,da Silveira, Carolina H.,Chaves, Otavio A.,Iglesias, Bernardo A.,Rodembusch, Fabiano S.,Lüdtke, Diogo S.
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- Bisoxazoline ligand compound and synthetic method thereof
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The invention provides a bisoxazoline ligand compound and a synthetic method thereof. The method comprises the following steps: synthesizing (tert-butoxycarbonyl)-L-phenylalanine methyl ester 2 by using L-phenylalanine methyl ester hydrochloride 1, synthe
- -
-
Paragraph 0053-0056; 0065-0068; 0077-0779
(2020/02/14)
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- Total Synthesis and Antimycobacterial Activity of Ohmyungsamycin A, Deoxyecumicin, and Ecumicin
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The ohmyungsamycin and ecumicin natural product families are structurally related cyclic depsipeptides that display potent antimycobacterial activity. Herein the total syntheses of ohmyungsamycin A, deoxyecumicin, and ecumicin are reported, together with the direct biological comparison of members of these natural product families against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). The synthesis of each of the natural products employed a solid-phase strategy to assemble the linear peptide precursor, involving a key on-resin esterification and an optional on-resin dimethylation step, before a final solution-phase macrolactamization between the non-proteinogenic N-methyl-4-methoxy-l-tryptophan amino acid and a bulky N-methyl-l-valine residue. The synthetic natural products possessed potent antimycobacterial activity against Mtb with MIC90’s ranging from 110–360 nm and retained activity against Mtb in Mtb-infected macrophages. Deoxyecumicin also exhibited rapid bactericidal killing against Mtb, sterilizing cultures after 21 days.
- Hawkins, Paige M. E.,Tran, Wendy,Nagalingam, Gayathri,Cheung, Chen-Yi,Giltrap, Andrew M.,Cook, Gregory M.,Britton, Warwick J.,Payne, Richard J.
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supporting information
p. 15200 - 15205
(2020/10/23)
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- Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides
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Organic halides are important building blocks in synthesis, but their use in (photo)redox chemistry is limited by their low reduction potentials. Halogen-atom transfer remains the most reliable approach to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that a-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp3-sp3, sp3-sp2, and sp2-sp2 carbon-carbon bonds under mild conditions with high chemoselectivity.
- Constantin, Timothée,Juliá, Fabio,Leonori, Daniele,Regni, Alessio,Sheikh, Nadeem S.,Zanini, Margherita
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p. 1021 - 1026
(2020/03/10)
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- Asymmetric Synthesis of Functionalized Phenylalanine Derivatives via Rh-Catalyzed Conjugate Addition and Enantioselective Protonation Cascade
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The asymmetric conjugate addition of arylboronic acids to N-phthalimidodehydroalanine 1i catalyzed by Rh(I)/L1a enables the facile preparation of chiral functionalized phenylalanines. The reaction proceeds by a conjugate addition and enantioselective protonation cascade, affording a rhodium enolate that undergoes re-face protonation. The reaction tolerates various arylboronic acids and can be used in the gram-scale synthesis of (S)-phenylalanine hydrochloride, demonstrating the reaction scope and the synthetic feasibility of the process.
- Jian, Jia-Hong,Zeng, Hao-Wei,Kuo, Ting-Shen,Wu, Ping-Yu,Wu, Hsyueh-Liang
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supporting information
p. 9468 - 9472
(2019/11/28)
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- Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement
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The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.
- Gomes, Juliana C.,Cianni, Lorenzo,Ribeiro, Jean,dos Reis Rocho, Fernanda,da Costa Martins Silva, Samelyn,Batista, Pedro Henrique Jatai,Moraes, Carolina Borsoi,Franco, Caio Haddad,Freitas-Junior, Lucio H.G.,Kenny, Peter W.,Leit?o, Andrei,Burtoloso, Antonio C.B.,de Vita, Daniela,Montanari, Carlos A.
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supporting information
(2019/09/30)
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- Design and Optimization of a Continuous Stirred Tank Reactor Cascade for Membrane-Based Diazomethane Production: Synthesis of α-Chloroketones
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The development of a continuous diazomethane generator comprising a continuous stirred tank reactor (CSTR) cascade and membrane separation technology is reported. This reactor concept was applied for the telescoped three-step synthesis of a chiral α-chloroketone, a key building block for many HIV protease inhibitors, via a modified Arndt-Eistert reaction starting from N-protected l-phenylalanine. The initial mixed anhydride was generated in a coil reactor and directly introduced into the CSTR diazomethane cascade. The use of a semipermeable Teflon membrane (AF-2400) allowed the generation of anhydrous diazomethane, which diffuses through the membrane into the CSTR where it is immediately consumed by the anhydride to furnish the corresponding diazoketone. The subsequent halogenation with concentrated HCl was performed downstream in batch and allowed production of the α-chloroketone on a multigram scale, with a productivity of 1.54 g/h (5.2 mmol/h).
- Wernik, Michaela,Poechlauer, Peter,Schmoelzer, Christoph,Dallinger, Doris,Kappe, C. Oliver
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supporting information
p. 1359 - 1368
(2019/08/12)
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- Intramolecular Diels-Alder Cycloaddition Approach toward the cis-Fused Δ5,6-Hexahydroisoindol-1-one Core of Cytochalasins
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Synthesis of the cis-fused Δ5,6-hexahydroisoindol-1-one core of cytochalasins B2-B5, K, Z8, Z9, Z12-Z15, and Z17 has been established starting from an intramolecular D
- Xu, Jingjing,Lin, Benguo,Jiang, Xiuqing,Jia, Zejun,Wu, Jinlong,Dai, Wei-Min
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supporting information
p. 830 - 834
(2019/01/26)
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- Cu(OTf)2-Promoted 1,4-addition of alkyl bromides to dehydroalanine
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Zn/Cu(OTf)2-mediated addition of alkyl bromides to dehydroalanine (Dha) derivatives including dipeptides and tripeptides in good to high yields under an aqueous medium was developed. This protocol allows selective and biocompatible access to various amino acid units from Dha derivatives.
- Shin, Jung-Ah,Kim, Jiheon,Lee, Hongsoo,Ha, Sura,Lee, Hee-Yoon
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p. 4558 - 4565
(2019/05/01)
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- BABIPhos Family of Biaryl Dihydrobenzooxaphosphole Ligands for Asymmetric Hydrogenation
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Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An efficient route toward various analogues was also established, giving access to phosphines with different electronic and steric properties. The newly obtained ligands demonstrated high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and trisubstituted enamides. This new class of ligands is complementary to previously described bidentate benzooxaphosphole ligands BIBOP.
- Li, Guisheng,Zatolochnaya, Olga V.,Wang, Xiao-Jun,Rodríguez, Sonia,Qu, Bo,Desrosiers, Jean-Nicolas,Mangunuru, Hari P. R.,Biswas, Soumik,Rivalti, Daniel,Karyakarte, Shuklendu D.,Sieber, Joshua D.,Grinberg, Nelu,Wu, Ling,Lee, Heewon,Haddad, Nizar,Fandrick, Daniel R.,Yee, Nathan K.,Song, Jinhua J.,Senanayake, Chris H.
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supporting information
p. 1725 - 1729
(2018/04/14)
-
- NOVEL CHIRAL DIHYDROBENZOOXAPHOSPHOLE LIGANDS AND SYNTHESIS THEREOF
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This invention relates to novel phosphorous ligands useful for organic transformations. Methods of making and using the ligands in organic synthesis are described. The invention also relates to processes for preparing the novel ligands.
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-
Paragraph 0241
(2018/06/15)
-
- Unlocking the potential of phenacyl protecting groups: CO2-based formation and photocatalytic release of caged amines
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Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical biology and material research applications. A robust, highly efficient, and sustainable method for the formation of phenacyl-based carbamate esters was developed using CO2 for the in situ preparation of the intermediate carbamates. Our mild and broadly applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection protocol using visible light. A key feature of the [Ru(bpy)3](PF6)2-catalyzed method is the use of ascorbic acid as reductive quencher in a neutral, buffered, two-phase acetonitrile/water mixture, granting fast and highly selective deprotection for all presented examples.
- Speckmeier, Elisabeth,Klimkait, Michael,Zeitler, Kirsten
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p. 3738 - 3745
(2018/04/14)
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- COMPOUNDS AS MODULATORS OF TIGIT SIGNALLING PATHWAY
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The present invention relates to compound of formula (I) as therapeutic agents to modulate the TIGIT signalling pathway. The invention also encompasses the use of the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the treatment of diseases or disorders mediated by TIGIT.
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Page/Page column 84
(2018/03/28)
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- VISTA SIGNALING PATHWAY INHIBITORY COMPOUNDS USEFUL AS IMMUNOMODULATORS
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The present invention relates to VISTA signaling pathway inhibitory compounds of formula (I) which are useful as immune modulators for the treatment of various disease conditions including various types of cancer. The invention also encompasses the use of
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Page/Page column 69
(2018/03/28)
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- Synthesis, biological evaluation, and molecular modeling studies of chiral chloroquine analogues as antimalarial agents
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In a focused exploration, we designed, synthesized, and biologically evaluated chiral conjugated new chloroquine (CQ) analogues with substituted piperazines as antimalarial agents. In vitro as well as in vivo studies revealed that compound 7c showed potent activity (in vitro 50% inhibitory concentration, 56.98 nM for strain 3D7 and 97.76 nM for strain K1; selectivity index in vivo [up to at a dose of 12.5 mg/kg of body weight], 3,510) as a new lead antimalarial agent. Other compounds (compounds 6b, 6d, 7d, 7h, 8c, 8d, 9a, and 9c) also showed moderate activity against a CQ-sensitive strain (3D7) and superior activity against a CQ-resistant strain (K1) of Plasmodium falciparum. Furthermore, we carried out docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of all in-house data sets (168 molecules) of chiral CQ analogues to explain the structure-activity relationships (SAR). Our new findings specify the significance of the H-bond interaction with the side chain of heme for biological activity. In addition, the 3D-QSAR study against the 3D7 strain indicated the favorable and unfavorable sites of CQ analogues for incorporating steric, hydrophobic, and electropositive groups to improve the antimalarial activity.
- Kondaparla, Srinivasarao,Debnath, Utsab,Dola, Vasantha Rao,Sinha, Manish,Katti, Seturam B.,Soni, Awakash,Srivastava, Kumkum,Puri, Sunil K.
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- Efficient synthesis of novel conjugated 1,3,4-oxadiazole-peptides
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We were interested in the design and synthesis of novel bioisosteric analogues of leuprolide acetate containing the oxadiazole moiety at the C- or N-terminal of the peptide. An efficient approach for the synthesis of 2-amino-1,3,4-oxadiazoles through the reaction of hydrazide with ammonium thiocyanate and desulfurization reaction of the thiosemicarbazides using different coupling reagents was employed. These compounds are bioisosteres of the amide bond. Furthermore, the coupling of 2-amino-1,3,4-oxadiazoles at the C-terminal of leuprolide analogues was carried out, using a coupling reagent in the solution phase. On the other hand, the addition of a 2-amino-1,3,4-oxadiazole to the N-terminal of the peptide sequence was carried out through the reaction of the 2-amino-1,3,4-oxadiazole with succinic anhydride that led to the formation of a carboxylic acid moiety. Addition of the synthesized oxadiazole containing carboxylic acid to the peptide sequence was performed using a coupling reagent and on the surface of the resin. The synthesized peptides containing the oxadiazole moiety at the C- or N-terminal of the peptide sequence are peptidomimetics of leuprolide acetate. All of the synthesized peptides were purified using preparative HPLC and their structures were confirmed using HR-MS (ESI).
- Golmohammadi, Farhad,Balalaie, Saeed,Hamdan, Fatima,Maghari, Shokoofeh
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p. 4344 - 4351
(2018/03/21)
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- Method for selective removal of t-butyloxycarboryl from nitrogen
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The invention discloses a method for selective removal of t-butyloxycarboryl from nitrogen. According to the synthesis method, directed at a reaction substrate having t-butyloxycarboryl and another acyl protecting group on a molecular nitrogen atom, in the presence of a selectfluor reagent, reaction is carried out in a solution for selective removal of t-butyloxycarboryl and retention of another acyl protecting group. The synthesis method provided by the invention is novel and efficient, is not reported in literature, and can be widely used in total synthesis and drug intermediate synthesis.
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-
Paragraph 0024-0025; 0026-0028
(2018/03/26)
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- Total Synthesis of Ecumicin
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The first total synthesis of the potent anti-mycobacterial cyclic depsipeptide natural product ecumicin is described. Synthesis was achieved via a solid-phase strategy, incorporating the synthetic non-proteinogenic amino acids N-methyl-4-methoxy-l-tryptophan and threo-β-hydroxy-l-phenylalanine into the growing linear peptide chain. The synthesis employed key on-resin esterification and dimethylation steps as well as a final macrolactamization between the unusual N-methyl-4-methoxy-l-tryptophan unit and a bulky N-methyl-l-valine residue. The synthetic natural product possessed potent antimycobacterial activity against the virulent H37Rv strain of Mycobacterium tuberculosis (MIC90 = 312 nM).
- Hawkins, Paige M. E.,Giltrap, Andrew M.,Nagalingam, Gayathri,Britton, Warwick J.,Payne, Richard J.
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supporting information
p. 1019 - 1022
(2018/02/23)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE CARBOXYLIC ACID ESTER
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Provided is a method for producing an optically active carboxylic acid ester at a high yield and with high enantioselectivity using dynamic kinetic resolution, said optically active carboxylic acid ester having an α-nitrogen substituent. This method for producing an optically active carboxylic acid ester includes a step in which racemic carboxylic acid represented by formula (a) and a specific alcohol or phenol derivative are reacted in a polar solvent having a dipole moment of at least 3.5 in the presence of an acid anhydride and an asymmetric catalyst, one enantiomer of the racemic carboxylic acid is selectively esterified, and the other enantiomer is racemized. In formula (a), Ra1 represents a nitrogen-containing heteroaromatic ring group bonded to an assymetric carbon via a nitrogen atom constituting a ring, and Ra2 is an organic group.
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Paragraph 0732; 0763; 0764
(2017/01/26)
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- A method for preparing may compared to the department he intermediate and intermediate thereof and use thereof
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The invention relates to the field of medicinal chemical synthesis, in particular to a cobicistat intermediate preparing method, an intermediate and application thereof. The cobicistat intermediate (a compound (4)) preparing method includes the steps that a compound (5) is prepared into an organic metal compound (5'), and the compound (5') reacts with a compound (6) to prepare the compound (4) (see the reaction process in the description). The new reaction raw material compound (5) or (6) is provided to obtain the new compound (4) preparing method, the overall yield of the reaction can be increased, usage of toxic reagents is avoided, side reactions are reduced, and the cobicistat intermediate preparing method is suitable for industrial production. Further, the compound (4) is used as the intermediate for preparing a compound (1), by-products in the prior art are avoided, usage of toxic reagents is avoided, cost is saved, and the intermediate is beneficial for environment maintenance and suitable for industrial production.
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-
Paragraph 0067-0069
(2017/11/16)
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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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supporting information
p. 2127 - 2132
(2017/10/31)
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- Amidation of unactivated ester derivatives mediated by trifluoroethanol
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A catalytic amidation protocol mediated by 2,2,2-trifluoroethanol has been developed, facilitating the condensation of unactivated esters and amines, furnishing both secondary and tertiary amides. The complete scope and limitations of the method are described, along with modified conditions for challenging substrates such as acyclic secondary amines and chiral esters with retention of chiral integrity.
- McPherson, Christopher G.,Caldwell, Nicola,Jamieson, Craig,Simpson, Iain,Watson, Allan J. B.
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supporting information
p. 3507 - 3518
(2017/04/26)
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- Synthesis and antiproteasomal activity of novel O-benzyl salicylamide-based inhibitors built from leucine and phenylalanine
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Inhibition of protein degradation is one of strategies for suppression of uncontrolled proliferation of cancer cells. Proteolytic degradation in cells is mainly ensured by proteasome and its inhibition by bortezomib showed benefit in clinical use for the treatment of multiple myeloma. We report here the library of antiproteasomal O-benzyl salicylamides built from leucine and phenylalanine. Prepared compounds displayed antiproliferative activity on K562, CEM and U266 cancer cell lines, ranging from high micromolar to submicromolar GI50 values. The most potent compounds (series 4 and 6) were further assayed for their inhibition of chymotrypsin-like protease activity of the 26S proteasome in U266 cells. The majority of compounds inhibited the proteasome in mid-nanomolar concentrations (IC50 ranging from 57 to 197 nM) and it correlated with cellular potency. In a cell based assay involving green fluorescence protein (GFP) fused to a short degron that is rapidly degraded by a proteasome the compounds induced accumulation of GFP, visualised and quantified by live-cell imaging. Levels of polyubiquitinated proteins in U266 cells treated by compound 4m were also analyzed by immunoblotting, revealing a typical high molecular mass smear of ubiquitin conjugates. Finally, apoptotic cell death in treated U266 cells was detected biochemically by measuring the activity of caspases 3 and 7 in lysates and by immunoblotting of caspase 7, its substrate poly(ADP-ribose)polymerase, and Mcl-1, which all together showed changes typical for apoptosis. All these observations were in agreement with expected cellular mechanism of action and confirmed proteasome targeting by prepared O-benzyl salicylamides.
- Jorda, Radek,Du?ek, Jan,?ezní?ková, Eva,Pauk, Karel,Magar, Pratibha P.,Imramovsky, Ale?,Kry?tof, Vladimír
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supporting information
p. 142 - 158
(2017/04/26)
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- Preparation method of (S)-4-amino-2-methyl-5-phenyl-1-cyclopenten-3-ketone
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The invention relates to the field of chemistry, in particular to a new preparation method of (S)-4-amino-2-methyl-5-phenyl-1-cyclopenten-3-ketone, namely an oprozomib key synthetic intermediate as a drug for treating multiple myeloma. The new preparation method comprises the following steps: firstly performing carboxyl and amino protection on a starting material, namely L-phenylalanine, successively condensing with diethyl ethylphosphonate under the existence of alkali, performing HWE reaction on beta-ketophosphate obtained and formaldehyde under the existence of the alkali and finally obtaining the key intermediate. The method is simple, convenient and easy to implement, cheap and easy to obtain in raw material, lower in cost and better in yield, thereby having potential production values.
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Paragraph 0023; 0024
(2017/01/02)
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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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- Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry
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Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization.
- Mondal, Milon,Radeva, Nedyalka,Fanlo-Virgós, Hugo,Otto, Sijbren,Klebe, Gerhard,Hirsch, Anna K. H.
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p. 9422 - 9426
(2016/08/05)
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- A PRODUCING METHOD OF D-FORM OR L-FORM AMINO ACID DERIVATIVES HAVING A THIOL GROUP
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This invention provides a producing method of an optical active D-form and/or L-form amino acid having a thiol group on its side chain by a simple method with good yield. This invention provides a producing method of an amino acid derivative having a thiol group on its side chain, and an intermediate thereof, wherein the producing method is characterized by producing an intermediate composition comprising a D-form and L-form of amino acid derivate having a thiol group at β -position, reacting D- or L-amino acid selective hydrolytic enzyme, and isolating the hydrolyzed D- or L-amino acid derivative.
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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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- 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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- Nonenzymatic, enantioconvergent dynamic kinetic resolution (DKR) of racemic 2-(1H-pyrrol-1-yl)alkanoic acids as α-amino acid equivalents
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We report an effective dynamic kinetic resolution (DKR) system of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which consists of a rapid racemization step via an activating substrate and an enantio-discriminating step via catalytic esterification. The combination of pivalic anhydride as an activating agent, bis(α-naphthyl)methanol as an achiral alcohol, (R)-BTM as a chiral acyl-transfer catalyst, and Hunig's base converted racemic 2-(1H-pyrrol-1-yl)alkanoic acids to the corresponding chiral carboxylates, which can be transformed into chiral α-amino acid derivatives with maintained high enantiopurity.
- Tokumaru, Eri,Tengeiji, Atsushi,Nakahara, Takayoshi,Shiina, Isamu
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p. 1768 - 1770
(2016/02/18)
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- Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-ones via Peptide-Catalyzed Atroposelective Bromination
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We report the development of a tertiary amine-containing β-turn peptide that catalyzes the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin-4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad substrate scope. The structure of the free catalyst and the peptide-substrate complex were explored using X-ray crystallography and 2D-NOESY experiments. Quinazolinone rotational barriers about the chiral anilide axis were also studied using density functional theory calculations and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event is stereodetermining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. The observation of stereoisomerically stable monobromides stimulated the conversion of the tribromide products to other atropisomerically defined products of interest. For example, (1) a dehalogenation Suzuki-Miyaura cross-coupling sequence delivers ortho-arylated derivatives, and (2) a regioselective Buchwald-Hartwig amination procedure installs para-amine functionality. Stereochemical information was retained during these subsequent transformations.
- Diener, Matthew E.,Metrano, Anthony J.,Kusano, Shuhei,Miller, Scott J.
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supporting information
p. 12369 - 12377
(2015/10/12)
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- Hydroxyl-Directed Cross-Coupling: A Scalable Synthesis of Debromohamigeran e and Other Targets of Interest
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A hydroxyl functional group positioned β to a pinacol boronate can serve to direct palladium-catalyzed cross-coupling reactions. This feature can be used to control the reaction site in multiply borylated substrates and can activate boronates for reaction that would otherwise be unreactive.
- Blaisdell, Thomas P.,Morken, James P.
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supporting information
p. 8712 - 8715
(2015/07/27)
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- AURISTATIN ANALOGUES AND THEIR CONJUGATES WITH CELL-BINDING MOLECULES
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This invention relates to analogues of auristatins, in particular monomethyl auristatin F (MMAF), as cytotoxic agents, conjugates of such cytotoxic agents with a cell-binding agent, the preparation and the therapeutic uses of these cytotoxic agents and conjugates thereof to arrest or retard abnormal cell growth and /or proliferation.
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Page/Page column 6; 71; 72
(2015/11/18)
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- The Role of the Amino Protecting Group during Parahydrogenation of Protected Dehydroamino Acids
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A series of dehydroamino acids endowed with different protective groups at the amino and carboxylate moieties and with different substituents at the double bond have been reacted with parahydrogen. The observed ParaHydrogen Induced Polarization (PHIP) effects in the 1H NMR spectra are strongly dependent on the amino protecting group. DFT calculations allowed us to establish a relationship between the structures of the reaction intermediates (whose energies depend on the amido substitution) and the observed PHIP patterns.
- Cerutti, Erika,Viale, Alessandra,Nervi, Carlo,Gobetto, Roberto,Aime, Silvio
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p. 11271 - 11279
(2015/12/01)
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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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- Design, synthesis and evaluation of novel indole derivatives as AKT inhibitors
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Herein, we describe the discovery and synthesis of a new series of 1,2,4,7-tetra-substituted indole derivatives as novel AKT inhibitors by optimization of a weak hit methyl 4-(2-aminoethoxy)-1H-indole-2-carboxylate (1). Both representative compounds 6a and 6o exhibited the most potent inhibitory activities against AKT1, with inhibition rates of 72.5% and 78.6%, respectively, at concentrations of 10 nM. In addition, compounds 6a and 6o also potently inhibited the phosphorylation of the downstream GSK3 protein and displayed slightly better anti-proliferative activities in a prostate cancer cell line.
- Yang, Dezhi,Wang, Peng,Liu, Jianzhen,Xing, Hualu,Liu, Yang,Xie, Wencheng,Zhao, Guisen
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p. 366 - 373
(2014/01/17)
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- General solvent-free highly selective N-tert-butyloxycarbonylation strategy using protic ionic liquid as an efficient catalyst
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A simple, rapid and solvent-free protocol is described for the chemo-selective transformation of amines to tert-butyloxycarbonyl protected derivatives (NHBoc) using Boc2O and imidazolium trifluoroacetate protic ionic liquid (5-20 mol%). Unwanted side products such as isocyanate, urea or N,N-di-Boc were not detected. The scope of the protection strategy was successfully explored for substrate alcohols, phenols and thiol at elevated temperatures. Optically pure amino acids, amino acid esters and amino alcohols were efficiently converted to the corresponding N-Boc protected derivatives in excellent yields without racemization at the chiral center. The distinct advantages of this method are: operational simplicity, cleaner reaction, high selectivity, excellent yield, rapid reaction convergence, easy preparation and recyclability of the catalyst.
- Majumdar, Swapan,De, Jhinuk,Chakraborty, Ankita,Maiti, Dilip K.
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p. 24544 - 24550
(2014/07/07)
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- A rapid entry to amino acid derived diverse 3,4-dihydropyrazines and dihydro[1,2,3]triazolo[1,5-a]pyrazines through 1,3-dipolar cycloaddition
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An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolopyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from amino acid derived common intermediates with high yields is described. Moreover, one-pot access to optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium-copper co-catalytic system has also been achieved in this work. The easy substrate availability and operational simplicity make the process suitable for further exploration. This journal is the Partner Organisations 2014.
- Bera, Saurav,Panda, Gautam
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p. 3976 - 3985
(2014/06/09)
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- Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers, part I: Core region
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Ritonavir (RTV), an HIV-1 protease inhibitor (PI), is also a potent mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) and has been widely prescribed as a pharmacoenhancer. As a boosting agent for marketed PIs, it reduces pill burden, and improves compliance. Removal of the hydroxyl group from RTV reduces, but does not eliminate HIV PI activity and does not affect CYP3A inhibition. Herein we report the discovery of a novel series of CYP3A inhibitors that are devoid of antiviral activity. The synthesis and evaluation of analogs with extensive modifications of the 1,4-diamine core along with the structure activity relationships with respect to anti-HIV activity, CYP3A inhibitory activity, selectivity against other CYP enzymes and the human pregnane X receptor (PXR) will be discussed.
- Liu, Hongtao,Xu, Lianhong,Hui, Hon,Vivian, Randy,Callebaut, Christian,Murray, Bernard P.,Hong, Allen,Lee, Melody S.,Tsai, Luong K.,Chau, Jennifer K.,Stray, Kirsten M.,Cannizzaro, Carina,Choi, You-Chul,Rhodes, Gerry R.,Desai, Manoj C.
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p. 989 - 994
(2014/02/14)
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- Antiplasmodial activity of new 4-aminoquinoline derivatives against chloroquine resistant strain
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Emergence and spread of multidrug resistant strains of Plasmodium falciparum has severely limited the antimalarial chemotherapeutic options. In order to overcome the obstacle, a set of new side-chain modified 4-aminoquinolines were synthesized and screened against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. The key feature of the designed molecules is the use of methylpiperazine linked α, β3- and γ-amino acids to generate novel side chain modified 4-aminoquinoline analogues. Among the evaluated compounds, 20c and 30 were found more potent than CQ against K1 and displayed a four-fold and a three-fold higher activity respectively, with a good selectivity index (SI = 5846 and 11,350). All synthesized compounds had resistance index between 1.06 and >14.13 as against 47.2 for chloroquine. Biophysical studies suggested that this series of compounds act on heme polymerization target.
- Sinha, Manish,Dola, Vasanth R.,Agarwal, Pooja,Srivastava, Kumkum,Haq, Wahajul,Puri, Sunil K.,Katti, Seturam B.
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p. 3573 - 3586
(2014/07/07)
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- A simple, rapid, and efficient N-Boc protection of amines under ultrasound irradiation and catalyst-free conditions
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A green and simple approach for the N-Boc protection on structurally diverse amines under ultrasound irradiation is described. Selective N-Boc protection was achieved in excellent isolated yield in a short reaction time at room temperature. Mild conditions, inexpensive and an easily available reagent, and absence of any auxiliary substances are the main advantages of this procedure. Graphical abstract: [Figure not available: see fulltext.]
- Amira, Aicha,K'Tir, Hacene,Berredjem, Malika,Aouf, Nour-Eddine
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p. 509 - 515
(2014/03/21)
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