- Total syntheses of Hexahydropyrrolo[2,3-b]indole Alkaloids, (+)-pseudophrynamine 270 and (+)-pseudophrynamine 272A
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A general strategy for asymmetric approach to the hexahydropyrrolo[2,3-b]indole alkaloids sharing a vicinal quaternary-tertiary centers has been disclosed via Pd(0)-catalyzed N-deacylative allylations (N-DaA) (dr > 20:1). Utilizing this strategy, asymmetric total syntheses of pseudophrynamines 270 (3c) and 272A (3b) have been achieved from a 3-substituted N-acyl indole 8 (pro-nucleophile) with allyl alcohol (pro-electrophile).
- Maity, Arindam,Munda, Mintu,Niyogi, Sovan,Kumar, Nivesh,Bisai, Alakesh
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- Preparation method of chiral alpha-methyl arylethylamine
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The invention provides a preparation method of chiral alpha-methyl arylethylamine, and relates to the technical field of organic synthesis medicines. Boc-amino acid methyl ester is used as an initial raw material, Boc-amino alcohol is obtained through reduction, Boc-amino alcohol reacts with thionyl chloride and is oxidized through sodium periodate to obtain a sulfonamide compound, and then the sulfonamide compound is reduced through sodium borohydride promoted by lewis acid and a protecting group is removed under the acidic condition to obtain a target compound. According to the method, raw materials are cheap and easy to obtain, a single optical isomer product is obtained by using chiral raw materials, the problem of column chromatography resolution is solved, generation of a large amount of solid wastes and isomers is avoided, atom economy is improved, the product purity is high, the yield is high, and the production cost is effectively reduced. In addition, the mild reduction system is used for replacing the original high-pressure hydrogenation reaction, the process operation is relatively simple, and the method is more suitable for large-scale industrial production.
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Paragraph 0053-0054
(2021/06/09)
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- ANTIBODY DRUG CONJUGATES COMPRISING ECTEINASCIDIN DERIVATIVES
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Drug conjugates having formula [D-(X) b -(AA) w -(T) g -(L)-] n -Ab wherein: D is a drug moiety having the following formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer th
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Page/Page column 182
(2020/05/29)
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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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- A catalytic N-deacylative alkylation approach to hexahydropyrrolo[2,3-b]indole alkaloids
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A versatile unprecedented strategy to diversely functionalized hexahydropyrrolo[2,3-b]indole alkaloids is described in high chemical yields. The synthesis features a key Pd(0)-catalyzed deacylative alkylation of N-acyl 3-substituted indoles using only 1 mol% of Pd(PPh3)4. The scope of this methodology is further defined in the asymmetric synthesis of pyrroloindolines using a diastereoselective approach.
- Kumar, Nivesh,Maity, Arindam,Gavit, Vipin R.,Bisai, Alakesh
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p. 9083 - 9086
(2018/08/21)
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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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- Design, synthesis, and evaluation of novel Akt1 inhibitors based on an indole scaffold
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A new series of potential Akt1 inhibitors with indole scaffold were designed and synthesized. The antiproliferative activity against PC-3 cell line and enzyme inhibitory activity against Akt1 were evaluated. Among them, some compounds showed much more potent antiproliferative activity and stronger Akt1 inhibitory activity compared to the positive control of GSK690693. In particular, compound 19b exhibited the most potent inhibitory activity against Akt1 with inhibition rate of 70.3% at a concentration of 10?nm. Furthermore, compound 19b could dose dependently reduce the phosphorylation of the downstream GSK3β protein in the PC-3 cell line and displayed fivefold higher antiproliferative activity against PC-3 cell line with IC50 value of 3.1?±?0.1?μm than positive control (15.5?±?0.4?μm). Herein, compound 19b may serve as a promising lead for further optimization and development of novel Akt1 inhibitors based on an indole scaffold.
- Yang, Dezhi,Tong, Dongdong,Zhang, Qian,Wang, Yongtao,Sun, Jing,Zhang, Fenghe,Zhao, Guisen
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p. 791 - 803
(2017/09/30)
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- Synthesis of fully protected, reverse N-prenylated (2S,3R)-3-hydroxytryptophan, a unique building block of the cyclomarins
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Reverse N-prenylated 3-hydroxytryptophan, the rather exotic amino acid of the cyclomarins, is obtained in enantio- and diastereomerically pure and fully protected form by a combination of a highly stereoselective addition of a zincated indole toward protected serinal and subsequent palladium-catalyzed N-prenylation.
- Barbie, Philipp,Kazmaier, Uli
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p. 9267 - 9275
(2015/09/07)
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- A multifaceted secondary structure mimic based on piperidine-piperidinones
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Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1-faf crystallized in a conformation that is estimated to be 0.91 kcal-mol-1 above the minimum energy solution state. Do we know, when designing a new peptidomimetic scaffold like the one shown, how it can resemble secondary structures? Design and modular synthesis of this elongated mimic is reported, and the structure is related to ideal and real structures at PPI interfaces.
- Xin, Dongyue,Perez, Lisa M.,Ioerger, Thomas R.,Burgess, Kevin
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p. 3594 - 3598
(2014/04/17)
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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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- Discovery of the first N -hydroxycinnamamide-based histone deacetylase 1/3 dual inhibitors with potent oral antitumor activity
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In our previous study, we designed and synthesized a novel series of N-hydroxycinnamamide-based HDAC inhibitors (HDACIs), among which the representative compound 14a exhibited promising HDACs inhibition and antitumor activity. In this current study, we report the development of a more potent class of N-hydroxycinnamamide-based HDACIs, using 14a as lead, among which, compound 11r gave IC50 values of 11.8, 498.1, 3.9, 2000.8, 5700.4, 308.2, and 900.4 nM for the inhibition of HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC6, and HDAC11, exhibiting dual HDAC1/3 selectivity. Compounds 11e, 11r, 11w, and 11y showed excellent growth inhibition in multiple tumor cell lines. In vivo antitumor assay in U937 xenograft model identified compound 11r as a potent, orally active HDACI. To the best of our knowledge, this work constitutes the first report of oral active N-hydroxycinnamamide-based HDACIs with dual HDAC1/3 selectivity.
- Li, Xiaoyang,Inks, Elizabeth S.,Li, Xiaoguang,Hou, Jinning,Chou, C. James,Zhang, Jian,Jiang, Yuqi,Zhang, Yingjie,Xu, Wenfang
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p. 3324 - 3341
(2014/05/20)
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- Development of N-hydroxycinnamamide-based histone deacetylase inhibitors with an indole-containing Cap group
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A novel series of histone deacetylase inhibitors combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment was designed and synthesized. Several compounds (17c, 17g, 17h, 17j, and 17k) exhibited comparable, even superior, total HDACs inhibitory activity and in vitro antiproliferative activities relative to the approved drug SAHA. A representative compound 17a with moderate HDACs inhibition was progressed to isoform selectivity profile, Western blot analysis, and in vivo antitumor assay. Although HDACs isoform selectivity of 17a was similar to that of SAHA, our Western blot results indicated that intracellular effects of 17a at 1 μM were class I selective. It was noteworthy that the effect on histone H4 acetylation of SAHA decreased with time, while the effect on histone H4 acetylation of 17a was maintained and even increased. Most importantly, compound 17a exhibited promising in vivo antitumor activity in a U937 xenograft model.
- Zhang, Yingjie,Yang, Penghui,Chou, C. James,Liu, Chunxi,Wang, Xuejian,Xu, Wenfang
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p. 235 - 238
(2013/03/28)
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- Microwave-enhanced solid-phase synthesis of N,N′-linked aliphatic oligoureas and related hybrids
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A practical and efficient microwave-assisted solid-phase method for the synthesis of N,N′-linked oligoureas and related amide/urea hybrid oligomers, featuring the use of succinimidyl (2-azido-2-substituted ethyl) carbamate monomers, is reported. The rate enhancement of urea formation under microwave irradiation combined with the mild conditions of the phosphine-based azide reduction makes this approach very effective for routine synthesis of oligoureas and possibly for library production.
- Douat-Casassus, Céline,Pulka, Karolina,Claudon, Paul,Guichard, Gilles
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supporting information; experimental part
p. 3130 - 3133
(2012/09/08)
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- From BACE1 Inhibitor to Multifunctionality of tryptoline and tryptamine triazole derivatives for alzheimer's disease
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Efforts to discover new drugs for Alzheimer's disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ1-42 induced neuronal cell death at 1 ?M were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ1-42 neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer's disease.
- Jiaranaikulwanitch, Jutamas,Govitrapong, Piyarat,Fokin, Valery V.,Vajragupta, Opa
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p. 8312 - 8333
(2012/10/18)
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- A facile synthesis and crystallographic analysis of N-protected β-amino alcohols and short peptaibols
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A facile, efficient and racemization-free method for the synthesis of N-protected β-amino alcohols and peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide, tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of β-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III β-turn being observed in the tripeptide alcohol crystals. This method is found to be compatible with Fmoc-, Boc- and other side-chain protecting groups.
- Jadhav, Sandip V.,Bandyopadhyay, Anupam,Benke, Sushil N.,Mali, Sachitanand M.,Gopi, Hosahudya N.
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p. 4182 - 4187
(2011/06/28)
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- Synthesis and binding properties of guanidinium biscarboxylates
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The ammonium ion binding site of the enzyme glutaminase HisF inspired us to design guanidinium biscarboxylates as potential self-organized ionophores in molecular recognition. The syntheses of the title compounds based on aliphatic and aromatic building b
- Spaeth, Andreas,Gonschor, Janina,Koenig, Burkhard
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experimental part
p. 1289 - 1308
(2012/06/15)
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- Copper-catalyzed cyclization of lodo-tryptophans: A straightforward synthesis of pyrroloindoles
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(Chemical Equation Presented) Pyrroloindoles are a key structural motif found in a wide number of biologically active alkaloids. Intramolecular copper-catalyzed coupling of readily accessible 2-iodo-tryptophan derivatives occurs in excellent yield, afford
- Coste, Alexis,Toumi, Mathieu,Wright, Karen,Razafimahaleo, Vanessa,Couty, Francois,Marrot, Jerome,Evano, Gwilherm
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supporting information; experimental part
p. 3841 - 3844
(2009/07/01)
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- Identification of a novel 3,5-disubstituted pyridine as a potent, selective, and orally active inhibitor of Akt1 kinase
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Based on lead compounds 2 and 3 a series of 3,5-disubstituted pyridines have been designed and evaluated for inhibition of AKT/PKB. Modifications at the 3 position of the pyridine ring led to a number of potent compounds with improved physical properties, resulting in the identification of 11g as a promising, orally active Akt inhibitor. The synthesis, structure-activity relationship studies, and pharmacokinetic data are presented in this paper.
- Thomas, Sheela A.,Li, Tongmei,Woods, Keith W.,Song, Xiaohong,Packard, Garrick,Fischer, John P.,Diebold, Robert B.,Liu, Xuesong,Shi, Yan,Klinghofer, Vered,Johnson, Eric F.,Bouska, Jennifer J.,Olson, Amanda,Guan, Ran,Magnone, Shayna R.,Marsh, Kennan,Luo, Yan,Rosenberg, Saul H.,Giranda, Vincent L.,Li, Qun
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p. 3740 - 3744
(2007/10/03)
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- Pseudosymmetry in azabicyclo[2.1.1]hexanes. A stereoselective construction of the bicyclic core of peduncularine
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Intramolecular photocycloaddition of 41 or its equivalent leads to the formation of photoadduct 25. While retro-Mannich fragmentation of the "b" bond in 25 leads to the formation of 44 (via 43), with the incorrect relative stereochemistry for the synthesi
- Ragains, Justin R.,Winkler, Jeffrey D.
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p. 4437 - 4440
(2007/10/03)
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- A facile and simple method for the reduction of N-protected amino acids and peptides to the corresponding alcohols
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A practical and chemoselective method for the reduction of N-protected amino acids and peptides including carboxylic acids to their corresponding alcohols is outlined.
- Srivastava, Tumul,Srivastava, Tushar K.,Haq,Katti, Seturam B.
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p. 516 - 517
(2007/10/03)
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- Synthesis of a fully protected (2S,3R)-N-(1′,1′-dimethyl-2′- propenyl)-3-hydroxytryptophan from tryptophan
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(2S,3R)-N-(1′,1′-Dimethyl-2′-propenyl)-3-hydroxytryptophan, a key amino acid of the anti-inflammatory cyclic peptide, cyclomarin C, has been synthesized stereoselectively, with full protection, from L-tryptophan for the first time.
- Wen, Shi-Jun,Zhang, Hong-Wang,Yao, Zhu-Jun
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p. 5291 - 5294
(2007/10/03)
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- An efficient method for the reduction of N-protected amino acids and peptides to the corresponding alcohols
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Reduction of pentachlorophenyl esters of Boc protected amino acids and peptides to the corresponding alcohols is described.
- Naqvi,Bhattacharya,Haq
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p. 424 - 425
(2007/10/03)
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- Potent and Selective Inhibitors of an Aspartyl Protease-like Endothelin Converting Enzyme Identified in Rat Lung
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Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed.Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series.Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity.Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity.Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D.Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing.Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors.
- Shiosaki, Kazumi,Tasker, Andrew S.,Sullivan, Gerard M.,Sorensen, Bryan K.,Geldern, Thomas W. von,et al.
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p. 468 - 478
(2007/10/02)
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- A facile synthesis of chiral N-protected β-amino alcohols
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Chiral N-protected β-amino alcohols are easily obtained by NaBH4 reduction of mixed anhydrides of N-protected α-amino acids in an organic/aqueous medium. The alcohols obtained from side chain or main chain reduction of N-protected aspartic acid are converted in good yields into lactones.
- Rodriguez,Llinares,Doulut,Heitz,Martinez
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p. 923 - 926
(2007/10/02)
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