- Tryptophanol‐derived oxazolopyrrolidone lactams as potential anticancer agents against gastric adenocarcinoma
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Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol‐derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therapeutic target in cancer. In this work, we developed a novel series of enantiomerically pure tryptophanol‐derived small molecules to target human gastric adenocarcinoma (AGS) cells. From an initial screening of fourteen compounds in AGS cell line, a hit compound was selected for optimization, leading to two derivatives selective for AGS gastric cells over other types of cancer cells (MDA‐MB‐231, A‐549, DU‐145, and MG‐63). More importantly, the compounds were non‐toxic in normal cells (HEK 293T). Additionally, we show that the growth inhibition of AGS cells induced by these compounds is mediated by apoptosis. Stability studies in human plasma and human liver microsomes indicate that the compounds are stable, and that the major metabolic transformations of these molecules are mono‐ and di‐hydroxylation of the indole ring.
- Espadinha, Margarida,Barcherini, Valentina,Gon?alves, Lídia M.,Molins, Elies,Antunes, Alexandra M. M.,Santos, Maria M. M.
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- Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros
-
NIMA-related kinase 1 (Nek1) has lately garnered attention for its widespread function in ciliogenesis, apoptosis, and the DNA-damage response. Despite its involvement in various diseases and its potential as a cancer drug target, no directed medicinal chemistry efforts toward inhibitors against this dark kinase are published. Here, we report the structure-guided design of a potent small-molecule Nek1 inhibitor, starting from a scaffold identified by kinase cross-screening analysis. Seven lead compounds were identified in silico and evaluated for their inhibitory activity. The top compound, 10f, was further profiled for efficacy, toxicity, and bioavailability in a zebrafish polycystic kidney disease model. Administration of 10f caused the expansion of fluorescence-labeled proximal convoluted tubules, supporting our hypothesis that Nek1-inhibition causes cystic kidneys in zebrafish embryos. Compound 10f displayed insignificant inhibition in 48 of 50 kinases in a selectivity test panel. The findings provide a powerful tool to further elucidate the function and pharmacology of this neglected kinase.
- Baumann, Georg,Meckel, Tobias,B?hm, Kevin,Shih, Yung-Hsin,Dickhaut, Mirco,Reichardt, Torben,Pilakowski, Johannes,Pehl, Ulrich,Schmidt, Boris
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- Bisindole alkaloid compound as well as synthesis method and application thereof
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The invention discloses a bisindole alkaloid compound as well as a synthesis method and application thereof. The compound has a structure as shown in formula I. In the formula I, R1 is independently selected from C1-C4 alkoxy or hydrogen; if R1 is alkoxy, n is 1 or 2; R2 is independently selected from C1-C4 alkyl groups or hydrogen; R3 is independently selected from a group consisting of C1-C4 alkoxy carbonyl groups or hydrogen; R4 is hydrogen; R5 is independently selected from a C1-C4 alkyl group or a C1-C4 hydroxyalkyl group; and R6 is independently selected from carbonyl, hydroxyl or hydrogen. The bisindole alkaloid compound can selectively relax pulmonary artery, inhibit proliferation of pulmonary artery endothelial cells and vascular smooth muscle cells, reduce right ventricular diastolic pressure of mice with pulmonary arterial hypertension and inhibit right ventricular hypertrophy. The bisindole alkaloid compound can resist drug addiction in a dose-dependent manner, has a chemical structure type different from that of an existing anti-addiction drug, and is expected to be developed into a novel anti-addiction drug.
- -
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Paragraph 0052-0053; 0071-0074
(2021/08/14)
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- 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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- An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4
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Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R1 side-group as phenyl or naphthalene and R2 as indole or naphthalene in different stereo configuration showed that (i) analogues with the R2-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R2-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055–0.085 μM vs. 0.130 μM, respectively).
- Samuels, Eric R.,Sevrioukova, Irina F.
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- Design and synthesis of novel monoterpenoid indole alkaloid-like analogues and their antitumour activities: In vitro
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A biomimetic synthetic strategy and combinatorial chemistry were used to synthesize 34 novel monoterpenoid indole alkaloid (MIA) analogues, and their cytotoxic activities against five cancer cell lines (SW-480, A-549, HL-60, SMMC-7721, and MCF-7) were determined using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Fourteen of these analogues (7, 16-18, and 23-32) showed significantly greater inhibition of tumour cell proliferation than cisplatin. Compounds 17 and 18 showed the highest cytotoxic activity against the HL-60 cell line with IC50 values of 0.90 μM and 0.43 μM, respectively. Compound 18 slightly induced apoptosis and arrested the cell cycle in SW-480, A-549, HL-60, SMMC-7721, and MCF-7 cells. Analysis of the primary structure-activity relationships reveals that the introduction of different substituent groups at the C-3, C-5, and C-6 positions of the indole moiety and the C-10 position of the genipin moiety might have an effect on the antitumour activity of the resulting compounds.
- Fang, Jiaqi,Huang, Tao,Xia, Mengyuan,Deng, Lulu,Hao, Xiaojiang,Wang, Yuehu,Mu, Shuzhen
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p. 3026 - 3037
(2018/05/03)
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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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supporting information
p. 9083 - 9086
(2018/08/21)
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- Palladium-Catalyzed Amide-Directed Enantioselective Hydrocarbofunctionalization of Unactivated Alkenes Using a Chiral Monodentate Oxazoline Ligand
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A Pd-catalyzed amide-directed enantioselective hydrocarbofunctionalization of unactivated alkenes with C-H nucleophiles has been developed using a chiral monodentate oxazoline (MOXin) ligand. Various indoles react at C3 position with aminoquinoline-coupled 3-alkenamides to give γ addition products in good to excellent yield and enantioselectivity. This study represents an important advance of the development of chiral monodentate oxazoline ligands, which have been underexplored for asymmetric catalysis.
- Wang, Hao,Bai, Zibo,Jiao, Tangqian,Deng, Zhiqiang,Tong, Huarong,He, Gang,Peng, Qian,Chen, Gong
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supporting information
p. 3542 - 3546
(2018/03/21)
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- ESTROGEN RECEPTOR MODULATORS
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Compounds of Formula (I) are estrogen receptor alpha modulators, where the variables in Formula (I) are described in the disclosure. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions that are estrogen receptor alpha dependent and/or estrogen receptor alpha mediated, including conditions characterized by excessive cellular proliferation, such as breast cancer.
- -
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Paragraph 0131
(2017/11/04)
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- Enantiopure indolo[2,3-a]quinolizidines: Synthesis and evaluation as NMDA receptor antagonists
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Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl D-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic δ-oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors.
- Pereira, Nuno A. L.,Sureda, Francesc X.,Pérez, Maria,Amat, Mercedes,Santos, Maria M. M.
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- High-Temperature Boc Deprotection in Flow and Its Application in Multistep Reaction Sequences
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A simplified Boc deprotection using a high-temperature flow reactor is described. The system afforded the qualitative yield of a wide variety of deprotected substrates within minutes using acetonitrile as the solvent and without the use of acidic conditions or additional workups. Highly efficient, multistep reaction sequences in flow are also demonstrated wherein no extraction or isolation was required between steps.
- Bogdan, Andrew R.,Charaschanya, Manwika,Dombrowski, Amanda W.,Wang, Ying,Djuric, Stevan W.
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supporting information
p. 1732 - 1735
(2016/05/19)
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- N-substituted benzenepropanamide or benzenepropenamide derivatives for use in the treatment of pain and inflammation
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Compounds for use in the treatment or prophylaxis of pain, including acute and chronic pain (e.g., nociceptive pain, neuropathic pain, headaches, migraine), represented by general formula (I) in which: the dotted line represents a single or a double bond; and R5 and R5′ are independently —H, —OH or —OR6, where R6 is a linear or branched C1-C4 alkyl; X is -0-, —CH2O—, —CH2CH2O—, —CH(CH3)CH2O— or —CH2CH(CH3)O—; Z is —CH2CH2O—, —CH(CH3)CH2O— or —CH2CH(CH3)O—; m is an integer of O or 1; and n is an integer of 0-50. The compounds of the invention are also effective for reducing inflammation and may be used alone or in combination with other analgesics.
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Page/Page column 9
(2015/12/17)
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- New chiral 4-substituted 2-cyanoethyl-oxazolines: Synthesis and assessment of some biological activities
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This paper describes the synthesis of new enantiomerically pure 2-cyanoethyl-oxazolines in one step starting from a wide range of amino alcohols and 4-ethoxy-4-iminobutanenitrile with high to good yields (73-96%) via an appropriate procedure which can be used for a selective synthesis of mono-oxazolines. A simple operation as well as a practical separation is additional eco-friendly attributes of this method. All the synthesized compounds were identified and characterized with their physicochemical features and their spectral data (1H NMR, 13C NMR and TOFMS ES+). Among the prepared mono-oxazolines, the mono-oxazoline (3a) [3-[(4S)-4-benzyl-4,5-dihydro-1,3-oxazol-2-yl] propanenitrile] was tested to detect some biological activities. This compound was studied in vitro given the various types of pharmacological properties characterizing these compounds such as antioxidant, antimicrobial and analgesic activities. The antioxidant activity and mechanism of (3a) were identified using various in vitro antioxidant assays including 1,1-diphenyl-2-picryl-hydrazyl (DPPH), and superoxide anion radicals (O2-) scavenging activity. In addition, compared to Quercetin, the tested synthetic product reveals a relatively-strong antiradical activity towards the DPPH (activity percentage of 81.22%) free radicals and significantly decreased the reactive oxygen species such as (O2 -) formation evaluated by the non-enzymatic (nitroblue tetrazolium/riboflavine) and the enzymatic (xanthine/xanthine oxidase) systems. Related activity values were, respectively, 66% and 60.30%. The oxazoline (3a) showed a high ability to reduce the O2- generation and proved to be a very potent radical scavenger. On the other hand, the analgesic property of the 3[(4S)-benzyl-4,5-dihydro-1,3-oxazol-2-yl] propanenitrile (3a) was demonstrated. The subcutaneous administration of (3a) produced a significant reduction in the number of abdominal constrictions amounting to 73.81% in the acetic acid writhing test in mice. In addition to these advances, the oxazoline (3a) has been investigated as an antimicrobial agent. Our results showed that this molecule exhibited various levels of antibacterial effect against all the tested bacterial strains.
- Hassani, Rym,Kacem, Yakdhane,Ben Mansour, Hedi,Ben Ammar, Hamed,Ben Hassine, Béchir
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- Stereoselectivity and conformational control in the synthesis of ajmaline and epi-ajmaline alkaloids
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Careful choice of the N-protecting group provides crucial conformational control, allowing ring-closure to the indole 3-position in the late stages of the synthesis of ajmaline alkaloids; the choice of protecting group and reducing agent can also provide access to either the natural or epi configuration at the indole 2-position.
- Bailey, Patrick D.,Beard, Mark A.,Cresswell, Mark,Dang, Hoa P.T.,Pathak, Ravindra B.,Phillips, Theresa R.,Price, Richard A.
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p. 1726 - 1729
(2013/04/24)
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- Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N-(2-aminophenyl)benzamide binding unit
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The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzamide 24a gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl) benzamides previously reported, an example of each ring system at 1 μM causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by 24a was observed, with respective IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.
- Marson, Charles M.,Matthews, Christopher J.,Yiannaki, Elena,Atkinson, Stephen J.,Soden, Peter E.,Shukla, Lena,Lamadema, Nermina,Thomas, N. Shaun B.
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p. 6156 - 6174
(2013/09/02)
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- A convenient one-step synthesis of stable β-amino alcohol N-boranes from α-amino acids
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Novel, non-cyclic -amino alcohol N-boranes are isolated from the sodium borohydride-sulfuric acid assisted direct reduction of a series of -amino acids. The reduction takes place in one step under mild conditions and affords the products in good yields. Georg Thieme Verlag Stuttgart · New York.
- Pinaka, Afroditi,Vougioukalakis, Georgios C.,Dimotikali, Dimitra,Psyharis, Vassilis,Papadopoulos, Kyriakos
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experimental part
p. 1057 - 1062
(2012/05/21)
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- Direct and selective functionalization of a tetrahydro-β-carboline at position 4
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The first example of direct functionalization of a tetrahydro-β- carboline (THBC) at position 4 is presented. Nucleophiles with various reactivity add to a transient intermediate generated in situ from this THBC. This reaction proceeds with a total control of the two created stereogenic centers.
- Rannoux, Claire,Roussi, Fanny,Retailleau, Pascal,Gueritte, Francoise
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supporting information; experimental part
p. 1240 - 1243
(2010/05/18)
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- Simply air: Vanadium-catalyzed oxidative kinetic resolution of methyl o-chloromandelate by ambient air
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Vanadium-catalyzed oxidative kinetic resolution (OKR) of methyl o-chloromandelate 2a, key intermediate of the well-known oral antiplatelet agent (S)-clopidogrel, was achieved by ambient air for the first time. The air oxidation system, which was composed of vanadium and tridentate Schiff base ligands derived from amino alcohols and salicylaldehyde derivatives, afforded an efficient and economic approach to the target intermediate with high enantioselectivities (>99% ee).
- Yin, Lu,Jia, Xian,Li, Xing Shu,Chan, Albert S.C.
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body text
p. 774 - 777
(2011/11/12)
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- Efficient synthesis of functionalized aziridinium salts
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(Chemical Equation Presented) Various aziridinium salts were efficiently prepared from bromination of a series of backbone substituted N,N-bisubstituted β-amino alcohols and isolated via flash column chromatography. The effect of C-substitution, N-substitution, solvent, leaving group, and counter-anions on formation of the isolable aziridinium salts was investigated. 2009 American Chemical Society.
- Chong, Hyun-Soon,Song, Hyun A.,Dadwal, Mamta,Sun, Xiang,Sin, Inseok,Chen, Yunwei
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supporting information; experimental part
p. 219 - 221
(2010/04/24)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 53
(2010/12/31)
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- Use of Syk Tyrosine Kinase Inhibitors for the Treatment of Cell Proliferative Disorders
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The invention relates to polyalkylene glycol compounds and their use in treating cell proliferative disorders, more specifically Syk tyrosine kinase-mediated disorders.
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Page/Page column 7
(2009/12/24)
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- Development of new HPLC chiral stationary phases based on native and derivatized cyclofructans
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An unusual class of chiral selectors, cyclofructans, is introduced for the first time as bonded chiral stationary phases. Compared to native cyclofructans (CFs), which have rather limited capabilities as chiral selectors, aliphatic-and aromatic-functionalized CF6s possess unique and very different enantiomeric selectivities. Indeed, they are shown to separate a very broad range of racemic compounds. In particular, aliphatic-derivatized CF6s with a low substitution degree baseline separate all tested chiral primary amines. It appears that partial derivatization on the CF6 molecule disrupts the molecular internal hydrogen bonding, thereby making the core of the molecule more accessible. In contrast, highly aromaticfunctionalized CF6 stationary phases lose most of the enantioselective capabilities toward primary amines, however they gain broad selectivity for most other types of analytes. This class of stationary phases also demonstrates high "loadability" and therefore has great potential for preparative separations. The variations in enantiomeric selectivity often can be correlated with distinct structural features of the selector. The separations occur predominantly in the presence of organic solvents.
- Sun, Ping,Wang, Chunlei,Breitbach, Zachary S.,Zhang, Ying,Armstrong, Daniel W.
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experimental part
p. 10215 - 10226
(2010/05/01)
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- 4-(1,3-Thiazol-2-yl)morpholine derivatives as inhibitors of phosphoinositide 3-kinase
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4-(1,3-Thiazol-2-yl)morpholine derivatives have been identified as potent and selective inhibitors of phosphoinositide 3-kinase. The SAR data of selected examples are presented and the in vivo profiling of compound 18 is shown to demonstrate the utility of this class of compounds in xenograft models of tumor growth.
- Alexander, Rikki,Balasundaram, Ahrani,Batchelor, Mark,Brookings, Daniel,Crepy, Karen,Crabbe, Tom,Deltent, Marie-France,Driessens, Frank,Gill, Andrew,Harris, Sue,Hutchinson, Gillian,Kulisa, Claire,Merriman, Mark,Mistry, Prakash,Parton, Ted,Turner, James,Whitcombe, Ian,Wright, Sara
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scheme or table
p. 4316 - 4320
(2009/04/06)
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- THIAZOLE DERIVATIVES AS KINASE INHIBITORS
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A series of thiazole derivatives which are substituted in the 2-position by a substituted morpholin-4-yl moiety, being selective inhibitors of P13 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
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Page/Page column 35-36
(2008/12/05)
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- HETEROARYL/ARYL PYRIMIDINE ANALOGS AND THEIR USE AS AGONISTS OF THE WNT-BETA-CATENIN CELLULAR MESSAGING SYSTEM
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The present invention relates to heteroaryl/aryl pyrimidine analogs, methods of making aryl/heteroaryl pyrimidine analogs, compositions comprising a aryl/heteroaryl pyrimidine analog, and methods for treating canonical Wnt-β-catenin cellular messaging system-related disorders comprising administering to a subject in need thereof an effective amount of a heteroaryl/aryl pyrimidine analog.
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Page/Page column 28
(2008/12/09)
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- FUSED THIAZOLE DERIVATIVES AS KINASE INHIBITORS
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A series of 5,6-dihydro-l,3-benzothiazol-7(4H)-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, being selective inhibitors of PD kinase enzymes, are accordingly of b.enefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
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Page/Page column 46-47
(2008/06/13)
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- Asymmetric synthesis of highly substituted azapolycyclic compounds via 2-alkenyl sulfoximines: Potential scaffolds for peptide mimetics
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The application of metalated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines for the synthesis of highly substituted aza(poly)cyclic ring systems is described. The method relies on a one-pot combination of a reagent-controlled allyl transfer reaction to α- or β-amino aldehydes, followed by a Michael-type cyclization of the intermediate vinyl sulfoximines generated in the first step. The sulfur-free target compounds are preferentially obtained by samarium iodide treatment of the sulfonimidoyl substituted heterocycles. In addition to this methodological work, initial results on the biological activity of selected examples are reported. Furthermore, a concept for the transformation of peptidic lead structures into non-peptide mimetics is described, and the relevance of the new approach to highly substituted azaheterocycles in this context is discussed.
- Reggelin, Michael,Junker, Bernd,Heinrich, Timo,Slavik, Stefan,Buehle, Philipp
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p. 4023 - 4034
(2007/10/03)
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- DABCO catalyzed reaction of various nucleophiles with activated alkynes leading to the formation of alkenoic acid esters, 1,4-dioxane, morpholine, and piperazinone derivatives
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The reaction of acids, alcohols, acylamides, 1,2-diols, 1,2-diamines or amino alcohols with activated alkynes catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) was systematically investigated. A series of unsaturated alkenoic acid esters or heterocycles were formed in the reaction of monobasic or dibasic nucleophiles in excellent yields, respectively.
- Fan, Ming-Jin,Li, Gao-Qiang,Liang, Yong-Min
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p. 6782 - 6791
(2007/10/03)
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- An asymmetric synthesis of both enantiomers of the indole alkaloid deplancheine
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(Chemical Equation Presented). We report a novel, facile and asymmetric approach to both enantiomers of the indole alkaloid deplancheine from a readily available, nonracemic chiral template. The natural product and its antipode are isolated with >95% ee.
- Allin, Steven M.,Thomas, Christopher I.,Doyle, Kevin,Elsegood, Mark R. J.
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p. 357 - 359
(2007/10/03)
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- IMPROVEMENTS IN OR RELATING TO COMPOUNDS FOR USE IN THE TREATMENT OF AIDS AND OTHER VIRAL DISEASES AND HIV-RELATED INFECTIONS AND COMPOSITIONS CONTAINING SUCH COMPOUNDS, METHODS OF TREATING SUCH DISEASES AND INFECTIONS AND METHODS OF MAKING SUCH COMPOUNDS AND COMPOSITIONS
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The present invention provides methods for treating Acquired Immunodeficiency Syndrome (AIDS) and other viral diseases and Human Immunodeficiency Virus (HIV) related infections by administering one or more compounds of formula I: wherein: the dotted line represents a single or a double bond; and R1 and R2 are the same or different and independently of each other represent - CH2OH, -CH2OR4, -CH(OH)CH3, -CH(OR4)CH3 or a group represented by the formula: or salts or hydrates thereof in a carrier which minimizes micellar formation or van der Waals attraction of molecules of said compound. The invention also provides S enantiomeric forms of such compounds which possess the ability to inhibit cell growth whilst being of low toxicity to such cells and methods of making such compounds.
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Page/Page column 31
(2008/06/13)
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- Chemoenzymatic preparation of the enantiomers of β-tryptophan ethyl ester and the β-amino nitrile analogue
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Racemic α-tryptophan was chemoselectively transformed into the enantiomers of β-tryptophan ethyl ester. The key step in achieving enantiopurity was the N-acylation of the 3-amino-4-(3-indolyl)butanenitrile intermediate with Candida antarctica lipase A (CAL-A). The enzymatic N-acylation of racemic β-tryptophan ethyl ester was also studied. CAL-A was highly (R)-enantioselective in the present kinetic resolutions, leading to a mixture of the butanamide product with an (R)-configuration and the unreacted starting material with an (S)-configuration at 50% conversion.
- Li, Xiang-Guo,Kanerva, Liisa T.
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p. 1709 - 1714
(2007/10/03)
-
- A practical approach to the fused β-carboline system. Asymmetric synthesis of indolo[2,3-a]indolizidinones via a diastereoselective intramolecular α-amidoalkylation reaction
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Fused β-carboline systems, as indolo[2,3-a]indolizidinones, indolo[2,3-a]quinolizidinones, their 2-oxa analogues, and benzo[a]indolo[2,3-a]indolizidinones are prepared efficiently via an RLi addition-N-acyliminium ion cyclisation sequence on readily available imides. In an enantioselective variant of these α-amidoalkylation reactions, the addition of MeLi to a chiral non-racemic imide derived from tryptophan yielded an oxo amide, which was cyclised diastereoselectively upon treatment with BF3·OEt2, to afford 5,11b-trans-indoloindolizidinone in moderate yield and high ee (99%).
- Ardeo, Ainhoa,García, Eva,Arrasate, Sonia,Lete, Esther,Sotomayor, Nuria
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p. 8445 - 8448
(2007/10/03)
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- Total synthesis of (-)-raumacline
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The total synthesis of (-)-raumacline from L-tryptophan was achieved, featuring a cis-specific Pictet-Spengler reaction, a stereoselective Dieckmann cyclization, and an epimerization step that allowed complete stereocontrol of five chiral centres.
- Bailey, Patrick D.,Clingan, Paul D.,Mills, Timothy J.,Price, Richard A.,Pritchard, Robin G.
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p. 2800 - 2801
(2007/10/03)
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- The synthesis of cyclic tetrapeptoid analogues of the antiprotozoal natural product apicidin
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A novel synthetic strategy is described which may be used to prepare analogues of the antimalarial, fungal metabolite apicidin. Compared to the natural product, one analogue shows potent and selective activity in vitro against the parasite Trypanosoma brucei and low mammalian cell toxicity.
- Murray, Peter J,Kranz, Michael,Ladlow, Mark,Taylor, Stephen,Berst, Frederic,Holmes, Andrew B,Keavey, Kenneth N,Jaxa-Chamiec, Albert,Seale, Peter W,Stead, Paul,Upton, Richard J,Croft, Simon L,Clegg, William,Elsegood, Mark R.J
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p. 773 - 776
(2007/10/03)
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- Synthesis of substituted-(l)-tryptophanols from an enantiomerically pure aziridine-2-methanol
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(Matrix Presented) Enantiomerically pure (l)-tryptophanol (5) was synthesized from 4(R)-iodomethyl-2-oxazolidinone (2) and indolylmagnesium bromide in three steps (52% overall yield). Using this procedure, we also prepared various tryptophanols with substituent(s) on the indole ring. Furthermore, optically active 4(R)-iodomethyl-2-oxazolidinone was readily prepared from an enantiomerically pure aziridine-2(S)-methanol in high yield.
- Pyun, Do Kyu,Lee, Cheol Hae,Ha, Hyun-Joon,Park, Chan Sun,Chang, Jae-Won,Lee, Won Koo
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p. 4197 - 4199
(2007/10/03)
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- Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption
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Cathepsin L, a lysosomal cysteine protease, is secreted by osteoclasts and participates in bone collagen degradation. In a search for cathepsin L inhibitors as antiosteoporotic agents, a series of peptide aldehyde derivatives were prepared by two synthetic approaches, DMSO oxidation of the corresponding alcohol derivatives and DIBAL-H reduction of the corresponding N,O-dimethylhydroxylamide derivatives, and evaluated for inhibitory activity against human cathepsin L and for inhibitory effects on bone resorption. Some of the peptide aldehyde derivatives including α-acylamino aldehyde derivatives showed potent activities. Among these compounds, N-(1- naphthalenylsulfonyl-L-isoleucyl-L-tryptophanal (12) was selected as a candidate for further investigation. Compound 12, a potent, selective, and reversible inhibitor of human cathepsin L with an IC50 of 1.9 nM, inhibited the release of Ca2+ and hydroxyproline from bone in in vitro bone culture system and also prevented bone loss in ovariectomized mice at an oral dose of 50 mg/kg.
- Yasuma, Tsuneo,Oi, Satoru,Choh, Nobuo,Nomura, Toshiyuki,Furuyama, Naoki,Nishimura, Atsushi,Fujisawa, Yukio,Sohda, Takashi
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p. 4301 - 4308
(2007/10/03)
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- New asymmetric route to bridged indole alkaloids: Formal enantiospecific syntheses of (-)-suaveoline, (-)-raumacline and (-)-Nb-methylraumacline
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The homologous nitrile 13 derived from L-tryptophan undergoes a modified Pictet-Spengler reaction with methyl propynoate, under conditions of kinetic control, to afford the cis-tetrahydro-β-carboline 15a (cis:trans = 77:23). After protection, Dieckmann-Thorpe cyclisation to the bridged keto nitrile 20 proceeds in 90% yield. Simple functional group modifications via the alcohol 21a and nitrile 22 (structures confirmed by X-ray crystallography) allow convergence with the tetracyclic α,β-unsaturated aldehyde 10, which is an advanced intermediate for the synthesis of a range of bridged indole alkaloids.
- Bailey, Patrick D.,Collier, Ian D.,Hollinshead, Sean P.,Moore, Madeleine H.,Morgan, Keith M.,Smith, David I.,Vernon, John M.
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p. 1209 - 1214
(2007/10/03)
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- Synthesis and Biological Evaluation of NK1 Antagonists Derived from L-Tryptophan
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The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan (3), which was derived from the screening lead N-ethyl-L-tryptophan benzyl ester, has been used as a starting point to identify high-affinity substance P receptor antagonists with improved in vivo activity.Altering the ester moiety to an amide or ether led to a substantial loss in binding affinity, but conversion to a ketone provided compounds with affinity comparable to the equivalent esters.A homochiral synthesis of the key intermediate amino ketone 15 was developed which allows its preparation on a la rge scale.From this intermediate a range of amine-containing acylamino derivatives were prepared with affinity optimized in the morpholinylbutyramide 16l which has an IC50 of 0.17 nM at the human NK1 receptor.In addition to improving affinity, the amino group also provided aqueous solubility for a number of these derivatives.When tested in vivo the quinuclidine derivative L-737,488 (16i) was found to be an orally active (ID50 = 1.8 mg/kg) inhibitor of substance P-induced dermal extravasation in the guinea pig.
- MacLeod, Angus M.,Cascieri, Margaret A.,Merchant, Kevin J.,Sadowski, Sharon,Hardwicke, Sarah,et al.
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p. 934 - 941
(2007/10/02)
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- Synthesis of New Chiral Auxiliaries Derived from (S)-Tryptophan
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The synthesis of chiral aminoalcohols 4 derived from (S)-tryptophan is described, by reaction of the protected amino acid 3 with various Grignard reagents.The aminoalcohols were transformed into the corresponding oxazolidin-2-ones 2 and acylated with 2-butenoyl chloride and 2-hexenoyl chloride, affording the imides 5a-e.The conformational analysis of both the oxazolidin-2-ones 2 and the Michael acceptors 5 was performed by means of 1H NMR, NOEDIF experiments and semiempirical AM1 calculations.
- Cardillo, Giuliana,Gentilucci, Luca,Tomasini, Claudia,Tomasoni, Laura
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p. 1947 - 1956
(2007/10/03)
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- A new asymmetric route to bridged indole alkaloids: Formal syntheses of (-)-suaveoline, (-)-raumacline and (-)-Nb-methylraumacline
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When the homologated nitrile 11 derived from L-tryptophan undergoes a modified Pictet-Spengler reaction with methyl propynoate, the resulting cis-tetrahydro-β-carboline 12a is ideally functionalised for cyclisation to the bridged ketonitrile 14; simple functional group modifications via the nitrile 15 (structure confirmed by X-ray crystallography) allow convergence with the tetracyclic α,β-unsaturated aldehyde 10, which is an advanced intermediate for the synthesis of a range of bridged indole alkaloids.
- Bailey,Collier,Hollinshead,Moore,Morgan,Smith,Vernon
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p. 1559 - 1560
(2007/10/02)
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- A new approach to indole alkaloids via indole chromium complexes
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The activating effect of pi complexation of a Cr(CO)3 unit allows selective nucleophilic substitution in indoles such as tryptophan derivatives and provides intermediates for the synthesis of clavicipitic acid and related indole natural products.
- Semmelhack,Knochel,Singleton
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p. 5051 - 5054
(2007/10/02)
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- Aldehyde derivatives and their use as calpain inhibitors
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Aldehyde derivatives with a specific calpain inhibiting activity and a platelet-aggregation inhibiting effect with formula (I) or formula (II): wherein R1 represents an aromatic hydrocarbon group, a heterocyclic group, or a group of-X-R3 in which X represents O,-S(O)m-(m = 0, 1, or 2), and R3 represents an aromatic hydrocarbon group, a heterocyclic group, or an alkyl group; Z represents R?-Y-or R?O-CH(R?)-in which Y represents a 3-to 7-membered nitrogen-containing saturated heterocyclic group, or a single cyclic saturated hydrocarbon group, R? represents an alkyl group, an alkenyl group, an alkynyl group, an acyl group, a sulfonyl group, an alkoxycarbonyl group, a carbamoyl group, or a thiocarbamoyl group, R? represents hydrogen, an alkyl group, or an aromatic hydrocarbon group, and R? represents an acyl group, a carbamoyl group, a thiocarbamoyl group, or an alkyl group; and n is an integer of 1 to 5. wherein R?, R?, R?, and R1? are defined in the specification.
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- MODELS OF FOLATE COFACTORS - 24. A ROUTE TO OPTICALLY ACTIVE OCTAHYDROINDOLOQUINOLIZINES
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L-(-)-Tryptophane derivatives react with 2-(3,3-dimethyl-3-ethoxycarbonyl-2-oxopropyl)hexahydropyrimidine to form optically active enamino esters.The latter cyclize under basic conditions to give indolylethylpyridinediones, which, upon treatment with acids give the title compounds.
- Huizenga, Reinald H.,Pandit, Upendra K.
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p. 6521 - 6528
(2007/10/02)
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- Synthesis of new indolactam analogues by microbial conversion
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Ten indolactam congeners with L-Ala, Abu, γ,δ-Δ-Nva, Nva, Nle, tert-Leu, Leu, Ile, allo-Ile. Phg instead ofL-Val in (-)-indolactam-Val, were synthesized from their seco-compounds (N-methyl-L-amino acidyl-L-tryptophonol) by microbial conversion.
- Kajiyama, Shin-Ichiro,Irie, Kazuhiro,Kido, Takae,Koshimizu, Koichi,Hayashi, Hideo,Arai, Motoo
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p. 5453 - 5462
(2007/10/02)
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- Synthesis of enantiomerically pure β-amino-α-methylene-γ-butyrolactones by way of ozonolysis of aromatic α-amino acids
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The (R) and (S) isomers of β-amino-α-methylene-γ-butyrolactone hydrochloride (4-amino-dihydro-3-methylene-2(3H)-furanone hydrochloride) have been synthesized from (R)- and (S)-tryptophan, respectively.A key step is the ozonolysis of N,O-diacetyl-2-amino-3-(3'-indolyl)-1-propanol. (S)-β-Amino-α-methylene-γ-butyrolactone hydrochloride has been synthesized also by an analogous route starting with (S)-phenylalanine.
- Hvidt, Torsten,Szarek, Walter A.,Maclean, David B.
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p. 779 - 782
(2007/10/02)
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- Asymmetric Induction. Part 3. Asymmetric Reduction of Ketones with Amine-boranes in the Presence of Acids
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Asymmetric reductions of a series of ketones with (+)-1-phenylethylamine-borane and boron trifluoride-diethyl ether are described; solvent and temperature effects have been studied, and the use of other acidic components has been explored.Asymmetric reductions have also been effected with α-amino-ester-boranes (14-23percent optical yields) and with diastereoisomeric amine-boranes containing chiral nitrogen atams. 2-Aminoethanols were prepared in high yield by reaction of α-amino-ester-boranes with boron trifluoride.
- Grundon, Michael F.,McCleery, David G.,Wilson, John W.
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p. 231 - 235
(2007/10/02)
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