- 4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads
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Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor XD14 and well-established HDAC inhibitors. The most promising new hybrids, 49 and 61, displayed submicromolar inhibitory activity against HDAC1-3 and 6, and BRD4(1), and possess potent antileukemia activity. 49 induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, 61, induced significantly more apoptosis than the related control compounds 62 (no BRD4(1) affinity) and 63 (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, 61 was well tolerated in an in vivo zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds.
- Ahlert, Heinz,Bhatia, Sanil,Borkhardt, Arndt,Breit, Bernhard,Gunther, Stefan,Hansen, Finn K.,Hugle, Martin,Kraft, Fabian B.,Mishra, Pankaj,Schaker-Hubner, Linda,Schliehe-Diecks, Julian,Scholer, Andrea,Warstat, Robin
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p. 14620 - 14646
(2021/10/20)
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- CONDENSED PYRROLES AS NOVEL BROMODOMAIN INHIBITORS
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Compounds of formula (1) or (2) and their use in the treatment of diseases or conditions for which a bromodomain inhibitor is indicated.
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Paragraph 0098-00100; 00103-00104
(2020/07/14)
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- 4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines
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Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI50 determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.
- Hügle, Martin,Regenass, Pierre,Warstat, Robin,Hau, Mirjam,Schmidtkunz, Karin,Lucas, Xavier,Wohlwend, Daniel,Einsle, Oliver,Jung, Manfred,Breit, Bernhard,Günther, Stefan
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p. 15603 - 15620
(2020/12/23)
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- Preparation method of high purity 2-benzyloxy bromoethane
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The invention relates to a preparation method of an important intermediate 2-benzyloxy bromoethane (formula I) of umeclidinium bromide. The conditions of the preparation method are mild and controllable; post-treatment is simple; yield is high; and the purity of prepared 2-benzyloxy bromoethane is high.
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- Triazine-Based Cationic Leaving Group: Synergistic Driving Forces for Rapid Formation of Carbocation Species
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A new triazine-based cationic leaving group has been developed for the acid-catalyzed alkylation of O- and C-nucleophiles. There are two synergistic driving forces, namely, stable C=O bond formation and charge-charge repulsive effects, involved in the rapid generation of the carbocation species in the presence of trifluoromethanesulfonic acid (～200 mol %). Considerable rate acceleration of benzylation, allylation, and p-nitrobenzylation was observed as compared to the reactions with less than 100 mol % of the acid catalyst. The triazine-based leaving group showed superior p-nitrobenzylation yield and stability in comparison to common leaving groups, trichloroacetimidate and bromide. A plausible reaction mechanism (the cationic leaving group pathway) was proposed on the basis of mechanistic and kinetic studies, NMR experiments, and calculations.
- Fujita, Hikaru,Kakuyama, Satoshi,Fukuyoshi, Shuichi,Hayakawa, Naoko,Oda, Akifumi,Kunishima, Munetaka
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p. 4568 - 4580
(2018/04/26)
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- Synthesis, antiproliferative and pro-apoptotic activity of 2-phenylindoles
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Breast cancer is the second most common cancer worldwide after lung cancer with the vast majority of early stage breast cancers being hormone-dependent. One of the major therapeutic advances in the clinical treatment of breast cancer has been the introduction of selective estrogen receptor modulators (SERMs). We describe the design and synthesis of novel SERM type ligands based on the 2-arylindole scaffold to selectively target the estrogen receptor in hormone dependent breast cancers. Some of these novel compounds are designed as bisindole type structures, while others are conjugated to a cytotoxic agent based on combretastatin A4 (CA4) which is a potent inhibitor of tubulin polymerisation. The indole compounds synthesised within this project such as 31 and 86 demonstrate estrogen receptor (ER) binding and strong antiproliferative activity in the ER positive MCF-7 breast cancer cell line with IC50values of 2.71?μM and 1.86?μM respectively. These active compounds induce apoptotic activity in MCF-7 cells with minimal effects on normal peripheral blood cells. Their strong anti-cancer effect is likely mediated by the presence of two ER binding ligands for 31 and an ER binding ligand combined with a cytotoxic agent for 86.
- Kelly, Patrick M.,Bright, Sandra A.,Fayne, Darren,Pollock, Jade K.,Zisterer, Daniela M.,Williams, D. Clive,Meegan, Mary J.
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p. 4075 - 4099
(2016/08/23)
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- Gold(I)-catalyzed synthesis of unsymmetrical ethers using alcohols as alkylating reagents
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A microwave-irradiated alcohol-protecting strategy based on gold catalysis utilizing benzyl alcohol, tert-butyl alcohol and triphenylmethanol as alkylating reagents has been developed. This protecting strategy has wide functional group tolerance with satisfactory yields for the majority of the selected alcohols. The mechanism of this transformation was probed with oxygen-18 isotope labelled alcohols assisted by GC-MS techniques and chemical kinetic experiments. This strategy provides an efficient, straightforward and alternative approach to the preparation of benzyl, tert-butyl and trityl ethers in organic synthesis.
- Liu, Yongxiang,Wang, Xiaoyu,Wang, Yanshi,Du, Chuan,Shi, Hui,Jin, Shengfei,Jiang, Chongguo,Xiao, Jianyong,Cheng, Maosheng
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p. 1029 - 1036
(2015/03/30)
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- SUBSTITUTED PYRAZOLYL-BASED CARBOXAMIDE AND UREA DERIVATIVES BEARING A PHENYL MOIETY SUBSTITUTED WITH AN O-CONTAINING GROUP AS VANILLOID RECEPTOR LIGANDS
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The invention relates to substituted pyrazolyl-based carboxamide and urea derivatives of formula (Q) as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
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Page/Page column 118
(2013/05/23)
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- A novel acid-catalyzed O-benzylating reagent with the smallest unit of imidate structure
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Formal trimerization of the smallest unit of benzyl imidate leads to 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT), which can be used as an acid-catalyzed O-benzylating reagent. The reaction of various functionalized alcohols with 0.4 equiv of TriBOT in the presence of trifluoromethanesulfonic acid afforded the benzyl ethers in good yields. TriBOT is an inexpensive stable crystalline solid with high atom economy.
- Yamada, Kohei,Fujita, Hikaru,Kunishima, Munetaka
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p. 5026 - 5029,4
(2012/12/12)
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- A novel acid-catalyzed O-benzylating reagent with the smallest unit of imidate structure
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Formal trimerization of the smallest unit of benzyl imidate leads to 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT), which can be used as an acid-catalyzed O-benzylating reagent. The reaction of various functionalized alcohols with 0.4 equiv of TriBOT in the presence of trifluoromethanesulfonic acid afforded the benzyl ethers in good yields. TriBOT is an inexpensive stable crystalline solid with high atom economy.
- Yamada, Kohei,Fujita, Hikaru,Kunishima, Munetaka
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p. 5026 - 5029
(2013/01/15)
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- Bivalent inhibitors for disrupting protein surface-substrate interactions and for dual inhibition of protein prenyltransferases
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Low-molecular-weight compounds that disrupt protein-protein interactions (PPIs) have tremendous potential applications as clinical agents and as chemical probes for investigating intracellular PPI networks. However, disrupting PPIs is extremely difficult due to the large, flat interfaces of many proteins, which often lack structurally defined cavities to which drug-like molecules could bind in a thermodynamically favorable manner. Here, we describe a series of bivalent compounds that anchor to the enzyme active site to deliver a minimally sized surface-binding module to the targeted surface involved in transient PPI with a substrate. These compounds are capable of significantly inhibiting enzymatic reactions involving protein surface-substrate interaction in the single-digit nanomole range. Inhibitors of farnesyltransferase (FTase), which possesses a negatively charged local area on its α-subunit, were designed by attaching a module derived from a branched monoamine-containing gallate to a conventional active-site-directed CVTM tetrapeptide using an alkyl spacer. A significant improvement in inhibitory activity (>200-fold) against farnesylation of the K-Ras4B peptide was observed when the gallate module was attached to the CVTM tetrapeptide. Furthermore, the bivalent compounds had submicromolar inhibitory activity against geranylgeranylation of the K-Ras4B peptide catalyzed by GGTase I, which has an a-subunit identical to that of FTase. The anchoring strategy we describe would be useful for designing a new class of PPI inhibitors as well as dual enzyme inhibitors targeting common surface structures.
- Machida, Shinnosuke,Kato, Nobuo,Harada, Kazuo,Ohkanda, Junko
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supporting information; experimental part
p. 958 - 963
(2011/04/16)
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- Synthesis of key fragments of leiodelide A
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The synthesis of all key fragments of the marine macrolide leiodelide A is described. The polyoxygenated northern subunit is derived from d-xylose, while the southern subunit is rapidly assembled via an aldol reaction and Horner-Wadsworth-Emmons olefination. This highly convergent approach will allow for rapid modification and assembly of several isomers of leiodelide A, which may be necessary considering the assignment of leiodelide B has been previously shown to be incorrect.
- Chellat, Mathieu F.,Proust, Nicolas,Lauer, Matthew G.,Stambuli, James P.
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supporting information; experimental part
p. 3246 - 3249
(2011/08/22)
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- Synthesis of 3'-O-phosphonoethyl nucleosides with an adenine and a thymine base moiety
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The synthesis and antiviral evaluation of new 3'-O-phosphonoethyl modified phosphonate nucleosides related to PMDTA and PMDTT is described. The reaction scheme starts from protected L-threose and the phosphonate group is introduced by the Arbuzov reaction. The 2'-OH as well as the 2'-deoxygenated nucleosides have been obtained. Unfortunately, none of these synthesized compounds shows activity against HIV and HCV.
- Huang, Qiuya,Herdewijn, Piet
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scheme or table
p. 337 - 351
(2010/10/02)
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- Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists
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A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M3 receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M3 antagonist with a very long in vivo duration of bronchoprotection.
- Lainé, Dramane I.,McCleland, Brent,Thomas, Sonia,Neipp, Christopher,Underwood, Brian,Dufour, Jeremy,Widdowson, Katherine L.,Palovich, Michael R.,Blaney, Frank E.,Foley, James J.,Webb, Edward F.,Luttmann, Mark A.,Burman, Miriam,Belmonte, Kristen,Salmon, Michael
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supporting information; experimental part
p. 2493 - 2505
(2010/03/04)
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- Cumyl: A better N-protecting group of α-diazo acetamides for intramolecular C-H insertion reaction and its application in the synthesis of pregabalin and 3-benzyloxy pyrrolidine
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Via intramolecular C-H insertion of N-cumyl α-diazo acetamides, γ-lactams were efficiently synthesized with excellent regioselectivity. A concise route for the preparation of pregabalin (79% overall yield) and 3-benzyloxy pyrrolidine (21% overall yield) were reported.
- Chen, Zhenliang,Chen, Zhiyong,Jiang, Yaozhong,Hu, Wenhao
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p. 1763 - 1764
(2007/10/03)
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- Novel flavonoids
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Novel flavonoids of formula (I) 1where A and E form together a C—C or C=C bond; R1, R2, R3, and R4 are H, OH, O(CH2)n— aromatic group, n=0-8; O(CH2)n N(CH3)q with n=0-8, q=0-3; O(CH2)n OH with n=1-8; O(CH2)n-halide with n=1-8; O(CH2)n COOH with n=0-8; O(CH2)n COOR′ with n=0-8 and R′ is C1-C8 alkyl or an aromatic group; O(CH2)n CONH R″ with n=0-8 and R″ is C1-C8 alkyl or an aromatic group, and sugars in mono-, di- or trimeric form or analogues thereof, with the proviso that R1 is not H, at least two of R2, R3 and R4 are H, and at most one of R1, R2, R3 and R4 is OH, are useful for the treatment of drug-induced toxicity, doxorubicin-induced cardiotoxicity, free radical mediated diseases, lung diseases, cancer, diabetes mellitus, cardiovascular disease, or arteriosclerosis.
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- Novel use of a selenoalkyne within untraditionally mild D?tz benzannulation processes; total synthesis of a Calceolaria andina L. natural hydroxylated naphthoquinone
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A total synthesis of the Calceolaria andina L. extract 2-(1,1-dimethyl-2-propenyl)-3-hydroxy-1,4-naphthalenedione is described incorporating the first reported D?tz benzannulation of a selenoalkyne. Importantly, it has been shown that it is possible to effect this annulation at ambient temperature under dry state conditions with a significant improvement in cyclisation yield.
- Caldwell,Colman,Kerr,Magennis
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p. 1428 - 1430
(2007/10/03)
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- Total syntheses of racemic albifloranine and its anti-addictive congeners, including 18-methoxycoronaridine
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Condensation of methyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino[4,5- b]indole-5-carboxylate (12) with 4-(1,3-dioxolan-2-yl)-6-benzyloxyhexanal (11a) provided the tetracyclic intermediates methyl (3aSR,4RS,11bRS)-3- benzyl-2,3,3a,4,5,7-hexahydro-4-[2-ζ-(1,3-dioxalan-2-yl)-4-benzyloxy)-1- butyl]-1H-pyrrolo[2,3-d]carbazole-6-carboxylates (14a,15a), which were further elaborated to afford racemic albifloranine (3). The first total synthesis of albifloranine was completed in 13 steps, with an overall 7% yield. Ester and ether derivatives of albifloranine were synthesized for evaluation as anti-addictive agents. Among these, 18-methoxycoronaridine (20b) stands out as a nontoxic agent that significantly reduces demand for morphine, cocaine, nicotine and alcohol in rats.
- Bandarage, Upul K.,Kuehne, Martin E.,Glick, Stanley D.
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p. 9405 - 9424
(2007/10/03)
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- SUBSTITUTED CYCLOALKANECARBOXYLIC ACID DERIVATIVES AS MATRIX METALLOPROTEASE INHIBITORS
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Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The compounds of the invention have the generalized formula STR1 wherein each T is a substituent g roup; x is 0, 1, or 2; the group D represents STR2 the subscript "e" is 2 or 3; the group R 14 represents a variety of possible substituent groups of the cycloalkyl ring between D and G; the subscript "k" is 0-2; and the group G represents M, STR3 in which M represents--CO 2 H,--CON(R 11) 2, or--CO 2 R 12 ; and R 13 represents any of the side chains of the 19 noncyclic occurring amino acids. "
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- CYCLIC IMIDE DERIVATIVES
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The invention relates to a compound of the formula I STR1 wherein R 1 is a cyclic imide group and X, Y, R 2, and R 3 are as defined herein. The invention further relates to pharmaceutical compositions containing, and methods of using, compounds of the formula I. Compounds of the formula I are useful in the treatment of diseases related to the production of matrix metalloproteinases and tumor necrosis factor.
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- DERIVATIVES OF SUBSTITUTED 4-BIARYLBUTYRIC ACID AS MATRIX METALLOPROTEASE INHIBITORS
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Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The presently claimed compounds have the generalized formula STR1 in which each T represents a substituent group; x is 0, 1, or 2; D represents STR2 δ is 0 or 1; U' represents O, S, or N, with the proviso that when U' is N, then δ=0, and when U' is O or S, then δ =1; R 14 is any of a variety of substituent groups; and G represents M, STR3 in which M represents--CO 2 H,--CON(R 11) 2, or--CO 2 R 12, R 11 represents H or an alkyl group, R 12 represents an alkyl group, and R. sup.13 represents any of the side chains of the 19 noncyclic naturally occurring amino acids; and pharmaceutically acceptable salts thereof.
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- Diagnostic imaging methods using rhenium and technetium complexes containing a hypoxia-localizing moiety
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Novel methods, processes and metal complexes attached to a hypoxia-localizing moiety comprising a metal, preferably radionuclide of rhenium or technetium; a hypoxia-localizing moiety; and, a complexing ligand, wherein said ligand and said radionuclide combined have cell membrane permeabilities greater than that of sucrose, are disclosed.
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- Selective derivatisation of aza macrocycles
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A range of selectively functionalised compounds derived from 1,4,7-triazacyclononane ([9]aneN3), including 4,7-bis(2-hydroxy-2-methylpropyl)-1,4,7-triazacyclononane-1-carbaldehyde (H2L1), 1-benzyl-4,7-bis(2-hydroxy-2-methylpropyl)-1,4,7-triazacyclononane (H2L2) and 1,4-bis(2-hydroxy-2-methylpropyl)-1,4,7-triazacyclononane (H2L3), has been prepared. The structure of H2L3·CHCl3 shows a disordered macrocyclic ring with the major conformer refining to a site occupancy of 0.663(8), and both disordered rings adopting a [333] conformation. The pendant alcohol arms were not disordered and were found to be hydrogen bonded to a CHCl3 solvate molecule with H ... O(1) and H ... O(4) distances of 1.73 and 1.81 A respectively. The structure of Na[Cu(H2L1)(NCMe)][BF4]2[NO 3] shows the copper(II) centre in the [Cu(H2L1)(NCMe)]2+ cation bound to two amine donors and two alcohol donors of H2L1 and to a MeCN molecule. The Cu-N bond lengths lie in the range 1.984(3)-2.015(3) A. Both alcohol donors are protonated, with one short Cu-O(16) bond of 1.963(3) A and one long Cu-O(21) bond of 2.252(3) A. There is also a sixth longer-range interaction of the copper(II) centre with the amide N [N(1)] of H2L1 at a distance of 2.611(5) A, confirmed by the loss of planarity of the C(2)-C(9)-N(1)-C(10)-O(11)-H(10) amide fragment to give a dihedral angle between the planes defined by C(2)-C(9)-N(1) and N(1)-C(10)-O(11)-H(10) of 27.1(4)°. The structure is completed by interaction of O(11) with a Na+ ion which itself bridges to BF4- counter anions leading to a central infinite core of [Na(BF4)2]- aggregates onto which are attached the [Cu(H2L1)(NCMe)]2+ cations. The complex [Cu(H2L2)(OH2)][NO3]2 shows the six-co-ordinate copper(II) centre bound to the three amine and two alcohol donors of H2L2 and to one water molecule. There are four short bonds [to N(7), N(4), O(40) and O(1)] in the range 1.961(5)-2.073(6) A and two longer bonds to N(1) and O(70) at 2.308(5) and 2.313(5) A respectively. The H atoms of the water molecule [O(1)] and one of the pendant arms [O(40)] also make hydrogen-bonding contacts with the nitrate counter ions.
- Blake, Alexander J.,Fallis, Ian A.,Gould, Robert O.,Parsons, Simon,Ross, Steven A.,Schroeder, Martin
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p. 4379 - 4387
(2007/10/03)
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- DESIGN AND REACTIVITY OF ORGANIC FUNCTIONAL GROUPS - 2-PYRIDYLSULFONATES AS NUCLEOFUGAL ESTERS: REMARKABLY MILD TRANSFORMATIONS INTO HALIDES AND OLEFINS
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The novel 2-pyridylsulfonate esters are excellent leaving groups for the preparation of bromides and olefins under very mild reaction conditions.Displacements occur with inversion of configuration.
- Hanessian, Stephen,Kagotani, Masahiro,Komaglou, Kossi
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p. 1115 - 1120
(2007/10/02)
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