- TETRAHYDRONAPHTHALENE AND TETRAHYDROISOQUINOLINE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
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The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end at least one of a Von Hippel-Lindau ligand, a cereblon ligand, Inhibitors of Apoptosis Proteins ligand, mouse double-minute homolog 2 ligand, or a combination thereof, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 1478; 1479
(2018/06/15)
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- Nickel-Catalyzed Carboxylation of Benzylic C-N Bonds with CO2
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A user-friendly Ni-catalyzed reductive carboxylation of benzylic C-N bonds with CO2 is described. This procedure outperforms state-of-the-art techniques for the carboxylation of benzyl electrophiles by avoiding commonly observed parasitic pathways, such as homodimerization or β-hydride elimination, thus leading to new knowledge in cross-electrophile reactions.
- Moragas, Toni,Gaydou, Morgane,Martin, Ruben
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supporting information
p. 5053 - 5057
(2016/04/26)
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- Glucosylceramide synthase inhibitors
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The invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, and for the treatment of cancer.
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Page/Page column 95
(2015/09/28)
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- Enantioselective Oxidative Aerobic Dealkylation of N-Ethyl Benzylisoquinolines by Employing the Berberine Bridge Enzyme
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N-Dealkylation methods are well described for organic chemistry and the reaction is known in nature and drug metabolism; however, to our knowledge, enantioselective N-dealkylation has not been yet reported. In this study, exclusively the (S)-enantiomers o
- Gandomkar, Somayyeh,Fischereder, Eva-Maria,Schrittwieser, Joerg H.,Wallner, Silvia,Habibi, Zohreh,Macheroux, Peter,Kroutil, Wolfgang
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supporting information
p. 15051 - 15054
(2016/01/25)
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- Designing new analogs for streamlining the structure of cytotoxic lamellarin natural products
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Despite the therapeutic potential of marine-derived lamellarin natural products, their preclinical development has been hampered by their lipophilic nature, causing very poor aqueous solubility. In order to develop more drug-like analogs, their structure was streamlined in this study from both the cytotoxic activity and lipophilicity standpoints. First, a modified total synthetic route was successfully devised to construct a library of 59 systematically designed lamellarin analogs, which were then subjected to cytotoxicity and log P determinations. Along with the 25 first-generation lamellarins previously synthesized in our laboratory, the structure-activity and structure-lipophilicity relationships were extensively evaluated. Our results clearly indicated the additional structural requirements around the lamellarin skeleton which, when combined with those reported previously, can provide invaluable guidance for further modifications to increase the aqueous solubility of these compounds.
- Tangdenpaisal, Kassrin,Worayuthakarn, Rattana,Karnkla, Supatra,Ploypradith, Poonsakdi,Intachote, Pakamas,Sengsai, Suchada,Saimanee, Busakorn,Ruchirawat, Somsak,Chittchang, Montakarn
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p. 925 - 937
(2015/03/31)
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- Vitamin D3 analogues that contain modified A- and seco-B-rings as hedgehog pathway inhibitors
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The hedgehog (Hh) signaling pathway is a developmental signaling pathway that has been implicated as a target for anti-cancer drug development in a variety of human malignancies. Several natural and synthetic vitamin D-based seco-steroids have been identified as potent inhibitors of Hh signaling with chemotherapeutic potential. These include the previously characterized analogue 4, which contains the northern CD-ring/side chain region of vitamin D3 (VD3) linked to an aromatic A-ring mimic through an ester bond. To further explore structure-activity relationships for this class of VD3-based Hh pathway inhibitors, we have designed, synthesized and evaluated several series of compounds that modify the length, composition, and stereochemical orientation of the ester linker. These studies have identified compounds 54 and 55, which contain an amine linker and an aromatic A-ring incorporating a para-phenol, as new lead compounds with enhanced potency against the Hh pathway (IC50 values Combining double low line 0.40 and 0.32 μM, respectively).
- Deberardinis, Albert M.,Raccuia, Daniel S.,Thompson, Evrett N.,Maschinot, Chad A.,Hadden, M. Kyle
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p. 156 - 171
(2015/02/19)
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- 1,2,3-Triazole-containing uracil derivatives with excellent pharmacokinetics as a novel class of potent human deoxyuridine triphosphatase inhibitors
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Deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as a 5-fluorouracil-based combination chemotherapy. We describe the design and synthesis of a novel class of human dUTPase inhibitors, 1,2,3-triazole-containing u
- Miyakoshi, Hitoshi,Miyahara, Seiji,Yokogawa, Tatsushi,Endoh, Kanji,Muto, Toshiharu,Yano, Wakako,Wakasa, Takeshi,Ueno, Hiroyuki,Chong, Khoon Tee,Taguchi, Junko,Nomura, Makoto,Takao, Yayoi,Fujioka, Akio,Hashimoto, Akihiro,Itou, Kenjirou,Yamamura, Keisuke,Shuto, Satoshi,Nagasawa, Hideko,Fukuoka, Masayoshi
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p. 6427 - 6437
(2012/09/22)
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- Biocatalytic enantioselective oxidative C-C coupling by aerobic C-H activation
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Bridging the gap: The berberine bridge enzyme (BBE) was employed for the first preparative oxidative biocatalytic C-C coupling that leads to a new intramolecular bond. This unique transformation requires O2 as sole stoichiometric oxidant and gives access to novel optically pure (S)-berbine 2 and (R)-1-benzyl-1,2,3,4-tetrahydroisoquinoline 1 alkaloid derivatives by kinetic resolution.
- Schrittwieser, Joerg H.,Resch, Verena,Sattler, Johann H.,Lienhart, Wolf-Dieter,Durchschein, Katharina,Winkler, Andreas,Gruber, Karl,MacHeroux, Peter,Kroutil, Wolfgang
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supporting information; experimental part
p. 1068 - 1071
(2011/04/22)
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- Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids
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A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.
- Schrittwieser, Joerg H.,Resch, Verena,Wallner, Silvia,Lienhart, Wolf-Dieter,Sattler, Johann H.,Resch, Jasmin,MacHeroux, Peter,Kroutil, Wolfgang
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experimental part
p. 6703 - 6714
(2011/10/18)
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- Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents
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The synthesis and antiproliferative activity of a new series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. These novel compounds are also substituted at position 3 of the β-lactam ring with an aryl ring. A number of analogues showed potent nanomolar activity in human MCF-7 and MDA-MB-231 breast cancer cell lines, displayed in vitro inhibition of tubulin polymerization, and did not cause significant cytotoxicity in normal murine breast epithelial cells. 4-(4-Methoxyaryl)-substituted compound 32, 4-(3-hydroxy-4-methoxyaryl)-substituted compounds 35 and 41, and the 3-(4-aminoaryl)-substituted compounds 46 and 47 displayed the most potent antiproliferative activity of the series. β-Lactam 41 in particular showed subnanomolar activity in MCF-7 breast cancer cells (IC50 = 0.8 nM) together with significant in vitro inhibition of tubulin polymerization and has been selected for further biochemical assessment. These novel β-lactam compounds are identified as potentially useful scaffolds for the further development of antitumor agents that target tubulin.
- O'Boyle, Niamh M.,Carr, Miriam,Greene, Lisa M.,Bergin, Orla,Nathwani, Seema M.,McCabe, Thomas,Lloyd, David G.,Zisterer, Daniela M,Meegan, Mary J.
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supporting information; experimental part
p. 8569 - 8584
(2011/02/28)
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- COMPOUNDS AND METHOD FOR REDUCING URIC ACID
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Uric acid in mammalian subjects is reduced and excretion of uric acid is increased by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In Formula (I) m is 0, 1, 2, 3 or 4; n is 0 or 1; m + n is not more than 4; t is 0 or 1; q is 0 or 1; and r is 0, 1 or 2. R6 is hydrogen, methyl or ethyl and R12 is hydrogen or methyl, or R6 is hydroxy and R12 is hydrogen, or R6 is O and R12 is absent, or R6 and R12 together are -CH2CH2-. R7 is hydrogen or alkyl having from 1 to 3 carbon atoms. One of R8 and R9 is alkyl having from 1 to 3 carbon atoms, and the other is hydrogen or alkyl having from 1 to 3 carbon atoms. R10 is hydrogen, halo, alkyl having from 1 to 3 carbon atoms or alkoxy having from 1 to 3 carbon atoms. X is C(O) and r is 0 and t is 0; or X is NH(R11) wherein R11 is hydrogen or alkyl having from 1 to 3 carbon atoms. A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from halo, hydroxy, methyl, ethyl, perfluoromethyl, methoxy, ethoxy, and perfluoromethoxy; or a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of Formula (I) by a ring carbon; or cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently monosubstituted by methyl or ethyl. The uric acid-lowering effects of the Compounds of Formula (I) are used to treat or prevent a variety of conditions including gout, hyperuricemia, elevated levels of uric acid that do not meet the levels customarily justifying a diagnosis of hyperuricemia, renal dysfunction, kidney stones, cardiovascular disease, risk for developing cardiovascular disease, tumor-lysis syndrome, and cognitive impairment.
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- BETA-LACTAMASE INHIBITORS
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Disclosed herein are alpha-aminoboronic acids and their derivatives which act as inhibitors of beta-lactamases. Also disclosed herein are pharmaceutical compositions comprising alpha-aminoboronic acids and methods of use thereof.
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Page/Page column 73-74
(2009/06/27)
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- 2-Benzyl and 2-phenyl-3-hydroxypropyl pivalates as protein kinase C ligands
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A series of 2-benzyl and 2-phenyl-3-hydroxypropyl pivalates designed to incorporate the principal pharmacophores of phorbol esters have been synthesized and tested as PKC-α ligands. Among the analogues, 13c exhibited the most potent binding affinity with a Ki = 0.7 μM. The synthesized analogues were subjected to molecular modeling analysis based on two alternative models of the phorbol pharmacophore and a docking study of 13c was carried out.
- Lee, Jeewoo,Lee, Ju-Hyun,Kim, Su Yeon,Perry, Nicholas A.,Lewin, Nancy E.,Ayres, Jolene A.,Blumberg, Peter M.
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p. 2022 - 2031
(2007/10/03)
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- Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERα-selective tetrahydroisoquinoline ligands
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We disclose herein the discovery of estrogen receptor α (ERα) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERα ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERα and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17β-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERα-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERα over ERβ.
- Renaud, Johanne,Bischoff, Serge Fran?ois,Buhl, Thomas,Floersheim, Philipp,Fournier, Brigitte,Geiser, Martin,Halleux, Christine,Kallen, Joerg,Keller, Hansjoerg,Ramage, Paul
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p. 364 - 379
(2007/10/03)
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- Ethers of 3-hydroxyphenylacetic acid as selective gamma-hydroxybutyric acid receptor ligands
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Gamma-hydroxybutyric acid (GHB) is a drug of abuse, a therapeutic, and purportedly a neurotransmitter with a complex mechanism of action in vivo due to direct actions at GABAB as well as GHB receptors and because of its metabolism to GABA. Here
- Chen, Weibin,Wu, Huifang,Hernandez, R. Jason,Mehta, Ashok K.,Ticku, Maharaj K.,France, Charles P.,Coop, Andrew
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p. 3201 - 3202
(2007/10/03)
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- GFAT INHIBITORS
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Compounds of formula (I) are provided as well as pharmaceutically acceptable salts and esters thereof, wherein the substituents are as disclosed in the specification. The compounds have utility for the treatment of type 2 diabetes mellitus.
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- Estrogen receptor modulators: Identification and structure-activity relationships of potent ERα-selective tetrahydroisoquinoline ligands
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As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC50s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERα-ligand binding domain (LBD)301-553/C→S triple mutant was solved to 2.28 A?. An overlay of this X-ray crystal structure with that reported for the complex of ERαLBD301-553/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.
- Renaud, Johanne,Bischoff, Serge Fran?ois,Buhl, Thomas,Floersheim, Philipp,Fournier, Brigitte,Halleux, Christine,Kallen, Joerg,Keller, Hansjoerg,Schlaeppi, Jean-Marc,Stark, Wilhelm
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p. 2945 - 2957
(2007/10/03)
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- Compounds and methods for modulation of estrogen receptors
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Compounds that modulate the estrogen receptor (ER) are disclosed, as well as pharmaceutical compositions containing the same. In a specific embodiment, the compounds are selective for ER-β over ER-α. Methods are disclosed for modulating ER-β in cell and/o
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- A convenient synthesis of Δ7,8-Morphinan-6-one and its direct oxidation to 14-hydroxy-Δ7,8-morphinan-6-one
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Synthesis of Δ7,8-morphinan-6-one by Grewe cyclization and bromoketalization reaction as crucial steps is described. Introduction of a hydroxyl group at 14-position is demonstrated by direct oxidation with MnO2 in the presence of silica gel.
- Passarella, Daniele,Consonni, Alessandra,Giardini, Alessandra,Lesma, Giordano,Silvani, Alessandra
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p. 1981 - 1983
(2007/10/03)
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- Compounds and methods for modulation of estrogen receptors
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Compounds that modulate the estrogen receptor (ER) are disclosed, as well as pharmaceutical compositions containing the same. In a specific embodiment, the compounds are selective modulators for ER-β over ER-α. Methods are disclosed for modulating ER-β in
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- Efficient synthesis of 1-Benzyloxyphenyl-3-phenylacetones
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1-[(Benzyloxy)phenyl]-3-phenylacetones 1a-c have been conveniently synthesized by acylation of the PhCH2Li-DABCO complex with their respective N-methyl O-methyl hydroxamates 5a-c. In four steps, ketones 1a-c having ortho-, meta- and para-benzyloxy substituents were obtained in 42-51% overall yields from commercially available 2-(hydroxyphenyl)acetic acids.
- Mannekens,Tourwe,Lubell
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p. 1214 - 1216
(2007/10/03)
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- Regioselective synthesis of 1,8-dihydroxytetralins through a tandem reduction/intramolecular hydroxyalkylation of 4-(3-hydroxyphenyl)alkanoates
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A series of 4-(3-hydroxyphenyl)butanoates 3 has been prepared and transformed into 1,8-dihydroxytetralins of general formula 2 by treatment with 2 equivalents of DIBALH followed by quenching with aqueous NH4Cl. A possible mechanism for this novel totally regioselective intramolecular hydroxyalkylation is suggested and the factors affecting the stability of 1,8-dihydroxytetralins 2 are also discussed.
- Guanti, Giuseppe,Banfi, Luca,Riva, Renata
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p. 11945 - 11966
(2007/10/02)
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- Tandem Reduction / Intramolecular Hydroxyalkylation of (3-Hydroxyphenyl)alkanoates: a New Regioselective Approach to 1,8-Dihydroxytetralins
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4-(3-hydroxyphenyl)-butanoates 4, on treatment with DIBALH, followed by hydrolytic work-up, undergo a novel completely regioselective intramolecular hydroxyalkylation reaction to give 1,8-dihydroxytetralins.The yield of the reaction depends heavily on the structure of starting material, best results being achieved with 3,3-disubstituted butanoates.
- Guanti, Giuseppe,Banfi, Luca,Narisano, Enrica,Riva, Renata,Thea, Sergio
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p. 3919 - 3922
(2007/10/02)
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- Convenient Preparation of Arylacetic Acids by Tetracarbonylcobaltate Anion Catalysed Carbonylation
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Tetracarbonylcobaltate catalyst -, has been prepared in 6 hr by pressure carbonylation of cobalt salt in aq alkaline solution containing cyanide catalyst.Carbonylation of arylchloromethyl derivatives in aq methanolic solutions using this catalyst affords arylacetic acids in good yields.
- Rao, B. Nageswara,Adapa, Srinivas R.,Pardhasaradhi, M.
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- Biosynthesis of Fungal Metabolites. Terrein, a Metabolite of Aspergillus terreus Thom
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Terrein, a metabolite of Aspergillus terreus Thom, is biosynthesised from 3,4-dihydro-6,8-dihydroxy-3-methylisocoumarin by contraction of an aryl ring.The direction of the ring contraction has been investigated using acetate as precursor.
- Hill, Robert A.,Carter, Rachel H.,Staunton, James
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p. 2570 - 2576
(2007/10/02)
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