- Water-soluble inhibitors of ABCG2 (BCRP) – A fragment-based and computational approach
-
A good balance between hydrophilicity and lipophilicity is a prerequisite for all bioactive compounds. If the hydrophilicity of a compound is low, its solubility in water will be meager. Many drug development failures have been attributed to poor aqueous solubility. ABCG2 inhibitors are especially prone to be insoluble since they have to address the extremely large and hydrophobic multidrug binding site in ABCG2. For instance, our previous, tariquidar-related ABCG2 inhibitor UR-MB108 (1) showed high potency (79 nM), but very low aqueous solubility (78 nM). To discover novel potent ABCG2 inhibitors with improved solubility we pursued a fragment-based approach. Substructures of 1 were optimized and the fragments ‘enlarged’ to obtain inhibitors, supported by molecular docking studies. Synthesis was achieved, i.a., via Sonogashira coupling, click chemistry and amide coupling. A kinetic solubility assay revealed that 1 and most novel inhibitors did not precipitate during the short time period of the applied biological assays. The solubility of the compounds in aqueous media at equilibrium was investigated in a thermodynamic solubility assay, where UR-Ant116 (40), UR-Ant121 (41), UR-Ant131 (48) and UR-Ant132 (49) excelled with solubilities between 1 μM and 1.5 μM – an up to 19-fold improvement compared to 1. Moreover, these novel N-phenyl-chromone-2-carboxamides inhibited ABCG2 in a Hoechst 33342 transport assay with potencies in the low three-digit nanomolar range, reversed MDR in cancer cells, were non-toxic and proved stable in blood plasma. All properties make them attractive candidates for in vitro assays requiring long-term incubation and in vivo studies, both needing sufficient solubility at equilibrium. 41 and 49 were highly ABCG2-selective, a precondition for developing PET tracers. The triple ABCB1/C1/G2 inhibitor 40 qualifies for potential therapeutic applications, given the concerted role of the three transporter subtypes at many tissue barriers, e.g. the BBB.
- Antoni, Frauke,Wifling, David,Bernhardt, Günther
-
-
Read Online
- Efficient Pyrazolo[5,4-f]quinoxaline Functionalized Os(II) Based Emitter with an Electroluminescence Peak Maximum at 811 nm
-
Upon fusing the pyrazinyl pyrazole entity in giving pyrazolo[3,4-f]quinoxaline chelate, the corresponding Os(II) based NIR emitter exhibited “invisible” and efficient electroluminescence with a peak maximum at 811 nm. A maximum external quantum efficiency
- Zhu, Ze-Lin,Wang, Sheng-Fu,Fu, Li-Wen,Tan, Ji-Hua,Cao, Chen,Yuan, Yi,Yiu, Shek-Man,Zhang, Ye-Xin,Chi, Yun,Lee, Chun-Sing
-
supporting information
(2021/12/09)
-
- Enantiomerically Pure Quinoline-Based κ-Opioid Receptor Agonists: Chemoenzymatic Synthesis and Pharmacological Evaluation
-
Racemic K-opioid receptor (KOR) agonist 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aSR)-8-(pyrrolidin-1-yl)-3,4,4a,5,6,7,8,8a-octahydroquinolin-1(2H)-yl]ethan-1-one ((±)-4) was prepared in a diastereoselective synthesis. The first key step of the synthesis was the diastereoselective hydrogenation of the silyl ether of 1,2,3,4-tetrahydroquinoin-8-ol ((±)-9) to afford cis,cis-configured perhydroquinoline derivative (±)-10. Removal of the TBDMS protecting group led to a β-aminoalcohol that reacted with SO2Cl2 to form an oxathiazolidine. Nucleophilic substitution with pyrrolidine resulted in the desired cis,trans-configured perhydroquinoline upon inversion of the configuration. In order to obtain enantiomerically pure KOR agonists 4 (99.8 % ee) and ent-4 (99.0 % ee), 1,2,3,4-tetrahydroquinolin-8-ols (R)-8 (99.1 % ee) and (S)-8 (98.4 % ee) were resolved by an enantioselective acetylation catalyzed by Amano lipase PS-IM. The absolute configuration was determined by CD spectroscopy. The 4aR,8S,8aS-configured enantiomer 4 showed sub-nanomolar KOR affinity (Ki=0.81 nM), which is more than 200 times higher than the KOR affinity of its enantiomer ent-4. In the cAMP assay and the Tango β-arrestin-2 recruitment assay, 4 behaved as a KOR agonist. Upon incubation of human macrophages, human dendritic cells, and mouse myeloid immune cells with 4, the number of cells expressing co-stimulatory receptor CD86 and proinflammatory cytokines interleukin 6 and tumor necrosis factor α was significantly reduced; this indicates the strong anti-inflammatory activity of 4. The anti-inflammatory effects correlated well with the KOR affinity: (4aR,8S,8aS)-4 was slightly more potent than the racemic mixture (±)-4, and the distomer ent-4 was almost inactive.
- Martin, Benedikt,Schepmann, Dirk,Bernal, Freddy A.,Schmidt, Thomas J.,Che, Tao,Loser, Karin,Wünsch, Bernhard
-
supporting information
p. 1408 - 1420
(2020/07/06)
-
- Visible-Light-Induced C2 Alkylation of Pyridine N-Oxides
-
A photoredox catalytic method has been developed for the direct C2 alkylation of pyridine N-oxides. This reaction is compatible with a range of synthetically relevant functional groups for providing efficient synthesis of a variety of C2-alkylated pyridine N-oxides under mild conditions. Mechanistic studies are consistent with the generation of a radical intermediate along the reaction pathway.
- Zhang, Wen-Man,Dai, Jian-Jun,Xu, Jun,Xu, Hua-Jian
-
p. 2059 - 2066
(2017/02/26)
-
- HCV PROTEASE INHIBITORS
-
This invention relates to the compounds of formula (I) shown below. Each variable in formula (I) is defined in the specification. These compounds can be used to treat hepatitis C virus infection.
- -
-
Page/Page column 18
(2008/12/07)
-
- Iridium catalysts with bicyclic pyridine-phosphinite ligands: Asymmetric hydrogenation of olefins and furan derivatives
-
(Chemical Equation Presented) Superior bicyclics: Iridium catalysts as 1 derived from pyridine-phosphinite ligands considerably extend the scope of asymmetric hydrogenation. In addition to various unfunctionalized and functionalized olefins, furans, and benzofurans, for which no catalysts were known before, are also hydrogenated with high enantioselectivity (see scheme).
- Kaiser, Stefan,Smidt, Sebastian P.,Pfaltz, Andreas
-
p. 5194 - 5197
(2007/10/03)
-
- Kinetic resolution of diols and pyridyl alcohols by cu(II)(borabox)- catalyzed acylation
-
Boron-bridged bisoxazoline (borabox) ligands have been used in the copper(II)-catalyzed benzoylation of pyridyl alcohols and 1,2-diols. Efficient kinetic resolution of 1,2-diols was achieved using both borabox and bisoxazoline (box) ligands. Borabox ligands induced high selectivities in the benzoylation of suitable pyridyl alcohols, where they outperformed bisoxazolines. In addition, highly enantioselective Cu(II)(borabox)-catalyzed benzoylation has been used for the synthesis of both enantiomers of a pyridyl alcohol.
- Mazet, Clement,Roseblade, Stephen,Koehler, Valentin,Pfaltz, Andreas
-
p. 1879 - 1882
(2007/10/03)
-
- 1,3-BENZOTHIAZINONE DERIVATIVES AND USE THEREOF
-
This invention provides a compound represented by the formula (I) :wherein R1 is a hydrogen atom, a halogen atom, hydroxy, nitro, optionally halogenated alkyl, alkoxy optionally having substituents, acyl or amino optionally having substituents;R2 is pyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl, each of which may have substituents;n is 1 or 2; or a salt. And this invention provides a safe pharmaceutical comprising the compound of the formula (I) , which has an excellent apoptosis inhibitory effect and MIF binding effect, for preventing and/or treating heart disease, nervous degenerative disease, cerebrovascular disease, central nervous infectious disease, traumatorathy, demyelinating disease, bone and articular disease, kidney disease, liver disease, osteomyelodysplasia, AIDS, cancer, and the like.
- -
-
-
- Tetrahydrobenzindole derivatives
-
Compounds containing tetrahydrobenzindole which bind to serotonin receptor and are useful in treatment or prevention of disease induced by abnormality of central peripheral serotonin controlling functions.
- -
-
-
- Synthetic studies on thiostrepton family of peptide antibiotics: Synthesis of the tetrasubstituted dihydroquinoline portion of siomycin D1
-
The tetrasubstituted dihydroquinoline portion of siomycin D1, a member of the thiostrepton family of peptide antibiotics, was synthesized from 5,6,7,8-tetrahydroquinoline featuring the modified Reissert-Henze reaction, the homolytic aromatic su
- Higashibayashi, Syuhei,Mori, Tomonori,Shinko, Kazuyuki,Hashimoto, Kimiko,Nakata, Masaya
-
p. 111 - 122
(2007/10/03)
-
- 1-Imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: Syntheses and evaluation of dual inhibitors of thromboxane A2 synthase and aromatase
-
A series of 1-imidazolyl(alkyl)-substituted quinoline, isoquinoline, naphthalene, benzo[b]furan, and benzo[b]thiophene derivatives was synthesized as dual inhibitors of thromboxane A2 synthase (P450 TxA2) and aromatase (P450 arom). Dual inhibition of these enzymes could be a novel strategy for the treatment of mammary tumors and the prophylaxis of metastases. The most potent dual inhibitors, 5-(2-imidazol-1-ylethyl)-7,8-dihydroquinoline (31) (P450 TxA2:IC50 = 0.29/μM; P450 arom: IC50 = 0.50/μM) and its 5,6- saturated analogue 30 (P450 TxA2:IC50 = 0.68/μM; P450 arom: IC50 = 0.38/μM), showed a stronger inhibition of both target enzymes than the reference compounds (dazoxiben: IC50 = 1.1/μM; aminoglutethimide: IC50 = 18.5/μM). For the determination of the in vivo activity, the influence of selected compounds on serum TxB2 concentration was examined in rats. Compound 30 (8.5 mg/kg body weight) led to a reduction of the TxB2 serum level of 78%, 71%, and 51% after 3, 5, and 8 h, respectively (dazoxiben: 60%, 34%, and 36%). Selectivity was studied toward some enzymes of the steroidogenic and eicosanoid pathways. P450 17 was inhibited by selected compounds only at high concentrations. Compound 30 inhibited P450 scc by 13% (25/μM). Compound 31 did not affect cyclooxygenase and lipoxygenase.
- Jacobs, Christoph,Frotscher, Martin,Dannhardt, Gerd,Hartmann, Rolf W.
-
p. 1841 - 1851
(2007/10/03)
-
- A series of non-quinoline cysLT1 receptor antagonists: SAR study on pyridyl analogs of Singulair
-
The structure-activity relationship of a series of styrylpyridine analogs of MK-0476 (montelukast, Singular) is described. This work has led to the identification of a number of potent and orally active cysLT1 receptor (LTD4 receptor) antagonists including 2ab (L-733,321) as an optimized candidate.
- Guay, Daniel,Gauthier,Dufresne,Jones,McAuliffe,McFarlane,Metters,Prasit,Rochette,Roy,Sawyer,Zamboni
-
p. 453 - 458
(2007/10/03)
-