- Demonstrating Ligandability of the LC3A and LC3B Adapter Interface
-
Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).
- Hartmann, Markus,Huber, Jessica,Kramer, Jan S.,Heering, Jan,Pietsch, Larissa,Stark, Holger,Odadzic, Dalibor,Bischoff, Iris,Fürst, Robert,Schr?der, Martin,Akutsu, Masato,Chaikuad, Apirat,D?tsch, Volker,Knapp, Stefan,Biondi, Ricardo M.,Rogov, Vladimir V.,Proschak, Ewgenij
-
p. 3720 - 3746
(2021/05/04)
-
- Identification of Interleukin-8-Reducing Lead Compounds Based on SAR Studies on Dihydrochalcone-Related Compounds in Human Gingival Fibroblasts (HGF-1 cells) in Vitro
-
Background: In order to identify potential activities against periodontal diseases, eighteen dihydrochalcones and structurally related compounds were tested in an established biological in vitro cell model of periodontal inflammation using human gingival fibroblasts (HGF-1 cells). Methods: Subsequently to co-incubation of HGF-1 cells with a bacterial endotoxin (Porphyromonas gingivalis lipopolysaccharide, pgLPS) and each individual dihydrochalcone in a concentration range of 1 μM to 100 μM, gene expression of interleukin-8 (IL-8) was determined by qPCR and cellular interleukin-8 (IL-8) release by ELISA. Results: Structure–activity analysis based on the dihydrochalcone backbone and various substitution patterns at its aromatic ring revealed moieties 20,4,40,60-tetrahydroxy 3-methoxydihydrochalcone (7) to be the most effective anti-inflammatory compound, reducing the pgLPS-induced IL-8 release concentration between 1 μM and 100 μM up to 94%. In general, a 2,4,6-trihydroxy substitution at the A-ring and concomitant vanilloyl (4-hydroxy-3-methoxy) pattern at the B-ring revealed to be preferable for IL-8 release inhibition. Furthermore, the introduction of an electronegative atom in the A,B-linker chain led to an increased anti-inflammatory activity, shown by the potency of 4-hydroxybenzoic acid N-vanillylamide (13). Conclusions: Our data may be feasible to be used for further lead structure designs for the development of potent anti-inflammatory additives in oral care products.
- Hans, Joachim,Ley, Jakob P.,Pfeiffer, Stefanie,Schueller, Katharina,Somoza, Veronika,Walker, Jessica
-
-
- Design, synthesis, and biological activity of a novel series of benzofuran derivatives against oestrogen receptor-dependent breast cancer cell lines
-
A docking study of a novel series of benzofuran derivatives with ERα was conducted. In this study, we report the synthesis of a novel series of benzofuran derivatives and evaluation of their anticancer activity in vitro against MCF-7 human breast cancer cells, as well as their potential toxicity to ER-independent MDA-MB-231 breast cancer cells, human renal epithelial HEK-293 cells, and human immortal keratinocytes (HaCaT cells) by using the MTT colorimetric assay. The screening results indicated that the target compounds exhibited anti-breast cancer activity. The target compound 2-benzoyl-3-methyl-6-[2-(morpholin-4-yl)ethoxy]benzofuran hydrochloride (4e) exhibited excellent activity against anti-oestrogen receptor-dependent breast cancer cells and low toxicity. The preliminary structure-activity relationships of the target benzofuran derivatives have been summarised. In conclusion, the novel benzofuran scaffold may be a promising lead for the development of potential oestrogen receptor inhibitors.
- Hu, Chun,Hu, Jian-Shu,Huang, Er-Fang,Jin, Li-Ping,Jin, Zhe,Wan, David Chi-Cheong,Wang, Lin,Xie, Qian,Zhang, Bing-Qi
-
-
- Design, synthesis and anti-TMV activities of novel chromone derivatives containing dithioacetal moiety
-
Thirty-five novel chromone derivatives containing dithioacetal moiety were designed, synthesized, and their anti-TMV activities were evaluated through half-leaf method. The results showed compound c23 illustrates highly curative, protective and inactivating activities against TMV at 500 mg/L, with the values of 68.8%, 58.8%, 86.0% respectively, which were superior to that of Ribavirin (42.3%, 49.8%, 68.4%, respectively) and similar to that of Ningnanmycin (59.4%, 52.4%, 88.4%, respectively). The EC50 value of inactivating activities of compound c23 is 9.3 mg/L, which was better than that of Ribavirin (135.2 mg/L), and equivalent to that of Ningnanmycin (8.8 mg/L). Furthermore, compound c23 can destroy the integrity of TMV-CP, resulting in reduced infectivity of TMV. Meanwhile, compound c23 can combine with TMV protein coat and hydrolyze TMV protein coat to impact the process of self-assembling of TMV, with the association constant (Kd) 4.5 mg/L. This finding suggests that chromone derivatives containing dithioacetal moiety can be used as new antiviral agent.
- Hu, Deyu,Huang, Maoxi,Jiang, Donghao,Li, Miao,Song, Baoan,Zan, Ningning
-
-
- MODULATORS OF STIMULATOR OF INTERFERON GENES (STING)
-
The present invention relates to compounds of formula (I) and salts, stereoisomers, tautomers or N-oxides thereof that are useful as modulators of STING (Stimulator of Interferon Genes). The present invention further relates to the compounds of formula (I) for use as a medicament and to a pharmaceutical composition comprising said compounds.
- -
-
Page/Page column 60
(2020/01/08)
-
- Design, synthesis and QSAR study of 2′-hydroxy-4′-alkoxy chalcone derivatives that exert cytotoxic activity by the mitochondrial apoptotic pathway
-
Eleven 4′-alkoxy chalcones were synthesized and biologically evaluated for their antiproliferative activity against four human tumor cell lines (PC-3, MCF-7, HF-6, and CaSki). Compounds 3a-3d and 3f were selective against PC-3, with IC50 values ranging from 8.08 to 13.75 μM. In addition, chalcones 3a-3c did not affect the normal fibroblasts BJ cells. The most active and selective compounds were further evaluated for their effect on the progression of cell cycle in PC-3 cells, and chalcones 3a and 3c induced a G2/M phase arrest. Furthermore, it was found that these three chalcones induced the mitochondrial apoptotic pathway by regulating Bax and Bcl-2 transcripts and by increasing caspase 3/7 activation. Otherwise, the QSAR model indicates that the double bond of the α,β-unsaturated carbonyl, as well as the planar structure geometry, are important to the biological activity of the synthetized chalcones. Based on these studies, it was concluded that withdrawing substituents in ring A, decrease the antiproliferative activity. This is related to the possible mechanism of action of these compounds, where a Michael addition needs to take place in order to be a potent anticancer agent.
- Marquina, Silvia,Maldonado-Santiago, Maritza,Sánchez-Carranza, Jessica Nayelli,Antúnez-Mojica, Mayra,González-Maya, Leticia,Razo-Hernández, Rodrigo Said,Alvarez, Laura
-
-
- One-pot two-step synthesis of 3-iodo-4-aryloxy coumarins and their Pd/C-catalyzed annulation to coumestans
-
An efficient protocol for the synthesis of various coumestans from the intramolecular annulation of 3-iodo-4-aryloxy coumarins through C-H activation has been developed. When 3-iodo-4-aryloxy coumarins were treated with 10% Pd/C (0.3 mol% Pd) in the presence of sodium acetate, the corresponding coumestans were produced in good to excellent yield. Reusability of the palladium catalyst was investigated in up to three consecutive cycles and it was found that the yield of the reaction was almost unaltered. Sequential iodination and O-arylation of 4-hydroxy coumarins leading to the 3-iodo-4-aryloxy coumarins were also achieved in a one-pot two-step process starting from aryl iodides in high yield. Pivalic acid was revealed to be the most effective additive for the later method to produce 3-iodo-4-phenoxy coumarins. Different functional groups bearing electron-donating as well as withdrawing groups are also tolerant to the reaction conditions.
- Panda, Niranjan,Mattan, Irshad
-
p. 7716 - 7725
(2018/03/01)
-
- 6-[2-hydroxyl-3-(alkylamino)propoxy]benzofuran compound and application thereof
-
The invention belongs to the technical field of medicines and relates to a 6-[2-hydroxyl-3-(alkylamino)propoxy]benzofuran compound and an application thereof. The 6-[2-hydroxyl-3-(alkylamino)propoxy]benzofuran compound comprises a stereoisomer and pharmacologically applicable salt of the compound and has the general structural formula shown in the description, wherein R is shown in the claims andspecification. The 6-[2-hydroxyl-3-(alkylamino)propoxy]benzofuran compound and the pharmacologically applicable salt-additive salt of the compound can be mixed with an existing medicine for use or used alone to be applied to a medicine for treating spastic diseases of vascular smooth muscle.
- -
-
Paragraph 0043; 0044; 0045
(2018/05/16)
-
- AUTOPHAGY INHIBITORS
-
A compound, which is a) a tetrahydrotriazine derivative of the formula (I), a tautomer, a pharmaceutically acceptable salt, a solvate or hydrate thereof, were the symbols have the meanings given in the description, or b) a coumarin derivative of the formula (II), a tautomer, a pharmaceutically acceptable salt, solvate or hydrate thereof, were the symbols have the meanings given in the description, is useful in a therapeutical method for inhibiting autophagy in a cell and for the treatment of cancer.
- -
-
Paragraph 0180; 182
(2017/07/14)
-
- Facile one-pot synthesis of aliphatic bridged diaryloxy compounds, cyclic and crown ethers under mild conditions
-
We report here the facile, room temperature, catalyst free, one pot synthesis of aliphatic bridged diaryloxy compounds, cyclic and crown ethers. Anhydrous potassium carbonate (K2CO3) as a mild base along with dimethyl sulfoxide gener
- Sakate, Sachin,Kamble, Sumit,Chikate, Rajiv,Rode, Chandrashekhar
-
p. 462 - 470
(2017/03/27)
-
- A rapid, solvent-free deprotection of methoxymethyl (MOM) ethers by pTSA; An eco-friendly approach
-
Background: Ease of preparation and alkaline stability of methoxymethyl (MOM) makes it an important hydroxyl protecting group. A number of methods are available for the deprotection of MOM. Though the methods are good in general, they use solvents, require prolonged reaction time and tedious work up. A solvent free, solid phase, fast deprotection of MOM has been developed and is the major theme of this paper. Methods: A mixture of MOM protected compounds and pTSA is triturated in a mortar (5 min) and left at room temperature for 30 min. On addition of water (4°C), pTSA, methanol and formaldehyde dissolved leaving the products as precipitates. Results: A series of different MOM ethers were deprotected by this method in good to excellent yield (85-98%). The compatibility of MOM in the presence of other protections such as methoxyl, benzyl, ester, amide, allyl and lactone was also established. Acetate protection is not stable under these conditions. Conclusion: An efficient, selective and high yielding deprotection MOM groups by pTSA under solvent free condition is described. The process is environment friendly since no solvent was used in the deprotection process. The reaction conditions are mild and should be useful for the deprotection of MOM derivatives of complex and labile molecules.
- Pandurangan, Nanjan
-
p. 231 - 235
(2017/07/15)
-
- New homoisoflavonoid analogues protect cells by regulating autophagy
-
As a special group of naturally occurring flavonoids, homoisoflavonoids have been discovered as active components of several traditional Chinese medicines for nourishing heart and mind. In this study, twenty homoisoflavonoid analogues, including different substitution groups on rings A and B, as well as heteroaromatic B ring, were synthesized and evaluated for their cardioprotective and neuroprotective activities. In a H2O2-induced H9c2 cardiomyocytes injury assay, nine homoisoflavonoid analogues showed promising activities in the same level as the positive control, diazoxide. Six cardioprotective compounds with representative structure diversities were then evaluated for their neuroprotective effects on MPP+ induced SH-SY5Y cell injury model. Furthermore, autophagy inducing monodansylcadaverine (MDC) fluorescence staining methods and molecular docking studies indicated the action mechanism of these compounds may involve autophagy regulating via class I PI3K signaling pathway.
- Gan, Li-She,Zeng, Lin-Wei,Li, Xiang-Rong,Zhou, Chang-Xin,Li, Jie
-
supporting information
p. 1441 - 1445
(2017/03/08)
-
- NOVEL ANALOGUES OF EPICATECHIN AND RELATED POLYPHENOLS
-
The present invention provides novel analogues of epicatechin and related polyphenols, their variously functionalized derivatives, process for preparation of the same, composition comprising these compounds and their method of use.
- -
-
Paragraph 0161; 0162
(2016/03/05)
-
- Origin of Spectral Features and Acid-Base Properties of 3,7-Dihydroxyflavone and Its Monofunctional Derivatives in the Ground and Excited States
-
Comprehensive spectral investigations of 3,7-dihydroxyflavone and its two derivatives, which each contain a methyl-blocked hydroxyl group, reveal complex radiation absorption in the 300-450 nm range and emission in the 370-650 nm range. The absorption and fluorescence characteristics of these compounds depend on the pH/H0 of the water/methanol media, which is caused by the existence of the compounds in various protolytic (cationic, neutral, anionic) and tautomeric forms. Combined analysis of steady-state, time-dependent and fluorescence decay spectral data enabled the identification of the emitting species, determination of their lifetimes with respect to radiative and nonradiative deactivation processes, fluorescence quantum yields, protolytic and tautomeric abilities under various conditions, and acidic dissociation constants of the cationic, neutral, and anionic forms of the compounds. Results of calculations carried out at the DFT and TD DFT levels of theory generally confirmed the experimental findings concerning tautomeric/protolytic transformations and equilibria. Computational methods also provided insight into possible tautomerization pathways. Electronically excited molecules are generally much more susceptible to tautomerization and acidic dissociation than ground-state ones. 3,7-Dihydroxyflavone exhibits distinguishable features among the compounds investigated and can be considered as potential spectral indicator of properties (polarity, hydrophobicity, hydrogen-bonding ability) and acidity/basicity of liquid environments.
- Serdiuk, Illia E.,Roshal, Alexander D.,B?azejowski, Jerzy
-
p. 4325 - 4337
(2016/07/11)
-
- 2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors
-
Based on a previous report that substituted 2-acetylphenols may be promising leads for the design of novel monoamine oxidase (MAO) inhibitors, a series of C5-substituted 2-acetylphenol analogs (15) and related compounds (two) were synthesized and evaluate
- Legoabe, Lesetja J.,Petzer, Anél,Petzer, Jacobus P.
-
p. 3635 - 3644
(2015/08/03)
-
- Phase transfer catalysis extends the scope of the Algar-Flynn-Oyamada synthesis of 3-Hydroxyflavones
-
The Algar-Flynn-Oyamada reaction is the classical method to synthesize 3-hydroxyflavones from chalcones. Despite its relative simplicity, the reaction has several drawbacks including variable and often low product yields. We have found that phase transfer
- Nhu, Duong,Hawkins, Bill C.,Burns, Christopher J.
-
p. 1102 - 1107
(2016/01/15)
-
- Single and double intramolecular proton transfers in the electronically excited state of flavone derivatives
-
In an attempt to create a flavone derivative able to take part in Excited State Intramolecular Double Proton Transfer (ESIDPT), we synthesized two carbonyl derivatives of 3,7-dihydroxyflavone, both containing two different proton-transfer sites as well as related carbonyl derivatives of 3-hydroxyflavone and 7-hydroxyflavone. All the examined hydroxyflavones were found to participate in the Excited State Intramolecular Proton Transfer (ESIPT). ESIPT which involves 3-hydroxyl and 4-carbonyl groups was found to have a higher barrier compared to ESIPT involving 7-hydroxyl and 6/8-carbonyl fragments. According to the data presented, 3,7-dihydroxy-2-phenyl-6-(3-phenylpropanoyl)-4H-chromen-4-one undergoes a two-stage ESIDPT with formation of an intermediate tautomer. This kind of ESIDPT leads to a tautomeric form with an abnormally low rate of radiative deactivation of the excited state, which conditions low fluorescence quantum yield. The behavior of 3,7-dihydroxy-4-oxo-2-phenyl-4H-chromene-8-carbaldehyde in the electronically excited state is similar to 3-hydroxyflavone derivatives, thus we conclude the occurrence of a single ESIPT in this compound.
- Serdiuk,Roshal
-
p. 102191 - 102203
(2015/12/11)
-
- Discovery of phenoxybutanoic acid derivatives as potent endothelin antagonists with antihypertensive activity
-
A series of phenoxybutanoic acid derivatives were synthesized and tested for their antagonistic activity on the contraction of the rat thoracic aortic ring induced by endothelin-1. Preliminary screening results showed that 6e and 6g with benzoheterocycles demonstrated significant antagonistic activities when compared to the reference compound BQ123. The results from additional assays for the binding affinity and selectivity for endothelin receptors showed that 6e was a selective ETA antagonist with a nanomolar IC50. Moreover, 6e was effective in relieving hypoxia-induced pulmonary arterial hypertension and right ventricular weight ratio. Therefore, 6e may have potential for further development as a therapeutic agent for the treatment of cardiovascular diseases.
- Cai, Jin,Liu, Ligang,Hong, Kwon Ho,Wang, Peng,Li, Lushen,Cao, Meng,Sun, Chunlong,Wu, Xiaoqing,Zong, Xi,Chen, Junqing,Ji, Min
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p. 657 - 667
(2015/02/19)
-
- Defining a minimum pharmacophore for simocyclinone D8 disruption of DNA gyrase binding to DNA
-
The increasing occurrence of drug-resistant bacterial infections in the clinic has created a need for new antibacterial agents. Natural products have historically been a rich source of both antibiotics and lead compounds for new antibacterial agents. The natural product simocyclinone D8 (SD8) has been reported to inhibit DNA gyrase, a validated antibacterial drug target, by a unique catalytic inhibition mechanism of action. In this work, we have used a deconstruction-reconstruction approach to prepare analogs of the coumarin subunit of SD8 and evaluated their ability to disrupt binding of the DNA gyrase enzyme to DNA in a surface plasmon resonance assay. This has led to a minimum pharmacophore required for disruption of binding. Springer Science+Business Media 2014.
- Gaskell, Lauren M.,Nguyen, Thuy,Ellis, Keith C.
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p. 3632 - 3643
(2014/08/05)
-
- NOVEL COMPOUNDS SUITABLE FOR THE TREATMENT OF DYSLIPIDEMIA
-
The present invention relates to compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation. The compounds of the present invention can be used to treat diseases such as hyperlipidemia and also have a beneficial effect on cholesterol.
- -
-
Page/Page column 32-33
(2014/12/12)
-
- Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells
-
Under hypoxia, cancer cells consume glucose and release lactate at a high rate. Lactate was recently documented to be recaptured by oxygenated cancer cells to fuel the TCA cycle and thereby to support tumor growth. Monocarboxylate transporters (MCT) are the main lactate carriers and therefore represent potential therapeutic targets to limit cancer progression. In this study, we have developed and implemented a stepwise in vitro screening procedure on human cancer cells to identify new potent MCT inhibitors. Various 7-substituted carboxycoumarins and quinolinone derivatives were synthesized and pharmacologically evaluated. Most active compounds were obtained using a palladium-catalyzed Buchwald-Hartwig type coupling reaction, which proved to be a quick and efficient method to obtain aminocarboxycoumarin derivatives. Inhibition of lactate flux revealed that the most active compound 19 (IC 50 11 nM) was three log orders more active than the CHC reference compound. Comparison with warfarin, a conventional anticoagulant coumarin, further showed that compound 19 did not influence the prothrombin time which, together with a good in vitro ADME profile, supports the potential of this new family of compounds to act as anticancer drugs through inhibition of lactate flux.
- Draoui, Nihed,Schicke, Olivier,Fernandes, Antony,Drozak, Xavier,Nahra, Fady,Dumont, Amélie,Douxfils, Jonathan,Hermans, Emmanuel,Dogné, Jean-Michel,Corbau, Romu,Marchand, Arnaud,Chaltin, Patrick,Sonveaux, Pierre,Feron, Olivier,Riant, Olivier
-
p. 7107 - 7117
(2013/11/06)
-
- Natural Products as Sources of New Fungicides (I): Synthesis and Antifungal Activity of Acetophenone Derivatives Against Phytopathogenic Fungi
-
Several series of 45 acetophenone derivatives bearing various alkyl or benzyl substituents were conveniently synthesized and their structures characterized by 1H and 13C NMR spectroscopy, HRMS and single-crystal X-ray analysis. Their in vitro antifungal activities against a panel of phytopathogenic fungi were evaluated by mycelial growth rate assay. Of them, 12 derivatives (e.g., 3a-c, 4c and 4e) exhibited more potent antifungal effects on some phytopathogens than a commercial fungicide hymexazol as positive control. In particular, compound 3b with IC50 values of 10-19μg/mL was found to be the most active in this series and might be a potential lead structure for further optimization. The preliminary structure-activity relationship (SAR) studies of a series of acetophenones are also discussed. A series of acetophenone derivatives have been synthesized and tested for their antifungal activities. Of them 12 derivatives exhibited more potent antifungal effects on some phytopathogens than a positive control hymexazol. Especially, compound 3b (IC50=10-19μg/mL) was found to be the most active and might be a potential lead structure. The SAR of these acetophenones is also discussed.
- Ma, Ya-Tuan,Fan, Hua-Fang,Gao, Yu-Qi,Li, He,Zhang, An-Ling,Gao, Jin-Ming
-
p. 545 - 552
(2013/06/05)
-
- Synthesis of chromenoindole derivatives from Robinia pseudoacacia
-
An unusual tetrahydrochromeno[4,3-b]indole type analogue of medicarpin has been isolated from the roots of the Black Locust and subsequently has been synthesized together with an aromatic derivative which shows considerable biological activity against a range of significant targets.
- Dejon, Lisa,Mohammed, Hamdoon,Du, Peng,Jacob, Claus,Speicher, Andreas
-
supporting information
p. 1580 - 1583
(2013/12/04)
-
- NOVEL ETHER LINKED COMPOUNDS AND IMPROVED TREATMENTS FOR CARDIAC AND CARDIOVASCULAR DISEASE
-
A compound of Formula (I), and its pharmaceutically acceptable salt or salts and physiologically hydrolysable derivatives in free form or salt form: wherein R1 is independently selected from F, CI, Br, CN, NH2, OH, CHO, COOH, oxo, C1-4alkyl, C1-4alkoxy, CONH2 (optionally mono- or di-substituted by C1-4alkyl) and SO2NH2, R2 is independently selected from C1-6allkyl substituted by R3 wherein the C1-6alkyl chain optionally comprises one or two heteroatoms select from O; R3 is selected from aryl, C3-6cycloalkyl, C3-6heterocyclyl and C3-6heteroaryl, wherein the heterocyclyl and heteroaryl rings are nitrogen containing; and wherein R3 is optonally substituted by one or more groups selected from R1; n1 is zero or an integer from 1 to 2; n2 is an integer from 1 to 2; and the sum of n1 and 2 is less than or equal to 2; R5 is selected from any group defined for R1 and R2; R6a and R6b are independently selected from H or C1-4alkyl; R7 is independently selected from F, CI, Br, CN, NH2, OH, CHO, COOH, oxo, C1-4alkyl, C1-4alkoxy, CONH2 (optionally mono- or di-substituted by C1-4alkyl) and SO2NH2, Q1, Q2 and Q3 are independently selected from H or any group defined for R1 and R2; or Q1 and Q2 or Q2 and Q3 together form a C5-6heteroaryl or C5-6heterocylclic ring; optionally containing one or two heteroatoms selected from N and O optionally substituted by any group selected from R5; Z is selected from linear C2-3 alkylene; X3 is O; X4 is selected from aryl, a 9-10 membered heteroaryl ring or a 9-10 membered heterocyclic ring, wherein the heteroaryl and heterocyclic rings contain one or more heteroatoms selected from N, and optionally additionally O, and wherein X4 is optionally substituted by one or two oxo moieties and is optionally substituted by one or more groups selected from R7; with the proviso that: (i) when X4 is phenyl then Q1 and Q2 or Q2 and Q3-together form an optionally substituted heteroaryl or heterocylclic ring as defined above; and (ii) when Q1, Q2 and Q3 are independently selected from H or any group defined for R1 and R2 then X4 is not phenyl except when R2 is C1-5alkyl substituted by R3 wherein R3 is C3-6heterocyclyl as defined above.
- -
-
Page/Page column 31
(2012/08/27)
-
- METHODS FOR SYNTHESIZING GLYCINOLS, GLYCEOLLINS I AND II, COMPOSITIONS OF SELECTED INTERMEDIATES, AND THERAPEUTIC USES THEREOF
-
Two distinct methods are disclosed and claimed for synthesizing glyceollin I plus glyceollin II as a mixture and as their pure forms. Stereochemical isomers and various synthetic intermediates are also synthesized and claimed for their novel compositions of matter. All compounds and their mixtures are claimed for use in formulations that are useful to treat or prevent cancer, or that have utility as selective estrogen receptor modulators, such formulations including enhanced or medical foods, dietary supplements and ethical pharmaceutical agents.
- -
-
Page/Page column 2; 3; 9
(2011/06/26)
-
- Biomimetic syntheses and antiproliferative activities of racemic, natural (-), and unnnatural (+) glyceollin i
-
A 14-step biomimetic synthetic route to glyceollin I (1.5% overall yield) was developed and deployed to produce the natural enantiomeric form in soy, its unnatural stereoisomer, and a racemic mixture. Enantiomeric excess was assessed by asymmetric NMR shift reagents and chiral HPLC. Antiproliferative effects were measured in human breast, ovarian, and prostate cancer cell lines, with all three chiral forms exhibiting growth inhibition (GI) in the low to mid μM range for all cells. The natural enantiomer, and in some cases the racemate, gave significantly greater GI than the unnatural stereoisomer for estrogen receptor positive (ER+) versus ER- breast/ovarian cell lines as well as for androgen receptor positive (AR+) versus AR - prostate cancer cells. Surprisingly, differences between ER + and ER- cell lines were not altered by media estrogen conditions. These results suggest the antiproliferative mechanism of glyceollin I stereoisomers may be more complicated than strictly ER interactions.
- Khupse, Rahul S.,Sarver, Jeffrey G.,Trendel, Jill A.,Bearss, Nicole R.,Reese, Michael D.,Wiese, Thomas E.,Boue, Stephen M.,Burow, Matthew E.,Cleveland, Thomas E.,Bhatnagar, Deepak,Erhardt, Paul W.
-
experimental part
p. 3506 - 3523
(2011/07/30)
-
- Synthesis and antifungal activities of natural and synthetic biflavonoids
-
The synthesis of some natural and synthetic biflavonoids was performed in good overall yields starting from readily available materials via high yielding aldol and Ullmann condensations. Some of these compounds, especially bichalcones, display an interesting activity against fungi, higher than that of the corresponding monomers.
- Sagrera, Gabriel,Bertucci, Ana,Vazquez, Alvaro,Seoane, Gustavo
-
experimental part
p. 3060 - 3073
(2011/06/27)
-
- An efficient total synthesis of resokaempferol 3-O-β-D-glucoside
-
Resokaempferol 3-O-β-D-glucoside, an artificial flavonol glycoside, was synthesized from 2,4-dihydroxyacetophenone in six steps and 40% overall yield via an efficient glycosylation method using NaH.
- Ren, Xuhong,Wang, Jingjing,Shen, Liu-Lan,Li, Wei,Muraoka, Osamu,Cheng, Maosheng
-
supporting information; experimental part
p. 1135 - 1137
(2011/11/30)
-
- Anti-AIDS agents 82: Synthesis of seco-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives as novel anti-HIV agents
-
Thirteen novel seco-DCK analogs (4-16) with several new skeletons were designed, synthesized and screened for in vitro anti-HIV-1 activity. Among them, three compounds (5, 13, and 16) showed moderate activity, and compound 9 exhibited the best activity with an EC50 value of 0.058 μM and a therapeutic index (TI) of 1000. The activity of 9 was better than that of 4-methyl DCK (2, EC50: 0.126 μM, TI: 301.2) in the same assay. Additionally, 9 also showed antiviral activity against a multi-RT inhibitor-resistant strain (RTMDR), which is insensitive to most DCK analogs. Compared with 2, compound 9 has a less complex structure, fewer hydrogen-bond acceptors, and a reduced log P value. Therefore, it is likely to exhibit better ADME, and appears to be a promising new lead for further development as an anti-HIV candidate.
- Tang, Jian,Qian, Keduo,Zhang, Bei-Na,Chen, Ying,Xia, Peng,Yu, Donglei,Xia, Yi,Yang, Zheng-Yu,Chen, Chin-Ho,Morris-Natschke, Susan L.,Lee, Kuo-Hsiung
-
scheme or table
p. 4363 - 4373
(2010/09/12)
-
- An efficient synthesis of a multipotent eicosanoid pathway modulator
-
An efficient, scalable synthesis of the multipotent eicosanoid pathway modulator 2-[3-[3[[5-ethyl-4'-fluoro-2-hydroxyl[1,1'-bi-phenyl]4-yl]oxy]- propoxy]2-propoxylphenoxy]benzoic acid (1) is described. The process consists of nine chemical steps with the
- Yates, Matthew H.,Koenig, Thomas M.,Kallman, Neil J.,Ley, Christopher P.,Mitchell, David
-
experimental part
p. 268 - 275
(2010/04/22)
-
- Counterattack mode differential acetylative deprotection of phenylmethyl ethers: Applications to solid phase organic reactions
-
A counterattack protocol for differential acetylative cleavage of phenylmethyl ether has been developed. The phenylmethyl moiety is liberated as benzyl bromide that is isolated and reused providing advantages in terms of waste minimization/utilization and atom economy. The applicability of this methodology has been extended for solid phase organic reactions with the feasibility of reuse of the solid support.
- Chakraborti, Asit K.,Chankeshwara, Sunay V.
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supporting information; experimental part
p. 1367 - 1370
(2009/07/04)
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- Simplified YM-26734 inhibitors of secreted phospholipase A2 group IIA
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Simplified analogs of YM-26734, a known inhibitor of secreted phospholipase A2 (sPLA2) group IIA, were synthesized and found to also display potent inhibition at low nanomolar concentrations. Analogs were based on the didodecanoylphl
- Oslund, Rob C.,Cermak, Nathan,Verlinde, Christophe L.M.J.,Gelb, Michael H.
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supporting information; experimental part
p. 5415 - 5419
(2009/05/30)
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- Survivin inhibitors
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Compounds that inhibit survivin, compositions containing the compounds and methods of treating diseases in which survivin is unregulated or overexpressed are disclosed.
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Page/Page column 23
(2010/11/26)
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- INHIBITORS OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE, AND COMPOSITIONS AND TREATMENTS USING THE SAME
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The present invention provides compounds of formula (4), and their pharmaceutically acceptable salts and solvates, which are useful as inhibitors of the Hepatitis C virus (HCV) polymerase enzyme and are also useful for the treatment of HCV infections in HCV-infected mammals. The present invention also provides pharmaceutical compositions comprising compounds of formula (4), their pharmaceutically acceptable salts and solvates. Furthermore, the present invention provides intermediate compounds and methods useful in the preparation of compounds of formula (4).
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Page/Page column 141
(2008/06/13)
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- NOVEL CYLOPENTA[B]BENZOFURAN DERIVATIVES AND THE UTILIZATION THEREOF
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The invention relates to novel cyclopenta[b]benzofuran derivatives, to a method for the production thereof and to their utilization for the production of medicaments, especially for the prophylaxis and/or therapy of acute or chronic diseases which are cha
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Page/Page column 99
(2008/06/13)
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- A novel class of apical sodium-dependent bile acid transporter inhibitors: The amphiphilic 4-oxo-1-phenyl-1,4-dihydroquinoline derivatives
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A series of 4-oxo-1-phenyl-1,4-dihydroquinolines possessing a linker and an ammonio moiety were synthesized and found to inhibit the apical sodium-dependent bile acid transporter (ASBT). The potency of ASBT inhibition varied with the position and length o
- Kurata, Hitoshi,Suzuki, Sayaka,Ohhata, Yasuo,Ikeda, Takuya,Hasegawa, Toru,Kitayama, Ken,Inaba, Toshimori,Kono, Keita,Kohama, Takafumi
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p. 1183 - 1186
(2007/10/03)
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- Potential therapeutic antioxidants that combine the radical scavenging ability of myricetin and the lipophilic chain of vitamin E to effectively inhibit microsomal lipid peroxidation
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The flavonol myricetin, reacts with oxygen-centred galvinoxyl radicals 28 times faster than d-α-tocopherol (vitamin E), the main lipid-soluble antioxidant in biological membranes. Moreover, each myricetin molecule reduces twice as many such radicals as vitamin E. However, myricetin fails to protect vitamin E-deficient microsomes from lipid peroxidation as assessed by the formation of thiobarbituric acid reactive substances (TBARS). Novel and potentially therapeutic antioxidants have been prepared that combine the radical-scavenging ability of a myricetin-like head group with a lipophilic chain similar to that of vitamin E. C6-C12 alkyl chains are attached to the A-ring of either a 3,3′,4 ′,5′-tetrahydroxyflavone or a 3,2 ′,4′,5′-tetrahydroxyflavone head group to give lipophilic flavonoids (ClogP=4 to 10) that markedly inhibit iron-ADP catalysed oxidation of microsomal preparations. Orientation of the head group as well as total lipophilicity are important determinants of antioxidant efficacy. MM2 models indicate that our best straight chain 7-alkylflavonoids embed to the same depth in the membrane as vitamin E. The flavonoid head groups are prepared by aldol condensation followed by Algar-Flynn-Oyamada (AFO) oxidation or by Baker-Venkataraman rearrangement. The alkyl tails are introduced by Suzuki or Negishi palladium-catalysed cross-coupling or by cross-metathesis catalysed by first generation Grubbs catalyst, which tolerate phenolic hydroxyl and ketone groups.
- Bennett, Christopher J.,Caldwell, Stuart T.,McPhail, Donald B.,Morrice, Philip C.,Duthie, Garry G.,Hartley, Richard C.
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p. 2079 - 2098
(2007/10/03)
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- INHIBITORS OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE, AND COMPOSITIONS AND TREATMENTS USING THE SAME
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The invention relates to compounds of the formula (I) and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R1and R2, are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula (I), and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula (I). The invention also relates to methods of preparing the compounds of formula (I).
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- Structural requirement of isoflavonones for the inhibitory activity of interleukin-5
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Sophoricoside isolated from Sophora japonica is a glycoside of isoflavonone as an inhibitor of interleukin (IL)-5. To identify structural requirements of this isoflavonone for its inhibitory activity against IL-5, isoflavonones, isoflavanones, and their glycosides were prepared and their inhibitory activity was tested against IL-5. Among them, 5-benzyloxy-3-(4-hydroxyphenyl)chromen-4-one (4b, 87.9% inhibition at 50 μM, IC50=15.3 μM) shows the most potent activity, comparable with that of sophoricoside. The important structural requirements of these isoflavonone analogs exhibiting the inhibitory activity against IL-5 were recognized as (1) planarity of chromen-4-one ring, (2) existence of phenolic hydroxyl at 4-position of B ring, and (3) introduction of benzyloxy at 5-position, which may act as a bulky group for occupying hydrophobic pocket in putative binding site. However the glucopyranosyl moiety of sophoricoside is not an essential motif for the activity.
- Jung, Sang-Hun,Cho, Soo-Hyun,Hung Dang, The,Lee, Jee-Hyun,Ju, Jung-Hun,Kim, Mi-Kyung,Lee, Seung-Ho,Ryu, Jae-Chun,Kim, Youngsoo
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p. 537 - 545
(2007/10/03)
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- 1,2-AZOLE DERIVATIVES WITH HYPOGLYCEMIC AND HYPOLIPIDEMIC ACTIVITY
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A compound represented by the formula (1) wherein ring A is a ring optionally having 1 to 3 substituents; ring B is a 1,2-azole ring which may further have 1 to 3 substituents; Xa, Xb and Xc are the same or different and each is a bond, - O -, - S - and the like; Ya is a divalent aliphatic hydrocarbon residue having 1 to 20 carbon atoms; Yb and Yc are the same or different and each is a bond or a divalent aliphatic hydrocarbon residue having 1 to 20 carbon atoms; ring C is a monocyclic aromatic ring which may further have 1 to 3 substituents; and R represents -OR4 (R4 is hydrogen atom or optionally substituted hydrocarbon group) and the like, or a salt thereof or a prodrug thereof is useful as an agent for the prophylaxis or treatment of diabetes and the like.
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- LY294002-geldanamycin heterodimers as selective inhibitors of the PI3K and PI3K-related family
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Several LY294002-GM heterodimers were synthesized with the intent of modulating their activity in the presence of hsp90 and thereby creating selective inhibitors of PI3K and PI3K-related family.
- Chiosis, Gabriela,Rosen, Neal,Sepp-Lorenzino, Laura
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p. 909 - 913
(2007/10/03)
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- Simplified catechin-gallate inhibitors of HIV-1 reverse transcriptase
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Systematic simplification of the molecular structures of epicatechin gallate and epigallocatechin gallate to determine the minimum structural characteristics necessary for HIV-1 reverse transcriptase inhibition in vitro resulted in several compounds that strongly inhibited the native as well as the A17 double mutant (K103N Y181C) enzyme, which is normally insensitive to most known nonnucleoside inhibitors.
- Tillekeratne,Sherette,Grossman,Hupe,Hupe,Hudson
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p. 2763 - 2767
(2007/10/03)
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- Structure-activity requirements for flavone cytotoxicity and binding to tubulin
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A series of 79 flavones related to centaureidin (3,6,4'-trimethoxy- 5,7,3'-trihydroxyflavone, 1) was screened for cytotoxicity in the NCI in vitro 60-cell line human tumor screen. The resulting cytotoxicity profiles of these flavones were compared for deg
- Beutler, John A.,Hamel, Ernest,Vlietinck, Arnold J.,Haemers, Achiel,Rajan, Padinchare,Roitman, James N.,Cardellina II, John H.,Boyd, Michael R.
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p. 2333 - 2338
(2007/10/03)
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- Polymer-bound triphenylphosphine as traceless reagent for Mitsunobu reactions in combinatorial chemistry: Synthesis of aryl ethers from phenols nad alcohols
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The synthesis of aryl ethers from phenols and alcohols using polymer- bound triphenylphosphine and diethyl azodicarboxylate (DEAD) is described. The polymer-bound triphenylphosphines are easily removed by filtration from the reaction products. This method
- Tunoori, Ashok Rao,Dutta, Dinah,Georg, Gunda I.
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p. 8751 - 8754
(2007/10/03)
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- Photoactive coumarin derivatives
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A new class of 3,4-dihydrocoumarin derivatives which are useful as photoactive compounds in a wide variety of applications including photoresists and other opto-electronic applications are disclosed and claimed. Preferred embodiments include ether, ester, carbonate, and sulfonate derivatives of 5-hydroxy, 6-hydroxy, and 7-hydroxy-3-diazo-4-oxo-3,4-dihydrocoumarins. These compounds exhibit very high photosensitivity in the deep ultraviolet (DUV) region (ca. 250 nm), and therefore, are useful as photoactive compounds in DUV photoresist formulations.
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- Process for preparing photoactive coumarin derivatives
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Novel processes for the preparation of a new class of coumarin derivatives, which are useful as photoactive compounds in a wide variety of applications including photoresists and other opto-electronic applications, are disclosed and claimed. The process involves a multi-step synthetic method for the preparation of ether, ester, carbonate, or sulfonate derivative of 5-hydroxy, 6-hydroxy, or 7-hydroxy-3-diazo-4-oxo-3,4-dihydrocoumarin starting from the corresponding dihydroxyacetophenone. The compounds formed from the process of the present invention exhibit very high photosensitivity in the deep ultraviolet (DUV) region (ca. 250 nm), and therefore, are useful as photoactive compounds in DUV photoresist formulations.
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- Leukotriene antagonists for use in the treatment or prevention of alzheimer's disease
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This invention provides methods for the treatment or prevention of Alzheimer's disease which comprises administering to a mammal in need thereof an effective amount of a compound having activity as a leukotriene antagonist.
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- SUBSTITUTED PHENYL PHENOL LEUKOTRIENE ANTAGONISTS
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Antagonists having a substituted phenyl phenol or a substituted phenolic biphenyl structure, and various derivatives thereof, are specific leukotriene antagonists. Their structures, use and synthesis are disclosed. Also, pharmaceutical formulations are disclosed for use in applications treating diseases or conditions characterized by excessive release of leukotriene B 4, one of the metabolites of arachidonic acid.The primary LTB 4 antagonistic structures are represented as: STR1
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- USE OF PLA2 INHIBITORS AS TREATMENT FOR ALZHEIMER'S DISEASE
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This invention provides methods for the treatment or prevention of Alzheimer's disease in a mammal which comprises administering to a mammal in need thereof an effective amount of an inhibitor of phospholipase A2. This invention also provides a series of compounds which are useful as inhibitors of phospholipases A2, especially cytosolic phospholipase A2.
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- 1,2,4-TRIOXYGENATED BENZENE DERIVATIVES USEFUL AS LEUKOTRIENE ANTAGONISTS
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This invention provides 1,2,4-trioxygenated benzene derivatives which are leukotriene B 4 antagonists, formulations of those derivatives, and a method of using those derivatives for the treatment of conditions characterized by an excessive release of leukotrienes.
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