- Wittig-Horner-Emmons reactions of triethyl 3-methyl-phosphonocrotonate with 3-formylchroniones en route to benzophenone-based retinoid candidates
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Wittig-Horner-Emmons (WHE) reaction conditions were used in conjunction with other reactions to prepare benzophenone-based retinoid candidates. The chromone nucleus was reacted with triethyl 3-methyl-phosphonocrotonate to afford benzophenones following a known rearrangement of a reaction intermediate. Confirmations of the structure of rearranged products are provided in the form of the X-ray crystal structures and speculation regarding the mechanism for the rearrangements is included. The method provides a facile route to substituted benzophenone-based candidate ligands for retinoic acid receptors (RARs) or for a wide variety of other applications.
- Sun, Weilin,Desai, Shyam,Piao, Huri,Carroll, Patrick,Canney, Daniel J.
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- Designed Spiroketal Protein Modulation
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Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially b
- Scheepstra, Marcel,Andrei, Sebastian A.,Unver, M. Yagiz,Hirsch, Anna K. H.,Leysen, Seppe,Ottmann, Christian,Brunsveld, Luc,Milroy, Lech-Gustav
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- Anticancer effects of synthetic hexahydrobenzo [g]chromen-4-one derivatives on human breast cancer cell lines
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Background: Cancer results from a series of molecular changes that alter the normal function of cells. Breast cancer is the second leading cause of cancer death in women. To develop novel anticancer agents, new series of chromen derivatives were synthesized and evaluated for their cytotoxic activity against human breast cancer cell lines. Method: The growth inhibitory activities of synthesized hexahydrobenzo chromen-4-one were screened against six human cancer cell lines using an in vitro cell culture system (MTT assay). Fluorochrome staining (acridine orange/ethidium bromide double staining) and DNA fragmentation by the diphenylamine method were used to investigate the effects of most potent compounds on the process of apoptosis in breast cancer cell lines. To determine the mechanism of apoptosis, ROS and NOX production in treated breast cancer cells with compounds was evaluated. Results: The cytotoxicity data of tested compounds demonstrate these compounds had varying degree of toxicity. Compound 7h was the most potent compound with IC50?=?1.8?±?0.6?μg/mL against T-47D cell line. Analyses of the compounds treated (MCF-7, MDA-MB-231, and T-47D) cells by acridine orange/ethidium bromide double staining and DNA fragmentation by the diphenylamine method showed that the synthetic compounds induce apoptosis in the cells. A significant increase in ROS production was observed in T-47D cells treated with IC50 value of compound 7g. Incubation with IC50 value of synthetic compounds increased the NOX production in cell lines, especially T-47D cells. Conclusion: Our results show that most compounds have a significant anti-proliferative activity against six human cancer cell lines. The observations confirm that chromen derivatives have induced the cell death through apoptosis.
- Pordeli, Mahboobeh,Nakhjiri, Maryam,Safavi, Maliheh,Ardestani, Sussan Kabudanian,Foroumadi, Alireza
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- A Modular Approach to Dibenzo-fused ?-Lactams: Palladium-Catalyzed Bridging-C?H Activation
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Tricyclic ring systems possessing a dibenzo structure joined to a seven-membered heterocyclic ring frequently show important biological activities. However, a modular approach to these molecules based on efficient intermolecular reaction of readily available chemicals is lacking. Herein, an unprecedented palladium-catalyzed formal [4+3] annulation for modular construction of these tricyclic systems is described. This reaction features easily accessible reactants (o-haloarylaldehydes and N-tosylhydrazones), broad substrate scope, and excellent functional group compatibility. The synthetic potential is demonstrated by the easy scale-up reactions, late-stage modification of complex molecules, and collective synthesis of bioactive molecules and approved drugs.
- Huang, Xueliang,Ma, Liyao,Xia, Jiajin,Xin, Luoting,Yu, Yinghua,Zhu, Lei
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supporting information
p. 18261 - 18266
(2020/08/21)
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- METHOD FOR PRODUCING AN ARENE WITH AN AROMATIC C-N BOND ORTHO TO AN AROMATIC C-O BOND
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A method for producing an arene with an aromatic C—N bond ortho to an aromatic C—O bond from a hydroxy arene comprising said aromatic C—O bond is provided. This method comprising the steps a) ortho-oxygenating the hydroxy arene to produce an ortho-quinone, b) condensating the ortho-quinone with a nitrogen nucleophile to generate a compound of Formula (IVa) or (IVb), and c) allowing 1,5-hydrogen atom shift of the compound of Formula (IVa) or (IVb), thereby producing arenes with a C—N bond ortho to a C—O bond of Formula (Va) and (Vb), respectively:
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Paragraph 0350; 0351
(2017/03/28)
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- Bioisosteric replacement and related analogs in the design, synthesis and evaluation of ligands for muscarinic acetylcholine receptors
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Previous structure-activity relationship studies involving a series of lactone-based muscarinic ligands identified a lead compound containing a diphenylmethylpiperazine moiety (4; IC50 = 340 nM). The purpose of the present work is to investigate 1,3-benzodioxoles, 4,4-diethyl substituted tetrahydrofurans, 5-substituted oxazolidinones and chromones as bioisosteric replacements for the lactone ring in a novel series of muscarinic ligands. The approach provided compounds with improved % inhibition values and identified a non-selective muscarinic ligand with an IC50 value of 280 nM. The structure-activity relationship for this new series will be discussed. Selected compounds were evaluated in preliminary assays for subtype selectivity and were found to be non-selective.
- Bhandare, Richie R.,Canney, Daniel J.
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p. 361 - 375
(2014/05/20)
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- SUBSTITUTED DIHYDRO BENZOCYCLOALKYLOXYMETHYL OXAZOLOPYRIMIDINONES, PREPARATION AND USE THEREOF
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The present invention relates to a series of substituted dihydro benzocycloalkyl-oxymethyl oxazolopyrimidinones of formula (I) as defined herein. This invention also relates to methods of making these compounds including novel intermediates. The compounds
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Page/Page column 26-27
(2011/04/19)
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- THERAPEUTIC DRUG FOR ADULT T-CELL LEUKEMIA
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An object is to provide a novel therapeutic drug for adult T-cell leukemia having an ATL cell specific antitumor effect. The therapeutic drug for adult T-cell leukemia according to the invention is characterized by containing a compound represented by the formula I or a prodrug thereof, wherein R1 is H, OH, an alkoxy group, an acyl group, or a thioacyl group, R2 is an acyl group, a thioacyl group, CONR7R8, or CSNR7R8 (R7 and R8 being each independently H, an alkyl group containing 1 to 3 carbon atoms, or a phenyl group), or R1 and R2 together may form a ring, X1 and X2 may be the same or different and are each —CR3R4—, —SiR3R4— or oxygen, and R3 and R4 may be the same or different and are each an alkyl group containing 1 to 6 carbon atoms.
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Page/Page column 6
(2011/08/02)
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- Heterocycle-bridged and conformationally constrained retinoids: Synthesis of 4-(7,8,9,10-Tetrahydro-7,7,10,10-tetramethyl-4H-benzo[6,7]chromeno-[4,3-d]thiazole-2-yl)benzoic acid
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Retinoids are a class of synthetic and natural compounds structurally related to retinoic acid. In a search for discovery of a new class of heterocycle-bridged and conformationally constrained retinoids, here we report the synthesis of 4-(7,8,9,10-tetrahydro-7,7,10,10-tetramethyl-4H-benzo[6,7]chromeno[4,3-d]thiazole-2-yl)benzoic acid (10) starting from 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-ol (13). Several approaches was attempted to obtain target compound 10. Structure elucidation of synthesized compounds has been made on the basis of elemental analysis and spectral data (1H NMR, IR and MS).
- Lamei, Navid,Foroumadi, Alireza,Emami, Saeed,Amini, Mohsen,Shafiee, Abbas
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p. 1951 - 1956
(2011/06/19)
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- Discovery of tetrahydrotetramethylnaphthalene analogs as adult T-cell leukemia cell-selective proliferation inhibitors in a small chemical library constructed based on multi-template hypothesis
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Adult T cell leukemia (ATL), caused by infection of human T-lymphotropic virus type 1 (HTLV-1), has a poor prognosis and curative therapy is unavailable, so it is important to find or design superior lead compounds for the drug treatment of ATL. We used our micro-reversed fragment-based drug design hypothesis and multi-template hypothesis to extract the tetrahydrotetramethylnaphthalene (TMN) skeleton from tamibarotene, a useful medicament for the treatment of acute promyelocytic leukemia (APL). Structural development of TMN yielded highly ATL cell-selective growth inhibitors, including 2-acetyl-3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (6). Structure-activity relationship analysis suggests the existence of a specific target molecule for ATL cell-selective inhibition of proliferation through G2 arrest.
- Nakamura, Masahiko,Hamasaki, Takayuki,Tokitou, Maiko,Baba, Masanori,Hashimoto, Yuichi,Aoyama, Hiroshi
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experimental part
p. 4740 - 4746
(2009/10/10)
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- Aza-retinoids as novel retinoid X receptor-specific agonists
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A new structurally simple series of potent lipophilic aza-retinoids RXR agonists has been developed. SAR studies for the N-alkyl-azadienoic acids described here demonstrate that the RXR activity profile is sensitive to the N-alkyl chain length. Further, we have expanded the work to include azadienoic acids, which exhibited many accessible conformations leading to a better understanding of the SAR around the series.
- Farmer, Luc J.,Marron, Kristen S.,Canan Koch, Stacie S.,Hwang,Kallel, E. Adam,Zhi, Lin,Nadzan, Alex M.,Robertson, Dave W.,Bennani, Youssef L.
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p. 2352 - 2356
(2007/10/03)
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- 5,6,7,8-Tetrahydronaphthalen-2-yl-7-fluoroalkyl-heptatrienoic acid derivatives having serum glucose reducing activity
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Compounds of the formula where the variables have the meaning defined in the specification are capable of reducing serum glucose levels in diabetic mammals without the undesirable side effect of reducing serum thyroxine levels.
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- NONCYCLIC 1,3-DICARBONYL COMPOUNDS AS DUAL PPAR AGONISTS WITH POTENT ANTIHYPERGLYCEMIC AND ANTIHYPERLIPIDEMIC ACTIVITY
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Disclosed are the preparation and pharmaceutical use of novel noncyclic 1,3-dicarbonyl compounds of formula I, wherein ring A, ring B, R', R2, R3, R4, R5, X, Y, Z, Q, Ar and n are as defined in the specification. These compounds, as peroxisome proliferator-activated receptor (PPAR) dual agonists for both RXR/PPARgamma and RXRIPPARalpha heterodimers, are useful in the treatment and/or prevention of type 2 diabetes and associated metabolic syndrome such as hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease, and other cardiovascular disorders.
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- Tricyclic retinoids, methods for their production and use
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Tricyclic retinoids having activity for retinoic acid receptors and/or retinoid X receptors are provided. Also provided are pharmaceutical compositions incorporating such tricyclic retinoid compounds and methods for their therapeutic use.
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- Tricyclic retinoids, methods for their production and use
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Tricyclic retinoids having activity for retinoic acid receptors and/or retinoid X receptors are provided. Also provided are pharmaceutical compositions incorporating such tricyclic retinoid compounds and methods for their therapeutic use.
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- Tricyclic retinoids, methods for their production and use
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Tricyclic retinoids having activity for retinoic acid receptors and/or retinoid X receptors are provided. Also provided are pharmaceutical compositions incorporating such tricyclic retinoid compounds and methods for their therapeutic use.
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- Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity
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The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (BARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. The pharmacophoric groups necessary to confer RXR selectivity were established by evaluating the ability of 21 conformationally restricted retinoids to activate the TREpal retinoic acid receptor response element for gene transcription in the presence of one of the three PAR subtypes or RXRα. In contrast to those retinoids selective for the RARs, these RXR-selective retinoids have one less atom in the bridge linking the hydrophobic and carboxylic acid termini of the retinoid skeleton. Therefore, a one-carbon bridge replaces the 19-methyl group and 9E-double bond of 9-cis-retinoic acid and is further functionalized by inclusion in an isopropylidene group, a dioxolane ring, or a cyclopropane ring for optimal RXRα activity and selectivity. In addition, the β-geranylidene and 20-methyl-(11E,13E)- dienoic acid groups of 9-cis-retinoic acid are replaced by a 5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl ring and a 4-carboxylphenyl ring, respectively, for optimal activation and selectivity. RXRα selectivity is reduced on replacement of the 4-carboxylphenyl group by a 2-carboxyl-5- thienyl group or the 9-cis-retinoic acid methylpentadienoic acid terminus.
- Dawson,Jong,Hobbs,Cameron,Chao,Pfahl,Lee -,Shroot,Pfahl
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p. 3368 - 3383
(2007/10/03)
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- Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids
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Two series of potent retinoid X receptor (RXR)-selective compounds were designed and synthesized based upon recent observation that (E)-4-[2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB) binds and transactivates only the retinoic acid receptor (RAR) subtypes whereas (E)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthalenyl)-1-propenyl]benzoic acid (3-methyl TTNPB) binds and transactivates both the RAR and RXR subfamilies. Addition of functional groups such as methyl, chloro, bromo, or ethyl to the 3-position of the tetrahydronaphthalene moiety of 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- 2-naphthyl)carbonyl]benzoic acid (5a) and 4-[1-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydro-2-naphthyl)ethenyl]benzoic acid (6a) results in compounds which elicit potent and selective activation of the RXR class. Such RXR-selective compounds offer pharmacological tools for elucidating the biological role of the individual retinoid receptors with which they interact. Activation profiles in cotransfection and competitive binding assays as well as molecular modeling calculations demonstrate critical structural determinants that confer selectivity for members of the RXR subfamily. The most potent compound of these series, 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (6b), is the first RXR-selective retinoid (designated as LGD1069) to enter clinical trials for cancer indications.
- Boehm,Zhang,Badea,White,Mais,Berger,Suto,Goldman,Heyman
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p. 2930 - 2941
(2007/10/02)
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- Diphenylheteroalkyl derivatives, the preparation thereof and drugs and cosmetics prepared therefrom
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Diphenylheteroalkyl derivatives of the formula I STR1 where A and R1 -R6 have the meanings specified in the description, and the preparation thereof are described. The substances are suitable for controlling diseases and as cosmetic
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- Oxidized diphenylheteroalkanes
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Oxidized diphenylheteroalkanes of the formula I STR1 where R1 to R6 and A have the meanings specified in the description, and the preparation thereof are described. The substances are suitable for controlling diseases and as cosmetic agents.
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- Tetralin esters of phenols or benzoic acids having retinoid like activity
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Retinoid-like activity is exhibited by compounds of the formula STR1 where the R groups are independently hydrogen, or lower alkyl; A is --C(O)O--, --OC(O)--, --C(O)S--, or --SC(O)--; n is 0-5; and Z is H, --COB where B is --OH or a pharmaceutically acceptable salt, or B is --OR 1 where R 1 is an ester-forming group, or B is --N(R) 2 where R is hydrogen or lower alkyl, or Z is --OE where E is hydrogen or an ether-forming group or --COR 2 where R 2 is hydrogen, lower alkyl, phenyl or lower alkyl phenyl, or Z is --CHO or an acetal derivative thereof, or Z is --COR 3 where R 3 is --(CH 2) m CH 3 where m is 0-4 and the sum of n and m does not exceed 4.
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- Polycyclic heterocyclic compounds, a process for their preparation and their use in human and veterinary medicine
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A polycyclic heterocyclic compound has the formula STR1 wherein n is 1 or 2, R1 l represents (i) lower alkyl, (ii) --CH2 OH or (iii) STR2 R2 represents (a) hydrogen, (b) STR3 or (c)--OR3, R3 represents hydrogen, C1 -C20 alkyl mono or polyhydroxyalkyl, aryl or aralkyl optionally substituted, the residue of a sugar or STR4 wherein p is 1, 2, or 3, and r' and r" represent hydrogen, lower alkyl, mono or polyhydroxyalkyl, aryl optionally substituted, amino acid residue, aminated sugar residue, or together form a heterocycle, X represents oxygen, sulfur, SO, SO2 or --NR4, Y represents CR4 or a nitrogen atom and R4 represents hydrogen or lower alkyl. This polycyclic heterocyclic compound can be used in human and veterinary medicine and especially in the topical or systemic treatment of determatologic diseases.
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