- Synthesis and pharmacological evaluation of some thiolupinine derivatives
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A small set of 9-(lupinylthio)xanthene, -thioxanthenes and α-(lupinylthio)diphenylmethanes was prepared and found to inhibit the angiotensin II-induced contractions of guinea pig ileum. Some of these compounds were also moderately active in vitro as tracheal relaxants and one compound was more active than aspirin against arachidonic acid-induced platelet aggregation.
- Novelli, Federica,Tasso, Bruno,Sparatore, Fabio
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- PhI(OAc)2and iodine-mediated synthesis ofN-alkyl sulfonamides derived from polycyclic aromatic hydrocarbon scaffolds and determination of their antibacterial and cytotoxic activities
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The development of new approaches toward chemo- and regioselective functionalization of polycyclic aromatic hydrocarbon (PAH) scaffolds will provide opportunities for the synthesis of novel biologically active small molecules that exploit the high degree of lipophilicity imparted by the PAH unit. Herein, we report a new synthetic method for C-X bond substitution that is speculated to operateviaa N-centered radical (NCR) mechanism according to experimental observations. A series of PAH sulfonamides have been synthesized and their biological activity has been evaluated against Gram-negative and Gram-positive bacterial strains (using a BacTiter-Glo assay) along with a series of mammalian cell lines (using CellTiter-Blue and CellTiter-Glo assays). The viability assays have resulted in the discovery of a number of bactericidal compounds that exhibit potency similar to other well-known antibacterials such as kanamycin and tetracycline, along with the discovery of a luciferase inhibitor. Additionally, the physicochemical and drug-likeness properties of the compounds were determined experimentally and usingin silicoapproaches and the results are presented and discussed within.
- Hopkins, Megan D.,Ozmer, Garett L.,Witt, Ryan C.,Brandeburg, Zachary C.,Rogers, David A.,Keating, Claire E.,Petcoff, Presley L.,Sheaff, Robert J.,Lamar, Angus A.
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supporting information
p. 1133 - 1144
(2021/02/16)
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- MODULATORS OF HSD17B13 AND METHODS OF USE THEREOF
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The disclosure relates to compounds and pharmaceutical compositions capable of modulating the hydroxysteroid 17-beta dehydrogenase (HSD17B) family member proteins including inhibiting the HSD17B member proteins, e.g. HSD17B13. The disclosure further relates to methods of treating liver diseases, disorders, or conditions with the compounds and pharmaceutical compositions disclosed herein, in which the HSD17B family member protein plays a role.
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Paragraph 0339
(2021/01/23)
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- Probe-dependent negative allosteric modulators of the long-chain free fatty acid receptor FFA4
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High-affinity and selective antagonists that are able to block the actions of both endogenous and synthetic agonists of G protein-coupled receptors are integral to analysis of receptor function and to support suggestions of therapeutic potential. Although there is great interest in the potential of free fatty acid receptor 4 (FFA4) as a novel therapeutic target for the treatment of type II diabetes, the broad distribution pattern of this receptor suggests it may play a range of roles beyond glucose homeostasis in different cells and tissues. To date, a single molecule, 4-methyl- N-9H-xanthen-9-yl-benzenesulfonamide (AH-7614), has been described as an FFA4 antagonist; however, its mechanism of antagonism remains unknown. We synthesized AH-7614 and a chemical derivative and demonstrated these to be negative allosteric modulators (NAMs) of FFA4. Although these NAMs did inhibit FFA4 signaling induced by a range of endogenous and synthetic agonists, clear agonist probe dependence in the nature of allosteric modulation was apparent. Although AH-7614 did not antagonize the second long-chain free fatty acid receptor, free fatty acid receptor 1, the simple chemical structure of AH-7614 containing features found in many anticancer drugs suggests that a novel close chemical analog of AH-7614 devoid of FFA4 activity, 4-methyl-N-(9H-xanthen-9-yl)benzamide (TUG-1387), will also provide a useful control compound for future studies assessing FFA4 function. Using TUG-1387 alongside AH-7614, we show that endogenous activation of FFA4 expressed by murine C3H10T1/2 mesenchymal stem cells is required for induced differentiation of these cells toward a more mature, adipocyte-like phenotype.
- Watterson, Kenneth R.,Hansen, Steffen V.F.,Hudson, Brian D.,Alvarez-Curto, Elisa,Raihan, Sheikh Zahir,Azevedo, Carlos M.G.,Martin, Gabriel,Dunlop, Julia,Yarwood, Stephen J.,Ulven, Trond,Milligan, Graeme
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p. 630 - 641
(2017/05/22)
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- Steric structure–activity relationship of cyproheptadine derivatives as inhibitors of histone methyltransferase Set7/9
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Set7/9 is a histone lysine methyltransferase, but it is also thought to be involved in a wide variety of pathophysiological functions. We previously identified cyproheptadine, which has a characteristic butterfly-like molecular conformation with bent tricyclic dibenzosuberene and chair-form N-methylpiperidine moieties, as a Set7/9 inhibitor. In this work, we synthesized several derivatives in order to examine the steric structure–inhibitory activity relationship. We found that even a small change of molecular shape due to reduction or replacement of the 10,11-olefinic bond of the tricyclic ring generally resulted in a drastic decrease of the inhibitory activity. Our results should be useful not only for development of more potent and selective inhibitors, but also for the construction of novel inhibitor scaffolds.
- Fujiwara, Takashi,Ohira, Kasumi,Urushibara, Ko,Ito, Akihiro,Yoshida, Minoru,Kanai, Misae,Tanatani, Aya,Kagechika, Hiroyuki,Hirano, Tomoya
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p. 4318 - 4323
(2016/08/23)
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- Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis agents
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Abstract Two series of phenothiazine derivatives were designed and synthesized. All compounds were tested for anti-tuberculosis activities against Mycobacterium tuberculosis H37RV. In comparison with mother compound of chlorpromazine, compound 6e shows promising anti-tuberculosis activity and much less mammalian cell cytotoxicity, compound 6e merits to be further explored as new anti-tuberculosis agents.
- He, Chun-Xian,Meng, Hui,Zhang, Xiang,Cui, Hua-Qing,Yin, Da-Li
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supporting information
p. 951 - 954
(2015/08/18)
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- Steric Effects on the Primary Isotope Dependence of Secondary Kinetic Isotope Effects in Hydride Transfer Reactions in Solution: Caused by the Isotopically Different Tunneling Ready State Conformations?
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The observed 1° isotope effect on 2° KIEs in H-transfer reactions has recently been explained on the basis of a H-tunneling mechanism that uses the concept that the tunneling of a heavier isotope requires a shorter donor-acceptor distance (DAD) than that of a lighter isotope. The shorter DAD in D-tunneling, as compared to H-tunneling, could bring about significant spatial crowding effect that stiffens the 2° H/D vibrations, thus decreasing the 2° KIE. This leads to a new physical organic research direction that examines how structure affects the 1° isotope dependence of 2° KIEs and how this dependence provides information about the structure of the tunneling ready states (TRSs). The hypothesis is that H- and D-tunneling have TRS structures which have different DADs, and pronounced 1° isotope effect on 2° KIEs should be observed in tunneling systems that are sterically hindered. This paper investigates the hypothesis by determining the 1° isotope effect on α- and β-2° KIEs for hydride transfer reactions from various hydride donors to different carbocationic hydride acceptors in solution. The systems were designed to include the interactions of the steric groups and the targeted 2° H/D's in the TRSs. The results substantiate our hypothesis, and they are not consistent with the traditional model of H-tunneling and 1° /2° H coupled motions that has been widely used to explain the 1° isotope dependence of 2° KIEs in the enzyme-catalyzed H-transfer reactions. The behaviors of the 1° isotope dependence of 2° KIEs in solution are compared to those with alcohol dehydrogenases, and sources of the observed "puzzling" 2° KIE behaviors in these enzymes are discussed using the concept of the isotopically different TRS conformations. (Figure Presented).
- Maharjan, Binita,Raghibi Boroujeni, Mahdi,Lefton, Jonathan,White, Ormacinda R.,Razzaghi, Mortezaali,Hammann, Blake A.,Derakhshani-Molayousefi, Mortaza,Eilers, James E.,Lu, Yun
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p. 6653 - 6661
(2015/06/08)
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- Direct coupling reaction of diaryl methanol with ketones or aldehydes catalyzed by AlCl3
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A novel coupling reaction of diaryl methanols with ketones or aldehydes has been developed under the catalysis of AlCl3. Various ketones and aldehydes could couple with 9H-xanthen-9-ol smoothly, affording coupling products in 48%-88% yields. A plausible mechanism using AlCl3 to activate both diaryl methanol and ketone or aldehyde is proposed.
- Zhu, Zhiqiang,Bai, Peng,Wang, Tiantian,Huang, Zhizhen
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supporting information
p. 1176 - 1182
(2015/01/16)
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- Organocatalytic asymmetric alkylation of aldehydes by SNreaction of alcohols
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Work-alcoholic! The elusive enantioselective catalytic α-alkylation of aldehydes, a widely sought transformation, was brought to execution by the use of alcohols capable of forming stabilized carbocations (see scheme, TFA=trifluoroacetic acid).
- Cozzi, Pier Giorgio,Benfatti, Fides,Zoli, Luca
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supporting information; experimental part
p. 1313 - 1316
(2009/06/30)
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- A rational approach towards the nucleophilic substitutions of alcohols "on water"
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(Chemical Equation Presented) Walking on water: Which alcohols react with nucleophiles on the surface of water? The correlations introduced by Mayr et al., in which electrophiles are characterized by the parameter E, gives practical indications about the reactivity of alcohols with nucleophiles in pure water. Stable carbocations generated from the alcohols and characterized by E -2.5 readily react with nucleophiles in pure water at 80°C, without added Bronsted or Lewis acids.
- Cozzi, Pier Giorgio,Zoli, Luca
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supporting information; body text
p. 4162 - 4166
(2009/03/11)
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- Calcium channel blockers comprising two benzhydril moieties
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Certain piperazine substituted compounds are described which are useful in altering calcium channel activity.
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- Calcium channel inhibitors comprising benzhydril spaced from piperazine
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Certain piperazine substituted compounds are described which are useful in altering calcium channel activity.
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- CALCIUM CHANNEL BLOCKERS COMPRISING TWO BENZHYDRIL MOIETIES
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Certain piperazine substituted compounds are described which are useful in altering calcium channel activity.
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- New method for the preparation of dibenzo[b,f][1,4]thiazepines
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The S-amination of 9H-thioxanthen-9-ol (2a) and 9-substituted derivatives 2b-e (Me (b), Et (c), iPr (d), Ph (e)) with O- mesitylenesulfonylhydroxylamine (MSH) was carried out. The expected product, 10-amino-9-hydroxy-9-isopropyl-9H-thioxanthenium mesitylenesulfonate (3d), was obtained in 78% yield from the corresponding thioxanthen-9-ol 2d. However, in the case of 2a-c and 2e the reaction led instead to dibenzo[b, f][1,4]thiazepines 6a-c and 6e in moderate yields.
- Fujii, Takayoshi,Hao, Wei,Yoshimura, Toshiaki
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p. 246 - 250
(2007/10/03)
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- Selective serotonin receptor antagonists and therapeutic applications thereof
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Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (SPAN) and derivatives thereof are provided as selective serotonin receptor antagonists. The compounds are selective, high affinity antagonists of 5-HT2 serotonin receptors. The compounds are useful as antidepressant and antianxiety agents.
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- Benzylphosphonic acid inhibitors of human prostatic acid phosphatase
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A series of α-substituted benzylphosphonic acids is described as inhibitors of human prostatic acid phosphatase, an enzyme has been used as a model to study aryl phosphatases. The most potent inhibitors in this series are 2-trifluoromethylbenzhydrylphosphonic acid (9 μM), and α-(2-phenylethyl)benzylphosphonic acid (14 μM). The structure-activity studies suggest that bulk tolerance beyond the phosphate binding area limits the steric or hydrophobic contribution to inhibitor potency achieved through α-carbon substitution.
- Schwender,Beers,Malloy,Cinicola,Wustrow,Demarest,Jordan
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p. 311 - 314
(2007/10/03)
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- Synthesis and antitumor activity of some new 2-chloroethylnitrosoureas
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The synthesis of a series of N-(2-chloroethyl)-N'-(9H-xanthen-9-yl)-N-nitrosoureas and N-(2-chloroethyl)-N'-(9H-thioxanthen-9-yl)-N-nitrosoureas is described. The title compounds were evaluated against NSCLCN6 L16 bronchial epidermoid carcinoma in vitro and some of them were found to be active. N-(2-chloroethyl)-N'-(2-methoxy-9H-xanthen-9-yl)-N-nitrosourea (8e) was active against leukemia P388 tumor system in mice.
- Filippatos,Papadaki-Valiraki,Roussakis,Verbist
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p. 451 - 456
(2007/10/02)
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- Cyclic amino acids and derivatives thereof
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Novel cyclic amino acids which are useful in preparing biologically active peptides as well as a process for the preparation of D and L enantiomers of the cyclic amino acids are described where an N-protected derivative of the racemic cyclic amino acid is treated with (-)cinchonidine and the resulting salt resolved into the desired enantiomers, as well as derivatives thereof and valuable intermediates used in the process.
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- Synthesis and biological activity of 11-[4-(cinnamyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e]oxepin derivatives, potential agents for the treatment of cerebrovascular disorders
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A series of 11-[4-(cinnamyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e]oxepins and related compounds were synthesized and evaluated for their protective activities against complete ischemia, normobaric hypoxia, lipidperoxidation and convulsion. Structure-activity relationship studies of this series led to the finding of (E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-yl)-4-(3-phenyl-2-prop enyl)piperazine dimaleate (50), AJ-3941 with the most appropriate property for combined pharmacological activities. Compound 50 also shows an inhibitory effect against cerebral edema as well when orally given to rats.
- Kurokawa,Sato,Masuda,Yoshida,Ochi,Zushi,Fujiwara,Naruto,Uno,Matsumoto
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p. 2564 - 2573
(2007/10/02)
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- Zn/OH- REDUCTIONS OF ORGANIC COMPOUNDS IN DIMETHYLSULFOXIDE ; A NEW SIMPLE METHOD OF PREPARING RADICAL ANIONS
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A new method of preparing radical anions from a variety of organic substrates is proposed that involves the use of Zn/KOH in DMSO as electron source.
- Handoo, Kishan L.,Gadru, Kanchan
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p. 1371 - 1372
(2007/10/02)
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