- Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles
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We recently established that drugs used for the treatment and the prophylaxis of breast cancers, such as tamoxifen, were potent inhibitors of cholesterol-5,6-epoxide hydrolase (ChEH), which led to the accumulation of 5,6α-epoxy-cholesterol (5,6α-EC) and 5,6β-epoxy-cholesterol (5,6β-EC). This could be considered a paradox because epoxides are known as alkylating agents with putative carcinogenic properties. We report here that, as opposed to the carcinogen styrene-oxide, neither of the ECs reacted spontaneously with nucleophiles. Under catalytic conditions, 5,6β-EC remains unreactive whereas 5,6α-EC gives cholestan-3β,5 α-diol-6β-substituted compounds. These data showed that 5,6-ECs are stable epoxides and unreactive toward nucleophiles in the absence of a catalyst, which contrasts with the well-known reactivity of aromatic and aliphatic epoxides. These data rule out 5,6-EC acting as spontaneous alkylating agents. In addition, these data support the existence of a stereoselective metabolism of 5,6α-EC. Copyright
- Paillasse, Michael R.,Saffon, Nathalie,Gornitzka, Heinz,Silvente-Poirot, Sandrine,Poirot, Marc,De Medina, Philippe
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experimental part
p. 718 - 725
(2012/06/18)
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- Substituted 1,2,3,4-tetrahydroquinolin-6-yloxypropanes as β3-adrenergic receptor agonists: Design, synthesis, biological evaluation and pharmacophore modeling
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In search of potent β3-adrenergic receptor agonists, a series of novel substituted 1,2,3,4-tetrahydroquinolin-6-yloxypropanes has been synthesized and evaluated for their β3-adrenergic receptor agonistic activity (ranging from -17.73% to 90.64% inhibition at 10 μM) using well established Human SK-N-MC neuroblastoma cells model. Four molecules viz. 11, 15, 22 and 23 showed β3-AR agonistic IC50 value of 0.55, 0.59, 1.18 and 1.76 μM, respectively. These four candidates have been identified as possible leads for further development of β3-adrenergic receptor agonists for obesity and Type-II diabetes pharmacotherapy. The free OH and NH functions are found to be essential for β3-adrenergic receptor agonistic activity. Among the synthesized β3-adrenergic receptor agonists having 1,2,3,4-tetrahydroquinoline scaffold, the N-benzyl group is found to be superior over N-arylsulfonyl group. A putative pharmacophore model has been modeled considering the above four active molecules which distinguishes well between the active and inactive molecules.
- Shakya, Neeraj,Roy, Kuldeep K.,Saxena, Anil K.
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supporting information; experimental part
p. 830 - 847
(2009/07/25)
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- POLYCYCLIC COMPOUNDS WHICH MODULATE THE CB2 RECEPTOR
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Compounds of formula (I) are disclosed. Compounds according to the invention are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treati
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Page/Page column 10-11
(2008/12/05)
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- COMPOUNDS WHICH MODULATE THE CB2 RECEPTOR
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Compounds are provided which bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, the compounds having the general formula (I) wherein, R1, R2, A, Y, X, Ar1 and Ar2 have the meanings given in the specification, and the preparation and use thereof. The compounds are valuable CB2 receptor modulators.
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Page/Page column 18
(2008/06/13)
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- 2-Aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridines as broad-spectrum inhibitors of human herpesvirus polymerases
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A novel series of 2-aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides have been identified as potent antivirals against human herpesviruses. These compounds demonstrate broad-spectrum inhibition of the herpesvirus polymerases HCMV, HSV-1, EBV, and VZV with high specificity compared to human DNA polymerases.
- Schnute, Mark E.,Anderson, David J.,Brideau, Roger J.,Ciske, Fred L.,Collier, Sarah A.,Cudahy, Michele M.,Eggen, MariJean,Genin, Michael J.,Hopkins, Todd A.,Judge, Thomas M.,Kim, Euibong J.,Knechtel, Mary L.,Nair, Sajiv K.,Nieman, James A.,Oien, Nancee L.,Scott, Allen,Tanis, Steven P.,Vaillancourt, Valerie A.,Wathen, Michael W.,Wieber, Janet L.
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p. 3349 - 3353
(2008/02/07)
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- Facile synthesis of aminoalcohols by ring opening of epoxides under solvent free conditions
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The convenient cleavage of symmetrical and unsymmetrical epoxides with either aromatic or aliphatic amine under solvent free conditions is reported. The reactions were carried out in a sealed ampoule at 90°C to give regioselectively the corresponding β-amino alcohol in one pot in high yields.
- Huerta, Gloria,Contreras-Ordonez, Guadalupe,Alvarez-Toledano,Santes, Victor,Gomez, Elizabeth,Toscano, Ruben A.
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p. 2393 - 2406
(2007/10/03)
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- Derivatives of 2-amino-1-phenylethanol having antiulcer activity
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Derivatives of 2-amino-1-phenylethanol were prepared from substituted amines and benzoin, stilbene oxide or styrene oxide to give compounds of Formula: STR1 where R is H or (un)substituted phenyl and C is a linking group or terminal group. The compounds of this invention can inhibit ulceration in in-vivo studies in rats.
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- Piperidinylcamphorsulfonyl oxytocin antagonists
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Spirocyclic compounds of the formula: are oxytocin and vasopressin antagonists useful in the treatment of pre-term labor, dysmenorrhea and for the stoppage of labor preparatory to cesarean delivery, timing of parturition, uterine hyperactivity, endometriosis, hypertension, congestive heart failure, hyponatremia and cognitive disorders.
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- Substituted dialkanolamines, sulfur analogs and condensed 1,4-oxazine derivatives thereof in viral disease treatment
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Substituted dialkanolamines, oxazine and sulfur analogs thereof, useful in treating shipping fever syndrome in mammals are disclosed having the formula: STR1 wherein: Ar is STR2 Z is oxygen or sulfur; R is selected from hydrogen, loweralkyl or STR3 R1 R2, R3, R4, R5, R6 and R7 are selected from hydrogen or loweralkyl; and STR4 when taken together may form a lowercycloalkyl ring or R5 with --ZR2 when taken together may form a 5-membered saturated oxygen or sulfur containing heterocyclic ring; X is selected from hydrogen, halo, loweralkoxy, loweralkyl, trifluoromethyl or dimethylamino and when X is more than 1, it may be the same radical or different; y is 0, 1 or 2; n is one, or zero and when n is 1, the stereoisomers thereof and when n is zero the dotted line becomes an oxygen-carbon bond forming an oxazine ring and the pharmaceutically acceptable acid addition salts thereof.
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- Synthesis of Monoaza Crown Ethers from N,N-Diamines and Oligoethylene Glycol Di(p-toluenesulfonates) or Corresponding Dichlorides
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Monoaza crown ethers were prepared in satisfactory yields by the one-step reaction between diethanolamine or N,N-diamines and oligoethylene glycol di(p-toluenesulfonates) or corresponding dichlorides in t-butyl alcohol/dioxane in the presence of sodium or potassium t-butoxide.The reaction conditions in the preparation of monoaza 15- and 18-crown ethers were studied.Various monoaza crown ethers having substituents were also prepared and their properties were investigated.
- Maeda, Hirokazu,Furuyoshi, Shigeo,Nakatsuji, Yohji,Okahara, Mitsuo
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p. 212 - 218
(2007/10/02)
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- SYNTHESIS AND ABSOLUTE CONFIGURATION OF SUBSTITUTED MORPHOLINES
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We studied methods of stereospecific synthesis that enabled us to obtain variously substituted morpholinic compounds and to determine their absolute configuration.From a study of the chiroptical properties of synthetic N-(2-pyridyl-N-oxide) derivatives of optically active morpholines, it was possible to correlate the sign of the Cotton effect with the absolute configuration.This correlation agrees with that previously established for derivatives of the piperidine type.By evaluating the various contributions to the Cotton effect of substituents in positions 2 and 3, we established the absolute configuration of bicyclic compounds condensed in the two positions mentioned above.
- Bettoni, Giancarlo,Franchini, Carlo,Perrone, Roberto,Tortorella, Vincenzo
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p. 409 - 415
(2007/10/02)
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- Steroidal anaesthetics of the pregnane and 19-norpregnane series
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Steroid anaesthetics of the pregnane and 19-norpregnane series are described, the steroids having a 3α-hydroxy group, a 17α-hydrogen atom, a 20-oxo group and at the 21-position a cyano, azido or basic amino group.
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