Untitled

Chauzov, V. A.; Parchinskii, V. Z.; Sciences, N.D. Zelinsky Institute of Organic Chemistry E. V. SinelshchikovaRussian Academy of; Parfenov, N. N.; Petrosyan, V. A.

doi:10.1023/a:1019661618450

Cited by 9 publications

(12 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All compounds from the 5474 family (except OBCP-2M) were also obtained from ChemBridge. OBCP-2M was synthesized according to reported procedures for analogous compounds (23,24 Plasmids-Many of the plasmids used in these studies were generous gifts from colleagues: pGST-ER␣-LBD (ER␣ residues 282-595) from Dr. Peter Kushner (University of California, San Francisco, CA), pCR3.1.SRC1 from Dr. Ming-Jer Tsai and Dr. Sophia Y. Tsai (Baylor College of Medicine, Houston, TX), p3ϫERE-Luc from Dr. Donald McDonnell (Duke University, Durham, NC), pCMV5-hER␤ (full-length ER␤) and p6ϫHis-ER␤ LBD (residues 256 -505) from Dr. Benita Katzenellenbogen (University of Illinois, Champaign, IL), HEGO/pSG5 (full-length ER␣) from Dr. Pierre Chambon (Institute of Genetics and Molecular and Cellular Biology, Strasbourg, France), pAR and p3ϫARE-Luc from Dr. Shutsung Liao (University of Chicago, Chicago, IL), and pMCSG7 from Dr. Frank Collart (Argonne National Laboratory, Argonne, IL). pCMV-␤gal was obtained from Invitrogen.…”

Section: Methodsmentioning

confidence: 99%

Identification of Ligands with Bicyclic Scaffolds Provides Insights into Mechanisms of Estrogen Receptor Subtype Selectivity

Hsieh

Rajan

Sharma

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Estrogen receptors ␣ (ER␣) and ␤ (ER␤) have distinct functions and differential expression in certain tissues. These differences have stimulated the search for subtype-selective ligands. Therapeutically, such ligands offer the potential to target specific tissues or pathways regulated by one receptor subtype without affecting the other. As reagents, they can be utilized to probe the physiological functions of the ER subtypes to provide information complementary to that obtained from knock-out animals. A fluorescence resonance energy transfer-based assay was used to screen a 10,000-compound chemical library for ER agonists. From the screen, we identified a family of ER␤-selective agonists whose members contain bulky oxabicyclic scaffolds in place of the planar scaffolds common to most ER ligands. These agonists are 10 -50-fold selective for ER␤ in competitive binding assays and up to 60-fold selective in transactivation assays. The weak uterotrophic activity of these ligands in immature rats and their ability to stimulate expression of an ER␤ regulated gene in human U2OS osteosarcoma cells provides more physiological evidence of their ER␤-selective nature. To provide insight into the molecular mechanisms of their activity and selectivity, we determined the crystal structures of the ER␣ ligandbinding domain (LBD) and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator complexed with the ligands OBCP-3M, OBCP-2M, and OBCP-1M. These structures illustrate how the bicyclic scaffolds of these ligands are accommodated in the flexible ligand-binding pocket of ER. A comparison of these structures with existing ER structures suggests that the ER␤ selectivity of OBCP ligands can be attributed to a combination of their interactions with Met-336 in ER␤ and Met-421 in ER␣. These bicyclic ligands show promise as lead compounds that can target ER␤. In addition, our understanding of the molecular determinants of their subtype selectivity provides a useful starting point for developing other ER modulators belonging to this relatively new structural class. Estrogen receptors ␣ (ER␣)4 and ␤ (ER␤) are ligand-inducible transcription factors that are involved in regulating cell growth, proliferation, and differentiation in various normal and cancerous tissues (1-3). Although the two subtypes of ER bind the endogenous estrogen, 17␤-estradiol (E2), with similar affinity (4), they differ in size, share modest sequence identity (47%), and are encoded by different genes (5, 6). Studies of knock-out mice have also shown that the two subtypes have distinct functions and are differentially expressed in certain tissues (1). These differences have stimulated the search for subtype-specific ligands that can elicit tissue-or cell-specific ER activity. In particular, the dominance of ER␣ expression in the breast and uterus (7) suggests that ER␤-selective ligands may offer some of the benefits of hormone replacement therapy such as a decrease in the risk of colorectal cancer (8) without increasing the risk of breast ...

show abstract

Section: Methodsmentioning

confidence: 99%

Identification of Ligands with Bicyclic Scaffolds Provides Insights into Mechanisms of Estrogen Receptor Subtype Selectivity

Hsieh

Rajan

Sharma

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Such an approach has been used by us earlier. 11 1 H NMR spectra of reaction mixtures obtained in entries 4-6 (see Table 1) exhibited the following signals, δ: 3.84, 3.90 (both s, 3 H each, 2 MeO); 6.59 (d), 6.60 (s), 7.54 (d) (3 H, C 6 H 3 ); 7.90, 8.60 (both s, 2 H, H triazole), which were assigned to 1,3 di methoxy 4 (1,2,4 triazol 1 yl)benzene. 1 H NMR spectra of re action mixtures obtained in entry 1 (see Table 2) exhibited the following signals, δ: 3.89, 3.91 (both s, 6 H, 2 MeO); 7.02 (m, 1 H, H arom.…”

Section: Methodsmentioning

confidence: 99%

Anodic azolation of 1,2- and 1,3-dimethoxybenzenes

Petrosyan

Burasov

2010

Russ Chem Bull

Self Cite

View full text Add to dashboard Cite

Electrochemical azolation of 1,2 and 1,3 dimethoxybenzenes with tetrazole, pyrazole and triazole derivatives in MeCN in an undivided cell with Pt electrodes proceeds through the formation of intermediate arenonium cations of the ipso structure. Nature of the starting arenes and the corresponding intermediate arenonium cations determine composition and yields of the target products.In the preceding publications, 1-3 we have revealed the regularities of electrosynthesis of N arylazoles using gal vanostatic electrolysis of an azole (AzH) (pyrazole, tri azole, their substituted derivatives, tetrazole) and 1,4 di methoxybenzene (1,4 DMB) in an undivided cell.According to the concept proposed (Scheme 1), radi cal cation 2 emerged in the first step undergoes the ipso attack by the azole nucleophile to form radical 3, oxid izing further to arenonium cation 4. The ipso reaction of cation 4 with a nucleophile leads to hydrolytically labile product of the ipso bisaddition 7, whereas the rearrange ment of this cation to cation 5 with subsequent deproto nation, to the product of ortho substitution 6.Based on the pK a II values (see Ref. 4), the azoles studied were conventionally divided 1,3 to the highly basic (3,5 di methylpyrazole (DMP), 1,2,4 triazole (TA)) and poorly basic (4 nitropyrazole (NP), 3 nitro 1,2,4 triazole (NTA), tetrazole (T)). This allowed us to relate the yields and ratios of products 6 and 7 with acidity and basicity of azoles and medium, as well as with effects of different additives (for example, collidine (CL)).As it has been found earlier, 1,2 the key steps in the electrochemical N dimethoxyphenylation of azoles are the competing irreversible ortho interaction of arenonium cat ion 4 with the azole and reversible ipso interaction of the same species (see Scheme 1). Scheme 1AH = AzH, AzH 2 + , AcOH; B = AzH, collidine (CL)

show abstract

“…The above general trends of electrochemical N di methoxyphenylation of azoles (see Scheme 4) are pre sented based on the view of generation of arenium cations (4,8) as the key intermediates, which undergo various, in particular, acid catalyzed transformations along the way to the target products. The proposed mechanism (see Scheme 4) may be validated by obtaining independent experimental evidence for generation of arenium cat ions 4 and 8.…”

Section: Data Presented Inmentioning

confidence: 99%

“…Note that in this case, the step 4 → 7 (see Scheme 1) should be reversible, although the driving force of the back reaction (7 → 4) has remained obscure, together with the reasons for dependence of the yield and ratio of products 6 and 7 on the acid base properties of the initial azoles and the medium. [4][5][6] Therefore, this work aims at the development of the views on N dimethoxyphenylation of azoles and experi mental substantiation of the steps involving the arenium cation as the key intermediate of the process. It should be emphasized that some of these issues have already been addressed in the study of electrochemical N dimethoxy phenylation in MeOH.…”

mentioning

confidence: 99%

Arenium cation as the key intermediate of the electrosynthesis of N-(2,5-dimethoxyphenyl)azoles. A new approach to the synthesis of N-(dimethoxyphenyl)azoles

Petrosyan

Burasov

2007

Russ Chem Bull

Self Cite

View full text Add to dashboard Cite

Arenium cation as the key intermediate of the electrosynthesis of N (2,5 dimethoxyphenyl)azoles. A new approach to the synthesis of N (dimethoxyphenyl)azolesData on the effect of the acid base properties of the medium on the yield and composition of the products of N dimethoxyphenylation of azoles (pyrazole, triazole, their substituted derivatives, and tetrazole) upon galvanostatic electrolysis of azole-1,4 dimethoxybenzene mixtures in nucleophilic (MeOH) and neutral (MeCN) media were considered and the trends of this process were discussed. The generation of arenium cations (1,4 dimethoxy 1 azolylbenzenium in MeCN and 1,1,4 trimethoxybenzenium in MeOH) as the key intermediates of electrosynthesis of N (dimethoxyphenyl)azoles, was proved experimentally. A new approach to the synthesis of N (dimethoxyphenyl)azoles through electrosynthesis of 1,1,4,4 tetra methoxycyclohexa 2,5 diene by electrooxidation of 1,4 dimethoxybenzene in MeOH as the first step and the reaction of this quinone diketal with azoles as the second step was suggested. The efficiency of this route to N (dimethoxyphenyl)azoles is comparable with the efficiency of the purely electrochemical one step process.

show abstract

Untitled

Cited by 9 publications

References 3 publications

Identification of Ligands with Bicyclic Scaffolds Provides Insights into Mechanisms of Estrogen Receptor Subtype Selectivity

Identification of Ligands with Bicyclic Scaffolds Provides Insights into Mechanisms of Estrogen Receptor Subtype Selectivity

Anodic azolation of 1,2- and 1,3-dimethoxybenzenes

Arenium cation as the key intermediate of the electrosynthesis of N-(2,5-dimethoxyphenyl)azoles. A new approach to the synthesis of N-(dimethoxyphenyl)azoles

Contact Info

Product

Resources

About