- Synthesis and functional analysis of novel bivalent estrogens
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The steroid hormone estrogen plays a critical role in female development and homeostasis. Estrogen mediates its effects through binding and activation of specific estrogen receptors alpha (ERα) and beta (ERβ), members of the steroid/nuclear receptor family of ligand-induced transcription factors. Due to their intimate roles in genomic and nongenomic signaling pathways, these hormones and their receptors have been also implicated in the pathologies of a variety of cancers and metabolic disorders, and have been the target of large therapeutic development efforts. The binding of estrogen to its respective receptors initiates a cascade of events that include receptor dimerization, nuclear localization, DNA binding and recruitment of co-regulatory protein complexes. In this manuscript, we investigate the potential for manipulating steroid receptor gene expression activity through the development of bivalent steroid hormones that are predicted to facilitate hormone receptor dimerization events. Data are presented for the development and testing of novel estrogen dimers, linked through their C-17 moiety, that can activate estrogen receptor alpha (ERα)-mediated transcription events with efficacy and potency equal to or greater than that of ERα's cognate ligand, 17β-estradiol. These bivalent estrogen structures open the door to the development of a variety of steroid therapeutics that could dramatically impact future drug development in this area.
- Wendlandt, Alison E.,Yelton, Sharon M.,Lou, Dingyuan,Watt, David S.,Noonan, Daniel J.
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- Hydrogen-bonded supramolecular polymers from derivatives of α-amino-ε-caprolactam: A bio-based material
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Hydrogen-bonded supramolecular polymers were prepared from the derivatives of α-amino-ε-caprolactam (ACL), obtained from a renewable resource. Several self-complimentary bis- or tetra-caprolactam monomers were synthesized by varying the number of carbons of the spacer between the hydrogen-bonding end groups. Physical properties of these hydrogen-bonded polymers were clearly demonstrated by differential scanning colorimetry, solid-state NMR, and X-ray powder diffraction analyses. The supramolecular behavior was also supported by fiber formation from the melt for several of these compounds, and stable glassy materials were prepared from the physical mixtures of two different biscaprolactams. The self-association ability of ACL was also used by incorporating ACL at the chain ends of low-molecular weight Jeffamine (M n = 900 g/mol) using urea and amide linkages. The transformation of this liquid oligomer at room temperature into a self-standing, transparent film clearly showed the improvement in mechanical properties obtained by the introduction of terminal hydrogen-bonding groups. Finally, the use of monomers with a functionality of four gave rise to network formation either alone or combination with bifunctional monomers.
- Tarkin-Tas, Eylem,Lange, Christopher A.,Mathias, Lon J.
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Read Online
- A process for preparing a fatty acid derivative method and its application (by machine translation)
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The invention discloses a method for preparing a fatty acid derivative method and its application. The first method is the long-chain fatty acid and thionyl chloride reaction, to obtain the acyl chloride; acyl chloride of preparing butanol reaction, then remove chlorine group, and get long-chain fatty acid uncle ding zhi; then and N - hydroxysuccinimide reaction, long-chain fatty acid succinimide and high yield butylacrylate; then with the L - glutamic acid - 1 - tert-butyl reaction, to obtain tert-butyl long-chain fatty acyl - L - Glu - OtBu; with the N - hydroxysuccinimide reaction, to obtain tert-butyl long-chain fatty acyl - L - Glu (OSu)- OtBu; finally [...] butyl long-chain fatty acyl - L - Glu (OSu)- OtBu tert-butyl in removing, and get long-chain fatty acid derivatives. The method routes the operation is simple, quality is controllable, is suitable for industrial production, and low cost, simple purification at the same time, suitable for use in the preparation of high purity insulin analogs. (by machine translation)
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Paragraph 0133-0136
(2018/04/01)
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- Structural Analysis and Inclusion Mechanism of Native and Permethylated α-Cyclodextrin-Based Rotaxanes Containing Alkylene Axles
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Native α-cyclodextrin- (α-CD) and permethylated α-CD (PMeCD)-based rotaxanes with various short alkylene chains as axles can be synthesized through a urea end-capping method. Native α-CD tends to form [3]- or [5]pseudorotaxanes and not [2]- or [4]pseudorotaxanes, which indicates that the coupled CDs act as a single fragment. End-capping reactions of the pseudorotaxanes with C18 and C24 axle lengths do not occur because the axle termini are covered by the densely stacked CDs. The number of PMeCDs on the pseudorotaxane is flexible and mainly depends on the axle length. Peracetylated α-CD (PAcCD)-based rotaxanes are synthesized through O-acetylation of the α-CD-based rotaxanes without any decomposition of the rotaxanated structures. The structures of PMeCD-based [3]- and [4]rotaxanes, and the molecular dynamics calculations on [3]pseudorotaxanes, indicate that the tail face of PMeCDs is regularly directed toward the axle termini. On the basis of the results obtained, it can be concluded that the directions and numbers of CDs in rotaxanes containing short alkylene chains depend on 1)the interactions between CDs, 2)the length of the alkylene axle, and 3)the interactions between the axle end and tail face of the CD. Come on in! Native and permethylated α-cyclodextrin (CD)-based rotaxanes with various short alkylene axles are synthesized with a urea end-capping method. The directions and number of the CD wheels depend on the interactions between CDs, the axle length, and the interactions between axle ends and the tail face of the CDs (see figure).
- Akae, Yosuke,Koyama, Yasuhito,Sogawa, Hiromitsu,Hayashi, Yoshihiro,Kawauchi, Susumu,Kuwata, Shigeki,Takata, Toshikazu
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supporting information
p. 5335 - 5341
(2016/04/09)
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- Synthesis and binding profile of haloperidol-based bivalent ligands targeting dopamine D2-like receptors
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Homodimers of dopamine D2-like receptors are suggested to be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsychotics. This study describes the development of a series of novel bivalent molecules with a pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investigated in comparison to their monomeric analogues for their D2long, D2short, D3, and D4 receptor binding and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.
- Salama, Ismail,L?ber, Stefan,Hübner, Harald,Gmeiner, Peter
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supporting information
p. 3753 - 3756
(2014/09/16)
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- Homobivalent ligands of the atypical antipsychotic clozapine: Design, synthesis, and pharmacological evaluation
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To date all typical and atypical antipsychotics target the dopamine D 2 receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4′ position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D 2 receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.
- McRobb, Fiona M.,Crosby, Ian T.,Yuriev, Elizabeth,Lane, J. Robert,Capuano, Ben
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supporting information; experimental part
p. 1622 - 1634
(2012/04/17)
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- One-pot synthesis of permethylated α-CD-based rotaxanes having alkylene chain axles and their structural characteristics
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Permethylated i-CD-based rotaxanes with short alkylene chains as an axle were synthesized through urea end-capping in one pot: Products were [2]rotaxane and [3]rotaxane. The headto-head structure of [3]rotaxane obtained as a single isomer was confirmed by the characteristic 1HNMR peak shifts and X-ray single-crystal structure analysis.
- Akae, Yosuke,Arai, Takayuki,Koyama, Yasuhito,Okamura, Hisashi,Johmoto, Kohei,Uekusa, Hidehiro,Kuwata, Shigeki,Takata, Toshikazu
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supporting information; experimental part
p. 806 - 808
(2012/09/22)
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- Design, synthesis, and activity of membrane-disrupting bolaphiles
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Four new classes of bolaphiles ("double-headed" single-chain surfactants) have been prepared, via condensation of an homologous series of linear saturated, olefinic, and acetylenic α,ω-dicarboxylic acids with hexaethylene glycol, and evaluated for their ability to induce the release of 5(6)-carboxyfluorescein (CF) entrapped within large unilamellar vesicles derived from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Operationally, the membrane-disrupting activity of the bolaphiles has been found to vary by a factor of ca. 100, when the total number of carbon atoms which separate the carboxylate moieties range from 12 to 24; the most active bolaphile is approximately three times more active than Triton X-100. When the affinity of the bolaphiles toward POPC membranes is considered, the intrinsic membrane-disrupting activity varies by a factor of ca. 230. A "loop" model is proposed to account for the general trends in bolaphile activity that are observed, where the depth of loop penetration and loop width are presumed to be the key factors involved in determining membrane-disrupting activity. The potential utility of these surfactants as antimicrobial agents, and as anti-HIV agents in particular, is briefly discussed.
- Jayasuriya, Nimal,Bosak, Stanislav,Regen, Steven L.
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p. 5844 - 5850
(2007/10/02)
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- INTRAMOLECULAR END-TO-END REACTIONS OF PHOTOACTIVE TERMINAL GROUPS LINKED BY POLYMETHYLENE CHAINS.
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Intramolecular end-to-end reactions of a pair of photoactive terminal groups, dibenz left bracket b,f right bracket azepine (DBA) chromophores, linked by a series of polymethylene chains (DBA-CO(CH//2)//nCO-DBA, n equals 2-30) were studied by two different approaches. One approach is to measure the intramolecular deactivation rate constants of the excited triplet state of terminal DBA groups by the nanosecond laser photolysis and the other is to measure the intramolecular photocyclization rates of these bichromophoric compounds by the quantitative product analysis with GPC. The excited triplet state of the DBA group is the intermediate of the reaction.
- Ashikaga,Ito,Yamamoto,Nishijima
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p. 198 - 204
(2007/10/02)
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- Micelle-Mimetic Ionene Polyelectrolytes
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The properties of a series of linear cationic polyelectrolytes of the -ionene type (dimethylammonium charge centers interconnected by alternating chain segments containing n and m CH2 groups, respectively) have been investigated in aqueous solution.Ionenes with short segments, i.e., the -ionene and the -ionenes with m -ionenes with m > 14 are quite distinct.Thus, increasing m beyond 14 results in a progressive increase in the net degree of bromide counterion association to the ionene (conductivity data), enhanced solubilization of hydrophobic substrates (pyrene) in a progressively less aqueous environment, a gradual increase in the fluorescence anisotropy of an ionene-adsorbed anionic fluorescein derivative, and an increase in the selctivity of chloride/bromide counterion exchange at the ionene surface.These m-dependent changes in solution properties, which correlate nicely with the m-dependent onset and rise of catalytic activity (acceleration of the rate of alkaline hydrolysis of p-nitrophenyl octanoate), are consistent with a change in ionene conformation, going from extended to progressively more compact (globular or micellelike) as the segment length m is increased beyond 14.Indeed, the observed effects of the -, -, and -ionenes on reaction rate can be quantitatively reproduced by using the pseudophase ion-exchange formalism originally developed for micellar systems.The marked similarity between the -ionene and the CTAB micelle with respect to counterion binding, counterion-exchange selectivity, substrate solubilization, and catalytic rate enhancement suggests that amphiphilic ionenes of this type should be excellent prototypes for the rational design of micelle-mimetic polyelectrolytes.
- Soldi, Valdir,Erismann, Norma de Magalhaes,Quina, Frank H.
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p. 5137 - 5143
(2007/10/02)
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