208399-66-0Relevant articles and documents
Conformational restriction design of thiophene-biphenyl-DAPY HIV-1 non-nucleoside reverse transcriptase inhibitors
Sang, Yali,Han,Pannecouque, Christophe,De Clercq, Erik,Zhuang, Chunlin,Chen
, (2019/08/20)
Conformational restriction is a promising strategy in the development of DAPY-type non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, eighteen thiophene-biphenyl-DAPY derivatives were designed and synthesized as potent HIV-1 NNRTIs in which halogen and methyl groups were introduced to explore the conformationally constrained effects. Molecular docking and dynamic simulation analysis indicated that substituents on different positions of the biphenyl ring induced different dihedral angles and binding conformations, further explaining their anti-viral activities. The 2′-fluoro and 3′-chloro substitutions could form electrostatic or halogen-bonding interactions with adjacent residues of the RT enzyme. The 2′-methyl group contributed to enlarge the dihedral angle of biphenyl ring and was positioned to a space-filling hydrophobic pocket. Notably, compounds 22 and 23 with two methyl groups exhibited potent biological activity against WT HIV-1-infected MT-4 cells (EC50 = 14 and 17 nM, respectively) and RT enzyme (EC50 = 27 and 42 nM, respectively). In particular, 23 exhibited much lower cytotoxicity (CC50 = 264.19 μM) and higher selectivity index (SI = 18,564) than etravirine. Taken together, a rational conformational model for further design of DAPYs is proposed, providing a new guidance for the development of NNRTIs.
Fast and Tight Boronate Formation for Click Bioorthogonal Conjugation
Akgun, Burcin,Hall, Dennis G.
supporting information, p. 3909 - 3913 (2016/03/19)
A new click bioorthogonal reaction system was devised to enable the fast ligation (kON≈340 m-1 s-1) of conjugatable derivatives of a rigid cyclic diol (nopoldiol) and a carefully optimized boronic acid partner, 2-methyl-5-carboxymethylphenylboronic acid. Using NMR and fluorescence spectroscopy studies, the corresponding boronates were found to form reversibly within minutes at low micromolar concentration in water, providing submicromolar equilibrium constant (Keq≈105-106 m-1). Efficient protein conjugation under physiological conditions was demonstrated with model proteins thioredoxin and albumin, and characterized by mass spectrometry and gel electrophoresis.
Identification and structure-activity relationships of a novel series of estrogen receptor ligands based on 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide
Wang, Pengcheng,Min, Jian,Nwachukwu, Jerome C.,Cavett, Valerie,Carlson, Kathryn E.,Guo, Pu,Zhu, Manghong,Zheng, Yangfan,Dong, Chune,Katzenellenbogen, John A.,Nettles, Kendall W.,Zhou, Hai-Bing
experimental part, p. 2324 - 2341 (2012/05/20)
To develop estrogen receptor (ER) ligands having novel structures and activities, we have explored compounds in which the central hydrophobic core has a more three-dimensional topology than typically found in estrogen ligands and thus exploits the unfilled space in the ligand-binding pocket. Here, we build upon our previous investigations of 7-oxabicyclo[2.2.1]heptene core ligands, by replacing the oxygen bridge with a sulfoxide. These new 7-thiabicyclo[2.2.1] hept-2-ene-7-oxides were conveniently prepared by a Diels-Alder reaction of 3,4-diarylthiophenes with dienophiles in the presence of an oxidant and give cycloadducts with endo stereochemistry. Several new compounds demonstrated high binding affinities with excellent ERα selectivity, but unlike oxabicyclic compounds, which are transcriptional antagonists, most thiabicyclic compounds are potent, ERα-selective agonists. Modeling suggests that the gain in activity of the thiabicyclic compounds arises from their endo stereochemistry that stabilizes an active ER conformation. Further, the disposition of methyl substituents in the phenyl groups attached to the bicyclic core unit contributes to their binding affinity and subtype selectivity.
ERβ ligands. 3. Exploiting two binding orientations of the 2-phenylnaphthalene scaffold to achieve ERβ selectivity
Mewshaw, Richard E.,Edsall Jr., Richard J.,Yang, Cuijian,Manas, Eric S.,Xu, Zhang B.,Henderson, Ruth A.,Keith Jr., James C.,Harris, Heather A.
, p. 3953 - 3979 (2007/10/03)
The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein. Several compounds predicted to adopt orientations similar to that of genistein when bound to ERβ were observed to have slightly higher ER affinity and selectivity than genistein. The second orientation we exploited, which was different from that of genistein when bound to ERβ, resulted in the discovery of several compounds that had superior ER selectivity and affinity versus genistein. X-ray structures of two ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode and suggested that substituents at positions 1 and 8 were responsible for inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined and found to be effective in two models of inflammation, suggesting that targeting ER may be therapeutically useful in treating certain chronic inflammatory diseases.
ERβ ligands. Part 2: Synthesis and structure-activity relationships of a series of 4-hydroxy-biphenyl-carbaldehyde oxime derivatives
Yang, Cuijian,Edsall Jr., Richard,Harris, Heather A.,Zhang, Xiaochun,Manas, Eric S.,Mewshaw, Richard E.
, p. 2553 - 2570 (2007/10/03)
A series of biphenyl carbaldehyde oximes (6) was prepared and shown to have significant selectivity for the estrogen receptor-β (ERβ). The exploitation of the oxime moiety as a hydrogen bond donating group, which mimicked the C-ring of genistein makes these compounds unique. Molecular modeling studies showed the oxime moiety hydrogen bonding to the histidine residue, which was supported by the structure-activity relationships. The most potent compounds in this study had IC50 values in a radioligand binding assay of between 8-35nM. Among the most selective compounds were 6i and 6s (49- and 31-fold ERβ selective, respectively).
The synthesis of angularly fused polyaromatic compounds by using a light-assisted, base-mediated cyclization reaction
Pathak, Rakhi,Vandayar, Kantharuby,Van Otterlo, Willem A. L.,Michael, Joseph P.,Fernandes, Manuel A.,De Koning, Charles B.
, p. 3504 - 3509 (2007/10/03)
The synthesis of substituted polyaromatic compounds that contain at least four benzene rings fused together in an angular fashion is described. Suzuki coupling of 1-bromo-3,4-dihydronaphthalene-2-carbaldehyde with a number of aromatic boronic acids affords products such as 1-(1,4-dimethoxy-3-methyl-2-naphthyl)-3,4-dihydronaphthalene-2-carbaldehyde. Exposure of these dihydronaphthalenes to potassium tert-butoxide and DMF at 80°C yields polyaromatic compounds such as 9,14-dimethoxynaphtho[1,2-a]anthracene.
Substituted phenyl naphthalenes as estrogenic agents
-
, (2008/06/13)
This invention provides estrogen receptor modulators of formula I, having the structure 1wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10, are as defined in the specification, or a pharmaceutically acceptable salt thereof.
Convenient synthesis and transformation of 2,6-dichloro-4-iodopyridine
Mello, Jesse V.,Finney, Nathaniel S.
, p. 4263 - 4265 (2007/10/03)
(Matrix Presented) We describe a convenient scalable synthesis of 2,6-dichloro-4-iodopyridine and demonstrate its utility by stepwise elaboration to a number of 2,4,6-trisubstituted pyridines.
A novel method for the synthesis of substituted naphthalenes and phenanthrenes
De Koning, Charles B.,Michael, Joseph P.,Rousseau, Amanda L.
, p. 787 - 797 (2007/10/03)
A new method for the synthesis of substituted naphthalenes and phenanthrenes was discussed. A formal synthesis of tanshinone I was also studied. Natural products that contain a naphthalene or phenanthrene nucleus often exhibit biological activity, which makes them attractive targets in organic synthesis. The results showed that the reaction can be proceed through at least two different pathways.
