57186-65-9Relevant articles and documents
Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D 3 analogues with aromatic side chains attached at C-17
Liu, Chao,Zhao, Guo-Dong,Mao, Xinliang,Suenaga, Tsutomu,Fujishima, Toshie,Zhang, Cheng-Mei,Liu, Zhao-Peng
, p. 569 - 575 (2014/11/07)
Two new analogues of the steroid hormone 1α,25-dihydroxyvitamin D3 with aromatic side chains attached at C-17 were designed to investigate their effects on VDR, HL-60 cell differentiation and tumor cell proliferation. These analogues were prepared by the classical photochemical ring opening approach. After the protection of both the 1α- and 3β-hydroxyl in 1α-hydroxydehydroepiandrosterone with TBS groups, followed by bromination with NBS and debromination in the presence of γ-collidine, the diene intermediate was obtained. Hydrazone formation followed by iodine oxidation gave a vinyl iodide. The aromatic side chain at C-17 was introduced via the Negishi coupling of the resulting intermediate with an in situ generated zinc reagent with the substituted aryl bromide (CD-side chain) in the presence of catalytic amount of Pd(PPh3)4. After the removal of the TBDMS and MOM protective groups, followed by UV irradiation and the subsequent thermal reaction, the 1α,25-(OH) 2-D3 analogues with a substituted phenyl ring attached at C-17 to replace the C-20 and C-21 were prepared. In the VDR competitive binding assay, compounds 2 and 3 almost lost their binding ability, and were only 0.01% and 0.015% as potent as the 1α,25-dihydroxyvitamin D3. However, compounds 2 and 3 were as potent as 1α,25-(OH)2-D3 in inducing HL-60 cell differentiation at concentrations of 30, 100, 300, 1000 nM, respectively. Moreover, compounds 2 and 3 exhibited similar or better antiproliferative potency against MCF-7 human breast cancer cells, the IC 50 values for analogues 2, 3 and the natural hormone were 7.08, 7.56, and 12.5 μM, respectively.
A dehydrohalogenation methodology for synthesizing terminal olefins under mild conditions
Berube, Marie,Kamal, Fatima,Roy, Jenny,Poirier, Donald
, p. 3085 - 3091 (2008/02/08)
A new methodology for preparing terminal olefins in good yield by dehydrohalogenation of primary alkyl iodide with tetrabutylammonium fluoride in dimethyl sulfoxide at room temperature is presented. Optimization of the mild reaction conditions and assays on various alkyl iodides are described. Georg Thieme Verlag Stuttgart.
2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1- yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability
Ornstein, Paul L.,Bleisch, Thomas J.,Arnold, M. Brian,Kennedy, Joseph H.,Wright, Rebecca A.,Johnson, Bryan G.,Tizzano, Joseph P.,Helton, David R.,Kallman, Mary Jeanne,Schoepp, Darryle D.,Hérin, Marc
, p. 358 - 378 (2007/10/03)
In this paper we describe the synthesis of a series of α-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the α-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity of these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1- aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 ± 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 ± 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (ip) administration and readily penetrated into the brain. This compound, however, had only limited (~5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (ip, 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.
