198545-90-3Relevant academic research and scientific papers
Highly selective chiral N-substituted 3α-[bis(4'- fluorophenyl)methoxy]tropane analogues for the dopamine transporter: Synthesis and comparative molecular field analysis
Robarge, Michael J.,Agoston, Gregory E.,Izenwasser, Sari,Kopajtic, Theresa,George, Clifford,Katz, Jonathan L.,Newman, Amy Hauck
, p. 1085 - 1093 (2000)
In a continuing effort to further characterize the role of the dopamine transporter in the pharmacological effects of cocaine, a series of chiral and achiral N-substituted analogues of 3α-[bis(4'-fluorophenyl)methoxy]tropane (5) has been prepared as potential selective dopamine transporter ligands. These novel compounds displaced [3H]WIN 35,428 binding from the dopamine transporter in rat caudate putamen with K(i) values ranging from 13.9 to 477 nM. Previously, it was reported that 5 demonstrated a significantly higher affinity for the dopamine transporter than the parent drug, 3α- (diphenylmethoxy)tropane (3; benztropine). However, 5 remained nonselective over muscarinic m1 receptors (dopamine transporter, K(i) = 11.8 nM; m1, K(i) = 11.6 nM) which could potentially confound the interpretation of behavioral data, for this compound and other members of this series. Thus, significant effort has been directed toward developing analogues that retain high affinity at the dopamine transporter but have decreased affinity at muscarinic sites. Recently, it was discovered that by replacing the N-methyl group of 5 with the phenyl-n-butyl substituent (6) retention of high binding affinity at the dopamine transporter (K(i) = 8.51 nM) while decreasing affinity at muscarinic receptors (K(i) = 576 nM) was achieved, resulting in 68-fold selectivity. In the present series, a further improvement in the selectivity for the dopamine transporter was accomplished, with the chiral analogue (S)N-(2-amino-3-methyl-n-butyl)-3α-[bis(4'- fluorophenyl)methoxy]tropane (10b) showing a 136-fold selectivity for the dopamine transporter versus muscarinic m1 receptors (K(i) = 29.5 nM versus K(i) = 4020 nM, respectively). In addition, a comparative molecular field analysis (CoMFA) model was derived to correlate the binding affinities of all the N-substituted 3α-[bis(4'-fluorophenyl)methoxy]tropane analogues that we have prepared with their 3D-structural features. The best model (q2 = 0.746) was used to accurately predict binding affinities of compounds in the training set and in a test set. The CoMFA coefficient contour plot for this model, which provides a visual representation of the chemical environment of the binding domain of the dopamine transporter, can now be used to design and/or predict the binding affinities of novel drugs within this class of dopamine uptake inhibitors.
Homochiral versus Heterochiral Trifluoromethylated Pseudoproline Containing Dipeptides: A Powerful Tool to Switch the Prolyl-Amide Bond Conformation
Chaume, Grégory,Simon, Julien,Lensen, Nathalie,Pytkowicz, Julien,Brigaud, Thierry,Miclet, Emeric
, p. 13602 - 13608 (2017/12/26)
The design of constrained peptides is of prime importance in the development of bioactive compounds and for applications in supramolecular chemistry. Due to its nature, the peptide bond undergoes a spontaneous cis-trans isomerism, and the cis isomers are much more difficult to stabilize than the trans forms. By using oxazolidine-based pseudoprolines (ψPro) substituted by a trifluoromethyl group, we show that the cis peptide bond can be readily switched from 0% to 100% in Xaa-ψPro dipeptides. Our results prove that changing the configuration of the Cα in Xaa or in ψPro is sufficient to invert the cis:trans populations while changing the nature of the Xaa side chain finely tuned the conformers ratio. Moreover, a strong correlation is found between the puckering of the oxazolidine ring and the peptide bond conformation. This finding highlights the role of the trifluoromethyl group in the stabilization of the peptide bond geometry. We anticipate that such templates will be very useful to constrain the backbone geometry of longer peptides.
Efficient amide bond formation through a rapid and strong activation of carboxylic acids in a microflow reactor
Fuse, Shinichiro,Mifune, Yuto,Takahashi, Takashi
supporting information, p. 851 - 855 (2014/01/23)
The development of highly efficient amide bond forming methods which are devoid of side reactions, including epimerization, is important, and such a method is described herein and is based on the concept of rapid and strong activation of carboxylic acids. Various carboxylic acids are rapidly (0.5 s) converted into highly active species, derived from the inexpensive and less-toxic solid triphosgene, and then rapidly (4.3 s) reacted with various amines to afford the desired peptides in high yields (74 %-quant.) without significant epimerization (≤3 %). Our process can be carried out at ambient temperature, and only CO2 and HCl salts of diisopropylethyl amine are generated. In the long history of peptide synthesis, a significant number of active coupling reagents have been abandoned because the highly active electrophilic species generated are usually susceptible to side reactions such as epimerization. The concept presented herein should renew interest in the use of these reagents. In the fast lane: The title reaction is described for the synthesis of peptides. Various carboxylic acids including easily epimerizable amino acids were rapidly converted into highly electrophilic species, and then reacted with various amines, including less nucleophilic N-methyl amino acids, to afford the desired peptides in high yields without significant epimerization. Copyright
Total synthesis of chloptosin: A dimeric cyclohexapeptide
Oelke, Alexander J.,Antonietti, Francesca,Bertone, Leonardo,Cranwell, Philippa B.,France, David J.,Goss, Rebecca J. M.,Hofmann, Tatjana,Knauer, Stephan,Moss, Steven J.,Skelton, Paul C.,Turner, Richard M.,Wuitschik, Georg,Ley, Steven V.
supporting information; experimental part, p. 4183 - 4194 (2011/06/17)
Here we describe in full our investigations into the synthesis of the dimeric cyclohexapeptide chloptosin in 17 linear steps. Particularly, this work features an organocatalytic tandem process for the synthesis of the embedded piperazic acids, in which a differentially protected azodicarboxylate is used together with pyrrolidinyl tetrazole as the catalyst. The central biaryl bond is being formed by Stille coupling of two sterically demanding ortho-chloropyrroloindole fragments. The inherent flexibility of the synthetic strategy proved beneficial as the route could be adjusted smoothly during the progression of the synthesis programme. Copyright
Total synthesis of NW-G01, a cyclic hexapeptide antibiotic, and 34-epi-NW-G01
Shibahara, Setsuya,Matsubara, Takaaki,Takahashi, Keisuke,Ishihara, Jun,Hatakeyama, Susumi
supporting information; experimental part, p. 4700 - 4703 (2011/11/06)
NW-G01, a cyclic hexapeptide antibiotic, and 34-epi-NW-G01 were synthesized by the highly stereoselective convergent approach for the first time, thereby unambiguously determining the absolute structure of NW-G01.
