77450-03-4Relevant academic research and scientific papers
Accessible chiral linker to enhance potency and selectivity of neuronal nitric oxide synthase inhibitors
Jing, Qing,Li, Huiying,Roman, Linda J.,Martasek, Pavel,Poulos, Thomas L.,Silverman, Richard B.
supporting information, p. 56 - 60 (2014/02/14)
The three important mammalian isozymes of nitric oxide synthase (NOS) are neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Inhibitors of nNOS show promise as treatments for neurodegenerative diseases. Eight easily synthesized compounds containing either one (20a,b) or two (9a-d; 15a,b) 2-amino-4-methylpyridine groups with a chiral pyrrolidine linker were designed as selective nNOS inhibitors. Inhibitor 9c is the best of these compounds, having a potency of 9.7 nM and dual selectivity of 693 and 295 against eNOS and iNOS, respectively. Crystal structures of nNOS complexed with either 9a or 9c show a double-headed binding mode, where each 2-aminopyridine headgroup interacts with either a nNOS active site Glu residue or a heme propionate. In addition, the pyrrolidine nitrogen of 9c contributes additional hydrogen bonds to the heme propionate, resulting in a unique binding orientation. In contrast, the lack of hydrogen bonds from the pyrrolidine of 9a to the heme propionate allows the inhibitor to adopt two different binding orientations. Both 9a and 9c bind to eNOS in a single-headed mode, which is the structural basis for the isozyme selectivity.
Design, synthesis, and antileukemic activity of stereochemically defined constrained analogues of FTY720 (Gilenya)
Fransson, Rebecca,McCracken, Alison N.,Chen, Bin,McMonigle, Ryan J.,Edinger, Aimee L.,Hanessian, Stephen
supporting information, p. 969 - 973 (2013/10/22)
FTY720 functions as an immunosuppressant due to its effect on sphingosine-1-phosphate receptors. At doses well above those needed for immunosuppression, FTY720 also has antineoplastic actions. Our published work suggests that at least some of FTY720's anticancer activity is independent of its effects on S1P receptors and due instead to its ability to induce nutrient transporter down-regulation. Compounds that trigger nutrient transporter loss but lack FTY720's S1P receptor-related, dose-limiting toxicity have the potential to be effective and selective antitumor agents. In this study, a series of enantiomerically pure and stereochemically diverse O-substituted benzyl ethers of pyrrolidines was generated and tested for the ability to kill human leukemia cells. The stereochemistry of the hydroxymethyl was found to be a key determinant of compound activity. Moreover, phosphorylation of this group was not required for antileukemic activity.
Design and stereoselective synthesis of four peptide nucleic acid monomers with cyclic structures in backbone
Watanabe, Akiko,Kiyota, Naotoshi,Yamasaki, Tetsuo,Tanda, Kazuhiro,Miyagoe, Tatsunori,Sakamoto, Masanori,Otsuka, Masami
scheme or table, p. 1132 - 1139 (2011/11/05)
Four isomers of the monomer of peptide nucleic acid (PNA) were derived from (2S,4R)-4-hydroxyproline; they had different stereochemistries at the C 2 and C4 positions in the pyrrolidine ring. These different backbone conformations corresponding to four different stereochemistries were realized through a combination of inversions at the C2 and the C4 positions in pyrrolidine ring. The obtained backbone frameworks were reacted with N-benzoyl thymine to give the corresponding PNA monomers. Spectroscopic comparison of the resultant monomers confirmed their stereochemistries.
Synthesis and Biological Evaluation of 4-Purinylpyrrolidine Nucleosides
Peterson, Mark L.,Vince, Robert
, p. 2787 - 2797 (2007/10/02)
The synthesis of several novel carbocyclic purine nucleosides that incorporate a nitrogen in place of carbon 3 of the cyclopentyl moiety are described.These analogues are all derived from the key stereochemically defined intermediate N-(tert-butoxycarbonyl)-O--trans-4-hydroxy-D-prolinol (19), which was accessible in 61.1percent overall yield for a five-step sequence starting from cis-4-hydroxy-D-proline.The heterocyclic bases, 6-chloropurine and 2-amino-6-chloropurine, are efficiently introduced onto the pyrrolidine ring via a Mitsunobu-type coupling procedure with triphenylphosphine and diethyl azodicarboxylate.Standard transformations and removal of protecting groups gave the cis-adenine (26), hypoxanthine (27), 2,6-diaminopurine (28), and guanine (29) D-prolinol derivatives.In addition, a related sequence from trans-4-hydroxy-L-proline provided the enantiomeric L-prolinol guanine derivative (36).Lastly, the 6-(dimethylamino)purine analogue, 37, was coupled to N-(benzyloxycarbonyl)-p-methoxy-L-phenylalanine to provide, after deprotection, the novel puromycin-like analogue 39.The analogues 26-29, 36, and 39 were all evaluated for antitumor and, except for 39, for antiviral activity.These compounds failed to appreciably inhibit the growth of P388 mouse leukemia cells in vitro at concentrations up to 100 μg/mL.In addition, they did not exhibit noticeable activity against the human immunodeficiency virus or herpes simplex virus type 1 at concentrations as high as 100 μM.The adenine analogue, 26, did, however, prove to be a substrate for adenosine deaminase.It possessed an affinity for the enzyme only 50percent less than that of adenosine with a Ki = 85 μM.
Transition-Metal-Catalyzed Asymmetric Organic Synthesis via Polymer-Attached Optically Active Phosphine Ligands. 5. Preparation of Amino Acids in High Optical Yield via Catalytic Hydrogenation
Baker, Gregory L.,Fritschel, Scott J.,Stille, John R.,Stille, John K.
, p. 2954 - 2960 (2007/10/02)
Two new optically active phosphinopyrrolidine monomers were prepared by the reaction of (2S,4S)-4-(diphenylphosphino)-2-pyrrolidine and (2R,4R)-4-(diphenylphosphino)-2-pyrrolidine with acryloyl chloride to give N-acryloyl-(2S,4S)-4-(diphenylphosphino)-2-pyrrolidine (1) and N-acryloyl-(2R,4R)-4-(diphenylphosphino)-2-pyrrolidine (2).Copolymerization of 1 and 2 with hydrophilic comonomers and a divinyl monomer provided cross-linked insoluble polymers containing 3-5percentof 1 or 2 that would swell in polar solvents.Exchange of rhodium (I) onto the polymer gave catalysts which were active for the asymmetric hydrogenation of N-acyl α-amino acids in high optical yields, the phosphine derived from the enantiomer of the naturally occurring 4-hydroxyproline giving (S)-amino acids.The catalysts could be reused with no loss in selectivity by simple filtration.
