201484-12-0Relevant articles and documents
Development of a new method for synthesis of tandem hairpin pyrrole-imidazole polyamide probes targeting human telomeres
Kawamoto, Yusuke,Bando, Toshikazu,Kamada, Fukumi,Li, Yue,Hashiya, Kaori,Maeshima, Kazuhiro,Sugiyama, Hiroshi
, p. 16468 - 16477 (2013)
Pyrrole-imidazole (PI) polyamides bind to the minor groove of DNA in a sequence-specific manner without causing denaturation of DNA. To visualize telomeres specifically, tandem hairpin PI polyamides conjugated with a fluorescent dye have been synthesized, but the study of telomeres using these PI polyamides has not been reported because of difficulties synthesizing these tandem hairpin PI polyamides. To synthesize tandem hairpin PI polyamides more easily, we have developed new PI polyamide fragments and have used them as units in Fmoc solid-phase peptide synthesis. Using this new method, we synthesized four fluorescent polyamide probes for the human telomeric repeat TTAGGG, and we examined the binding affinities and specificities of the tandem hairpin PI polyamides, the UV-vis absorption and fluorescence spectra of the fluorescent polyamide probes, and telomere staining in mouse MC12 and human HeLa cells. The polyamides synthesized using the new method successfully targeted to human and mouse telomeres under mild conditions and allow easier labeling of telomeres in the cells while maintaining the telomere structure. Using the fluorescent polyamides, we demonstrated that the telomere length at a single telomere level is related to the abundance of TRF1 protein, a shelterin complex component in the telomere.
Total and Semisyntheses of Polymyxin Analogues with 2-Thr or 10-Thr Modifications to Decipher the Structure-Activity Relationship and Improve the Antibacterial Activity
Li, Jian,Guan, Dongliang,Chen, Feifei,Shi, Weiwei,Lan, Lefu,Huang, Wei
, p. 5746 - 5765 (2021/06/01)
Herein, we report the total and semisyntheses of a series of polymyxin analogues with 2-Thr and 10-Thr modifications to reveal the structure-activity relationship (SAR), which has not been fully elucidated previously. We employed two total-synthetic strategies to facilitate the diversified replacements on 2-Thr or 10-Thr, respectively. Moreover, semisynthetic approaches were utilized to achieve selective esterification of 2-Thr or dual esterification of both 2- and 10-Thr. Based on the results of in vitro antibacterial assays, SAR analysis implicated that the replacement of 2-/10-Thr with amino acids carrying hydrophobic side chains can maintain the activity against Pseudomonas aeruginosa but had varied effects on other tested Gram-negative bacteria. The aminoacetyl esterification on 2-/10-Thr achieved excellent antibacterial activity, and the compound 76 exhibited 2-8-fold higher activity against different strains and lower toxicity toward the HK-2 cell line. This work explored the SAR of polymyxin 2-/10-Thr and provided a promising strategy for the development of novel polymyxin derivatives.
Reagent-Based Diversity-Oriented Synthesis of Triazolo[1,5- A[[1,4]diazepine Derivatives from Polymer-Supported Homoazidoalanine
Králová, Petra,Soural, Miroslav
, p. 7963 - 7974 (2021/06/28)
Herein, we report the synthesis of skeletally different triazolo[1,5-a][1,4]diazepines starting from immobilized homoazidoalanine. After sulfonylation with 2/4-nitrobenzenesulfonyl chlorides and Mitsunobu alkylation with various alkynols, the corresponding N-substituted nitrobenzenesulfonamides were obtained. Their catalyst-free Huisgen cycloaddition provided immobilized and functionalized triazolo[1,5-a][1,4]diazepines as the key intermediates for further modification. Using the concept of diversity-oriented, reagent-based synthesis, the key intermediates were subsequently converted to heterocycles bearing [5 + 7 + 5], [5 + 7 + 6], and [5 + 7 + 7] scaffolds. Furthermore, the synthesis of spirocyclic triazolodiazepines was developed.
Preparation method of N alpha-fluorenylmethoxycarbonyl-N gamma-(4, 4-dimethyl-2,6-dioxocyclohexylidene) ethyl-butyric acid
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Paragraph 0017-0021, (2019/10/17)
The invention provides a preparation method of (2S)-4-[[1-(4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl] amino]-2-[[(9H-fluoren-9-ylmethoxy) carbonyl] amino] butyric acid, and mainly solves the technical problems that an existing preparation method is com
Optimized syntheses of Fmoc azido amino acids for the preparation of azidopeptides
Pícha, Jan,Budě?ínsky, Milo?,Machá?ková, Kate?ina,Collinsová, Michaela,Jirá?ek, Ji?í
, p. 202 - 214 (2017/04/06)
The rise of CuI-catalyzed click chemistry has initiated an increased demand for azido and alkyne derivatives of amino acid as precursors for the synthesis of clicked peptides. However, the use of azido and alkyne amino acids in peptide chemistry is complicated by their high cost. For this reason, we investigated the possibility of the in-house preparation of a set of five Fmoc azido amino acids: β-azido l-alanine and d-alanine, γ-azido l-homoalanine, δ-azido l-ornithine and ω-azido l-lysine. We investigated several reaction pathways described in the literature, suggested several improvements and proposed several alternative routes for the synthesis of these compounds in high purity. Here, we demonstrate that multigram quantities of these Fmoc azido amino acids can be prepared within a week or two and at user-friendly costs. We also incorporated these azido amino acids into several model tripeptides, and we observed the formation of a new elimination product of the azido moiety upon conditions of prolonged couplings with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/DIPEA. We hope that our detailed synthetic protocols will inspire some peptide chemists to prepare these Fmoc azido acids in their laboratories and will assist them in avoiding the too extensive costs of azidopeptide syntheses. Experimental procedures and/or analytical data for compounds 3–5, 20, 25, 26, 30 and 43–47 are provided in the supporting information.
Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein–Protein Interaction in Ovarian Cancer
Wiedmann, Mareike M.,Tan, Yaw Sing,Wu, Yuteng,Aibara, Shintaro,Xu, Wenshu,Sore, Hannah F.,Verma, Chandra S.,Itzhaki, Laura,Stewart, Murray,Brenton, James D.,Spring, David R.
supporting information, p. 524 - 529 (2017/01/07)
There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor
A Nα-fluorenylmethyloxycarbonyl-Nγ-tert-butoxy carbonyl-L-2,4-diamino-butyric acid synthetic method (by machine translation)
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Paragraph 0014, (2016/10/09)
This invention involves a kind of Nα-fluorenylmethyloxycarbonyl-Nγ-tert-butoxy carbonyl-L-2,4-diamino-butyric acid synthetic method. Mainly solves the problems that the prior method for preparing more existent steps of and avoid the use of palladium carbon cause very difficult problems of processing technology. The technical scheme of the invention is:a kind of Nα-fluorenylmethyloxycarbonyl-Nγ-tert-butoxy-carbonyl-L-2,4-diamino-butyric acid synthetic method, a Nα-fluorenylmethyloxycarbonyl-Nγ-tert-butoxy-carbonyl-L-2,4-diamino-butyric acid synthetic method, its characteristic is to include the following steps: 1st-step reaction, suspension Fmoc-Gln-OH with acetonitrile, ethyl acetate and water mixed solvent, adding diethyla acid iodophenylamino reaction post-processed to obtain Fmoc-Dab-OH; 2nd-step reaction, acetone and Fmoc-Dab-OH under the condition of the water by adding (Boc) 2 O, for adjusting NaOH pH= 7.5-8, by treatment after reaction Fmoc-Dab (Boc)-OH. The present invention provides large-scale production method for Fmoc-Dab (Boc)-OH. (by machine translation)
Structural evaluation of tandem hairpin pyrrole-imidazole polyamides recognizing human telomeres
Hirata, Akiyoshi,Nokihara, Kiyoshi,Kawamoto, Yusuke,Bando, Toshikazu,Sasaki, Asuka,Ide, Satoru,Maeshima, Kazuhiro,Kasama, Takeshi,Sugiyama, Hiroshi
, p. 11546 - 11554 (2014/10/15)
A polyamide containing N-methylpyrrole (Py) and N-methylimidazole (Im), designated PIPA, binds with high affinity and specificity to specific nucleotide sequences in the minor groove of double-helical DNA. Based on a recent report of the synthesis of PIPA for telomere visualization, the present paper focused on the size of the connecting part (hinge region) of two PIPA segments of the tandem hairpin PIPA, Dab(Im-Im-Py)-Py-Py-Py-Im-[Hinge]-Dab(Im-Im-Py)-Py-Py-Py- Im-βAla-NH(CH2)3N(CH3)-(CH 2)3NH-[Dye]. The present paper also describes the characterization of binding by measuring the thermal melting temperature and surface plasmon resonance and by specific staining of telomeres (TTAGGG)n in human cells. Microheterogeneity was also investigated by high-resolution mass spectrometry. We found that the optimal compound as the hinge segment for telomere staining was [-NH(C2H4O)2(C 2H4)CO-] with tetramethylrhodamine as the fluorescent dye.
Strategy for "Detoxification" of a cancer-derived histone mutant based on mapping its interaction with the methyltransferase PRC2
Brown, Zachary Z.,Müller, Manuel M.,Jain, Siddhant U.,Allis, C. David,Lewis, Peter W.,Muir, Tom W.
supporting information, p. 13498 - 13501 (2015/02/02)
The histone methyltransferase PRC2 plays a central role in genomic stability and cellular development. Consequently, its misregulation has been implicated in several cancers. Recent work has shown that a histone H3 mutant, where the PRC2 substrate residue Lys27 is replaced by methionine, is also associated with cancer phenotypes and functions as an inhibitor of PRC2. Here we investigate the mechanism of this PRC2 inhibition through kinetic studies and photo-cross-linking. Efficient inhibition is dependent on (1) hydrophobic lysine isosteres blocking the active site, (2) proximal residues, and (3) the H3 tail forming extensive contacts with the EZH2 subunit of PRC2. We further show that naturally occurring post-translational modifications of the same H3 tail, both proximal and distal to K27M, can greatly diminish the inhibition of PRC2. These results suggest that this potent gain of function mutation may be "detoxified by modulating alternate chromatin modification pathways.
Efficient synthesis of Fmoc-protected azido amino acids
Lau, Yu Heng,Spring, David R.
experimental part, p. 1917 - 1919 (2011/10/01)
The efficient two-step synthesis of Fmoc-protected L-azidoalanine and L-azidohomoalanine from readily available Fmoc-protected asparagine and glutamine, respectively, is reported. The synthetic route proceeds in good yield, requires no extra purification steps, and can be carried out on gram scale. The resulting azido amino acids are of sufficient purity for solid-phase peptide synthesis, as demonstrated in the synthesis of a model pentapeptide. Georg Thieme Verlag Stuttgart New York.
