72083-62-6Relevant articles and documents
Modulation of DNA-polyamide interaction by β-alanine substitutions: A study of positional effects on binding affinity, kinetics and thermodynamics
Wang, Shuo,Wilson, W. David,Aston, Karl,Koeller, Kevin J.,Harris, G. Davis,Rath, Nigam P.,Bashkin, James K.
, p. 7523 - 7536 (2014)
Hairpin polyamides (PAs) are an important class of sequence-specific DNA minor groove binders, and frequently employ a flexible motif, β-alanine (β), to reduce the molecular rigidity to maintain the DNA recognition register. To better understand the diverse effects that β can have on DNA-PA binding affinity, selectivity, and especially kinetics, which have rarely been reported, we have initiated a detailed study for an eight-heterocyclic hairpin PA and its β derivatives with their cognate and mutant sequences. With these derivatives, all internal pyrroles of the parent PA are systematically substituted with single or double βs. A set of complementary experiments have been conducted to evaluate the molecular interactions in detail: UV-melting, biosensor-surface plasmon resonance, circular dichroism and isothermal titration calorimetry. The β substitutions generally weaken the binding affinities of these PAs with cognate DNA, and have large and diverse influences on PA binding kinetics in a position- and number-dependent manner. The DNA base mutations have also shown positional effects on the binding of a single PA. Besides the β substitutions, the monocationic Dp group [3-(dimethylamino)propylamine] in parent PA has been modified into a dicationic Ta group (3,3′-diamino-N-methyldipropylamine) to minimize the frequently observed PA aggregation with ITC experiments. The results clearly show that the Ta modification not only maintains the DNA binding mode and affinity of PA, but also significantly reduces PA aggregation and allows the complete thermodynamic signature of eight-ring hairpin PA to be determined for the first time. This combined set of results significantly extends our understanding of the energetic basis of specific DNA recognition by PAs.
Fluorous synthesis of minor groove binding agents related to distamycin
Mamidyala, Sreeman K.,Firestine, Steven M.
, p. 7431 - 7434 (2006)
Minor groove binding agents related to distamycin have been shown to target specific DNA sequences with high affinity. We report a new method for the preparation of these agents using fluorous synthesis in which the fluorous tag is located on what will become the cationic tail of the molecule. We demonstrate that fluorous synthesis yields both simple and complex polyamides in good yields and in high purity.
Ortho -Fluoroazobenzene derivatives as DNA intercalators for photocontrol of DNA and nucleosome binding by visible light
Heinrich, Benedikt,Bouazoune, Karim,Wojcik, Matthias,Bakowsky, Udo,Vázquez, Olalla
, p. 1827 - 1833 (2019/02/20)
We report a high-affinity photoswitchable DNA binder, which displays different nucleosome-binding capacities upon visible-light irradiation. Both photochemical and DNA-recognition properties were examined by UV-Vis, HPLC, CD spectroscopy, NMR, FID assays,
Discovery of D-amino acid oxidase inhibitors based on virtual screening against the lid-open enzyme conformation
Szilágyi, Bence,Skok, ?iga,Rácz, Anita,Frlan, Rok,Ferenczy, Gy?rgy G.,Ila?, Janez,Keser?, Gy?rgy M.
, p. 1693 - 1698 (2018/05/05)
D-Amino acid oxidase (DAAO) inhibitors are typically small polar compounds with often suboptimal pharmacokinetic properties. Features of the native binding site limit the operational freedom of further medicinal chemistry efforts. We therefore initiated a structure based virtual screening campaign based on the X-ray structures of DAAO complexes where larger ligands shifted the loop (lid opening) covering the native binding site. The virtual screening of our in-house collection followed by the in vitro test of the best ranked compounds led to the identification of a new scaffold with micromolar IC50. Subsequent SAR explorations enabled us to identify submicromolar inhibitors. Docking studies supported by in vitro activity measurements suggest that compounds bind to the active site with a salt-bridge characteristic to DAAO inhibitor binding. In addition, displacement of and interaction with the loop covering the active site contributes significantly to the activity of the most potent compounds.
Synthesis of pyrrole-imidazole polyamide oligomers based on a copper-catalyzed cross-coupling strategy
Shiga, Naoki,Takayanagi, Shihori,Muramoto, Risa,Murakami, Tasuku,Qin, Rui,Suzuki, Yuta,Shinohara, Ken-ichi,Kaneda, Atsushi,Nemoto, Tetsuhiro
, p. 2197 - 2200 (2017/04/27)
Pyrrole-imidazole (Py-Im) polyamides are useful tools for chemical biology and medicinal chemistry studies due to their unique binding properties to the minor groove of DNA. We developed a novel method of synthesizing Py-Im polyamide oligomers based on a Cu-catalyzed cross-coupling strategy. All four patterns of dimer fragments could be synthesized using a Cu-catalyzed Ullmann-type cross-coupling with easily prepared monomer units. Moreover, we demonstrated that pyrrole dimer, trimer, and tetramer building blocks for Py-Im polyamide synthesis were accessible by combining site selective iodination of the pyrrole/pyrrole coupling adduct.
Synthesis of isoquinolinone-based tricycles as novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors
Chen, Jianyang,Peng, Haixia,He, Jinxue,Huan, Xiajuan,Miao, Zehong,Yang, Chunhao
, p. 2669 - 2673 (2014/06/09)
The isoquinolinone-based tricyclic compounds were designed and synthesized. Preliminary biological study of these compounds provided potent compounds 17a, 33b, 33c, 33d, and 33g with low nanomolar IC50s against PARP-1 enzyme.
Synthesis of cationic glyco-oligoamide for DNA-carbohydrate interaction studies
Taladriz-Sender, Andrea,Vicent, Cristina
, p. 656 - 664 (2013/11/19)
We are using carbohydrate-based ligands, glyco-oligoamides, as a strategy to obtain structural and thermodynamic information on carbohydrate-minor groove DNA binding. In order to improve the solubility of the first generation of neutral ligands type 1 in
Sugara-oligoamides: Synthesis of DNA minor groove binders
Badaea, Concepcion,Souard, Florence,Vicent, Cristina
, p. 10870 - 10881 (2013/02/22)
Sugar-oligoamides have been designed and synthesized as structurally simple carbohydrate-based ligands to study carbohydratea-minor groove DNA interactions. Here we report an efficient solution-phase synthetic strategy to obtain two broad families of sugara-oligoamides. The first type, structure vector A (-Py[Me]-γ-Py-Ind), has a methyl group present as a substituent on the nitrogen of pyrrole B, connected to the C terminal of the oligoamide fragment. The second type, structure vector B (-Py[(CH2) 11OH]-γ-Py-Ind), has an alkyl chain present on the nitrogen of pyrrole B connected to the C terminal of the oligoamide fragment and has been designed to access to di-and multivalent sugara-oligoamides. By using sequential DIPC/HOBt coupling reactions, the oligoamide fragment-Py[R]-γ-Py-Ind has been constructed. The last coupling reaction between the anomeric amino sugar and the oligoamide fragment was carried out by activating the acid derivative as a BtO-ester, which has been performed by using TFFH. The isolated esters (BtO-Py[R]-γ-Py-Ind) were coupled with selected amino sugars using DIEA in DMF. The synthesis of two different selective model vectors (vector A (1) and vector B (2)) and two types of water-soluble sugara-oligoamide ligands, with vector A structure (compounds 3a-7) and with vector B structure (compound 8), was carried out.
Solution-phase parallel synthesis of novel membrane-targeted antibiotics
Vooturi, Sunil K.,Firestine, Steven M.
experimental part, p. 151 - 160 (2010/10/19)
The increase in the incidence of antibiotic-resistant infections is a major concern to healthcare workers and requires the development of novel antibacterial agents. Recently, we described a series of benzophenonecontaining antibiotics which displayed activity against antibiotic-resistant bacteria. We have shown that these agents function by disrupting the bacterial membrane. To further explore these compounds, a practical and efficient solution-phase parallel synthesis method was developed which allowed us to prepare combinatorial libraries of these agents. Using this method, we prepared 218 compounds in 58 reactions. All of the compounds were characterized by HPLC and MALDI-TOF mass spectrometry. Analysis of this library for antibacterial activity identified six compounds which displayed MTC values of 2.0 mg/T. against Staphylococcus aureus. Examination of the structure-function relationships of these agents revealed that cationic groups were required and that cyclic, aliphatic amines were crucial for activity. Using the information generated here, we speculate on how the various structural features of the molecule are necessary for the interaction with the bacterial membrane.
An asymmetric C8/C8′-tripyrrole-linked sequence-selective pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer DNA interstrand cross-linking agent spanning 11 DNA base pairs
Tiberghien, Arnaud C.,Evans, David A.,Kiakos, Konstantinos,Martin, Christopher R.H.,Hartley, John A.,Thurston, David E.,Howard, Philip W.
, p. 2073 - 2077 (2008/12/21)
A novel sequence-selective extended PBD dimer 4 has been synthesized that binds with high affinity to an interstrand cross-linking site spanning 11 DNA base pairs. Despite its molecular weight (984.07) and length, the molecule has significant DNA interstrand cross-linking potency (～100-fold greater than the clinically used agent melphalan) and sub-micromolar cytotoxicity in a number of tumour cell lines, suggesting that it readily penetrates cellular and nuclear membranes to reach its DNA target.
