- Design and synthesis of a peptide derivative of ametantrone targeting the major groove of the d(GGCGCC)2 palindromic sequence
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In oncology, some DNA intercalating agents have been used in chemotherapy for years to eradicate cancer cells, but these drugs generally suffer from a lack of selectivity for malignant tissues and consequently induce major side-effects. We report herein the design and synthesis of an antitumor intercalating agent ametantrone complemented with two identical peptide arms including a central Lys residue in order to selectively target palindromic sequences of DNA of malignant cells. The peptide arms are linked to the ametantrone core through 1,2,3-triazole. According to our docking prediction, this compound should be double-stranded β-sheet structured, and it has been designed to interact with two guanine residues upstream from a central d(CpG)2 intercalation site on each DNA strand, owing to the H-bonds involving the Lys terminal side chain ammonium group of the peptide arms. This new ametantrone derivative has been obtained thanks to a convergent synthetic pathway, whose key steps were double nucleophilic substitution performed on the ametantrone core, followed by "double-site" 1,3-dipolar cycloaddition affording the 1,4-disubstituted triazole linker almost quantitatively. Preliminary binding assays performed by mass spectrometry proved its accuracy for DNA palindromic sequences. The cytotoxicity of this compound was evaluated on three cancer cell lines and one healthy cell line, and compared to that of mitoxantone, a dihydroxylated analog of ametantrone. Such a peptide derivative was about ten-fold less cytotoxic than mitoxantrone on these cancer cell lines, but about fifty times less cytotoxic on healthy cells. This study could open new avenues towards the design of targeted intercalating agents.
- Braud, Emmanuelle,De Franco, Michele,Demange, Luc,Ethève-Quelquejeu, Mélanie,Garbay, Christiane,Gresh, Nohad,Ongaro, Alberto,Ribaudo, Giovanni,Zagotto, Giuseppe
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supporting information
p. 3624 - 3631
(2020/03/17)
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- Synthesis and spectroscopic studies of 5-arylidene-3-substituted tetramic acids as possible substrates for catalytic asymmetric hydrogenation
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A new series of 5-arylidene-3-substituted tetramic acids 6-19 have been synthesized by a condensation reaction of 3-butanoyl tetramic acid 3, 3-ethoxycarbonyl tetramic acid 4 and 3-acetyl tetramic acid 5 with a variety of substituted benzaldehydes. The st
- Athanasellis,Gavrielatos,Igglessi-Markopoulou
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p. 1203 - 1208
(2007/10/03)
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- An efficient synthesis of novel N-acetyl-3-alkanoyl and 3-dienoyl tetramic acids
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A general synthesis of N-acetyl-3-alkanoyl- and 3-dienoyl-tetramic acids is presented. The condensation of N-(N-acetylglycyloxy)succinimide with β-keto esters bearing alkanoyl or dienoyl groups furnishes the new 3-substituted N-acetyltetramic acids 6-9 and 16 in good yields. The key intermediates 4 and 5 have been isolated and subsequently cyclized to the corresponding tetramic acids. Spectral data for and the physical characteristics of all compounds are reported.
- Petroliagi, Margarita,Igglessi-Markopoulou, Olga
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p. 3543 - 3548
(2007/10/03)
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- Superactivation of thermolysin by acylation with amino acid N-hydroxysuccinimide esters.
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Synthesis of a series of active N-hydroxysuccinimide esters of aliphatic and aromatic amino acids has yielded a new class of reagents for the covalent modification of proteolytic enzymes such as thermolysin. The activities of aliphatic acyl amino acid thermolysins are from 1.7 to 3.6 times greater than that of the native enzyme when hydrolyzing durylacryloyl-Gly-Leu-NH2, the substrate employed most widely. By comparison, the aromatic acylamino acid derivatives are "superactive," their activities being as much as 70-fold greater. Apparently, the aromatic character of the amino acid introduced is a critical variable in the determination of the functional response. The increased activity is completely restored to that of the native enzyme by deacylation with nucleophiles, such as hydroxylamine, and the rate of restoration of native activity is a function of the particular acyl group incorporated. Preliminary evidence regarding the chemical properties of the modified enzyme suggests that tyrosine, rather than lysine, histidine, or arginine, may be the residue modified. The functional consequences of successive modification with different reagents, moreover, indicate that each of them reacts with the same protein residue. The competitive inhibitors beta-phenyl-propionyl-Phe and Zn-2+ do not prevent modification with these active esters. Hence, the site(s) of their inhibitory action differ(s) from that at which modification occurs. The structure of the substrate is also a significant variable which determines the rate at which each acyl amino acid thermolysin hydrolyzes peptides. Depending on the particular substrate, the activity of aromatic derivatives can be as much as 400-fold greater than that of the native enzyme, and the resultant activity patterns can be ordered in a series characteristic for each enzyme derivative.
- Blumberg,Vallee
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p. 2410,2411
(2007/10/05)
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