- Synthesis and in vitro evaluation of macromolecular antitumour derivatives based on phenylenediamine mustard
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Poly-[N-(2-hydroxyethyl)-l-glutamine] (PHEG) and poly(ethylene glycol) (PEG)-grafted PHEG conjugates of N,N-di(2-chloroethyl)-4-phenylenediamine mustard (PDM) were synthetised. A collagenase-sensitive oligopeptide spacer was selected to link the cytotoxic agent PDM onto the polymeric carrier. First, the oligopeptide-drug conjugate, l-pro-l-leu-gly-l-pro-gly-PDM, was prepared. In a second step, the low molecular weight PDM derivative and PEG-NH2 were coupled to a N,N-disuccinimidylcarbonate activated PHEG. Dynamic laser light scattering measurements indicated the formation of aggregates. The presence of human serum albumin had no significant effect on the diameter of the conjugates. The hydrolytic stability of the conjugates was investigated in buffer solutions. The conjugates showed an improved stability compared to the parent nitrogen mustard. The enzymatic degradation studies of the polymeric conjugates were performed in the presence of collagenase type IV (Clostridiopeptidase A; EC 3.4.24.3), cathepsin B (EC 3.4.22.1), cathepsin D (EC 3.4.23.5) and tritosomes. Only the bacterial collagenase type IV was able to cleave the spacer releasing free PDM and its peptidyl derivative, gly-l-pro-gly-PDM. The in vitro cytotoxicity of the conjugates was evaluated against HT1080 fibrosarcoma cells and MDA adenocarcinoma cells. All conjugates showed low toxicity towards these cell lines.
- De Winne, Katleen,Seymour, Leonard W.,Schacht, Etienne H.
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p. 159 - 168
(2007/10/03)
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- Carbamic acid compounds comprising an amide linkage as hdac inhibitors
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This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the formula (1) wherein: A is an aryl group; Q1 is an aryl leader group having a backbone of at least 2 carbon atoms; J is an amide linkage selected from: —NR1C(═O)—and —C(═O)NR1—; R1 is an amido substituent; and, Q2 is an acid leader group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and, e.g., to inhibit proliferative conditions, such as cancer and psoriasis.
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- Probing the functional requirements of the L-haba side-chain of amikacin - Synthesis, 16S A-site rRNA binding, and antibacterial activity
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The l-amino group in amikacin was acylated with a variety of 2-hydroxy aminocarboxylic acids to probe the effect of acylation on ribosomal binding and antibacterial activity. The N-hydroxy urea analogue of amikacin (8a) in which the 2-S-hydroxyl-bearing carbon was replaced by an N-OH group was equally active against S. aureus and E. coli in vitro. The analogous tobramycin variant 9 was more active than amikacin.
- Hanessian, Stephen,Kornienko, Alexander,Swayze, Eric E.
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p. 995 - 1007
(2007/10/03)
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- STUDIES ON LACTAMS IX. A CONVENIENT SYNTHESIS OF LACTAM RINGS
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The auto-cyclization reaction has been employed for the synthesis of lactam rings by means of reduction from ω-carbobenzoxyamino acid active esters in high dilution method.
- Ogura, Haruo,Takeda, Kazuyoshi
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p. 467 - 468
(2007/10/02)
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