41324-66-7Relevant articles and documents
A class of novel conjugates of substituted purine and Gly-AA-OBzl: Synthesis and evaluation of orally analgesic activity
Kang, Guifeng,Zhao, Ming,Zhang, Xiaoyi,Peng, Li,Li, Chunbo,Mao, Wei,Ye, Weidong,Peng, Shiqi
supporting information; experimental part, p. 6157 - 6160 (2010/12/19)
Aimed at the chemotherapy of chronic pain two kinds of analgesic pharmacophores, substituted purine and Gly-AA-OBzl, were coupled via a five-step-reaction procedure and 19 novel conjugates N-[2-chloro-9- (tetrahydropyran-2-yl)-9H-purin-6-yl]-N-cyclopropylglycylamino acid benzylesters were provided. On mouse-tail flick model their in vivo analgesic activities were assayed. The results indicate that introducing Gly-OC2H 5 into the 6-position of the substituted purine leads to ambiguous increase of the analgesic activity, while introducing Gly-AA-OBzl into this position leads to significant increase of the analgesic activity.
Synthesis and cytotoxic activities of β-carboline amino acid ester conjugates
Zhao, Ming,Bi, Lanrong,Wang, Wei,Wang, Chao,Baudy-Floc'h, Michele,Ju, Jingfang,Peng, Shiqi
, p. 6998 - 7010 (2007/10/03)
β-Carboline represents a class of compounds with potent anti-tumor activity by intercalating with DNA. To further enhance the cytotoxic potency and bioavailability of β-carboline, a series of novel β-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were tested using a panel of human tumor cell lines. In addition, the membrane permeability of these compounds was evaluated in vitro using a Caco-2 cell monolayer model. The β-carboline amino acid ester conjugates demonstrated improved cytotoxic activity compared to the parental β-carbolines. In particular, the Lys/Arg conjugates were the most potent analogs with an IC50 value of 4 and 1 μM against human cervical carcinoma cells. The low interaction energy of Arg conjugate based on molecular modeling may contribute to its enhanced cytotoxicity. Taken together, this study provided new insights into structure-activity relationships in the β-carboline amino acid ester conjugates and identified the β-carboline Lys/Arg conjugates as promising lead compounds for further in vivo biological and molecular evaluation.
The relative catalytic efficiency of β-lactamase catalyzed acyl and phosphyl transfer
Slater, Martin J.,Laws, Andrew P.,Page, Michael I.
, p. 77 - 95 (2007/10/03)
Phosphonamidates which bear a simple resemblance to penicillin type structures have been synthesised as potential inhibitors of β-lactamases: -ethyl N-(benzyloxycarbonyl) amidomethyl phosphonyl amides, PhCH2OCONHCH2P(O)(OEt)NR2, the amines HNR2 being L-proline, D-proline, L-thiazolidine, and o-anthranilic acid. The proline derivatives completely and irreversibly inactivated the class C β-lactamase from Enterobacter cloacae P99, in a time-dependent manner, indicative of covalent inhibition. The inactivation was found to be exclusive to the class C enzyme and no significant inhibition was observed with any other class of β-lactamase. The anthranilic acid derivative exhibited no appreciable inactivation of the β-lactamases. The phosphonyl proline and phosphonyl thioproline derivatives were separated into their diastereoisomers and their individual second order rate constants for inhibition were found to be 7.72 ± 0.37 and 8.3 × 10-2 ± 0.004 M-1 s-1 for the L-proline derivatives, at pH 7.0. The products of the inhibition reaction of each individual diastereoisomer, analyzed by electrospray mass spectroscopy, indicate that the more reactive diastereoisomers phosphonylate the enzyme by P-N bond fission with the elimination of proline. Conversely, gas chromatographic detection of ethanol release by the less reactive proline diastereoisomer suggests phosphonylation occurs by P-O bond fission. The enzyme enhances the rate of phosphonylation with P-N fission by at least 106 compared with that effected by hydroxide-ion. The pH dependence of the rate of inhibition of the β-lactamase by the more reactive diasteroisomer is consistent with the reaction of the diprotonated form of the enzyme, EH2, with the inhibitor, I (or its kinetic equivalents EH with IH). This pH dependence and the rate enhancement indicate that the enzyme appears to use the same catalytic apparatus for phosphonylation as that used for hydrolysis of β-lactams. The stereochemical consequences of nucleophilic displacement at the phosphonyl centre are discussed.
