Synthesis and evaluation of the cytotoxicity of apoptolidinones A and D

Apoptolidins A-D are microbial secondary metabolites shown to be selectively cytotoxic against several cancer cell lines and noncytotoxic against normal cells. Total syntheses of apoptolidinones A and D are reported. The efficient synthetic strategy leading to the apoptolidinones features construction of the common 20-membered macrolactone by an intramolecular Suzuki reaction and stereocontrolled aldol reactions establishing the C19/C20 and C22/C23 stereocenters. In contrast to apoptolidin A, the aglycones apoptolidinone A and D were shown to be noncytotoxic when evaluated against human lung cancer cells (H292).     

Chemical properties of oxopropenyl adducts of purine and pyrimidine nucleosides and their reactivity toward amino acid cross-link formation

N2-oxopropenyldeoxyguanosine (2) forms in duplex DNA by modification of dG residues with base propenal or malondialdehyde. The pKa of 2 was estimated to be 6.9 from the pH dependence of its ring-closing to the pyrimidopurinone derivative 1. The acidity of 2 may be an important determinant of its miscoding properties and its reactivity to nucleophiles in DNA or protein. To test this hypothesis, analogous N-oxopropenyl derivatives of dA (4), dC (5), and N1-methyl-dG (6) were synthesized and their pKa's were determined by optical titration. The N-oxopropenyl derivatives of dA and dC both exhibited pKa's of 10.5, whereas the N-oxopropenyl derivative of N1-methyldG exhibited a pKa of 8.2. Cross-linking of 2, 4, 5, and 6 to N(alpha)-acetyl-lysine was explored at neutral pH. Adduct 2 did not react with N(alpha)-acetyl-lysine, whereas 4-6 readily formed cross-links. The structures of the cross-links were elucidated, and their stabilities were investigated. The results define the acidity of oxopropenyl deoxynucleosides and highlight its importance to their reactivity toward nucleophiles. This study also identifies the structures of a potential novel class of DNA-protein cross-links.     

Synthesis of substituted benzo[b]thiophenes by acid-catalyzed cyclization of thiophenylacetals and ketones

Benzo[b]thiophenes substituted at the 3 position with methyl or carboxymethyl and at the 5 position with methyl, methoxy, chloro, bromo and nitro were prepared by cyclization of thiophenyl-acetals and ketones using a suspension of polyphosphoric acid in refluxing chlorobenzene. The overall efficiency of this method is superior to literature procedures because of the lower temperature and the limited amount of PPA used.     

Kinetics and mechanism of the general-acid-catalyzed ring-closure of the malondialdehyde-DNA adduct, N2-(3-oxo-1-propenyl)deoxyguanosine (N2OPdG-), to 3-(2'-Deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-alpha]purin- 10(3H)-one (M1dG)

3-(2'-Deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one (M1dG) is the major product of the reaction of deoxyguanosine with malondialdehyde (MDA). M1dG blocks replication by DNA polymerases in vitro and is mutagenic in vivo. M1dG reacts with hydroxide to form the N2-(3-oxo-1-propenyl)deoxyguanosine anion (N2OPdG-). This reaction is pH-dependent and reverses under neutral and acidic conditions to form M1dG. Here we describe the kinetics and mechanism of the ring-closure reaction in both the nucleoside and oligonucleotides. Kinetic analysis of absorbance and fluorescence changes demonstrates that ring-closure is biphasic, leading to the rapid formation of an intermediate that slowly converts to M1dG in a general-acid-catalyzed reaction. The dependence of the rate of the rapid phase on pH reveals the pKa for protonated N2OPdG is 6.9. One-dimensional 1H NMR and DQF-COSY experiments identified two distinct intermediates, N2OPdG-H and 8-hydroxy-6,7-propenodeoxyguanosine (HO-Prene-dG), that are formed upon acidification of N2OPdG-. Characterization of ring-closure in single-stranded and in melted duplex oligonucleotides shows M1dG formation is also acid-catalyzed in single-stranded oligonucleotides and that the denaturation of an oligonucleotide duplex enhances ring-closure. This work details the complexity of ring-closure in the nucleoside and oligonucleotides and provides new insight into the role of duplex DNA in catalyzing ring-opening and ring-closing of M1dG and N2OPdG.     

New99mTc-diiodine substituted IDA derivative (DIIODIDA) for hepatobiliary imaging

A new diiodine substituted IDA derivative, 2,4-diiodine-6-methyl IDA (DIIODIDA) was synthesized and labeled with^99mTc. It was established that^99mTc-DIIODIDA had high radiochemical purity. Biodistribution and influence of bilirubin on^99mTc-DIIODIDA biokinetics has been studied in rats and compared to the corresponding results for^99mTc-SOLCOIODIDA. Related to^99mTc-SOLCOIODIDA,^99mTc-DIIODIDA has much better biliary exretion (55.18 versus 43.63%). No change of^99mTc-DIIODIDA biokinetics, under influence of bilirubin was noticed. Biliary excretion of^99mTc-SOLCOIODIDA has been reduced for about 60%. The protein binding of^99mTc-DIIODIDA and^99mTc-SOLCOIODIDA were also determined, using in vitro method of precipitation. These results showed that^99mTc-DIIODIDA hepatobiliary imaging agent is superior to the presently used^99mTc-monoiodine IDA derivatives.     

一般n阶特征量泛函的Euler-Lagrange方程及与定量因果原理、相对性原理和广义牛顿三定律的统一

本文获得了有各种相互作用的一般n阶特征量泛函,其耦合系数反映了不同特征量泛函之间的耦合强度.依据定量因果原理,导出了一般n阶特征量泛函的变分原理,获得了一般n阶特征量泛函的Euler-Lagrange方程,它的不同系数可拟合不同的物理现实,如从线性到任意n阶非线性物理系统,使复杂难解的任意n阶非线性物理系统变得具体可解.并获得了该对称变换下不变的m个的守恒量,以及它们之间的关系和统一描述.依据定量因果原理导出了相对性原理,证明了绝对加速参考系、牵连参考系和相对参考系的力都有来自加速度和质量变化的贡献.利用定量因果原理自然导出了广义牛顿第一定律和广义牛顿第二定律,而且还导出了一个新定律,即广义牛顿第三定律,亦即平移不变性系统合力为零定理.进而将研究结论应用于对银河系的修正引力势、分子势、夸克禁闭势等,且其结果与物理实验一致.     

On relative stability of linear stationary feedback control systems with time delay

A method is presented whereby the absolute and relative stabilityof linear control systems containing transport lag can be determined.As a result feedback systems with variable time delay and loopgain, may be investigated in straightforward manner.