Biosynthese von 3-Acetylpyridin-adenin-dinucleotidphosphat (3-APADP) aus Nicotinamid-adenin-dinucleotidphosphat (NADP)

Summary Enzymic conversion of nicotinamide-adenine-dinucleotide (NADP) to Acetylpyridine-adenine-dinucleotidephosphate (APADP) by the transglycosidase activity of brain NAD(P)-nucleosidase was studied and isolation and some properties of these acetylpyridine analogues of NADP are described.Without reducing the transglycosidase activity, the hydrolysis of NADP is inhibited by its own cleavage-product nicotinamide. Therefore in presence of a high excess of 3-Acetylpyridine or 4-Acetylpyridine, the antimetabolites can be transmitted to 2-Phospho-adenosine-diphosphateribose (ARPPR), forming the analogues of NADP.The hydrolytic activity of the nucleosidase split 3-APADP faster than NADP and 4-APADP. Following application of 80–100 mg/kg 3-Acetylpyridine 40% of the total NADP of the brain was found as 3-APADP.

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Abkürzungen NAD Nicotinamid-adenin-dinucleotid (DPN) - NADP Nicotinamid-adenin-dinucleotidphosphat (TPN) - 3-APAD 3-Acetylpyridin-adenin-dinucleotid - 3-APADP 3-Acetylpyridin-adenin-dinucleotidphosphat - 4-APADP 4-Acetylpyridin-adenin-dinucleotidphosphat - 2-5-ADP Adenosin-2-5-diphosphat - ARPPR 2-Phosphoadenosindiphosphatribose Mit 4 TextabbildungenMit Unterstützung der Deutschen Forschungsgemeinschaft.     

Synthesis and antiproliferative activity of novel 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives.

Several new 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives 5 and 6 were synthesized and tested for their in vitro antiproliferative activity against Raji, K562, and K562-R cell lines. The pharmacological screening showed that some 2, 6, or 7-substituted quinazolinones 5 posses a significant antiproliferative activity, with a percentage growth inhibition ranging from 44.8% to 100% at 50 microM, which was higher than that showed by the unsubstituted derivative 5a previously synthesized. For the most active compounds 5d, 5f, and 5g the IC50 were recorded.     

药源性血液病(3)

药源性溶血性贫血(DHA)在药物引起的血液学不良反应中,DHA相对少见。据WHO药物不良反应国际监督调查研究中心估计,DHA占主要药源性血液系统不良反应的10%。1总论1.1发病机制及分类(表1)1.1.1药物氧化性溶血多为急性溶血。见于遗传性红细胞酶缺乏和某些血红蛋白分子病。患者红细胞对特定药物或其代谢产物的氧化性应激极为敏感,易至功能损伤,红细胞寿命缩短。人每天约有3%的血红蛋白转变为Met-Hb,持续产生少量活性氧。所以说红细胞是活性氧的最佳发源地,又是活性氧发病学分类缺陷部位疾病名药物氧化性溶血遗传性酶缺乏磷酸戊糖旁路GSH…     

2(或3)-甲基及2(或3)-(N-哌啶甲(扌牚))-酪氨酸的合成

交感神经的兴奋导致血压升高,而去甲肾上腺素是传递交感神经兴奋的化学介质.去甲肾上腺素系从酪氨酸在体内经过一系列生化反应而得,若干与酪氨酸代谢产物有关的类似物如α-甲基儿茶酚丙氨酸(Ⅰ)、α-甲基间酪氨酸(Ⅱ)等在动物试验中有明显的生理活性,临床上亦具有明显的降压作用.作者拟从对抗去甲肾上腺素的形成出发,合成若干酪氨酸的类似物,以寻找降低血压药物.从酪氨酸变成去甲肾上腺素的代谢     

Synthesis of 3-(3-pyridyl)- and 3-(3-benzo[b]thienyl)-D-alanine

The DL-arylamino acid ethyl ester derivatives of β-(3-pyridyl)-DL-alanine, and β-(3-benzo[b]thienyl)-DL-alanine were synthesized by diethyl acetamidomalonate condensation with the respective arylmethyl halides followed by partial hydrolysis to the monoethyl ester and decarboxylation. Each derivative was enzymatically resolved to a separable mixture of the corresponding N-acetyl-L-amino acid and the unchanged D amino acid derivative. Acidic hydrolysis of the latter gave the corresponding D-amino acid, the optical purity of which was established by HPLC analysis of the 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate (GITC) derivative. The free D amino acids were converted to D-BOC derivatives by reaction with di-tert-butyldicarbonate in tert-butyl alcohol, water and sodium hydroxide.     

Nonpeptide alpha(v)beta(3) antagonists. 1. Transformation of a potent, integrin-selective alpha(IIb)beta(3) antagonist into a potent alpha(v)beta(3) antagonist

Modification of the potent fibrinogen receptor (alpha(IIb)beta(3)) antagonist 1 generated compounds with high affinity for the vitronectin receptor alpha(v)beta(3). Sequential modification of the basic N-terminus of 1 led to the identification of the 5,6,7, 8-tetrahydro[1,8]naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor alpha(v)beta(3). The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to alpha(v)beta(3) is also reported.     

［Ln(Phen)2(5-Fu)3(NO3)］(NO3)2的合成、表征及体外抗肿瘤活性研究

目的研究稀土元素的生物化学作用和无机、有机抗肿瘤药物的协同作用。方法用稀土硝酸盐、邻菲罗啉(Phen)、氟尿嘧啶(5-Fu)合成了7种稀土配合物。用MTT,SRB法进行体外抗肿瘤活性研究。结果经过元素分析、摩尔电导率测定、差热分析、红外光谱测定和核磁共振谱测定，初步确定配合物化学式为［Ln(Phen)₂(5-Fu)₃(NO₃)］(NO₃)₂。配合物对K562(人粒细胞白血病细胞株)、CA(人肝癌细胞株)、SGC-7901(人胃癌细胞株)、HCT(人结肠癌细胞株)、GLC-82(人肺癌细胞株)和CNE(人鼻咽癌细胞株)增殖有很强的抑制作用。结论配合物产生了抗肿瘤协同作用。     

(3S)-3-(叔丁氧羰基氨基)-4-氧代丁酸甲酯的合成

L-门冬氨酸在氯化亚砜作用下选择性甲酯化生成L-门冬氨酸-4-甲酯盐酸盐,经二碳酸二叔丁酯保护氨基、与氯甲酸乙酯成混酐后经硼氢化钠还原得到(3S)-3-(叔丁氧羰基氨基)-4-羟基丁酸甲酯,最后经NaClO/TEMPO氧化得到西他列汀重要手性中间体(3S)-3-(叔丁氧羰基氨基)-4-氧代丁酸甲酯,总收率约41%。     

Discovery of two clinical histamine H(3) receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764)

The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.