Synthesis and antitumor activity of N

摘要：以STX-0119为先导化合物基于生物电子等排原理设计并合成25个N"-苯亚甲基-2-(3-吡啶基)喹啉-4-酰肼衍生物（产率：20.4-42.6%），通过1H NMR、MS、13C NMR确证了产物结构，采用MTT和台盼蓝法以以人乳腺癌MCF-7细胞、人肺癌A549细胞、人慢性粒细胞白血病K562细胞、人急性B淋巴细胞白血病RS4:11细胞为测试细胞株评价了目标化合物的体外抗肿瘤活性。目标化合物Ⅶr表现出最强的抗A549细胞增殖活性（IC50 = 7.42 ± 0.83 μmol/L），目标化合物Ⅶq表现出最强的抗RS4:11细胞增殖活性（IC50 = 2.4 ± 0.17 μmol/L）目标化合物Ⅶl不仅表现出最强的抗MCF-7细胞增殖活性（IC50 = 4.91 ± 0.33 μmol/L），而且也表现出最强抗K562细胞增殖活性（IC50 = 1.24 ± 0.19 μmol/L），分子对接结果显示其发挥抗肿瘤的作用可能与STAT3通路有关，值得进一步深入研究。 关键词：喹啉；酰肼；合成；抗肿瘤；生物电子等排     

含噻吩并[3,2-d]嘧啶的查尔酮类化合物的合成和抗增殖活性

运用药物分子片段原理及拼合原理,设计并合成了10个含噻吩并[3,2-d]嘧啶的查尔酮类衍生物,并对该类化合物的体外抗对肿瘤细胞增殖活性进行初步研究。目标化合物的结构通过1H NMR、13C NMR和HRMS (ESI)表征。以人肺腺癌细胞株A549、人肝癌细胞株HepG2和人前列腺癌细胞株PC-3三种肿瘤细胞为测试细胞株,采用MTT法评价了目标化合物的抗增殖活性。体外活性实验表明,10个化合物对三种肿瘤细胞株均具有很好的抑制活性。其中化合物Ⅶh活性突出,对三种肿瘤细胞株的IC50 值分别为0.87 μmol/L、2.43 μmol/L和2.02 μmol/L,优于阳性对照药索拉非尼。含噻吩并[3,2-d]嘧啶的查尔酮类化合物具有很好的抗肿瘤活性,值得进一步研究。     

4,5-二氢-1H-硫色烯[4,3-d]嘧啶类化合物合成及抗肿瘤细胞增殖活性研究

以苯硫酚为起始原料经Michael加成,环合得到硫色满酮,再利用3组分(醛、酮、氨基脒)反应合成了4,5-二氢-1H-硫色烯[4,3-d]嘧啶类目标化合物,所合成的5个目标化合物未见文献报道,其结构经核磁共振氢谱和质谱确证。采用MTT法,以吉非替尼(gefitinib)为阳性对照药,测定了目标化合物对肺腺癌A549细胞和非小细胞肺癌H460细胞的体外抗肿瘤增殖活性。化合物GDX1和GDX2对A549和H460的抑制活性较强,其IC50值分别为0.77、0.67、4.38、3.78μmol/L。实验表明4,5-二氢-1H-硫色烯[4,3-d]嘧啶类化合物是一类具有新型骨架结构的抗肿瘤化合物,值得进一步研究。     

大黄酸硝酸酯衍生物的设计、合成及抗肿瘤活性

以大黄酸为原料,利用其羧基与不同碳数的二溴烷烃反应得到相应的大黄酸酸溴代烷基酯,继而与硝酸银反应得到5个大黄酸硝酸酯衍生物,其结构经红外光谱、核磁共振氢谱和质谱确证。用噻唑蓝(MTT)法评价了目标化合物对人肝癌细胞HepG2增殖的影响,结果显示,所合成的目标化合物大黄酸硝酸酯衍生物3a～3e(IC50=8.50～56.4μmol/L)均具有一定的抗增值活性,且显著高于先导化合物大黄酸(IC_(50)=376μmol/L),其中,化合物3c(IC_(50)=8.50μmol/L)的抗增值作用最强,强于阳性对照药氟尿嘧啶(5-FU,IC_(50)=16.20μmol/L)。     

苯乙烯喹啉衍生物的合成及抗癌活性研究

以取代的苯胺和反式丁烯醛为原料,在盐酸中反应得到4个2 -甲基喹啉衍生物,所得产物再与芳香醛在冰醋酸中回流反应合成了10个苯乙烯喹啉衍生物,收率为64% ~ 78%。所得化合物的结构经1HNMR、MS、IR表征确认,并采用MTT法进行初步体外抗肿瘤活性筛选。结果表明,化合物Ⅱc对A 549和HCT 116细胞均有较高的抑制活性,IC50值分别为9.77和9.66 μmol/L,化合物Ⅱd对HCT 116细胞有较高的抑制活性,IC50值为9.80 μmol/L。     

帽蕊木抗氧化活性研究

用二苯代苦味肼基自由基(DPPH)、铁离子还原/抗氧化力测定法(FRAP)和2,2′-连氨-(3-乙基苯并噻唑啉-6-磺酸)二氨盐(ABTS)3种体外抗氧化活性分析方法,与阳性对照没食子酸丙酯(PG)、丁基羟基茴香醚(BHA)和二丁基羟基甲苯(BHT)比较,对帽蕊木进行了抗氧化活性评价。在帽蕊木叶和皮的6个提取物中,叶乙酸乙酯提取物清除DPPH和ABTS自由基的能力最强(IC50=2.24 mg/L和IC50=1.165 mg/L),强于阳性对照BHA(IC50=3.43 mg/L和IC50=1.675 mg/L)和BHT(IC50=18.79 mg/L和IC50=4.555 mg/L),弱于阳性对照PG(IC50=0.94 mg/L和IC50=0.885 mg/L);叶正丁醇提取物还原Fe3+能力最强(FRAP值=1 395.94μmol TE/g),皮正丁醇提取物次之(FRAP值=1 275.43μmol TE/g),都强于阳性对照BHT(FRAP值=238.11μmol TE/g),弱于阳性对照PG(5 159.97μmol TE/g)、BHA(2 573.96μmol TE/g)。结果表明,帽蕊木叶和皮的乙酸乙酯和正丁醇提取物都有很好的抗氧化活性,并且帽蕊木叶的活性强于茎皮。该文报道工作的新颖性已为河南大学图书馆2008年8月25日出具的第CX 2008007号《科技查新报告》所证实。     

羟基哌啶酮抗肿瘤药物的结构及抗肿瘤活性研究

通过X-ray单晶衍射表征药物(3E,5E)-N-苄基-3,5-二(4-羟基苯亚甲基)-4-哌啶酮盐酸盐(A)的结构。A(C_(26)H_(24)ClNO_3,Mr=433.91)结晶在triclinic晶系,P-1空间群,a=9.8813(4),b=11.1292(4),c=12.9552(5)?,α=98.058(3)°,β=108.134(4)°,γ=107.353(3)°,U=1248.93(8)?~3,Z=2。CCK-8法评价其对A549、SGC-7901、HePG2、Hela、K562等肿瘤细胞系的抗肿瘤活性及对正常细胞HUVEC的细胞毒性。结果显示,A对SGC7901、K562和Hela的活性较好,其中对K562的抑制活性最好,IC50=7.86μM。并且对正常细胞HUVEC的细胞毒性较小。     

瓜馥木抗肿瘤活性研究

目的研究瓜馥木和黄酮化合物抗肿瘤活性。方法以半数抑制浓度(IC50)为评价抗肿瘤活性强度的指标,采用MTT法测定瓜馥木提取物和黄酮化合物体外抗肿瘤活性。结果 5,6,7,8-四甲氧基黄酮、石油醚、氯仿和乙酸乙酯的提取物均能显著抑制SPCA-1肺腺癌细胞、SGC-7901胃癌细胞、BEL-7402肝癌细胞和K562白血病细胞增殖;水提取物只对K562白血病细胞有抑制作用。结论瓜馥木具有抗肿瘤活性。     

N-吡啶基-2-(4-芳氧苯氧基)丙酰胺的合成及抗肿瘤活性

以(R)-2-(4-羟基苯氧基)丙酸和氯代吡啶为起始原料,设计并合成了系列N-吡啶基-2-(4-芳氧苯氧基)丙酰胺化合物,其结构经1HNMR、LC-MS、13CNMR、IR和元素分析证实,对化合物立体构型与反应条件的关系进行了研究。采用MTT法测定了其对A549和Hela细胞系的活性,结果表明,所合成化合物具有不同程度的抗肿瘤活性,其中N-(3-硝基吡啶-2-基)-2-[4-[(6-氯喹喔啉-2-基)氧基]苯氧基]丙酰胺(Ⅳf)(IC50=0.007 mmol/L)比顺铂(IC50=0.026 mmol/L)抗肿瘤活性高。     

雌酚酮-17-(靛红取代)腙衍生物的合成及抗肿瘤活性评价

为寻找高效的潜在抗肿瘤药物,设计合成系列雌酚酮衍生物并测定其抗肿瘤活性。以雌酚酮为原料,合成7个雌酚酮-17-(靛红取代)腙衍生物。所有合成化合物都通过MS、~1HNMR和~(13)CNMR结构表征。另外,分别选用人肝癌细胞(HepG2)、人宫颈癌细胞(Hela)和人肺癌细胞(A549)对化合物的抗增殖活性进行评价。结果表明,雌酚酮-17-(5-溴靛红)腙对HepG2细胞和Hela细胞具有显著抑制活性,IC_(50)值分别为9. 46μmol/L和7. 30μmol/L。可进一步拓展取代底物,更深入地探索该类化合物的构效关系。     

Insect antifeedant properties of anthranoids from the genusVismia

Vismiones and ferruginins, representatives of a new class of lypophilic anthranoids from the genusVismia were found to inhibit feeding in larvae of species ofSpodoptera, Heliothis, and inLocusta migratoria.     

Direct observation of freeze-thaw instability of latex coatings via high pressure freezing and cryogenic SEM

Despite its industrial importance, the subject of freeze-thaw (F/T) stability of latex coatings has not been studied extensively. There is also a lack of fundamental understanding about the process and the mechanisms through which a coating becomes destabilized. High pressure (2100 bar) freezing fixes the state of water-suspended particles of polymer binder and inorganic pigments without the growth of ice crystals during freezing that produce artifacts in direct imaging scanning electron microscopy (SEM) of fracture surfaces of frozen coatings. We show that by incorporating copolymerizable functional monomers, it is possible to achieve F/T stability in polymer latexes and in low-VOC paints, as judged by the microstructures revealed by the cryogenic SEM technique. Particle coalescence as well as pigment segregation in F/T unstable systems are visualized. In order to achieve F/T stability in paints, latex particles must not flocculate and should provide protection to inorganic pigment and extender particles. Because of the unique capabilities of the cryogenic SEM, we are able to separate the effects of freezing and thawing, and study the influence of the rate of freezing and thawing on F/T stability. Destabilization can be caused by either freezing or thawing. A slow freezing process is more detrimental to F/T stability than a fast freezing process; the latter actually preserves suspension stability during freezing. Presented at the 82nd Annual Meeting of the Federation of Societies for Coatings Technology, October 27–29, 2004 in Chicago, IL. Tied for first place in The John A. Gordon Best Paper Competition.     

Many Drugs of Abuse May Be Acutely Transformed to Dopamine,Norepinephrine and Epinephrine In Vivo

It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as elevated heart rate and blood pressure, more rapid breathing, increased body temperature and sweating, and pupillary dilation, as well as the intoxicating or euphoric subjective properties of the drug. While many drugs of abuse are thought to achieve their intoxicating effects by modulating the monoaminergic neurotransmitter systems (i.e., serotonin, norepinephrine, dopamine) by binding to these receptors or otherwise affecting their synaptic signaling, this paper puts forth the hypothesis that many of these drugs are actually acutely converted to catecholamines (dopamine, norepinephrine, epinephrine) in vivo, in addition to transformation to their known metabolites. In this manner, a range of stimulants, opioids, and psychedelics (as well as alcohol) may partially achieve their intoxicating properties, as well as side effects, due to this putative transformation to catecholamines. If this hypothesis is correct, it would alter our understanding of the basic biosynthetic pathways for generating these important signaling molecules, while also modifying our view of the neural substrates underlying substance abuse and dependence, including psychological stress-induced relapse. Importantly, there is a direct way to test the overarching hypothesis: administer (either centrally or peripherally) stable isotope versions of these drugs to model organisms such as rodents (or even to humans) and then use liquid chromatography-mass spectrometry to determine if the labeled drug is converted to labeled catecholamines in brain, blood plasma, or urine samples.     

Ethanol and (−)-α-Pinene: Attractant Kairomones for Bark and Ambrosia Beetles in the Southeastern US

In 2002–2004, we examined the flight responses of 49 species of native and exotic bark and ambrosia beetles (Coleoptera: Scolytidae and Platypodidae) to traps baited with ethanol and/or (−)-α-pinene in the southeastern US. Eight field trials were conducted in mature pine stands in Alabama, Florida, Georgia, North Carolina, and South Carolina. Funnel traps baited with ethanol lures (release rate, about 0.6 g/day at 25–28°C) were attractive to ten species of ambrosia beetles (Ambrosiodmus tachygraphus, Anisandrus sayi, Dryoxylon onoharaensum, Monarthrum mali, Xyleborinus saxesenii, Xyleborus affinis, Xyleborus ferrugineus, Xylosandrus compactus, Xylosandrus crassiusculus, and Xylosandrus germanus) and two species of bark beetles (Cryptocarenus heveae and Hypothenemus sp.). Traps baited with (−)-α-pinene lures (release rate, 2–6 g/day at 25–28°C) were attractive to five bark beetle species (Dendroctonus terebrans, Hylastes porculus, Hylastes salebrosus, Hylastes tenuis, and Ips grandicollis) and one platypodid ambrosia beetle species (Myoplatypus flavicornis). Ethanol enhanced responses of some species (Xyleborus pubescens, H. porculus, H. salebrosus, H. tenuis, and Pityophthorus cariniceps) to traps baited with (−)-α-pinene in some locations. (−)-α-Pinene interrupted the response of some ambrosia beetle species to traps baited with ethanol, but only the response of D. onoharaensum was interrupted consistently at most locations. Of 23 species of ambrosia beetles captured in our field trials, nine were exotic and accounted for 70–97% of total catches of ambrosia beetles. Our results provide support for the continued use of separate traps baited with ethanol alone and ethanol with (−)-α-pinene to detect and monitor common bark and ambrosia beetles from the southeastern region of the US.     

Novel polyurethane coating technology through glycidyl carbamate chemistry

Glycidyl carbamate chemistry combines the excellent properties of polyurethanes with the crosslinking chemistry of epoxy resins. Glycidyl carbamate functional oligomers were synthesized by the reaction of polyfunctional isocyanate oligomers and glycidol. The oligomers were formulated into coatings with several amine functional crosslinkers at varying stoichiometric ratios and cured at different temperatures. Properties such as solvent resistance, hardness, and impact resistance were dependent on the composition and cure conditions. Most coatings had an excellent combination of properties. Studies were carried out to determine the kinetics of the curing reaction of the glycidyl carbamate functional oligomers with multifunctional and model amines. Detailed kinetic analysis of the curing reactions was also undertaken. The results indicated that the glycidyl carbamate functional group is more reactive than a glycidyl ether group. Presented at the 82nd Annual Meeting of the Federation of Societies for Coatings Technology, on October 27–29, 2004, in Chicago, IL.