黄芩素氨基酸衍生物的合成及体外细胞毒活性评价（英文）

目的：合成天然产物黄芩素的氨基酸衍生物并进行体外抗肿瘤活性评价。方法：氨基酸经酯化和酰化,在吡啶溶液中通过甲醛与黄芩素反应,制得黄芩素8位引入氨基酸侧链的衍生物;氨基酸经羧基保护和氨基酰化、黄芩素经羟基保护,制得黄芩素6位引入氨基酸侧链的衍生物。衍生物结构经质谱（MS）、核磁共振光谱（NMR）和红外光谱（IR）确证。结果：设计合成了未见文献报道的13个新的黄芩素衍生物,采用MTT法评价了目标化合物对人肝癌细胞HepG2生长的抑制活性。结论：化合物4c,4d,7a和7b显示较黄芩素高的体外抗肿瘤活性。     

关于4-苯基氨基喹唑啉衍生物的合成及体外抗白血病的活性研究

抗菌活性的喹唑啉类化合物在治疗癌症等方面表现出的抗菌性一直备受关注.本文以苯胺喹唑啉类化合物分子,以JANEX-1为先导化合物,结构修饰两个系列共18个目标化合物.合成了6个未见文献报道的关键中间体,其结构通过1H-NMR证实.体外抗人白血病K562细胞实验表明,目标化合物抗白血病活性高于JANEX-1.     

蛇床子素提取制备工艺的研究

蛇床子素 (Osthol)是伞形科植物蛇床子果实的主要有效成分 ,具有广谱抗菌作用。目的 :研究蛇床子素的提取工艺。方法 :采用水煎醇沉法、醇提水沉法、氯仿复提法三种方法提取蛇床子素 ,并对收膏率、含量、蛇床子素收率进行比较。结果 :水煎醇沉法不适宜作蛇床子素的提取方法 ;醇提水沉法蛇床子素含量 31.72 % ,收率95 .74 % ,适合作大生产或实验室的提取方法 ,氯仿复提法蛇床子素含量 6 3.85 % ,收率 94 .2 2 % ,适合制备高含量的蛇床子素。结论 :醇提水沉法和氯仿复提法是蛇床子素的良好提取方法。     

蛇床子素制备方法的研究

目的优选超临界CO2萃取蛇床子中蛇床子素工艺,建立制备型高效液相色谱(PHPLC)分离纯化萃取物中蛇床子素的方法。方法以总萃取物得率和萃取物中蛇床子素的量为指标,选取温度、压力和提取次数3个因素,按L9(34)正交设计优选蛇床子素超临界CO2萃取工艺。萃取物经甲醇超声溶解后,采用PHPLC法,色谱柱为:Zorbax SB-C18柱(250 mm×21.2 mm,7μm),流动相为甲醇-水(70∶30),柱温为25℃,体积流量为15 mL/min,检测波长为322 nm,进样量为5 mL,收集蛇床子素馏份,经真空冷冻干燥得蛇床子素单体。结果最佳萃取工艺为:温度50℃,压力25 MPa,提取3次(每次1 h),PHPLC法制备的蛇床子素用面积归一化法与外标法定量,质量分数为98.8%,1H-NMR鉴定结构,与文献数据一致。结论超临界CO2萃取蛇床子中蛇床子素提取效果好,工艺简单可行,PHPLC法制备高纯度蛇床子素,简便快捷,并适于大规模制备蛇床子素。     

毛叶假鹰爪素CB环衍生物的合成与抗肿瘤活性评价

 目的 合成具有抗肿瘤活性的毛叶假鹰爪素C的B环衍生物。方法 以2,4,6-三羟基苯乙酮为原料,经甲基化、O-甲基化、羟醛缩合3步反应制得目标产物,并以6个人肿瘤细胞株进行抗增殖活性评价。结果 制备了14个目标化合物,其中9个为新化合物。经¹H-NMR、¹³C-NMR,MS确证结构。结论 初步活性研究表明,除1i的目标化合物均具有一定程度的抗肿瘤活性,1h和1n活性优于毛叶假鹰爪素C,B环引入两个F原子对化合物抗肿瘤活性具有一定贡献。     

蛇床子化学成分的研究

从蛇床子醇提物中经硅胶柱层析分得5个结晶性化合物，经鉴定分别为佛手柑内酯（bergapten，Ⅰ）、蛇床子素（osthol，Ⅱ）、异虎耳草素（isopimpinellin，Ⅲ）、cnidimolB（Ⅳ）和别异欧前胡素（alloisoimperatorin，Ⅴ）。其中cnidimolB为非香豆素成分，其结构为色原酮，化合物Ⅴ是首次从该植物中分得。     

合成阿奇霉素工艺的改进

以红霉素肟A（I）为原料，经贝克曼重排制得红霉素醚化物，再采用金属催化剂还原，均不提出中间体，直接甲基化反应制得阿奇霉素（V），再经丙酮重结晶制得阿奇霉素二水化合物，总收率83．3％，HPLC纯度98．1％。     

蛇床子及其主要成分蛇床子素的抗过敏作用

研究发现蛇床子70％乙醇提取物及其中的2个香豆素衍生物蛇床子素、异茴香素均对化合物48/80诱导皮肤瘙痒有抑制作用,而不影响动物自发活动。本次采用鼠过敏模型研究蛇床子提取物(CM-ext)及其主要成分蛇床子素对与瘙痒相关的过敏反应的作用。     

淡豆豉抗菌活性及化学成分分析

目的:研究传统发酵中药淡豆豉的抗菌活性及化学成分。方法:淡豆豉80%乙醇提取物用适量蒸馏水混悬,依次用石油醚、乙酸乙酯及水饱和正丁醇萃取,得石油醚、乙酸乙酯、正丁醇萃取部分及水层,利用体外抗菌法筛选和追踪抗菌活性部分,采用硅胶柱色谱等方法及制备HPLC对抗菌活性最强部分进行分离纯化,得单体化合物,并根据化合物的理化性质和1H-NMR,13C-NMR,MS等波谱数据鉴定其结构。结果:淡豆豉80%乙醇提取物的乙酸乙酯萃取部分显示最强的抗菌活性,该有效部分对呼吸道致病菌及其他常见致病菌均显示较强的抗菌活性,正丁醇萃取部分和石油醚萃取部分次之。从乙酸乙酯萃取部分分离得到18个化合物,鉴定了其中11个化合物的化学结构,分别为大豆素(1),大豆苷(2),染料木素(3),染料木苷(4),黄豆黄素(5),黄豆黄苷(6),胡萝卜苷(7),胸腺嘧啶(8),腺嘌呤(9),尿嘧啶(10),尿苷(11)。结论:淡豆豉80%乙醇提取物的乙酸乙酯萃取部分抗菌效果明显。化合物1～6为异黄酮类;化合物7～11为首次从该药材中分离得到。     

抗肿瘤氟喹诺酮C-3(稠)杂环化合物双NFDE6二唑甲硫醚及其碘甲烷盐衍生物的合成(Ⅰ)

目的 寻找由抗菌氟喹诺酮向抗肿瘤氟喹诺酮转化的有效结构修饰途径。方法 以抗菌氟喹诺酮药物氧氟沙星1为原料,其相应的酰肼2与二硫化碳缩环合得C-3NFDE6二唑硫醇3中间体,然后分别与5-取代苯基-2-氯甲基-1,3,4-NFDE6二唑4a~4g缩合得含氟喹诺酮骨架的双NFDE6二唑甲硫醚5a~5g,接着用碘甲烷进行季铵化反应得相应的季铵盐6a~6g。用MTT方法评价了目标化合物5a~5g和6a~6g体外对肿瘤细胞的生长抑制活性。结果 合成了14个新的目标化合物,体外均显示潜在的抗癌活性（IC₅₀＜25 μmol·L）,其中季铵盐6a~6g的活性高于相应游离碱5a~5g的活性。结论 基于抗菌氟喹诺酮C-3杂环的抗肿瘤氟喹诺酮的设计值得进一步研究。     

氟喹诺酮C-3酰腙的合成与抗菌活性

 目的 评价氟喹诺酮C-3位羧基被酰腙替代对其抗菌活性影响,为进一步扩大结构修饰提供新的途径。方法 第三代氟喹诺酮类药物氧氟沙星及环丙沙星为起始原料,经肼解成其相应的酰肼,然后分别与芳香醛进行缩合得系列C-3酰腙目标化合物。用琼脂稀释法研究了目标化合物体外对标准菌株金黄色葡萄球菌(S. aureus ATCC29213)、大肠埃希氏菌(E. coli ATCC25922)、铜绿假单孢菌(P. aeruginosa ATCC2785)的生长抑制活性。结果 合成了12个新的目标酰腙化合物,体外活性结果表明,氧氟沙星类酰腙化合物表现出较弱的体外抗菌活性(其MIC＞128 μg·mL^-1),而多数环丙沙星类酰腙化合物却表现出较强的体外抗菌活性(其MIC＞8 μg·mL^-1),尤其是香草醛环丙酰腙(5d)对S. aureus及E. coli的MIC≥0.5 μg·mL^-1,对P. aeruginosa的MIC≥1.0 μg·mL^-1,其抗菌活性与对照环丙沙星相当(MIC≥0.5 μg·mL^-1),而优于氧氟沙星(MIC≥2.0 μg·mL^-1)。结论 抗菌药氟喹诺酮C-3位羧基被其他取代基替代值得进一步研究。
     

Two New Xanthones from Hypericum sampsonii and biological activity of the isolated compounds

Phytochemical investigation of the CH₂Cl₂ extract of the aerial part of Hypericum sampsonii yielded two new prenylated xanthones, hypericumxanthone A and B, together with three known xanthones. Their structures were elucidated by analysis of physical and spectral (UV, IR, mass and NMR) data and comparison of spectroscopic data with those reported previously. All these compounds were evaluated for in vitro antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA). Two new compounds were also tested for their cytotoxicity against human breast (MCF‐7), hepatoma (HepG2), colon (HT‐29) and lung (A549) tumour cell lines. Two new compounds showed moderate antibacterial activities at minimum inhibitory concentrations (MIC) of 16 and 32 µg/mL, respectively, whereas the positive standard antibacterial drug, vancomycin, showed an MIC of 8 µg/mL. The other compounds were inactive against MRSA. In addition, hypericumxanthone B showed weak inhibitory activities against four human tumour cell lines. Copyright © 2010 John Wiley & Sons, Ltd.     

In Vitro Antibacterial Activity and Synergistic Antibiotic Effects of Phlorotannins Isolated from Eisenia bicyclis Against Methicillin‐Resistant Staphylococcus aureus

Six phlorotannins, isolated from Eisenia bicyclis, were evaluated for antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentrations (MIC) of the compounds were in the range 32 to 64 µg/mL. Phlorofucofuroeckol‐A (PFF) exhibited the highest anti‐MRSA activity, with an MIC of 32 µg/mL. An investigation of the interaction between these compounds and the β‐lactam antibiotics ampicillin, penicillin, and oxacillin revealed synergistic action against MRSA in combination with compound PFF. To our knowledge, this is the first report on the anti‐MRSA activity of phlorotannins from E. bicyclis. The results obtained in this study suggest that the compounds derived from E. bicyclis can be a good source of natural antibacterial agents against MRSA. Copyright © 2012 John Wiley & Sons, Ltd.     

Antibacterial activity and synergistic antibiotic mechanism of trialdehyde phloroglucinol against methicillin-resistant Staphylococcus aureus

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has become a critical global concern. Identifying new anti-S. aureus agents or therapeutic strategies are urgently needed to treat S. aureus infection. The present study investigated the antibacterial activity of 16 phenolic compounds against MRSA, four of which exhibited antibacterial activity. Their antibacterial activities increased in a dose-dependent manner but showed different responses with the extension of treatment time. Trialdehyde phloroglucinol (TPG) and 2-nitrophloroglucinol (NPG) maintained stable antibacterial activity; however, that of dichlorophenol and myricetin decreased rapidly over 24 hr of treatment. Checkerboard and time-kill assays indicated that TPG and NPG exhibited strong synergistic antibacterial activities with penicillin or bacitracin. Microscopic observation and membrane integrity analysis showed that the combination of TPG and penicillin destroyed the MRSA cell membrane, resulting in the leakage of intracellular biomacromolecules, marked changes in surface zeta potential, and the collapse of membrane potential. Moreover, the combination significantly decreased penicillinase activity and penicillin-binding protein 2a mRNA expression, inhibiting MRSA growth. Taken together, these results demonstrated that the combination of the phloroglucinol derivative TPG and penicillin has significant synergistic anti-MRSA activity and can serve as a potential therapeutic strategy to treat MRSA infections.     

Antimicrobial activities of naphthazarins from Arnebia euchroma

Bioassay-directed fractionation of extract of Arnebia euchroma led to the isolation of alkannin (1), shikonin (2), and their derivatives (3-8) as the active principles against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The stereochemistry of alpha-methylbutyryl alkannin (8) is revealed for the first time, and the antimicrobial activity of 8 was compared with its corresponding diastereomer (9). The derivatives 3-9 showed stronger anti-MRSA activity [minimum inhibitory concentrations (MICs) ranged from 1.56 to 3.13 microg/mL] than alkannin or shikonin (MIC = 6.25 microg/mL). Anti-MRSA activity of derivatives was bactericidal with minimum bactericidal concentration (MBC)/MIC < or = 2. In a time-kill assay, the bactericidal activity against MRSA was achieved as rapidly as 2 h. The derivatives 3-9 were also active against vancomycin-resistant Enterococcus faecium (F935) and vancomycin-resistant Enterococcus faecalis (CKU-17) with MICs similar to those with MRSA. Aromatic ester derivatives were also synthesized for antimicrobial activity comparison. None of these compounds were active against Gram-negative bacteria tested. Their cytotoxicity was also evaluated on selected cancer cell lines, and they expressed their activity in the range 0.6-5.4 microg/mL (CD(50)). Our results indicate that the ester derivatives of alkannin are potential candidates of anti-MRSA and anti-VRE agents with antitumor activity.     

4-氨基-2-三氟甲基喹唑啉衍生物的合成及其体外抗肿瘤活性研究

目的 基于喹唑啉为母核设计发现新型抗肿瘤活性化合物。方法 以邻氨基苯甲酰胺和三氟乙酸酐为起始原料采用缩合、环化、氯代和偶联反应等合成了一系列4-氨基-2-三氟甲基喹唑啉衍生物(5a~5u)。采用四甲基偶氮唑盐(MTT)法评价所得目标化合物对人肺癌细胞A549、人宫颈癌细胞Hela、人白血病细胞K562、人前列腺癌细胞PC-3、人前列腺癌细胞LNCaP这5种肿瘤细胞的体外增殖抑制活性。结果 化合物5c在5 μmol·L^-1时对PC-3肿瘤细胞的抑制率为49.3%,化合物6a对LNCaP和K562、以及6b对PC-3的抑制率超过了50.0%。结论 本实验设计合成的4-氨基-2-三氟甲基喹唑啉类化合物多数具有一定的抗肿瘤活性,特别是4-氨基的N-甲基化产物6a、6b的体外抗肿瘤活性较原型化合物(5n与5u)显著增强,为该类化合物的进一步研究提供参考。     

Bioactive acylphloroglucinols from Hypericum densiflorum

Three acylphloroglucinol derivatives have been isolated from the hexane and acetone extracts of the aerial parts of Hypericum densiflorum Pursch. The compounds were characterized by NMR spectroscopy and mass spectrometry and identified as 4‐geranyloxy‐2,6‐dihydroxybenzophenone (1), 4‐geranyloxy‐1‐(2‐methylpropanoyl)‐ phloroglucinol (2) and 4‐geranyloxy‐1‐(2‐methylbutanoyl)‐phloroglucinol (3). Compounds 1–3 were evaluated for in vitro cell proliferation inhibitory activity against human breast (MCF‐7), lung (NCI H460), CNS (SF‐268), stomach (AGS) and colon (HCT‐116) tumor cell lines; antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA); inhibition of cyclooxygenase (COX‐1 and ‐2) enzymes; and antioxidant activity in the lipid peroxidation (LPO) assay. All three compounds showed moderate to strong antitumor, antibacterial, antioxidant and inhibition of COX‐2 activities. Also, this is the first reported occurrence of compound 3 in the Hypericum genus. Copyright © 2009 John Wiley & Sons, Ltd.     

Phytochemical studies on Stemona aphylla: isolation of a new stemofoline alkaloid and six new stemofurans

A new stemofoline alkaloid, (2'S)-hydroxy-(11S,12R)-dihydrostemofoline (3), new stemofurans M-R (8-13), and known compounds stemofoline (1), (2'S)-hydroxystemofoline (2), stemofuran E (4), stemofuran F (5), stemofuran J (6), and stilbostemin F (7) have been isolated from the root extracts of Stemona aphylla. The structures and relative configurations of these new compounds have been determined by spectroscopic data interpretation and from semisynthetic studies. These natural and semisynthetic alkaloids were tested for acetylcholinesterase inhibitory activities and were found to be 10-20 times less active than 1',2'-didehydrostemofoline itself. Stemofurans 4, 6, 8, 11, and 13 were tested for their antibacterial and antifungal activities. Three of these showed antibacterial activities against MRSA with MIC values of 15.6 μg/mL.     

Antibacterial activity of Curcuma longa L. against methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) has been emerging worldwide as one of the most important hospital and community pathogens. Therefore, new agents are needed to treat MRSA associated infections. The present study investigated the antimicrobial activity of ethyl acetate, methanol and water extracts of Curcuma longa L. (C. longa) against MRSA. The ethyl acetate extract of C. longa demonstrated a higher antibacterial activity than the methanol extract or water extract. Since the ethyl acetate extract was more active than the other extracts, the study examined whether the ethyl acetate extract could restore the antibacterial activity of beta-lactams and alter the MRSA invasion of human mucosal fibroblasts (HMFs). In the checkerboard test, the ethyl acetate extract of C. longa markedly lowered the MICs of ampicillin and oxacillin against MRSA. In the bacterial invasion assay, MRSA intracellular invasion was significantly decreased in the presence of 0.125-2 mg/mL of C. longa extract compared with the control group. These results suggest that the ethyl acetate extract of C. longa may have antibacterial activity and the potential to restore the effectiveness of beta-lactams against MRSA, and inhibit the MRSA invasion of HMFs.     

绿原酸衍生物的合成及体外抗肿瘤活性研究

目的设计并合成天然产物绿原酸的酰胺类衍生物,并对该系列化合物进行体外抗肿瘤活性研究。方法以绿原酸为起始原料,经保护、缩合、脱保护3步反应制得目标产物。采用噻唑蓝(MTT)法,考察所合成的目标化合物对人宫颈癌HeLa细胞、人肝癌HepG2细胞和人盲肠腺癌HCT-8细胞3种肿瘤细胞的体外增殖活性的影响。结果设计并合成了10个绿原酸取代的苯甲酰胺及苯乙酰胺类衍生物B1~B5、C1~C5,其结构均经1H-NMR、13C-NMR及HR-ESI-MS确定。抗肿瘤活性测试结果表明,10个绿原酸衍生物对3株肿瘤细胞株表现出不同程度的抑制效果,其中衍生物B2对HeLa细胞表现出良好的活性,且活性优于阳性对照药顺铂,所有的衍生物均对HCT-8细胞表现出抑制作用,且均优于阳性对照药顺铂。结论10个绿原酸衍生物均为新化合物,部分衍生物具有较好的抗肿瘤活性,值得进一步深入研究。