基于海洋天然产物oroidin的结构修饰及其衍生物的抑菌活性研究

目的 针对海洋天然产物oroidin进行衍生物的合成以及抑菌活性评价。 方法 以吡咯-2-羧酸为起始原料,经过卤素取代、酰胺缩合、还原胺化等反应,四步合成oroidin类似物,并对衍生物进行抑菌活性评价。 结果 总计合成了20个衍生物,通过抑菌活性测试,发现了对多种菌株如枯草芽孢杆菌、草分枝杆菌、大肠杆菌等有抑制活性的化合物,其中化合物21和24对枯草芽孢杆菌的MIC值都达到3.125 μmol?L?1。该类化合物可应用于抗菌药物的开发。     

海洋天然产物geodin系列衍生物的细胞毒活性评价及构效关系初步研究(英文）

摘 要：目的 目前癌症仍然是威胁人类健康的恶性疾病之一,临床使用的传统药物通常受到耐药性和副作用的限制,因此寻找新型高效的抗癌药物迫在眉睫。对具有grisan 骨架的海洋天然产物geodin (1) 及其衍生物（2?26）进行了细胞毒活性评价,并探究了其初步构效关系。方法 采用MTT法,用人非小细胞肺癌细胞系A549和人肝癌细胞系HepG2、Bel-7402对geodin (1) 及其衍生物（2?26）进行了细胞毒活性评价。结果 对Geodin 的4-OH修饰后得到的衍生物中,化合物2?4, 6, 7, 9?18和20?25表现出强到中等程度的细胞毒活性,IC50值在0.81 ~ 4.78 μM之间。特别是化合物16,对A549和HepG2细胞表现出强效的细胞毒活性,其IC50值分别为0.86和0.81 μM。结论 化合物16是一种潜在的抗癌先导化合物。     

海洋药物研究进展与发展趋势

迄今,人们已从各类海洋生物中分离获得14 500余种具有各种结构类型的海洋天然产物,其中20种已进入临床研究.运用新的研究方法和技术,开拓新的资源领域,将是解决药源问题的可行途径.笔者概述海洋药物的研究进展,展望海洋药物研究发展趋势.     

Antiviral and anticancer optimization studies of the DNA-binding marine natural product aaptamine

Aaptamine has potent cytotoxicity that may be explained by its ability to intercalate DNA. Aaptamine was evaluated for its ability to bind to DNA to validate DNA binding as the primary mechanism of cytotoxicity. Based on UV-vis absorbance titration data, the K(obs) for aaptamine was 4.0 (+/-0.2) x 10(3) which was essentially equivalent to the known DNA intercalator N-[2-(diethylamino)ethyl]-9-aminoacridine-4-carboxamide. Semi-synthetic core modifications were performed to improve the general structural diversity of known aaptamine analogs and vary its absorption characteristics. Overall, 26 aaptamine derivatives were synthesized which consisted of a simple homologous range of mono and di-N-alkylations as well as some 9-O-sulfonylation and bis-O-isoaaptamine dimer products. Each product was evaluated for activity in a variety of whole cell and viral assays including a unique solid tumor disk diffusion assay. Details of aaptamine's DNA-binding activity and its derivatives' whole cell and viral assay results are discussed.     

一种西沙群岛软珊瑚来源真菌中新天然产物pestalalactone的化学与生物活性研究

目的 从一株中国南海西沙群岛软珊瑚来源的真菌Pestalotiopsis sp. (ZJ-2009-7-6) 中分离鉴定具有生物活性的3-苯基苯并呋喃酮化合物。方法 运用多种色谱分离手段和现代波谱分析方法分离和鉴定化合物,最终得到了一个3-苯基苯并呋喃酮类新天然产物pestalalactone (1),并研究了该化合物在不同温度、不同溶剂条件下的优势构象变化;此外,还对化合物的抗藤壶幼虫Balanua amphitrite附着和抗细菌活性进行了评价。结果 分离鉴定了1个新天然产物 pestalalactone (1),发现该化合物以两种不可拆分的阻转异构体的形式 (1a/1b) 并存;核磁共振氢谱研究后发现在氘代吡啶和氘代氯仿中以1a优势构象存在,在氘代甲醇、氘代丙酮和氘代二甲亚砜中的优势构象却是1b,而温度的变化 (25°C–80°C) 并不引起该化合物构象的变化;该化合物显示出强的抗藤壶幼虫B. amphitrite附着活性,其EC₅₀值为2.30 μg/mL,同时也显示出较强的抗细菌活性,特别是对金黄色葡萄球菌Staphylococcus aureus的最小抑制活性为0.45 μg/mL。结论 从一株西沙群岛软珊瑚来源真菌中发现了一个具有重要抗藤壶幼虫B. amphitrite附着和抗菌活性的新天然产物pestalalactone (1),表明西沙群岛来源的海洋微生物具有重要的药用研究价值和应用开发前景。     

一株海洋真菌Penicillium chrysogenum次级代谢产物及其抗菌活性研究

目的 研究一株南海来源真菌Penicillium chrysogenum的次级代谢产物及抗菌活性。方法 运用硅胶柱层析、Sephadex LH-20凝胶柱层析和HPLC半制备等方法对次级代谢产物进行分离和纯化;通过NMR、MS等方法鉴定化合物结构;利用抗菌活性模型对其进行活性评价。结果 从真菌P. chrysogenum中分离鉴定了5个化合物,包括一个结构复杂的生物碱taichunamide H (1),一个带有脂肪链的蒽醌1-O-methyl-averantin (2),两个聚酮类化合物versicone A (3)和 versicone B (4) 以及一个联苯醚diorcinol (5);其中,2对致病菌Canidia albicans和 Staphylococcus aureus具有显著的抑制活性,MIC值分别为6.25 μM和12.5 μM;5对海洋污损菌Photobacterium halotolerans显示抑制活性,MIC值为 50 μM。结论 化合物3和 4为首次从青霉菌中分离得到;化合物2具有显著的抗菌活性,具有重要的研究和潜在开发价值。     

非曲霉(青霉)属海洋真菌新天然产物(1951-2014)

海洋真菌来源的天然产物因其化学结构新颖和生物活性多样成为极具潜力的药物开发资源,受到研究者的广泛关注。本文综述了从20世纪50年代头孢菌素类抗生素发现开始至2014年8月间已经报道的1123个非曲霉(青霉)属海洋真菌新天然产物的来源、结构及其生物活性。     

Low cytotoxicity of ecteinascidin 743 in yeast lacking the major endonucleolytic enzymes of base and nucleotide excision repair pathways

Ecteinascidin 743 (ET-743) is a promising antitumoral drug for the treatment of soft tissues sarcomas, becoming a good candidate for clinical trials. However, the molecular mechanism of how ET-743 induces cells death is poorly understood. The chemical structure of ET-743 suggests that it can form cytotoxic cross-links with proteins and DNA. Experiments with Escherichia coli and mammalian cells indicate that the nucleotide excision repair (NER) pathway promotes ET-743 cytotoxicity. We therefore analyzed cytotoxicity and tolerance to ET-743 in the yeast Saccharomyces cerevisiae, defective for NER and/or base excision repair (BER), either in single mutants or in combination with mutant alleles of genes encoding proteins involved in DNA translesion synthesis (TLS) and homologous recombination (HR). Treatment of haploid and diploid S. cerevisiae strains with ET-743 led to induced mutagenesis, mitotic gene conversion, and crossing-over. The results indicated that yeast strains lacking endonucleases of the NER and BER pathways are especially resistant for ET-743. The mutagenesis data points to a weak mutagenic activity of ET-743 in both WT and strains lacking BER/NER endonuclease, and that a mutant blocked in both BER and TLS totally lacks induced mutagenesis. The diploid strain shows an increase in the frequencies of crossing-over and mitotic recombination. These data lead us to propose a model for ET-743 action in eukaryotic cells, where the presence of BER and NER endonucleases results in cell death. However, ET-743 damage can be tolerated in BER and/or NER mutants by TLS (error-prone) or in combination with HR (error-free).     

诺斯卡品逆转人卵巢癌裸鼠移植瘤对顺铂耐药的作用及机制

目的：探讨微管抑制剂诺斯卡品（ NOS ）逆转人卵巢癌细胞株 SKOV3/DDP 裸鼠皮下移植瘤对顺铂（ DDP）耐药的作用及其机制。方法建立人卵巢癌裸鼠移植瘤模型,分为对照组、DDP组、NOS组、NOS与DDP联合组,每组6只。观察各组裸鼠饮食和精神状态,测量裸鼠的体重及移植瘤的体积,并绘制肿瘤生长曲线。用网搓法制备单细胞悬液,采用流式细胞术检测移植瘤细胞周期和细胞凋亡率的变化,细胞中X链锁凋亡抑制蛋白（ XIAP ）、半胱氨酸天冬氨酸蛋白酶（Caspase-3）、B细胞淋巴瘤/白血病-2（Bcl-2）和生存素（Survivin）蛋白表达。结果联合组裸鼠移植瘤体积明显小于对照组和其他用药组（ P ＜0ⅱ．05）。与对照组和DDP组比较,联合组皮下移植瘤细胞凋亡率显著增加（ P ＜0．05）,G2/M期细胞比例增多（ P ＜0．05）,细胞中XIAP、Bcl-2和Survivin蛋白表达降低（ P ＜0．05）, Caspase-3蛋白表达升高（ P ＜0．05）。结论 NOS增加了移植瘤细胞对DDP的敏感性,逆转其对DDP的多药耐药,其机制可能与XIAP、Bcl-2和Survivin蛋白表达的下调,Caspase-3蛋白表达的上调有关。     

卵巢癌患者血清CEA CA125 HE4 CA724联合检测的临床价值

目的:探讨血清CEA,CA125,HE4,CA724联合检测对早期卵巢癌患者诊断的临床价值。方法:选取45例健康体检者、45例卵巢癌患者和45例卵巢良性病变患者,采用酶联免疫法对所有患者血清CEA,CA125,HE4和CA724进行检测。结果:CEA,CA125,HE4和CA724水平卵巢癌患者血清明显比健康患者和卵巢良性病变患者水平高,组间比较差异有统计学意义,P<0.05;健康体检者血清与卵巢良性病变患者比较,差异无统计学意义,P>0.05。结论:血清CEA,CA125,HE4和CA724联合检测对早期卵巢癌患者诊断具有重要意义。     

多柔比星脂质体联合贝伐珠单抗治疗铂类耐药型复发性卵巢癌的临床疗效和安全性观察

目的 观察多柔比星脂质体联合贝伐珠单抗治疗铂类耐药型复发性卵巢癌患者的临床疗效及安全性。方法 选取我院2017年1月—2018年12月收治的76例铂类耐药型复发性卵巢癌患者,采用随机数字分组法分为对照组和观察组,每组38例。对照组患者给予多西他赛联合贝伐珠单抗化疗6个周期,观察组患者给予多柔比星脂质体联合贝伐珠单抗化疗6个周期。比较两组患者的临床疗效,药物不良反应,血清人附睾蛋白4(HE4)、糖类抗原125(CA125)水平变化,以及中位生存期（mOS）和中位无疾病进展生存期（mPFS）。结果 治疗后,观察组患者疾病控制率（DCR）、客观有效率（ORR）分别为76.32%、57.89%,高于对照组的52.63%、31.58%(P<0.05)。观察组患者血清HE4、CA125水平均低于对照组（P<0.05）。对照组患者恶心呕吐、白细胞减少、乏力等药物不良反应发生率高于观察组（P<0.05）,但观察组心脏毒性发生率高于对照组（P<0.05）。两组患者血小板减少、肝肾功能损伤、高血压等不良反应发生率相比较,差异无统计学意义（P>0.05）。观察组患者mOS、mP...     

Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.     

Innovation in Chemistry,Manufacturing, and Controls—A Regulatory Perspective From Industry

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.