Pharmaceutical Fronts最新文献_第9页

Efficient Synthesis and Docking Analysis of Selective CDK9 Inhibitor NVP-2 选择性CDK9抑制剂NVP-2的高效合成及对接分析

Pharmaceutical Fronts Pub Date : 2021-06-01 DOI: 10.1055/s-0041-1735144

Abdusaid Saidahmatov, Xuefeng Liang, Yuqiang Shi, Xu Han, Hong Liu

{"title":"Efficient Synthesis and Docking Analysis of Selective CDK9 Inhibitor NVP-2","authors":"Abdusaid Saidahmatov, Xuefeng Liang, Yuqiang Shi, Xu Han, Hong Liu","doi":"10.1055/s-0041-1735144","DOIUrl":"https://doi.org/10.1055/s-0041-1735144","url":null,"abstract":"Abstract Graphical Abstract NVP-2 (1), a potent and selective inhibitor of cyclin-dependent kinase 9 (CDK9), showed potent antitumor activity in preclinical studies. In this work, we designed and adopted a convergent synthetic route to efficiently synthesize NVP-2 (1). The key intermediate (7) was synthesized from malononitrile (2) and 1-bromo-2-(2-bromoethoxy)ethane (3) by successive cyclization, reduction, nucleophilic substitution with 2-bromo-6-fluoropyridine, and Suzuki–Miyaura reaction with (5-chloro-2-fluoropyridin-4-yl)boronic acid. Another key intermediate (11) was synthesized from (S)-1-methoxypropan-2-ol (8) by reaction with TsCl, electrophilic substitution reaction with tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate, and then by deprotection of Boc. Finally, a substitution reaction by the key intermediates (7) and (11) to afford the target product NVP-2 (1). The reaction conditions of the whole synthesis process were simple and mild, free of harsh conditions such as the microwave reaction and dangerous reagents in the original patent, and realized the efficient synthesis of NVP-2. In addition, we analyzed the binding mode of NVP-2 in the active pocket of CDK9 to provide reasonable design ideas for subsequent discovery of novel CDK9 inhibitors.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"20 1","pages":"e50 - e55"},"PeriodicalIF":0.0,"publicationDate":"2021-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79210760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Novel Telescoped Kilogram-Scale Process for Preparation of Obeticholic Acid 一种可伸缩的公斤级制备奥贝胆酸的新工艺

Pharmaceutical Fronts Pub Date : 2021-06-01 DOI: 10.1055/s-0041-1731757

Chengwei Li, Cai Wang, Chao Guo, Binhua Lv, You-fu Luo

引用次数: 0

Synthesis of a Novel PTH1–34 Analog with Increased Human Serum Albumin Affinity 提高人血清白蛋白亲和力的新型PTH1-34类似物的合成

Pharmaceutical Fronts Pub Date : 2021-03-01 DOI: 10.1055/s-0041-1731299

Sida Ruan, Yuanzhen Dong, Jianguang Lu, Menglu Zhao, Wei-gen Lu, Jun Feng

{"title":"Synthesis of a Novel PTH1–34 Analog with Increased Human Serum Albumin Affinity","authors":"Sida Ruan, Yuanzhen Dong, Jianguang Lu, Menglu Zhao, Wei-gen Lu, Jun Feng","doi":"10.1055/s-0041-1731299","DOIUrl":"https://doi.org/10.1055/s-0041-1731299","url":null,"abstract":"Abstract Parathyroid hormone (PTH)1–34 is an effective peptide drug for osteoporosis therapy. However, the half-life of PTH1–34 in vivo is short, leading to the need for frequent injections of this drug during its treatment. To prolong the half-life of PTH1–34, a novel PTH1–34 analog was generated based on fatty acid generation, and its synthesis process included recombinant protein expression, side-chain modification, and peptide decoration. The PTH1–34 variant was expressed in Escherichia coli, with a single Lys (position 27) retained as a modification site. The side chain, –AEEA-γGlu-C18 diacid, was synthesized using 2-chlorotrityl chloride resin as a solid support, and then was conjugated to the PTH1-34 variant to form PTH-Lys27-AGC. Reversed-phase chromatography confirmed a high final purity (>98%) of the target compound; in vitro bioactivity tests showed that PTH-1 receptor potency of PTH-Lys27-AGC was comparable to that of the native PTH1–34. A competitive human serum albumin binding test demonstrated a high albumin affinity of PTH-Lys27-AGC in comparison to PTH1–34. In summary, we developed a novel PTH1–34 analog, PTH-Lys27-AGC, which may be a long-acting agent for osteoporosis treatment in the future.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"16 1","pages":"e23 - e29"},"PeriodicalIF":0.0,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88821868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

The Expression of Recombinant Human Serum Albumin in the Mammary Gland of Transgenic Mice 重组人血清白蛋白在转基因小鼠乳腺中的表达

Pharmaceutical Fronts Pub Date : 2021-03-01 DOI: 10.1055/s-0041-1730985

Guihua Gong, Shuang-ting Han, Xiaoting Huang, Liqi Xie, Wei Zhang, Lei Xu, Youjia Hu

{"title":"The Expression of Recombinant Human Serum Albumin in the Mammary Gland of Transgenic Mice","authors":"Guihua Gong, Shuang-ting Han, Xiaoting Huang, Liqi Xie, Wei Zhang, Lei Xu, Youjia Hu","doi":"10.1055/s-0041-1730985","DOIUrl":"https://doi.org/10.1055/s-0041-1730985","url":null,"abstract":"Abstract Human serum albumin (HSA) is widely used in the clinic for the treatment of several diseases in large amount each year. With the increasing demands of HSA in clinic and limited blood resource, recombinant HSA (rHSA) is becoming an attractive and alternative source for HSA production. In this study, we aimed to express rHSA in the mammary glands of transgenic mice by using a tissue-specific promoter and other regulatory elements. An rHSA expression vector was constructed bearing the cDNA and first intron of HSA under the control of bovine αs1-casein promoter with a 2 × chicken β-globin insulator in the front. Transgenic mice were generated and reverse transcription polymerase chain reaction showed that rHSA was expressed only in the mammary gland, indicating the tissue specificity of the bovine αs1-casein promoter in directing transgene transcription in transgenic mice. Enzyme-linked immunosorbent assay test showed that rHSA was successfully secreted into the milk of transgenic mice with the highest level at 1.98 ± 0.12 g/L. Our results indicate the ability of the bovine αs1-casein promoter to induce successful expression of rHSA in the mammary gland of transgenic mice.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"141 1","pages":"e30 - e37"},"PeriodicalIF":0.0,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77399432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and Antitumor Activity of (3-Hydroxyacrylato-O,O′) Diammineplatinum(II) (3-羟基丙烯酸酯-O,O ')二胺铂(II)的合成及抗肿瘤活性

Pharmaceutical Fronts Pub Date : 2021-03-01 DOI: 10.1055/s-0041-1730956

Yongzhi Shu, Jun Lin, Baoquan Zhu, Quan-hai Liu, Bin-Shan Zhou, Haifeng Hu, D. Ju

引用次数: 0

Discovery of SIPI6473, a New, Potent, and Orally Bioavailable Multikinase Inhibitor for the Treatment of Non-small Cell Lung Cancer SIPI6473，一种新的、有效的、可口服的多激酶抑制剂，用于治疗非小细胞肺癌

Pharmaceutical Fronts Pub Date : 2021-03-01 DOI: 10.1055/s-0041-1731081

Xiu Gu, Zixue Zhang, Minru Jiao, Xinrui Peng, Jian-qi Li, Qingwei Zhang

引用次数: 1

Phenolic Constituents from the Stems of Morus nigra and their α-Glucosidase Inhibitory Activities 黑桑茎中酚类成分及其α-葡萄糖苷酶抑制活性

Pharmaceutical Fronts Pub Date : 2021-03-01 DOI: 10.1055/s-0041-1730957

Lingling Wang, Liangjin Xu, Mengjie Ma, Chun-yue Huang, Tong Wu, Xiao Hu

引用次数: 0

Synthesis of Natural Product-Like Tricyclic Higher-Carbon Sugar Nucleosides 天然产物样三环高碳糖核苷的合成

Pharmaceutical Fronts Pub Date : 2021-03-01 DOI: 10.1055/s-0041-1731300

Xiaohan Yuan, Shuai Wang, Xiao-ning Wang, Bin Yu, Hong-min Liu

引用次数: 0

Serum Pharmacochemistry Analysis Combined with Network Pharmacology Approach to Investigate the Antiosteoporosis Effect of Xianlinggubao Capsule in vivo 血清药物化学分析结合网络药理学方法研究仙灵骨保胶囊体内抗骨质疏松的作用

Pharmaceutical Fronts Pub Date : 2020-12-01 DOI: 10.1055/s-0041-1726301

Yun-hui Xu, Yi-Chun Sun, Jie Liu, Huixin Li, Chun-yue Huang, Yuan-Yuan Pang, Tong Wu, Xiao Hu

{"title":"Serum Pharmacochemistry Analysis Combined with Network Pharmacology Approach to Investigate the Antiosteoporosis Effect of Xianlinggubao Capsule in vivo","authors":"Yun-hui Xu, Yi-Chun Sun, Jie Liu, Huixin Li, Chun-yue Huang, Yuan-Yuan Pang, Tong Wu, Xiao Hu","doi":"10.1055/s-0041-1726301","DOIUrl":"https://doi.org/10.1055/s-0041-1726301","url":null,"abstract":"Abstract Xianlinggubao capsule (XLGB) is a traditional Chinese medicine multi-component herbal prescription and has been widely used in osteoporosis (OP) treatment. However, the underlying anti-OP mechanisms of XLGB have not been fully studied. In this study, an ovariectomized rat model of OP was established. The OP rats were orally administrated with XLGB, and then the main absorbed components in serum sample were assessed based on liquid chromatography-tandem mass spectrometry (LC-MS/MS). Subsequently, the potential anti-OP markers in XLGB were screened based on a network pharmacology strategy. Molecular docking analysis was used for confirmation. LC-MS showed 22 absorbed components in the serum sample of OP rat with XLGB treatment. Network pharmacology and pathway analysis suggested 19 potential anti-OP markers in XLGB. According to molecular docking process, most of the potential markers displayed strong interactions with the 22 absorbed components mentioned above. Besides, an absorbed component–potential marker–pathway network was further established. In conclusion, our data suggested the possible mechanisms for XLGB in OP treatment, in which the “multicomponents, multitargets, and multipathways” participated. Our article provided possible direction for drug discovery in OP and could help for exploring novel application of XLGB in clinical setting.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"50 1","pages":"e168 - e178"},"PeriodicalIF":0.0,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80953027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Determination of Tissue Distribution of Alisol G, a CB1R Antagonist, in Rats by Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry 超高效液相色谱-串联质谱法测定CB1R拮抗剂艾利索G在大鼠体内的组织分布

Pharmaceutical Fronts Pub Date : 2020-12-01 DOI: 10.1055/s-0041-1724032

Chengyu Gao, Jianqiang Xi, Dingzhong Song, Jie Yuan, Wusi Hao, Z. Cui, Zhi-hong Cheng

{"title":"Determination of Tissue Distribution of Alisol G, a CB1R Antagonist, in Rats by Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry","authors":"Chengyu Gao, Jianqiang Xi, Dingzhong Song, Jie Yuan, Wusi Hao, Z. Cui, Zhi-hong Cheng","doi":"10.1055/s-0041-1724032","DOIUrl":"https://doi.org/10.1055/s-0041-1724032","url":null,"abstract":"Abstract Peripheral CB1R blockers without crossing the blood–brain barrier (BBB) have demonstrated therapeutic benefits in metabolic syndromes, including obesity. Among them is Alisol G, a tetracyclic triterpene from Alismatis rhizoma (zexie), which can effectively reduce the weight of obese mice. Results from CP55940-induced [35S] GTPγS cannabinoid-type 1 receptor (CB1R) binding assay show an IC50 of 34.8 μmol/L for Alisol G, implicating its role as a CB1R antagonist. The purpose of our study is to assess whether Alisol G could serve as a peripheral CB1R antagonist for obesity treatment. In this study, we build a simple, reliable, and sensitive method to detect the concentration of Alisol G in rat tissue by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The results showed that Alisol G was mainly distributed in intestinal midgut, mucosa and small intestine, with little brain exposure. We suggested that intestine may be the main acting sites of Alisol G. Through comparison of brain and blood concentrations of Alisol G, our data showed that Alisol G cannot penetrate the BBB easily. In conclusion, Alisol G may represent a peripheral CB1R antagonist for the further treatment of obesity.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"101 1","pages":"e179 - e187"},"PeriodicalIF":0.0,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79340559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0