Cancer cells with varied KRAS mutations exhibit different sensitivity to SHP2 inhibition. A recent work published in Nature Communications revealed the underlying drug resistance mechanism of cancer cells harboring KRAS Q61H mutation to SHP2 inhibitors (SHP2i). 1 This work showed that KRAS Q61H mutation renders cancer cells resistant to SHP2i via decoupling KRAS from SHP2-mediated upstream nucleotide exchange factors for (guanine nucleotide exchange factor [GEF])/GTPase activating protein (GAP) regulation, providing newinsightsintotreatingcancerswithKRASQ61Hmutations. KRAS, the most frequently mutated RASisoform, isa proto-oncogene that encodes small GTPase transductor protein. In response to upstream signals, KRAS can switch between inactive guanosine diphosphate (GDP) state and active guano-sinetriphosphate (GTP) stateby GEFs, such as Sonof Sevenless (SOS),orGAPs. 2 KRASmutations,primarilyatcodons12,13,or 61, account for 86% of RAS mutations. In particular, glutamine
{"title":"KRAS Q61H Mutation Confers Cancer Cells with Acquired Resistance to SHP2 Inhibition","authors":"Yi-Hui Song, Xin-yu Yang, Bin Yu","doi":"10.1055/s-0042-1743411","DOIUrl":"https://doi.org/10.1055/s-0042-1743411","url":null,"abstract":"Cancer cells with varied KRAS mutations exhibit different sensitivity to SHP2 inhibition. A recent work published in Nature Communications revealed the underlying drug resistance mechanism of cancer cells harboring KRAS Q61H mutation to SHP2 inhibitors (SHP2i). 1 This work showed that KRAS Q61H mutation renders cancer cells resistant to SHP2i via decoupling KRAS from SHP2-mediated upstream nucleotide exchange factors for (guanine nucleotide exchange factor [GEF])/GTPase activating protein (GAP) regulation, providing newinsightsintotreatingcancerswithKRASQ61Hmutations. KRAS, the most frequently mutated RASisoform, isa proto-oncogene that encodes small GTPase transductor protein. In response to upstream signals, KRAS can switch between inactive guanosine diphosphate (GDP) state and active guano-sinetriphosphate (GTP) stateby GEFs, such as Sonof Sevenless (SOS),orGAPs. 2 KRASmutations,primarilyatcodons12,13,or 61, account for 86% of RAS mutations. In particular, glutamine","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82597373","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}
Guan Wang, Jin Li, Xiaoli Pan, Faqian Bu, Yufei Zhu, Ao-xue Wang, L. Ouyang
Tyrosinase (EC 1.14.18.1) plays an indispensable role in the rate-limiting steps of melanin biosynthesis, and its uncontrolled activity may result in various diseases, such as albinism, melanoma, freckles, etc. The inhibition of tyrosinase activity may provide a useful and efficient strategy to treat hyperpigmentation disorders. However, the widely used tyrosinase inhibitors, like α-arbutin, hydroquinone, and kojic acid, have many shortcomings, such as lower efficacy and much more side effects. Herein, we reported the use of homology modeling and multistep structure-based virtual screening for the discovery of novel tyrosinase inhibitors. In this study, 10 initial potential hits (compounds T1–T10) were evaluated for enzyme inhibition and kinetic study, with kojic acid being used as a control. Among them, the IC50 values of both T1 (11.56 ± 0.98 μmol/L) and T5 (18.36 ± 0.82 μmol/L) were superior to that of kojic acid (23.12 ± 1.26 μmol/L). Moreover, T1 and T5 were also identified as the effective noncompetitive tyrosinase inhibitors by the subsequent kinetic study. Above all, T1 and T5 may represent the promising drug candidates for hyperpigmentation therapy in pharmaceutical fields, as well as the effective whitening agents in cosmetic applications.
{"title":"Discovery of Tyrosinase Inhibitors: Structure-Based Virtual Screening and Biological Evaluation","authors":"Guan Wang, Jin Li, Xiaoli Pan, Faqian Bu, Yufei Zhu, Ao-xue Wang, L. Ouyang","doi":"10.1055/s-0041-1742095","DOIUrl":"https://doi.org/10.1055/s-0041-1742095","url":null,"abstract":"Tyrosinase (EC 1.14.18.1) plays an indispensable role in the rate-limiting steps of melanin biosynthesis, and its uncontrolled activity may result in various diseases, such as albinism, melanoma, freckles, etc. The inhibition of tyrosinase activity may provide a useful and efficient strategy to treat hyperpigmentation disorders. However, the widely used tyrosinase inhibitors, like α-arbutin, hydroquinone, and kojic acid, have many shortcomings, such as lower efficacy and much more side effects. Herein, we reported the use of homology modeling and multistep structure-based virtual screening for the discovery of novel tyrosinase inhibitors. In this study, 10 initial potential hits (compounds T1–T10) were evaluated for enzyme inhibition and kinetic study, with kojic acid being used as a control. Among them, the IC50 values of both T1 (11.56 ± 0.98 μmol/L) and T5 (18.36 ± 0.82 μmol/L) were superior to that of kojic acid (23.12 ± 1.26 μmol/L). Moreover, T1 and T5 were also identified as the effective noncompetitive tyrosinase inhibitors by the subsequent kinetic study. Above all, T1 and T5 may represent the promising drug candidates for hyperpigmentation therapy in pharmaceutical fields, as well as the effective whitening agents in cosmetic applications.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85948386","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}
J. Isaac, Aisha Daburi, Benneth Ifeanyi, K. Ben-Umeh, Abiodun Abigail Adedokun, P. Builders
Senna podocarpa (SP) leaves are used in folk medicines for treatment of burns and wounds as poultices on wound surface. However, to the best of our knowledge, the wound healing ability of this plant has not been scientifically evaluated. This work aimed to determine the wound healing potential of the crude extract of SP leaves, and to evaluate the benefit of its preparation as an emulgel. In this study, the formulations of 2.5% of SP emulgel (F1) and 7.5% of SP emulgel (F2) were prepared by mixing the emulsion phase with the gel phase in a ratio of 1:1, and then physical appearance, globule size, pH, viscosity, swelling, water activity, extrudability, occlusion, spreadability, stability, and wound healing ability were determined. Phytochemical screening showed the presence of alkaloids, saponins, tannins, cardiac glycosides, flavonoids, anthraquinones, and phenols within the hydro-ethanolic extract of SP leaves, and high flavonoid content is believed to be responsible for its healing attributes. Our formulations showed acceptable physical properties. Hematoxylin-eosin and Verhoeff–Van Gieson stain showed that F2 could induce the accumulation of fibroblasts, fibrocytes, inflammatory cells, gland cells, epidermal cells, adipocytes, and collagen in the process of wound healing in mice injured with hydrochloric acid. Encouragingly, the percent of wound contractions in mice treated with F1, F2, and SP leaf poultice were 64, 87, and 50, respectively, suggesting the superior healing properties exhibited by SP emulgel over SP leaf poultice, and this may due to the occlusive property of emulgels. In conclusion, F2 of crude extract of SP leaves has better pharmacological effects on burn and wound healing, and may represent a preferred choice to treat burn wounds in the future.
番泻叶在民间医药中用于烧伤和伤口的治疗，用作伤口表面的膏药。然而，据我们所知，这种植物的伤口愈合能力还没有得到科学的评估。本工作旨在确定SP叶粗提物的创面愈合潜力，并评价其制备成乳状物的效益。本研究以2.5% SP乳液(F1)和7.5% SP乳液(F2)为配方，将乳液相与凝胶相按1:1的比例混合，然后测定其物理外观、小球大小、pH、粘度、溶胀性、水活度、挤压性、遮挡性、展布性、稳定性和伤口愈合能力。植物化学筛选表明，SP叶水乙醇提取物中含有生物碱、皂苷、单宁、心苷、黄酮类、蒽醌类和酚类物质，黄酮类含量高被认为是其愈合特性的原因。我们的配方显示出可接受的物理性质。苏木精-伊红和verhoefff - van Gieson染色显示，F2可诱导盐酸损伤小鼠伤口愈合过程中成纤维细胞、纤维细胞、炎症细胞、腺体细胞、表皮细胞、脂肪细胞和胶原蛋白的积累。令人鼓舞的是，用F1、F2和SP叶膏药治疗的小鼠伤口收缩的百分比分别为64%、87%和50%，这表明SP乳膏比SP叶膏药表现出更好的愈合性能，这可能是由于凝胶的闭塞性。综上所述，SP叶粗提物F2对烧伤和创面愈合具有较好的药理作用，可能是未来治疗烧伤创面的首选。
{"title":"Senna podocarpa Emulgel: A Herbal Alternative for Chemical Burn Wound Treatment","authors":"J. Isaac, Aisha Daburi, Benneth Ifeanyi, K. Ben-Umeh, Abiodun Abigail Adedokun, P. Builders","doi":"10.1055/s-0042-1744474","DOIUrl":"https://doi.org/10.1055/s-0042-1744474","url":null,"abstract":"\u0000 Senna podocarpa (SP) leaves are used in folk medicines for treatment of burns and wounds as poultices on wound surface. However, to the best of our knowledge, the wound healing ability of this plant has not been scientifically evaluated. This work aimed to determine the wound healing potential of the crude extract of SP leaves, and to evaluate the benefit of its preparation as an emulgel. In this study, the formulations of 2.5% of SP emulgel (F1) and 7.5% of SP emulgel (F2) were prepared by mixing the emulsion phase with the gel phase in a ratio of 1:1, and then physical appearance, globule size, pH, viscosity, swelling, water activity, extrudability, occlusion, spreadability, stability, and wound healing ability were determined. Phytochemical screening showed the presence of alkaloids, saponins, tannins, cardiac glycosides, flavonoids, anthraquinones, and phenols within the hydro-ethanolic extract of SP leaves, and high flavonoid content is believed to be responsible for its healing attributes. Our formulations showed acceptable physical properties. Hematoxylin-eosin and Verhoeff–Van Gieson stain showed that F2 could induce the accumulation of fibroblasts, fibrocytes, inflammatory cells, gland cells, epidermal cells, adipocytes, and collagen in the process of wound healing in mice injured with hydrochloric acid. Encouragingly, the percent of wound contractions in mice treated with F1, F2, and SP leaf poultice were 64, 87, and 50, respectively, suggesting the superior healing properties exhibited by SP emulgel over SP leaf poultice, and this may due to the occlusive property of emulgels. In conclusion, F2 of crude extract of SP leaves has better pharmacological effects on burn and wound healing, and may represent a preferred choice to treat burn wounds in the future.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80019172","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}
In this study, the synthesis and biological evaluation of a variety of benzoheterocyclic-containing benzamide derivatives were described. Some of these compounds were proved to inhibiting the activity of histone deacetylase 1 (HDAC1) with IC50 values below the micromolar range, retarding proliferation of several human cancer cells, and surprisingly, not possessing toxicity to human normal cells and hERG K+ ion channels. Among those compounds, 3c was the most potent and efficacious derivative. Compound 3c was orally active and displayed excellent in vivo antitumor activity in a HCT-116 xenograft mice model.
{"title":"Design, Synthesis, and Evaluation of Benzoheterocyclic-Containing Derivatives as Novel HDAC1 Inhibitors","authors":"Minru Jiao, Bo Han, Xiu Gu, Hao Zhang, Aiyun Wang, Qingwei Zhang","doi":"10.1055/s-0042-1743487","DOIUrl":"https://doi.org/10.1055/s-0042-1743487","url":null,"abstract":"In this study, the synthesis and biological evaluation of a variety of benzoheterocyclic-containing benzamide derivatives were described. Some of these compounds were proved to inhibiting the activity of histone deacetylase 1 (HDAC1) with IC50 values below the micromolar range, retarding proliferation of several human cancer cells, and surprisingly, not possessing toxicity to human normal cells and hERG K+ ion channels. Among those compounds, 3c was the most potent and efficacious derivative. Compound 3c was orally active and displayed excellent in vivo antitumor activity in a HCT-116 xenograft mice model.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79967849","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}
Xin-Li Du, Yan-Na Ni, Jiang-Rong Ji, Ze-Hong Wan, Zhijing Hu, Y. Ge, Jian-qi Li, Guan Wang
Evidence suggested that the use of partial dopamine D2/D3 receptor agonists may be a better choice for the treatment of Parkinson's disease (PD), and the stimulation of 5-HT1A receptors (mainly via nondopaminergic mechanisms) alleviates motor and nonmotor disorders of PD, implying that the multitarget approach may provide a double bonus for the treatment of the disease. In this study, 20 novel 1-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazine derivatives were designed and synthesized using a bioisosterism approach, and their activities for D2/D3/5-HT1A receptors were further tested. The results showed that several compounds exhibited a multitarget combination of D2/5-HT1A agonism. Compounds 7b and 34c showed agonistic activities on D2/D3/5-HT1A receptor. The EC50 value of 7b for D2/D3/5-HT1A receptor were 0.9/19/2.3 nmol/L, respectively; and the EC50 value of 34c for D2/D3/5-HT1A receptor were 3.3/10/1.4 nmol/L, respectively. In addition, 34c exhibited good metabolic stability (the half-life T 1/2 = 159.7 minutes) in vitro, which is of great significance for the further exploration of multitarget anti-PD drugs.
{"title":"Synthesis and Biological Evaluation of a Series of Novel 1-(3-((6-Fluoropyridin-3-yl)oxy)propyl)piperazines as Dopamine/Serotonin Receptor Agonists","authors":"Xin-Li Du, Yan-Na Ni, Jiang-Rong Ji, Ze-Hong Wan, Zhijing Hu, Y. Ge, Jian-qi Li, Guan Wang","doi":"10.1055/s-0042-1743415","DOIUrl":"https://doi.org/10.1055/s-0042-1743415","url":null,"abstract":"Evidence suggested that the use of partial dopamine D2/D3 receptor agonists may be a better choice for the treatment of Parkinson's disease (PD), and the stimulation of 5-HT1A receptors (mainly via nondopaminergic mechanisms) alleviates motor and nonmotor disorders of PD, implying that the multitarget approach may provide a double bonus for the treatment of the disease. In this study, 20 novel 1-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazine derivatives were designed and synthesized using a bioisosterism approach, and their activities for D2/D3/5-HT1A receptors were further tested. The results showed that several compounds exhibited a multitarget combination of D2/5-HT1A agonism. Compounds 7b and 34c showed agonistic activities on D2/D3/5-HT1A receptor. The EC50 value of 7b for D2/D3/5-HT1A receptor were 0.9/19/2.3 nmol/L, respectively; and the EC50 value of 34c for D2/D3/5-HT1A receptor were 3.3/10/1.4 nmol/L, respectively. In addition, 34c exhibited good metabolic stability (the half-life T\u0000 1/2 = 159.7 minutes) in vitro, which is of great significance for the further exploration of multitarget anti-PD drugs.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82535307","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}
Yi Zhang, Xiao‐Rong Ma, Xiaohan Shan, Xiao-Wen Zhang, Jian-qi Li, Yu Liu
5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid (1) is a key intermediate for the synthesis of a family of promising SGLT2 inhibitors currently in preclinical and phase I studies for diabetes therapy. In this investigation, cheap, easily available dimethyl terephthalate was used as the raw starting material, and compound 1 was prepared effectively in six steps, including nitration, hydrolysis, hydrogenation, esterification, bromination, and diazotization. The preparation was run successfully on approximately 70 kg/batch with the total yield of 24%. This practical process was demonstrated to be scalable with a great yield and significant cost reduction.
{"title":"Novel and Practical Industrial Process Scale-Up of 5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid, a Key Intermediate in the Manufacturing of Therapeutic SGLT2 Inhibitors","authors":"Yi Zhang, Xiao‐Rong Ma, Xiaohan Shan, Xiao-Wen Zhang, Jian-qi Li, Yu Liu","doi":"10.1055/s-0042-1755195","DOIUrl":"https://doi.org/10.1055/s-0042-1755195","url":null,"abstract":"5-Bromo-2-chloro-4-(methoxycarbonyl)benzoic acid (1) is a key intermediate for the synthesis of a family of promising SGLT2 inhibitors currently in preclinical and phase I studies for diabetes therapy. In this investigation, cheap, easily available dimethyl terephthalate was used as the raw starting material, and compound 1 was prepared effectively in six steps, including nitration, hydrolysis, hydrogenation, esterification, bromination, and diazotization. The preparation was run successfully on approximately 70 kg/batch with the total yield of 24%. This practical process was demonstrated to be scalable with a great yield and significant cost reduction.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"7 1","pages":"e244 - e249"},"PeriodicalIF":0.0,"publicationDate":"2022-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85231517","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}
Lei Huang, Yi Zhang, Xiaohan Shan, Yu Liu, Jian-qi Li
Abstract (3 R ,4 S ,5 R ,6 R )-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2 H -pyran-2-one ( 1 ) is a key intermediate for the preparation of promising SGLT2 inhibitors currently undergoing clinical tests for diabetes therapy. However, fewer reports have demonstrated the preparation of compound 1 at an industrial scale. In this article, an efficient preparation of the intermediate for the industrial production was explored from commercially available methyl-α- D -glucopyranoside in seven steps, including TBS protection, benzyl protection, TBS removal, iodination, reduction, demethylation, and oxidation. The batch of the validation process was 42.82 kg with a HPLC purity of 99.31%. The main advantages of this approach are that the total cost is lower than the reported laboratory-scale synthetic method, the quality is reproducible, and the process is safe and environmentally friendly.
摘要(3 R,4 S,5 R,6 R)-3,4,5-三(苄基氧基)-6-甲基四氢-2 H -吡喃-2- 1(1)是制备SGLT2抑制剂的关键中间体，目前正在进行糖尿病治疗的临床试验。然而，在工业规模上证明化合物1的制备的报道较少。本文探索了以市售甲基-α- D -葡萄糖吡喃苷为原料，经TBS保护、苄基保护、TBS去除、碘化、还原、去甲基化和氧化7个步骤高效制备工业生产中间体的方法。该批验证工艺为42.82 kg, HPLC纯度为99.31%。该方法的主要优点是总成本低于实验室规模的合成方法，质量可重复性好，过程安全环保。
{"title":"Industrial-Scale Preparation of a Key Intermediate for the Manufacture of Therapeutic SGLT2 Inhibitors","authors":"Lei Huang, Yi Zhang, Xiaohan Shan, Yu Liu, Jian-qi Li","doi":"10.1055/s-0042-1750423","DOIUrl":"https://doi.org/10.1055/s-0042-1750423","url":null,"abstract":"Abstract (3 R ,4 S ,5 R ,6 R )-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2 H -pyran-2-one ( 1 ) is a key intermediate for the preparation of promising SGLT2 inhibitors currently undergoing clinical tests for diabetes therapy. However, fewer reports have demonstrated the preparation of compound 1 at an industrial scale. In this article, an efficient preparation of the intermediate for the industrial production was explored from commercially available methyl-α- D -glucopyranoside in seven steps, including TBS protection, benzyl protection, TBS removal, iodination, reduction, demethylation, and oxidation. The batch of the validation process was 42.82 kg with a HPLC purity of 99.31%. The main advantages of this approach are that the total cost is lower than the reported laboratory-scale synthetic method, the quality is reproducible, and the process is safe and environmentally friendly.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"1 1","pages":"e237 - e243"},"PeriodicalIF":0.0,"publicationDate":"2022-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84938818","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}
Yan-Na Ni, Xin-Li Du, Tao Wang, Yuanbin Chen, Xiang-qing Xu, Song Zhao, Jian-qi Li, Guan Wang
A total of 20 novel aryl piperazine derivatives were designed and synthesized, and their structures were confirmed by mass spectrometry and nuclear magnetic resonance analyses. Their 5-HT1A and sigma-1 receptor affinities were determined, and six of them showed high affinities (K i < 20 nmol/L) to both 5-HT1A and sigma-1 targets. Then, metabolic stability (T 1/2) tests of six compounds in rat and human liver microsomes were performed. Our data indicated that compound 27 has both high affinity for 5-HT1A and sigma-1 receptors (5-HT1A: K i = 0.44 nmol/L; sigma-1: K i = 0.27 nmol/L), and good metabolic stability (T 1/2 values are 21.7 and 24.6 minutes, respectively). Interestingly, results from the forced swimming test, mouse tail suspension test, and preliminary pharmacokinetic test suggested the marked antidepressant activity, good pharmacokinetic characteristics, and low toxicity of compound 27 in the two models. In conclusion, compound 27 has great value of further study as an active molecule of antidepressant drugs.
设计合成了20个新的芳基哌嗪衍生物，并通过质谱分析和核磁共振分析对其结构进行了确证。测定了它们的5-HT1A和sigma-1受体亲和性，其中6个对5-HT1A和sigma-1靶点均表现出高亲和性(ki < 20 nmol/L)。然后进行了6种化合物在大鼠和人肝微粒体中的代谢稳定性(t1 /2)试验。我们的数据表明，化合物27对5-HT1A和sigma-1受体都有很高的亲和力(5-HT1A: K i = 0.44 nmol/L;σ -1: K i = 0.27 nmol/L)，代谢稳定性好(t1 /2值分别为21.7和24.6分钟)。有趣的是，强迫游泳试验、小鼠悬尾试验和初步药代动力学试验结果表明，化合物27在两种模型中均具有明显的抗抑郁活性、良好的药代动力学特性和低毒性。综上所述，化合物27作为抗抑郁药物的活性分子具有进一步研究的价值。
{"title":"Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors","authors":"Yan-Na Ni, Xin-Li Du, Tao Wang, Yuanbin Chen, Xiang-qing Xu, Song Zhao, Jian-qi Li, Guan Wang","doi":"10.1055/s-0041-1740049","DOIUrl":"https://doi.org/10.1055/s-0041-1740049","url":null,"abstract":"A total of 20 novel aryl piperazine derivatives were designed and synthesized, and their structures were confirmed by mass spectrometry and nuclear magnetic resonance analyses. Their 5-HT1A and sigma-1 receptor affinities were determined, and six of them showed high affinities (K\u0000 i < 20 nmol/L) to both 5-HT1A and sigma-1 targets. Then, metabolic stability (T\u0000 1/2) tests of six compounds in rat and human liver microsomes were performed. Our data indicated that compound 27 has both high affinity for 5-HT1A and sigma-1 receptors (5-HT1A: K\u0000 i = 0.44 nmol/L; sigma-1: K\u0000 i = 0.27 nmol/L), and good metabolic stability (T\u0000 1/2 values are 21.7 and 24.6 minutes, respectively). Interestingly, results from the forced swimming test, mouse tail suspension test, and preliminary pharmacokinetic test suggested the marked antidepressant activity, good pharmacokinetic characteristics, and low toxicity of compound 27 in the two models. In conclusion, compound 27 has great value of further study as an active molecule of antidepressant drugs.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82252871","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}
The indole scaffold is one of the most important heterocyclic ring systems for pharmaceutical development, and serves as an active moiety in several clinical drugs. Fungi derived from marine origin are more liable to produce novel indole-containing natural products due to their extreme living environments. The indole alkaloids from marine fungi have drawn considerable attention for their unique chemical structures and significant biological activities. This review attempts to provide a summary of the structural diversity of marine fungal indole alkaloids including prenylated indoles, diketopiperazine indoles, bisindoles or trisindoles, quinazoline-containing indoles, indole-diterpenoids, and other indoles, as well as their known biological activities, mainly focusing on cytotoxic, kinase inhibitory, antiinflammatory, antimicrobial, anti-insecticidal, and brine shrimp lethal effects. A total of 306 indole alkaloids from marine fungi have been summarized, covering the references published from 1995 to early 2021, expecting to be beneficial for drug discovery in the future.
{"title":"Natural Indole Alkaloids from Marine Fungi: Chemical Diversity and Biological Activities","authors":"Jiao Li, Chunlin Zhuang","doi":"10.1055/s-0041-1740050","DOIUrl":"https://doi.org/10.1055/s-0041-1740050","url":null,"abstract":"The indole scaffold is one of the most important heterocyclic ring systems for pharmaceutical development, and serves as an active moiety in several clinical drugs. Fungi derived from marine origin are more liable to produce novel indole-containing natural products due to their extreme living environments. The indole alkaloids from marine fungi have drawn considerable attention for their unique chemical structures and significant biological activities. This review attempts to provide a summary of the structural diversity of marine fungal indole alkaloids including prenylated indoles, diketopiperazine indoles, bisindoles or trisindoles, quinazoline-containing indoles, indole-diterpenoids, and other indoles, as well as their known biological activities, mainly focusing on cytotoxic, kinase inhibitory, antiinflammatory, antimicrobial, anti-insecticidal, and brine shrimp lethal effects. A total of 306 indole alkaloids from marine fungi have been summarized, covering the references published from 1995 to early 2021, expecting to be beneficial for drug discovery in the future.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78709546","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}
A. Pawar, N. A. Shete, P. Jadhav, V. Deshmukh, J. Mehetre
Microsponge, a novel drug delivery system, is designed to deliver a pharmaceutically active ingredient efficiently at the minimum dose. Microsponge plays an important role in enhancing drug stability, reducing side effects, and modifying drug release profiles. It is mostly used for transdermal delivery. Recent studies also explored their use for oral administration. This study aimed to explore the potential use of the microsponge technique in improving the aqueous solubility and dissolution profile of pentoxifylline (PTX). In this study, microsponges were prepared by a quasi-emulsion solvent diffusion method by varying concentrations of carriers. Nine different ratios of the PTX:Eudragit E-100 with varying amounts of dichloromethane were used. All formulated microsponges were evaluated for %production yield, compatibility of drug excipient, encapsulation efficiency, in vitro drug release, and in vivo bioavailability, as well as recorded by scanning electron microscopy (SEM) and differential scanning calorimetry(DSC). Our data suggested that the aqueous solubility of PTX microsponges was four times greater than that of pure drug. The in vitro drug release of selected microsponges (M8) was found to be 70%; furthermore, the in vivo study suggested that the selected formulation significantly enhanced drug concentration in the plasma (9,219 ng/mL in 12 hours) in comparison to pure drug PTX (2,476 ng/mL in 12 hours). SEM showed that the prepared microsponges were spherical with porous nature. Fourier-transform infrared spectroscopy and DSC studies confirmed an absence of incompatibility among drugs and selected excipients. The pH of the selected gel was found to be 6.8, which was compatible with those of skin and oral formulations also. All above data suggested a highly successful and beneficial use of the microsponge technique in enhancing aqueous solubility, dissolution profile, and oral bioavailability of PTX. Microsponge-based delivery of PTX may represent an alternative strategy to improve the bioavailability of the drug.
{"title":"Enhancement of Aqueous Solubility, Dissolution Profile, and Oral Bioavailability of Pentoxifylline by Microsponges","authors":"A. Pawar, N. A. Shete, P. Jadhav, V. Deshmukh, J. Mehetre","doi":"10.1055/s-0041-1740242","DOIUrl":"https://doi.org/10.1055/s-0041-1740242","url":null,"abstract":"Microsponge, a novel drug delivery system, is designed to deliver a pharmaceutically active ingredient efficiently at the minimum dose. Microsponge plays an important role in enhancing drug stability, reducing side effects, and modifying drug release profiles. It is mostly used for transdermal delivery. Recent studies also explored their use for oral administration. This study aimed to explore the potential use of the microsponge technique in improving the aqueous solubility and dissolution profile of pentoxifylline (PTX). In this study, microsponges were prepared by a quasi-emulsion solvent diffusion method by varying concentrations of carriers. Nine different ratios of the PTX:Eudragit E-100 with varying amounts of dichloromethane were used. All formulated microsponges were evaluated for %production yield, compatibility of drug excipient, encapsulation efficiency, in vitro drug release, and in vivo bioavailability, as well as recorded by scanning electron microscopy (SEM) and differential scanning calorimetry(DSC). Our data suggested that the aqueous solubility of PTX microsponges was four times greater than that of pure drug. The in vitro drug release of selected microsponges (M8) was found to be 70%; furthermore, the in vivo study suggested that the selected formulation significantly enhanced drug concentration in the plasma (9,219 ng/mL in 12 hours) in comparison to pure drug PTX (2,476 ng/mL in 12 hours). SEM showed that the prepared microsponges were spherical with porous nature. Fourier-transform infrared spectroscopy and DSC studies confirmed an absence of incompatibility among drugs and selected excipients. The pH of the selected gel was found to be 6.8, which was compatible with those of skin and oral formulations also. All above data suggested a highly successful and beneficial use of the microsponge technique in enhancing aqueous solubility, dissolution profile, and oral bioavailability of PTX. Microsponge-based delivery of PTX may represent an alternative strategy to improve the bioavailability of the drug.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87781460","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}
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