M. H. Yahya, Sodeeq A. Babalola, A. Idris, A. Hamza, Nosakhare Igie, Isaiah Odeyemi, A. Musa, A. Olorukooba
Abstract Malaria remains a febrile infection of public health concern in many countries especially tropical countries in Africa and certain countries in Southern and North America such as Brazil, Costa Rica, Mexico, Dominican Republic, Colombia, and Ecuador. Hence this has made research into this area paramount. Acetophenones are active fragments in many compounds with promising antimalarial activity, such as chalcones. The aim of the present study was to investigate antimalarial activity of 3,5-diprenyl acetophenone ( I ) and 5-diprenyl acetophenone ( II ) in in vivo . In this study, compounds I and II were synthesized using an aromatic substitution reaction. The in-vivo antimalarial potential of compounds I and II was analyzed in Plasmodium berghei -infected mice. Our data showed that compound I (25, 50, and 100 mg/kg) had promising antimalarial activity, with parasitemia inhibited rate being 68.03, 65.16, and 69.75%, respectively. Compound II dose-dependently inhibited parasitemia levels, it demonstrated an infinitesimally higher activity (72.12%) when compared with compound I (69.75%) at 100 mg/kg dose. The two compounds passed the rule of three, Lipinski's rule of five, predicted plausible pharmacokinetic profile (ADME), and apparent safety profile, and demonstrated drug-like fragments. The study provided guidance in exploring novel antimalarial compounds based on the scaffolds of prenylated acetophenones.
{"title":"Therapeutic Potency of Mono- and Diprenylated Acetophenones: A Case Study of In-Vivo Antimalarial Evaluation","authors":"M. H. Yahya, Sodeeq A. Babalola, A. Idris, A. Hamza, Nosakhare Igie, Isaiah Odeyemi, A. Musa, A. Olorukooba","doi":"10.1055/s-0043-1764210","DOIUrl":"https://doi.org/10.1055/s-0043-1764210","url":null,"abstract":"Abstract Malaria remains a febrile infection of public health concern in many countries especially tropical countries in Africa and certain countries in Southern and North America such as Brazil, Costa Rica, Mexico, Dominican Republic, Colombia, and Ecuador. Hence this has made research into this area paramount. Acetophenones are active fragments in many compounds with promising antimalarial activity, such as chalcones. The aim of the present study was to investigate antimalarial activity of 3,5-diprenyl acetophenone ( I ) and 5-diprenyl acetophenone ( II ) in in vivo . In this study, compounds I and II were synthesized using an aromatic substitution reaction. The in-vivo antimalarial potential of compounds I and II was analyzed in Plasmodium berghei -infected mice. Our data showed that compound I (25, 50, and 100 mg/kg) had promising antimalarial activity, with parasitemia inhibited rate being 68.03, 65.16, and 69.75%, respectively. Compound II dose-dependently inhibited parasitemia levels, it demonstrated an infinitesimally higher activity (72.12%) when compared with compound I (69.75%) at 100 mg/kg dose. The two compounds passed the rule of three, Lipinski's rule of five, predicted plausible pharmacokinetic profile (ADME), and apparent safety profile, and demonstrated drug-like fragments. The study provided guidance in exploring novel antimalarial compounds based on the scaffolds of prenylated acetophenones.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"10 1","pages":"e15 - e24"},"PeriodicalIF":0.0,"publicationDate":"2022-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85811375","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}
Sodeeq A. Babalola, Nosakhare Igie, Isaiah Odeyemi
Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs are traditional medicines for the treatment of inflammation, yet associated with serious side effects. Hence, the need for discovering novel compounds with valuable clinical benefits is of great importance. In this study, 18 derivatives of p -nitrophenyl hydrazones were docked against COX-2, 5-LOX, and H + /K + ATPase, followed by predicting their drug-likeness and absorption, distribution, metabolism, and excretion (ADME) properties. From the docking analysis, 1-(4-nitrophenyl)-2-[(3,4,5-trimethoxyphenyl)methylidene]hydrazine ( 3 ), 4-hydroxy-2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]thiochroman-1,1-dioxide ( 6 ), 4-methoxy-2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]thiochroman-1,1-dioxide ( 8 ), 2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]-4-(trifluoromethyl)thiochroman-1,1-dioxide ( 11 ), 4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]benzenesulfonamide ( 13 ), 4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]-3-(trifluoromethyl)benzenesulfonamide ( 14 ), 5-methyl-6-{4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]phenyl}-2,3,4,5-tetrahydropyridazin-3-ol ( 16 ), and 5-methyl-6-{4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]phenyl}-4,5-dihydropyridazin-3(2 H )-one ( 17 ) showed promise as potent multi-target inhibitors of COX-2, 5-LOX, and H + /K + ATPase. These compounds are less COX-2 selective than the control (celecoxib). “Drug-likeness” analysis passed Lipinski's, Egan's, Veber's, Muegge's, and Ghose's rules. The compounds also passed Pfizer and GSK rules, as well as golden triangle's rule for identification of potent and metabolically stable drugs. The pharmacokinetic profiles of the compounds were excellent, safe, and compliant with their potential anti-inflammatory activity. The results of the study can be used for future optimization of those derivatives for better molecular interactions against COX-2, 5-LOX, and H + /K + ATPase, and inflammation-effective inhibition.
{"title":"Molecular Docking, Drug-Likeness Analysis, In Silico Pharmacokinetics, and Toxicity Studies of p -Nitrophenyl Hydrazones as Anti-inflammatory Compounds against COX-2, 5-LOX, and H + /K + ATPase","authors":"Sodeeq A. Babalola, Nosakhare Igie, Isaiah Odeyemi","doi":"10.1055/s-0042-1759688","DOIUrl":"https://doi.org/10.1055/s-0042-1759688","url":null,"abstract":"Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs are traditional medicines for the treatment of inflammation, yet associated with serious side effects. Hence, the need for discovering novel compounds with valuable clinical benefits is of great importance. In this study, 18 derivatives of p -nitrophenyl hydrazones were docked against COX-2, 5-LOX, and H + /K + ATPase, followed by predicting their drug-likeness and absorption, distribution, metabolism, and excretion (ADME) properties. From the docking analysis, 1-(4-nitrophenyl)-2-[(3,4,5-trimethoxyphenyl)methylidene]hydrazine ( 3 ), 4-hydroxy-2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]thiochroman-1,1-dioxide ( 6 ), 4-methoxy-2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]thiochroman-1,1-dioxide ( 8 ), 2-methyl-6-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]-4-(trifluoromethyl)thiochroman-1,1-dioxide ( 11 ), 4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]benzenesulfonamide ( 13 ), 4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]-3-(trifluoromethyl)benzenesulfonamide ( 14 ), 5-methyl-6-{4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]phenyl}-2,3,4,5-tetrahydropyridazin-3-ol ( 16 ), and 5-methyl-6-{4-[(2-(4-nitrophenyl)hydraz-1-ylidene)methyl]phenyl}-4,5-dihydropyridazin-3(2 H )-one ( 17 ) showed promise as potent multi-target inhibitors of COX-2, 5-LOX, and H + /K + ATPase. These compounds are less COX-2 selective than the control (celecoxib). “Drug-likeness” analysis passed Lipinski's, Egan's, Veber's, Muegge's, and Ghose's rules. The compounds also passed Pfizer and GSK rules, as well as golden triangle's rule for identification of potent and metabolically stable drugs. The pharmacokinetic profiles of the compounds were excellent, safe, and compliant with their potential anti-inflammatory activity. The results of the study can be used for future optimization of those derivatives for better molecular interactions against COX-2, 5-LOX, and H + /K + ATPase, and inflammation-effective inhibition.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"15 1","pages":"e250 - e266"},"PeriodicalIF":0.0,"publicationDate":"2022-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80145130","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 study aimed to investigate the factors affecting the stability of imipenem and cilastatin sodium for injection (IMI/CIL) to improve the quality and stability in IMI/CIL preparation. In this study, the effects of headspace oxygen (HO), water content, particle shape, and particle size on the stability of IMI/CIL were investigated. IMI/CIL was purged with air, premixed oxygen/nitrogen gas (5%/95%), or high-purity nitrogen (99.999%) at 20, 5, or 2% oxygen levels to prepare IMI/CIL with different HO levels. IMI/CIL was stored at 30, 45, and 75% relative humidity for 30 days to prepare IMI/CIL with different water contents. High-performance liquid chromatography method was used for analysis. The results showed that oxygen, water, particle shape, and particle size had significant effects on the stability of IMI/CIL, and free water content is a better predictor of the safety and stability of imipenem and cilastatin sodium than the total water content. The optimization scheme of the above parameters is proposed, which significantly improves the stability of IMI/CIL. This study led to a better understanding of the degradation mechanism of imipenem and cilastatin sodium, and could provide a reference for the selection and control of IMI/CIL process conditions. This study would contribute to the development of IMI/CIL with improved stability.
{"title":"Effect of Oxygen and Water on the Stability of Imipenem and Cilastatin Sodium for Injection","authors":"Meng Zhang, Chunyu Liu, Xiao-Yan Chen, Li-Na Yang, Chunmei Zhu, Jianhao Teng, Hao Wu, Fu-Li Zhang","doi":"10.1055/s-0042-1750043","DOIUrl":"https://doi.org/10.1055/s-0042-1750043","url":null,"abstract":"The study aimed to investigate the factors affecting the stability of imipenem and cilastatin sodium for injection (IMI/CIL) to improve the quality and stability in IMI/CIL preparation. In this study, the effects of headspace oxygen (HO), water content, particle shape, and particle size on the stability of IMI/CIL were investigated. IMI/CIL was purged with air, premixed oxygen/nitrogen gas (5%/95%), or high-purity nitrogen (99.999%) at 20, 5, or 2% oxygen levels to prepare IMI/CIL with different HO levels. IMI/CIL was stored at 30, 45, and 75% relative humidity for 30 days to prepare IMI/CIL with different water contents. High-performance liquid chromatography method was used for analysis. The results showed that oxygen, water, particle shape, and particle size had significant effects on the stability of IMI/CIL, and free water content is a better predictor of the safety and stability of imipenem and cilastatin sodium than the total water content. The optimization scheme of the above parameters is proposed, which significantly improves the stability of IMI/CIL. This study led to a better understanding of the degradation mechanism of imipenem and cilastatin sodium, and could provide a reference for the selection and control of IMI/CIL process conditions. This study would contribute to the development of IMI/CIL with improved stability.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91131327","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, Hua Chen, Weiwei Wang, Jian-qi Li, Yu Liu
In this study, an efficient and practical process for the synthesis of isavuconazonium sulfate (compound 1), an antifungal agent, was described. Highlights in the synthesis route are the usage of the ion exchange resin instead of H2SO4 to introduce the HSO4 − anion in the formulation of quaternary ammonium salt (1), and the reaction condition was further optimized to facilitate the scale-up. The overall yield of the process was 57.0% and the high-performance liquid chromatography purity of product was 97.25%, which was higher than that of the reference-listed drug.
{"title":"A Novel and Practical Synthesis of Isavuconazonium Sulfate via Anion Exchange Resin","authors":"Lei Huang, Yi Zhang, Hua Chen, Weiwei Wang, Jian-qi Li, Yu Liu","doi":"10.1055/s-0042-1747641","DOIUrl":"https://doi.org/10.1055/s-0042-1747641","url":null,"abstract":"In this study, an efficient and practical process for the synthesis of isavuconazonium sulfate (compound 1), an antifungal agent, was described. Highlights in the synthesis route are the usage of the ion exchange resin instead of H2SO4 to introduce the HSO4\u0000 − anion in the formulation of quaternary ammonium salt (1), and the reaction condition was further optimized to facilitate the scale-up. The overall yield of the process was 57.0% and the high-performance liquid chromatography purity of product was 97.25%, which was higher than that of the reference-listed drug.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87414981","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}
Lipid-based nanocarriers have been extensively investigated for drug delivery due to their advantages including biodegradability, biocompatibility, nontoxicity, and nonimmunogenicity. However, the shortcomings of traditional lipid-based nanocarriers such as insufficient targeting, capture by the reticuloendothelial system, and fast elimination limit the efficiency of drug delivery and therapeutic efficacy. Therefore, a series of multifunctional lipid-based nanocarriers have been developed to enhance the accumulation of drugs in the lesion site, aiming for improved diagnosis and treatment of various diseases. In this review, we summarized the advances and applications of lipid-based nanocarriers from traditional to novel functional lipid preparations, including liposomes, stimuli-responsive lipid-based nanocarriers, ionizable lipid nanoparticles, lipid hybrid nanocarriers, as well as biomembrane-camouflaged nanoparticles, and further discussed the challenges and prospects of this system. This exploration may give a complete idea viewing the lipid-based nanocarriers as a promising choice for drug delivery system, and fuel the advancement of pharmaceutical products by materials innovation and nanotechnology.
{"title":"Lipid-Based Nanocarrier Systems for Drug Delivery: Advances and Applications","authors":"Yanqi Zhao, Lijun Li, E. Zhou, Jiangyue Wang, Ying Wang, Lin-Miao Guo, Xinxin Zhang","doi":"10.1055/s-0042-1751036","DOIUrl":"https://doi.org/10.1055/s-0042-1751036","url":null,"abstract":"Lipid-based nanocarriers have been extensively investigated for drug delivery due to their advantages including biodegradability, biocompatibility, nontoxicity, and nonimmunogenicity. However, the shortcomings of traditional lipid-based nanocarriers such as insufficient targeting, capture by the reticuloendothelial system, and fast elimination limit the efficiency of drug delivery and therapeutic efficacy. Therefore, a series of multifunctional lipid-based nanocarriers have been developed to enhance the accumulation of drugs in the lesion site, aiming for improved diagnosis and treatment of various diseases. In this review, we summarized the advances and applications of lipid-based nanocarriers from traditional to novel functional lipid preparations, including liposomes, stimuli-responsive lipid-based nanocarriers, ionizable lipid nanoparticles, lipid hybrid nanocarriers, as well as biomembrane-camouflaged nanoparticles, and further discussed the challenges and prospects of this system. This exploration may give a complete idea viewing the lipid-based nanocarriers as a promising choice for drug delivery system, and fuel the advancement of pharmaceutical products by materials innovation and nanotechnology.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85534375","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}
Antibody drug conjugate (ADC) therapy has become one of the most promising approaches in cancer immunotherapy. The bispecific targeting could improve the specificity, affinity, and internalization of the ADC molecules. Prolactin preceptor (PRLR) and HER2 have crosstalk signaling in breast cancer, and PRLR undergoes a rapid internalization compared with HER2. To improve the efficacy of HER2 ADCs with enhancing the target specificity and internalization, we constructed a PRLR/HER2-targeting bispecific ADC (BsADC). We evaluated the characterization of PRLR × HER2 BsADC from the affinity and internalization, and further assessed its in vitro cytotoxicity in human breast-cancer cell lines (BT474, T47D, and MDA-MB-231) using Cell Count Kit-8 analysis. Our data demonstrated that PRLR × HER2 BsADC kept the affinity to two targeting antigens after conjugating drugs and exhibited higher internalization efficiency in comparison to HER2 ADC. Furthermore, PRLR × HER2 BsADC demonstrated to have superior antitumor activity in human breast cancer in vitro. In conclusion, our findings indicate that it is feasible through increasing the internalization of target antibody to enhance the antitumor activity and therapeutic potential that could be further evaluated in in vivo animal model.
{"title":"Generating a Bispecific Antibody Drug Conjugate Targeting PRLR and HER2 with Improving the Internalization","authors":"Huifang Zong, Baohong Zhang, Jianjia Zhu","doi":"10.1055/s-0042-1749334","DOIUrl":"https://doi.org/10.1055/s-0042-1749334","url":null,"abstract":"Antibody drug conjugate (ADC) therapy has become one of the most promising approaches in cancer immunotherapy. The bispecific targeting could improve the specificity, affinity, and internalization of the ADC molecules. Prolactin preceptor (PRLR) and HER2 have crosstalk signaling in breast cancer, and PRLR undergoes a rapid internalization compared with HER2. To improve the efficacy of HER2 ADCs with enhancing the target specificity and internalization, we constructed a PRLR/HER2-targeting bispecific ADC (BsADC). We evaluated the characterization of PRLR × HER2 BsADC from the affinity and internalization, and further assessed its in vitro cytotoxicity in human breast-cancer cell lines (BT474, T47D, and MDA-MB-231) using Cell Count Kit-8 analysis. Our data demonstrated that PRLR × HER2 BsADC kept the affinity to two targeting antigens after conjugating drugs and exhibited higher internalization efficiency in comparison to HER2 ADC. Furthermore, PRLR × HER2 BsADC demonstrated to have superior antitumor activity in human breast cancer in vitro. In conclusion, our findings indicate that it is feasible through increasing the internalization of target antibody to enhance the antitumor activity and therapeutic potential that could be further evaluated in in vivo animal model.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86414753","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 Xu, Yuchen Meng, Peng-Ju Guo, Ming Li, L. Shao, Jun-Hai Huang
PIM kinase is consequently emerging as a promising target for cancer therapeutics and immunomodulation. PIM kinases are overexpressed in a variety of hematological malignancies and solid tumors, and their inhibition has become a strong therapeutic interest. Currently, some pan-PIM kinase inhibitors are being developed under different phases of clinical trials. Based on the different scaffold structures, they can be classified into various subclasses. The X-ray structure of the kinase complex outlines the rationale of hit compound confirmation in the early stage. Structure–activity relationships allow us to rationally explore chemical space and further optimize multiple physicochemical and biological properties. This review focuses on the discovery and development of small-molecule pan-PIM kinase inhibitors in the current research, and hopes to provide guidance for future exploration of the inhibitors.
{"title":"Recent Research Advances in Small-Molecule Pan-PIM Inhibitors","authors":"Lei Xu, Yuchen Meng, Peng-Ju Guo, Ming Li, L. Shao, Jun-Hai Huang","doi":"10.1055/s-0042-1758692","DOIUrl":"https://doi.org/10.1055/s-0042-1758692","url":null,"abstract":"PIM kinase is consequently emerging as a promising target for cancer therapeutics and immunomodulation. PIM kinases are overexpressed in a variety of hematological malignancies and solid tumors, and their inhibition has become a strong therapeutic interest. Currently, some pan-PIM kinase inhibitors are being developed under different phases of clinical trials. Based on the different scaffold structures, they can be classified into various subclasses. The X-ray structure of the kinase complex outlines the rationale of hit compound confirmation in the early stage. Structure–activity relationships allow us to rationally explore chemical space and further optimize multiple physicochemical and biological properties. This review focuses on the discovery and development of small-molecule pan-PIM kinase inhibitors in the current research, and hopes to provide guidance for future exploration of the inhibitors.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"9 1","pages":"e207 - e222"},"PeriodicalIF":0.0,"publicationDate":"2022-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76196572","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}
Abstract Saxagliptin is a therapeutic drug for diabetes. The key synthesis process of the drug involves catalyzing 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid ( A ) into ( S )-3-hydroxyadamantane glycine ( B ), during which enzymes phenylalanine dehydrogenase mutant from Thermoactinomyces intermedius ( Ti PDHm) and formate dehydrogenase (FDH) were most often used for biocatalysis. However, the process was limited due to difficulty in enzyme preparation and a low conversion rate. This study focuses on co-expression of Ti PDHm and FDH in recombinant Escherichia coli , cell homogenate clarification, enzyme concentration as well as the optimized conditions of enzyme-catalyzed reaction. Our data showed that the wet weight density of bacteria reached 300 g/L, and the yields of Ti PDHm and FDH were 7674.24 and 2042.52 U/L, respectively. The combination of ammonium formate and polyethyleneimine favors the clarification of the bacteria homogenate. The clarified enzyme solution obtained can be concentrated by ultrafiltration and directly used in a reductive amination reaction in a high concentration of keto acid A . The reaction time was only 12 hours and the conversion rate reached 95%. Therefore, this process could provide a reference for enzyme-catalyzed preparation of saxagliptin on an industrial scale.
沙格列汀是一种治疗糖尿病的药物。该药物的关键合成过程是由2-(3-羟基-1-金刚烷基)-2-氧乙酸(A)催化生成(S)-3-羟基金刚烷甘氨酸(B)，其中最常用的生物催化酶是来自热放线菌中间的苯丙氨酸脱氢酶突变体(Ti PDHm)和甲酸脱氢酶(FDH)。然而，由于酶制备困难和转化率低，该工艺受到限制。本研究重点研究了Ti PDHm和FDH在重组大肠杆菌中的共表达、细胞匀浆澄清、酶浓度以及酶催化反应的优化条件。我们的数据显示，细菌的湿重密度达到300 g/L, Ti PDHm和FDH的产量分别为7674.24和2042.52 U/L。甲酸铵与聚乙烯亚胺的结合有利于细菌匀浆的澄清。得到的澄清酶溶液经超滤浓缩后，可直接用于高浓度酮酸a的还原性胺化反应。反应时间仅为12小时，转化率达95%。因此，该工艺可为沙格列汀的酶催化工业化制备提供参考。
{"title":"Process Study on the Enzyme-Catalyzed Preparation of Key Chiral Intermediates for Saxagliptin","authors":"Shan Li, Zongping Huang, Haoju Hua, Jianguang Lu, Wenjie Zhao, Jun Feng","doi":"10.1055/s-0042-1759851","DOIUrl":"https://doi.org/10.1055/s-0042-1759851","url":null,"abstract":"Abstract Saxagliptin is a therapeutic drug for diabetes. The key synthesis process of the drug involves catalyzing 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid ( A ) into ( S )-3-hydroxyadamantane glycine ( B ), during which enzymes phenylalanine dehydrogenase mutant from Thermoactinomyces intermedius ( Ti PDHm) and formate dehydrogenase (FDH) were most often used for biocatalysis. However, the process was limited due to difficulty in enzyme preparation and a low conversion rate. This study focuses on co-expression of Ti PDHm and FDH in recombinant Escherichia coli , cell homogenate clarification, enzyme concentration as well as the optimized conditions of enzyme-catalyzed reaction. Our data showed that the wet weight density of bacteria reached 300 g/L, and the yields of Ti PDHm and FDH were 7674.24 and 2042.52 U/L, respectively. The combination of ammonium formate and polyethyleneimine favors the clarification of the bacteria homogenate. The clarified enzyme solution obtained can be concentrated by ultrafiltration and directly used in a reductive amination reaction in a high concentration of keto acid A . The reaction time was only 12 hours and the conversion rate reached 95%. Therefore, this process could provide a reference for enzyme-catalyzed preparation of saxagliptin on an industrial scale.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"63 1","pages":"e267 - e274"},"PeriodicalIF":0.0,"publicationDate":"2022-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87171031","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}
Doxorubicin hydrochloride (DOX) is one of the widely used antineoplastic agents in treating various cancers, yet it is always associated with the occurrence of adverse reactions that limit its clinical use. Currently, encapsulating DOX in micelles may represent a promising strategy to reduce toxicity and side effects of the drug. This study aimed to explore a novel acitretin-based surfactant (ACMeNa) with good solid stability to encapsulate DOX to form micelles (ACM-DOX). In this work, ACM-DOX micelles were prepared by a microfluidic method free of organic solvents. The characteristics of ACM-DOX micelles were assessed, including morphology, particle size, stability, entrapment efficiency, and drug loading. An in vitro cytotoxicity experiment of the micelles on MDA-MB-231 (a human breast cancer cell line) was also performed. The micelle formation mechanism suggested that the insoluble ACMeNa/DOX complex was formed by electrostatic interaction, and subsequently encapsulated by self-assembly into micelles. The designed ACM-DOX micelles had an average particle size of 19.4 ± 0.2 nm and a zeta potential of −43.7 ± 2.4 mV, with entrapment efficiency and drug loading efficiency of 92.4 ± 0.5% and 33.4 ± 0.3%, respectively. The ACM-DOX micelles had worm-like structures under a Cryo-transmission electron microscope and exhibited good stability within 8 hours after reconstitution and 4- to 32-fold dilution of its reconstituted solution. ACM-DOX micelles released 80% of DOX within 24 hours in a medium of pH = 5.0, and its drug profile can be described by a first-order model. Moreover, ACM-DOX micelles showed cytotoxicity against MDA-MB-231 in a dose-dependent manner, and displayed a higher antitumor activity as compared with free DOX, with IC50 values of DOX and ACM-DOX micelles being 6.80 ± 0.50 and 4.64 ± 0.32 μg/mL, respectively. Given above, ACMeNa has great application potential as a DOX carrier for the treatment of cancers.
{"title":"Novel Worm-like Micelles for Hydrochloride Doxorubicin Delivery: Preparation, Characterization, and In Vitro Evaluation","authors":"Yaning Yang, Chen Ge, Jun He, Wei-gen Lu","doi":"10.1055/s-0042-1758191","DOIUrl":"https://doi.org/10.1055/s-0042-1758191","url":null,"abstract":"Doxorubicin hydrochloride (DOX) is one of the widely used antineoplastic agents in treating various cancers, yet it is always associated with the occurrence of adverse reactions that limit its clinical use. Currently, encapsulating DOX in micelles may represent a promising strategy to reduce toxicity and side effects of the drug. This study aimed to explore a novel acitretin-based surfactant (ACMeNa) with good solid stability to encapsulate DOX to form micelles (ACM-DOX). In this work, ACM-DOX micelles were prepared by a microfluidic method free of organic solvents. The characteristics of ACM-DOX micelles were assessed, including morphology, particle size, stability, entrapment efficiency, and drug loading. An in vitro cytotoxicity experiment of the micelles on MDA-MB-231 (a human breast cancer cell line) was also performed. The micelle formation mechanism suggested that the insoluble ACMeNa/DOX complex was formed by electrostatic interaction, and subsequently encapsulated by self-assembly into micelles. The designed ACM-DOX micelles had an average particle size of 19.4 ± 0.2 nm and a zeta potential of −43.7 ± 2.4 mV, with entrapment efficiency and drug loading efficiency of 92.4 ± 0.5% and 33.4 ± 0.3%, respectively. The ACM-DOX micelles had worm-like structures under a Cryo-transmission electron microscope and exhibited good stability within 8 hours after reconstitution and 4- to 32-fold dilution of its reconstituted solution. ACM-DOX micelles released 80% of DOX within 24 hours in a medium of pH = 5.0, and its drug profile can be described by a first-order model. Moreover, ACM-DOX micelles showed cytotoxicity against MDA-MB-231 in a dose-dependent manner, and displayed a higher antitumor activity as compared with free DOX, with IC50 values of DOX and ACM-DOX micelles being 6.80 ± 0.50 and 4.64 ± 0.32 μg/mL, respectively. Given above, ACMeNa has great application potential as a DOX carrier for the treatment of cancers.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"23 1","pages":"e284 - e294"},"PeriodicalIF":0.0,"publicationDate":"2022-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84611017","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}
Yong-Fu Qiu, L. Song, Gang-Long Jiang, Zhen Zhang, Xu-Yan Liu, Guan Wang
Anaplastic lymphoma kinase (ALK) is one of the most popular targets for anticancer therapies. In the past decade, the use of anaplastic lymphoma tyrosine kinase inhibitors (ALK-TKIs), including crizotinib and ceritinib, has been a reliable and standard options for patients with lung cancer, particularly for patients with nonsmall cell lung carcinoma. ALK-targeted therapies initially benefit the patients, yet, resistance eventually occurs. Therefore, resistance mechanisms of ALK-TKIs and the solutions have become a formidable challenge in the development of ALK inhibitors. In this review, based on the knowledge of reported ALK inhibitors, we illustrated the crystal structures of ALK, summarized the resistance mechanisms of ALK-targeted drugs, and proposed potential therapeutic strategies to prevent or overcome the resistance.
{"title":"Hallmarks of Anaplastic Lymphoma Kinase Inhibitors with Its Quick Emergence of Drug Resistance","authors":"Yong-Fu Qiu, L. Song, Gang-Long Jiang, Zhen Zhang, Xu-Yan Liu, Guan Wang","doi":"10.1055/s-0042-1758542","DOIUrl":"https://doi.org/10.1055/s-0042-1758542","url":null,"abstract":"Anaplastic lymphoma kinase (ALK) is one of the most popular targets for anticancer therapies. In the past decade, the use of anaplastic lymphoma tyrosine kinase inhibitors (ALK-TKIs), including crizotinib and ceritinib, has been a reliable and standard options for patients with lung cancer, particularly for patients with nonsmall cell lung carcinoma. ALK-targeted therapies initially benefit the patients, yet, resistance eventually occurs. Therefore, resistance mechanisms of ALK-TKIs and the solutions have become a formidable challenge in the development of ALK inhibitors. In this review, based on the knowledge of reported ALK inhibitors, we illustrated the crystal structures of ALK, summarized the resistance mechanisms of ALK-targeted drugs, and proposed potential therapeutic strategies to prevent or overcome the resistance.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"59 1","pages":"e223 - e236"},"PeriodicalIF":0.0,"publicationDate":"2022-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74216943","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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