Antimicrobial peptides (AMPs) are key components of innate immune systems. Because of their lasting potency, AMPs are regarded as useful candidates for developing the next generation of antimicrobials to meet the challenge of antibiotic resistance. According to CDC, 90% infections are related to the difficult-to-treat ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. In this lecture, I will discuss peptide design based on human cathelicidin LL-37, one of the best-studied host defense peptides. Both synthetic peptide library and structure-based design methods were utilized to identify the active regions. Although challenging, the determination of the 3D structure of LL-37 enabled the identification of the core antimicrobial region in 2006. However, the minimal region of LL-37 can be function-dependent. In 2014, we reported successful conversion of LL-37 into17BIPHE2, a stable, selective, and potent antimicrobial, antibiofilm, and anticancer peptide. The European group identified IG-24 derived P60.4 by using the peptide library approach. In 2018, they selected SAAP-148 as a candidate with a reduced binding to blood plasma. Interestingly, both 17BIPHE2 and SAAP-148 eliminated the ESKAPE pathogens and showed topical in vivo antibiofilm efficacy. In addition, a better antibiofilm outcome could be obtained when 17BIPHE2 was used in combination with traditional antibiotics. Finally, I summarize what we have learned from human LL-37 engineering. Video from the Keynote Speaker Dr. Guangshun Wang can be found: https://youtu.be/1OOpTs6Sszk
{"title":"Design potent peptide antibiotics against the ESKAPE pathogens based on human antimicrobial peptide LL-37","authors":"Guangshun Wang","doi":"10.3390/ECMC-4-05882","DOIUrl":"https://doi.org/10.3390/ECMC-4-05882","url":null,"abstract":"Antimicrobial peptides (AMPs) are key components of innate immune systems. Because of their lasting potency, AMPs are regarded as useful candidates for developing the next generation of antimicrobials to meet the challenge of antibiotic resistance. According to CDC, 90% infections are related to the difficult-to-treat ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. In this lecture, I will discuss peptide design based on human cathelicidin LL-37, one of the best-studied host defense peptides. Both synthetic peptide library and structure-based design methods were utilized to identify the active regions. Although challenging, the determination of the 3D structure of LL-37 enabled the identification of the core antimicrobial region in 2006. However, the minimal region of LL-37 can be function-dependent. In 2014, we reported successful conversion of LL-37 into17BIPHE2, a stable, selective, and potent antimicrobial, antibiofilm, and anticancer peptide. The European group identified IG-24 derived P60.4 by using the peptide library approach. In 2018, they selected SAAP-148 as a candidate with a reduced binding to blood plasma. Interestingly, both 17BIPHE2 and SAAP-148 eliminated the ESKAPE pathogens and showed topical in vivo antibiofilm efficacy. In addition, a better antibiofilm outcome could be obtained when 17BIPHE2 was used in combination with traditional antibiotics. Finally, I summarize what we have learned from human LL-37 engineering.\u0000Video from the Keynote Speaker Dr. Guangshun Wang can be found: \u0000https://youtu.be/1OOpTs6Sszk","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86611194","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}
Amani Direm, M. Abdelbaky, K. Sayın, A. Cornia, O. Abosede, S. García‐Granda
Two new penta-coordinated copper(II) complexes with mixed-ligands, namely: imidazole and citric acid have been synthesized and obtained from a one-pot reaction. The biological screening of the resulting compounds has shown that they could be considered as promising materials with interesting antimicrobial and antifungal inhibition activities. Moreover, the obtained biological results have been confirmed by undertaking chemical reactivity calculations.
{"title":"Biological activity of two new imidazole-based Cu(II) frameworks resulting from a one-pot reaction","authors":"Amani Direm, M. Abdelbaky, K. Sayın, A. Cornia, O. Abosede, S. García‐Granda","doi":"10.3390/ecmc-4-05859","DOIUrl":"https://doi.org/10.3390/ecmc-4-05859","url":null,"abstract":"Two new penta-coordinated copper(II) complexes with mixed-ligands, namely: imidazole and citric acid have been synthesized and obtained from a one-pot reaction. The biological screening of the resulting compounds has shown that they could be considered as promising materials with interesting antimicrobial and antifungal inhibition activities. Moreover, the obtained biological results have been confirmed by undertaking chemical reactivity calculations.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83661314","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}
D. Costa, Hueldem R. C. Teixeira, L. I. Hage-Melim
{"title":"Molecular docking and pharmacokinetic and toxicological predictions of natural compounds with anticholinestearase activity","authors":"D. Costa, Hueldem R. C. Teixeira, L. I. Hage-Melim","doi":"10.3390/ECMC-4-05773","DOIUrl":"https://doi.org/10.3390/ECMC-4-05773","url":null,"abstract":"","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81962106","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}
G. Duburs, B. Vigante, E. Bisenieks, A. Krauze, A. Plotniece, A. Sobolev, I. Domracheva, K. Pajuste
Complex, focused anticancer therapy approach has been developed in the Latvian Institute of Organic Synthesis by making use of privileged partially hydrogenated nitrogen-containing heterocycles, namely dihydropyridines, dihydropyrimidines, their oxidized heteroaromatic derivatives. Topics of research include: 1. Conventional approach by chemotherapy and synergism of anticancer drugs [1]; 2. Inhibition of multidrug resistance by inhibition of drug efflux pumps [2]; 3. Mitigation of cancer risk factors – e.g., hepatitis B virus chemotherapy for prevention of chronic liver diseases, because chronic hepatitis, in up to 40% of cases, progresses to cyrrhosis and further to hepatocellular carcinoma [3]; 4. Improvement of efficacy of cancer radiotherapy by use of radioprotectors to prevent damage of normal tissues. So, radioprotector diethone (dietone) for skin protection was discovered, elaborated, and developed as ointment. Compounds for protection of eyes, mucous tissues, salivary glands etc have been synthesized. Toxicity of dietone and novel radioprotectors is very low; 5.Amphiphilic compounds have been synthesized, nanoparticles for anticancer drug and gene delivery have been created, pleiotropic properties have been checked, inclusion of magnetic particles for targeted transport performed [4]. Acknowledgements The research was partially supported by the Latvian State Program Biomedicine. References 1.Bisenieks E., Duburs G. et al., Pharmaceutical combination of 5-fluorouracil and derivatives of 1,4-dihydropyridine. US 8492413B2, 2013. 2.Krauze A., Grinberga S. et al., Thieno[2,3-b]pyridines – a new class of multidrug resistance (MDR) modulators. Bioorg.Med.Chem. 2014, 22 (21), 5860-5870. 3.Sipola A., Dubova U., et al., Synthesis and evaluation of 1,4-dihydropyrimidine derivatives – hepatitis B virus capsid self-assembly inhibitors. EFMC International Symposium on Medicinal Chemistry. Ljubljana, Slovenia, 2018, P176. 4.Pajuste K. et al., Gene delivery agents possessing antiradical activity: Self-assembling cationic amphiphilic 1,4-dihydropyridine derivatives. New J.Chem. 2013, 37 (10), 3062-3075.
{"title":"Pleiotropic focused anticancer approach by dihydropyridines, dihydropyrimidines and heteroaromatic compounds","authors":"G. Duburs, B. Vigante, E. Bisenieks, A. Krauze, A. Plotniece, A. Sobolev, I. Domracheva, K. Pajuste","doi":"10.3390/ecmc-4-05778","DOIUrl":"https://doi.org/10.3390/ecmc-4-05778","url":null,"abstract":"Complex, focused anticancer therapy approach has been developed in the Latvian Institute of Organic Synthesis by making use of privileged partially hydrogenated nitrogen-containing heterocycles, namely dihydropyridines, dihydropyrimidines, their oxidized heteroaromatic derivatives. Topics of research include:\u00001. Conventional approach by chemotherapy and synergism of anticancer drugs [1];\u00002. Inhibition of multidrug resistance by inhibition of drug efflux pumps [2];\u00003. Mitigation of cancer risk factors – e.g., hepatitis B virus chemotherapy for prevention of chronic liver diseases, because chronic hepatitis, in up to 40% of cases, progresses to cyrrhosis and further to hepatocellular carcinoma [3];\u00004. Improvement of efficacy of cancer radiotherapy by use of radioprotectors to prevent damage of normal tissues. So, radioprotector diethone (dietone) for skin protection was discovered, elaborated, and developed as ointment. Compounds for protection of eyes, mucous tissues, salivary glands etc have been synthesized. Toxicity of dietone and novel radioprotectors is very low;\u00005.Amphiphilic compounds have been synthesized, nanoparticles for anticancer drug and gene delivery have been created, pleiotropic properties have been checked, inclusion of magnetic particles for targeted transport performed [4].\u0000\u0000Acknowledgements\u0000The research was partially supported by the Latvian State Program Biomedicine.\u0000\u0000References\u00001.Bisenieks E., Duburs G. et al., Pharmaceutical combination of 5-fluorouracil and derivatives of 1,4-dihydropyridine. US 8492413B2, 2013.\u00002.Krauze A., Grinberga S. et al., Thieno[2,3-b]pyridines – a new class of multidrug resistance (MDR) modulators. Bioorg.Med.Chem. 2014, 22 (21), 5860-5870.\u00003.Sipola A., Dubova U., et al., Synthesis and evaluation of 1,4-dihydropyrimidine derivatives – hepatitis B virus capsid self-assembly inhibitors. EFMC International Symposium on Medicinal Chemistry. Ljubljana, Slovenia, 2018, P176.\u00004.Pajuste K. et al., Gene delivery agents possessing antiradical activity: Self-assembling cationic amphiphilic 1,4-dihydropyridine derivatives. New J.Chem. 2013, 37 (10), 3062-3075.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85042986","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}
{"title":"Anti-inflammatory activity of new complex compounds SnCl4 with salicyloyl hydrazones benzaldehyde and 4-bromobenzaldehyde on different models of inflammation","authors":"E. Prokopchuk, I. Kravchenko, A. Alexandrova","doi":"10.3390/ecmc-4-05641","DOIUrl":"https://doi.org/10.3390/ecmc-4-05641","url":null,"abstract":"","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79465597","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}
Florence O. McCarthy, Kevin D. O’Shea, Hannah J. Winfield, Michael M. Cahill
{"title":"Synthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 Inhibition","authors":"Florence O. McCarthy, Kevin D. O’Shea, Hannah J. Winfield, Michael M. Cahill","doi":"10.3390/ECMC-4-05639","DOIUrl":"https://doi.org/10.3390/ECMC-4-05639","url":null,"abstract":"","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"221 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79873139","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}
Florence O. McCarthy, Kevin D. O’Shea, Michael M. Cahill, Larry T. Pierce
The 3,4,5-trimethoxyphenyl moiety is a common motif employed in anticancer drug discovery, due to its prevalence in a variety of important natural products such as Combretastatin. Work undertaken by our group and others has demonstrated that structural diversification of this template can lead to potent anticancer activity. The synthesis and biological evaluation of a series of novel indole-trimethoxyphenyl derivatives are described herein. The consolidation of the combretastatin and bisindolyl templates towards the inclusion of a novel heterocyclic headgroup proffered a versatile pharmacophore with which to pursue chemical diversification. Rationalising the enhancement of existing H-bonding interactions or potential exploitation of new contacts, the introduction of substituted maleimides constituted an overarching theme. This allowed for the evaluation of the effects pertaining to oxygen insertion, extended maleimide substitution and N-functionalisation. Photo-mediated dehydrogenation of a key synthetic intermediate offered access to trimethoxyphenylcarbazoles, representing the first time a panel of such congeners has been reported with further derivatisation also possible. Subsequent evaluation of anticancer activity of the indole-trimethoxyphenyl conjugates utilising the NCI-60 cell screen showed growth inhibitory profiles towards numerous cell lines including: A498 renal, IGROV1 ovarian, DU-145 prostate, SW-620 colon and MCF-7 breast cancer cell lines. The influence of structure on anticancer activity is described.
{"title":"Synthesis and anticancer activity of novel indole-trimethoxyphenyl conjugates","authors":"Florence O. McCarthy, Kevin D. O’Shea, Michael M. Cahill, Larry T. Pierce","doi":"10.3390/ECMC-4-05640","DOIUrl":"https://doi.org/10.3390/ECMC-4-05640","url":null,"abstract":"The 3,4,5-trimethoxyphenyl moiety is a common motif employed in anticancer drug discovery, due to its prevalence in a variety of important natural products such as Combretastatin. Work undertaken by our group and others has demonstrated that structural diversification of this template can lead to potent anticancer activity. The synthesis and biological evaluation of a series of novel indole-trimethoxyphenyl derivatives are described herein. The consolidation of the combretastatin and bisindolyl templates towards the inclusion of a novel heterocyclic headgroup proffered a versatile pharmacophore with which to pursue chemical diversification. Rationalising the enhancement of existing H-bonding interactions or potential exploitation of new contacts, the introduction of substituted maleimides constituted an overarching theme. This allowed for the evaluation of the effects pertaining to oxygen insertion, extended maleimide substitution and N-functionalisation. Photo-mediated dehydrogenation of a key synthetic intermediate offered access to trimethoxyphenylcarbazoles, representing the first time a panel of such congeners has been reported with further derivatisation also possible. Subsequent evaluation of anticancer activity of the indole-trimethoxyphenyl conjugates utilising the NCI-60 cell screen showed growth inhibitory profiles towards numerous cell lines including: A498 renal, IGROV1 ovarian, DU-145 prostate, SW-620 colon and MCF-7 breast cancer cell lines. The influence of structure on anticancer activity is described.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"10 3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80391098","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}
Cancer is the second leading cause of death worldwide, killing an estimated 1 in 6 people. Ellipticine (1) is a natural product which has potent anticancer activity and has been subject to extensive study since its discovery, in 1959, with the key aim of identifying derivatives with clinical application. Functionalisation of the ellipticine pharmacophore is key to developing potent and selective analogues. For example, generation of quaternary ellipticine salts, helps to overcome issues surrounding solubility and can improve selectivity whereas the most potent anticancer ellipticine derivatives have a hydroxyl or methoxy substituent at the 9-position. This work outlines the synthesis of quaternary ellipticine salts and their subsequent biological evaluation. Alkyl groups were introduced at the 6-position, as well as formyl or hydroxy groups at the 9-position, as these substituents have been previously shown to improve activity. Biological evaluation encompassed measurement of growth inhibition against twelve cancer cell lines and submission to the NCI 60 Cell Lines Screen. Substitution at the 9-position greatly improved activity, while increasing substituent size at the 6-position led to lower potency. A number of potent derivatives have been identified following biological evaluation, with long chain alkyl salts displaying sub-micromolar average GI50 values.
{"title":"Synthesis and evaluation of novel ellipticine salt derivatives as anticancer agents","authors":"Florence O. McCarthy, M. Mckee","doi":"10.3390/ECMC-4-05638","DOIUrl":"https://doi.org/10.3390/ECMC-4-05638","url":null,"abstract":"Cancer is the second leading cause of death worldwide, killing an estimated 1 in 6 people. Ellipticine (1) is a natural product which has potent anticancer activity and has been subject to extensive study since its discovery, in 1959, with the key aim of identifying derivatives with clinical application. \u0000Functionalisation of the ellipticine pharmacophore is key to developing potent and selective analogues. For example, generation of quaternary ellipticine salts, helps to overcome issues surrounding solubility and can improve selectivity whereas the most potent anticancer ellipticine derivatives have a hydroxyl or methoxy substituent at the 9-position. This work outlines the synthesis of quaternary ellipticine salts and their subsequent biological evaluation. Alkyl groups were introduced at the 6-position, as well as formyl or hydroxy groups at the 9-position, as these substituents have been previously shown to improve activity. \u0000Biological evaluation encompassed measurement of growth inhibition against twelve cancer cell lines and submission to the NCI 60 Cell Lines Screen. Substitution at the 9-position greatly improved activity, while increasing substituent size at the 6-position led to lower potency. A number of potent derivatives have been identified following biological evaluation, with long chain alkyl salts displaying sub-micromolar average GI50 values.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78008996","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}
{"title":"Systematic study of lipase-catalyzed resolution of propanolol precursors","authors":"A. Alcántara, Isabel Borreguero-Requejo","doi":"10.3390/ECMC-4-05633","DOIUrl":"https://doi.org/10.3390/ECMC-4-05633","url":null,"abstract":"","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80676892","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}
James Mc Keown, Clara Charleton, K. Ferris, Sara Noorani, Niamh M. O’Boyle, M. Meegan
CLL (Chronic Lymphocytic Leukaemia) is the most common leukaemia in the Western world. Classed as a clonal disorder of mature B-lymphocytes, CLL patient prognoses are broadly subdivided by the mutational status of the Immunoglobulin G Heavy Chain Variable region (IGHV) (with unmutated IGHV holding a better patient prognosis than the wild type variant)1. Structures related to tricyclic and tetracyclic anti-depressants (fluoxetine,maprotiline respectively) have previously been shown to exert potent, selective antiproliferative and pro-apoptotic effects in vitro and were met with marked success in related B cell malignancy cell lines, namely Burkitt’s Lymphoma (BL) cell lines DG-75 and MUTU-12. Based on these preliminary studies, libraries of structurally related novel ethanoanthracene compounds were designed, based on the proven effectiveness of nitrostyrene core moiety derivatives and literature evidence of selective toxicity of chalcone moieties in leukaemic cell lines3. The antiproliferative activity of each compound was determined using Alamar Blue assays on the two types of CLL cell lines: HG-3 and PGA-1, representative of bad and good prognosis respectively. The most promising activity was observed with maleimide dienophile based ethanoanthracene chalcones, particularly at a 10 µM across both cell lines. A ROS (reactive oxygen species) dependant activity was noted as both nitrostyrene and chalcone based analog biological activity markedly decreased on addition of NAC (N- acetyl cysteine) or Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). References Scarfo, L.; Ferreri, A. J. M.; Ghia, P., Critical Reviews in Oncology/Hematology, 2016, 104, 169-182. Mc Namara, Y. M., Bright, S.A., Byrne, A.J., Williams, D.C., Meegan, M.J., European Journal of Medicinal Chemistry 2014, 71, 333. Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z., Chemical Reviews, 2017, 117(12):7762-7810.
慢性淋巴细胞白血病(CLL)是西方世界最常见的白血病。作为一种成熟b淋巴细胞的克隆性疾病，CLL患者的预后可根据免疫球蛋白G重链可变区(Immunoglobulin G Heavy Chain Variable region, IGHV)的突变状态进行广泛细分(未突变的IGHV比野生型变体具有更好的患者预后)1。三环和四环抗抑郁药(分别为氟西汀和马普替林)相关的结构先前已被证明在体外发挥有效的、选择性的抗增殖和促凋亡作用，并在相关的B细胞恶性细胞系，即伯基特淋巴瘤(BL)细胞系DG-75和mu -12中取得了显著的成功。在这些初步研究的基础上，基于硝基苯乙烯核心部分衍生物的有效性和查尔酮部分在白血病细胞系中选择性毒性的文献证据，设计了结构相关的新型乙醇蒽化合物文库3。采用Alamar Blue法测定各化合物对预后较差和较好的两种CLL细胞系HG-3和PGA-1的抗增殖活性。以马来酰亚胺为基础的亲二烯基乙醇蒽查尔酮的活性最有希望，特别是在跨越两种细胞系的10µM处。在硝基苯乙烯和查尔酮的基础上添加NAC (N-乙酰半胱氨酸)或Trolox(6-羟基-2,5,7,8-四甲基铬-2-羧酸)后，生物活性显著降低。斯卡福，L.;A. J. M.费雷利;李建平，杨建平，中华血液学杂志，2016,33(4):379 - 382。Mc Namara, y.m.， Bright, s.a.， Byrne, a.j.， Williams, dc, Meegan, m.j.，欧洲药物化学杂志2014,71,333。壮族,c;张,w;盛,c;张,w;兴,c;苗忠。化学导报，2017,117(12):7762-7810。
{"title":"Ethanoanthracenes: Potential chemotherapeutics for chronic lymphocytic leukaemia (CLL)","authors":"James Mc Keown, Clara Charleton, K. Ferris, Sara Noorani, Niamh M. O’Boyle, M. Meegan","doi":"10.3390/ECMC-4-05623","DOIUrl":"https://doi.org/10.3390/ECMC-4-05623","url":null,"abstract":"CLL (Chronic Lymphocytic Leukaemia) is the most common leukaemia in the Western world. Classed as a clonal disorder of mature B-lymphocytes, CLL patient prognoses are broadly subdivided by the mutational status of the Immunoglobulin G Heavy Chain Variable region (IGHV) (with unmutated IGHV holding a better patient prognosis than the wild type variant)1. \u0000Structures related to tricyclic and tetracyclic anti-depressants (fluoxetine,maprotiline respectively) have previously been shown to exert potent, selective antiproliferative and pro-apoptotic effects in vitro and were met with marked success in related B cell malignancy cell lines, namely Burkitt’s Lymphoma (BL) cell lines DG-75 and MUTU-12. \u0000Based on these preliminary studies, libraries of structurally related novel ethanoanthracene compounds were designed, based on the proven effectiveness of nitrostyrene core moiety derivatives and literature evidence of selective toxicity of chalcone moieties in leukaemic cell lines3. \u0000The antiproliferative activity of each compound was determined using Alamar Blue assays on the two types of CLL cell lines: HG-3 and PGA-1, representative of bad and good prognosis respectively. The most promising activity was observed with maleimide dienophile based ethanoanthracene chalcones, particularly at a 10 µM across both cell lines. A ROS (reactive oxygen species) dependant activity was noted as both nitrostyrene and chalcone based analog biological activity markedly decreased on addition of NAC (N- acetyl cysteine) or Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). \u0000References \u0000 \u0000 Scarfo, L.; Ferreri, A. J. M.; Ghia, P., Critical Reviews in Oncology/Hematology, 2016, 104, 169-182. \u0000 Mc Namara, Y. M., Bright, S.A., Byrne, A.J., Williams, D.C., Meegan, M.J., European Journal of Medicinal Chemistry 2014, 71, 333. \u0000 Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z., Chemical Reviews, 2017, 117(12):7762-7810.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75606604","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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