Rachel A. Heylen, Nicola Cusick, Tom White, Emily J. Owen, Bethany L. Patenall, Martin Alm, Peter Thomsen, Maisem Laabei and A. Toby A. Jenkins
Catheter associated urinary tract infections (CAUTI) caused by urease-positive organisms can lead to catheter blockage: urease metabolizes urea in urine to ammonia causing an increase in pH and hence precipitation of struvite and apatite salts into the catheter lumen and bladder leading to blockage. Acetohydroxamic acid (AHA) is the only urease inhibitor currently approved for patient use, however, it is rarely used owing to its side effects. Here, we report the identification and development of new urease inhibitors discovered using a rational in silico drug design approach. A series of compounds were designed, the compounds were screened and filtered to identify three compounds which were tested in in vitro urease activity assays. N,N′-Bis(3-pyridinylmethyl)thiourea (Bis-TU) outperformed AHA in activity assays and was tested in an in vitro bladder model, where it significantly extended the lifetime of the catheter compared to AHA. Bis-TU was delivered via a diffusible balloon catheter directly to the site of activity, thus demonstrating localized drug delivery. This cost-effective drug design approach allowed the identification of a potent urease inhibitor, which could be improved through iterative repeats of the method, and the process of design could be utilized to target other diseases.
由尿素酶阳性微生物引起的导尿管相关性尿路感染(CAUTI)可导致导尿管堵塞:尿素酶将尿液中的尿素代谢为氨,导致 pH 值升高,从而使导尿管管腔和膀胱中的结石和磷灰石盐沉淀,导致堵塞。乙酰羟肟酸(AHA)是目前唯一获准用于患者的尿素酶抑制剂,但由于其副作用而很少使用。在此,我们报告了利用合理的硅学药物设计方法鉴定和开发新脲酶抑制剂的情况。我们设计了一系列化合物,并对这些化合物进行了筛选和过滤,最终确定了三个化合物,并对其进行了体外脲酶活性测试。N,N′-双(3-吡啶基甲基)硫脲(Bis-TU)在活性测定中的表现优于 AHA,并在体外膀胱模型中进行了测试,与 AHA 相比,它显著延长了导管的使用寿命。Bis-TU 通过可扩散的球囊导管直接输送到活动部位,从而实现了局部给药。通过这种经济有效的药物设计方法,我们鉴定出了一种强效尿素酶抑制剂,并可通过反复重复该方法对其进行改进,设计过程还可用于针对其他疾病的治疗。
{"title":"Rational design and in vitro testing of new urease inhibitors to prevent urinary catheter blockage†","authors":"Rachel A. Heylen, Nicola Cusick, Tom White, Emily J. Owen, Bethany L. Patenall, Martin Alm, Peter Thomsen, Maisem Laabei and A. Toby A. Jenkins","doi":"10.1039/D4MD00378K","DOIUrl":"10.1039/D4MD00378K","url":null,"abstract":"<p >Catheter associated urinary tract infections (CAUTI) caused by urease-positive organisms can lead to catheter blockage: urease metabolizes urea in urine to ammonia causing an increase in pH and hence precipitation of struvite and apatite salts into the catheter lumen and bladder leading to blockage. Acetohydroxamic acid (AHA) is the only urease inhibitor currently approved for patient use, however, it is rarely used owing to its side effects. Here, we report the identification and development of new urease inhibitors discovered using a rational <em>in silico</em> drug design approach. A series of compounds were designed, the compounds were screened and filtered to identify three compounds which were tested in <em>in vitro</em> urease activity assays. <em>N</em>,<em>N</em>′-Bis(3-pyridinylmethyl)thiourea (Bis-TU) outperformed AHA in activity assays and was tested in an <em>in vitro</em> bladder model, where it significantly extended the lifetime of the catheter compared to AHA. Bis-TU was delivered <em>via</em> a diffusible balloon catheter directly to the site of activity, thus demonstrating localized drug delivery. This cost-effective drug design approach allowed the identification of a potent urease inhibitor, which could be improved through iterative repeats of the method, and the process of design could be utilized to target other diseases.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 3597-3608"},"PeriodicalIF":4.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00378k?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sunil Kumar, Bishnu Prasad Pandey, Mohamed A Abdelgawad, Mohammed M Ghoneim, Rania B Bakr, Hoon Kim, Bijo Mathew
A total of 18 heterocyclic derived conjugated dienones (CD1-CD18) were evaluated for their potential monoamine oxidase (MAO)-A/-B inhibitory activity. Among the analyzed molecules, CD11 and CD14 showed notable inhibitory potentials against MAO-B, with half-maximal inhibitory concentration (IC50) values of 0.063 ± 0.001 μM and 0.036 ± 0.008 μM, respectively. In contrast, CD1, CD2 and CD3 showed comparable inhibitory activities toward MAO-A, with IC50 values of 3.45 ± 0.07, 3.23 ± 0.24, and 3.15 ± 0.10 μM, respectively. Derivatives of thiophene (CD13-CD17) exhibited selectivity indices greater than 250 for MAO-B. Both lead compounds exhibited similar potencies to safinamide and were more potent than pargyline. According to kinetic analysis, CD11 and CD14 exhibited competitive inhibition of MAO-B activity, with Ki values of 12.67 ± 3.85 nM and 4.5 ± 0.62 nM, respectively. Furthermore, the reversibility test results indicated that the inhibitions were reversible. Molecular docking and molecular dynamics simulation studies can provide insights into the probable binding interactions of CD11 and CD14 with MAO-B. CD11 demonstrated a bipartite contact with Tyr326 and Phe343, whereas CD14 showed contact with Pro102 and Tyr435 via aromatic hydrogen bonds. These results indicated that both compounds have high-affinity binding interactions ( -10.13 and -9.90 kcal mol-1, respectively) at the active site of MAO-B. Furthermore, we used SwissADME to estimate ADME, and both lead compounds demonstrated blood-brain barrier penetration. The study results indicated that all the compounds evaluated demonstrated potent inhibition of MAO-B activity, which was comparable to the efficacy of reference medications. It is necessary to do further investigations on the lead molecules to see whether they may be used to treat different neurodegenerative illnesses.
{"title":"Inhibition of monoamine oxidases by heterocyclic derived conjugated dienones: synthesis and <i>in vitro</i> and <i>in silico</i> investigations.","authors":"Sunil Kumar, Bishnu Prasad Pandey, Mohamed A Abdelgawad, Mohammed M Ghoneim, Rania B Bakr, Hoon Kim, Bijo Mathew","doi":"10.1039/d4md00608a","DOIUrl":"10.1039/d4md00608a","url":null,"abstract":"<p><p>A total of 18 heterocyclic derived conjugated dienones (CD1-CD18) were evaluated for their potential monoamine oxidase (MAO)-A/-B inhibitory activity. Among the analyzed molecules, CD11 and CD14 showed notable inhibitory potentials against MAO-B, with half-maximal inhibitory concentration (IC<sub>50</sub>) values of 0.063 ± 0.001 μM and 0.036 ± 0.008 μM, respectively. In contrast, CD1, CD2 and CD3 showed comparable inhibitory activities toward MAO-A, with IC<sub>50</sub> values of 3.45 ± 0.07, 3.23 ± 0.24, and 3.15 ± 0.10 μM, respectively. Derivatives of thiophene (CD13-CD17) exhibited selectivity indices greater than 250 for MAO-B. Both lead compounds exhibited similar potencies to safinamide and were more potent than pargyline. According to kinetic analysis, CD11 and CD14 exhibited competitive inhibition of MAO-B activity, with <i>K</i> <sub>i</sub> values of 12.67 ± 3.85 nM and 4.5 ± 0.62 nM, respectively. Furthermore, the reversibility test results indicated that the inhibitions were reversible. Molecular docking and molecular dynamics simulation studies can provide insights into the probable binding interactions of CD11 and CD14 with MAO-B. CD11 demonstrated a bipartite contact with Tyr326 and Phe343, whereas CD14 showed contact with Pro102 and Tyr435 <i>via</i> aromatic hydrogen bonds. These results indicated that both compounds have high-affinity binding interactions ( -10.13 and -9.90 kcal mol<sup>-1</sup>, respectively) at the active site of MAO-B. Furthermore, we used SwissADME to estimate ADME, and both lead compounds demonstrated blood-brain barrier penetration. The study results indicated that all the compounds evaluated demonstrated potent inhibition of MAO-B activity, which was comparable to the efficacy of reference medications. It is necessary to do further investigations on the lead molecules to see whether they may be used to treat different neurodegenerative illnesses.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11487422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Majlen A Dilweg, Tamara A M Mocking, Pantelis Maragkoudakis, Gerard J P van Westen, Laura H Heitman, Adriaan P IJzerman, Willem Jespers, Daan van der Es
The norepinephrine transporter (NET), encoded by the SLC6A2 gene, is one of three key monoamine neurotransmitter transporters. Inhibition of NET-mediated reuptake of norepinephrine by monoamine reuptake inhibitors has been the main therapeutic strategy to treat disorders such as depression, ADHD and Parkinson's disease. Nevertheless, lack of efficacy as well as risk of adverse effects are still common for these treatments underscoring the necessity to improve drug discovery efforts for this target. In this study, we developed new inhibitors based on 4-((2-(3,4-dichlorophenyl)cyclopentyl)amino)butan-1-ol (8), a potent NET inhibitor, which emerged from earlier virtual screening efforts using a predictive proteochemometric model. Hence, we optimized the N,2-substituted cycloalkylamine scaffold in three regions to design twenty new derivatives. To establish structure-activity relationships for these NET inhibitors, all novel compounds were tested utilizing an impedance-based 'transporter activity through receptor activation' assay. Moreover, all stereoisomers of the most potent compound (27) were synthesized and evaluated for their inhibitory potencies. Initial screening indicated that modifications in the cyclopentylamine moiety and phenyl substitutions decreased NET inhibition compared to 8, emphasizing the importance of the five-membered ring, secondary amine and dichloro-substitution pattern in NET binding. Substituting the original butylalcohol at the R2 position with a rigid cyclohexanol yielded lead compound 27, with potency similar to reference inhibitor nisoxetine. Pharmacological characterization of all eight stereoisomers of 27 revealed varying inhibitory potencies, favoring a trans-orientation of the N,2-substituted cyclopentyl moiety. Molecular docking highlighted key interactions and the impact of a hydrophilic region in the binding pocket. This study presents a novel set of moderate to highly potent NET inhibitors, elucidating the influence of molecular orientation in the NET binding pocket and offering valuable insights into drug discovery efforts for monoamine transport-related treatments.
由 SLC6A2 基因编码的去甲肾上腺素转运体(NET)是三大单胺神经递质转运体之一。通过单胺再摄取抑制剂抑制 NET 介导的去甲肾上腺素再摄取一直是治疗抑郁症、多动症和帕金森病等疾病的主要治疗策略。然而,这些治疗方法仍然普遍存在疗效不佳和不良反应风险的问题,这凸显了针对这一靶点改进药物研发工作的必要性。在本研究中,我们开发了基于 4-((2-(3,4-二氯苯基)环戊基)氨基)丁-1-醇 (8) 的新抑制剂,它是一种强效的 NET 抑制剂,是早期使用预测性蛋白化学计量学模型进行虚拟筛选的结果。因此,我们对 N,2-取代环烷基胺支架的三个区域进行了优化,设计出 20 种新的衍生物。为了建立这些 NET 抑制剂的结构-活性关系,我们利用基于阻抗的 "通过受体激活转运体活性 "测定法对所有新型化合物进行了测试。此外,还合成了最强化合物(27)的所有立体异构体,并对其抑制效力进行了评估。初步筛选结果表明,与 8 相比,环戊胺分子的修饰和苯基取代降低了对 NET 的抑制作用,这强调了五元环、仲胺和二氯取代模式在 NET 结合中的重要性。用刚性环己醇取代 R 2 位上的原始丁基醇,得到了先导化合物 27,其药效与参考抑制剂尼索西汀相似。27 的所有八种立体异构体的药理特征均显示出不同的抑制效力,N,2-取代环戊基的反式取向更受青睐。分子对接突显了关键的相互作用以及结合袋中亲水区域的影响。这项研究提出了一组新的中度到高度有效的 NET 抑制剂,阐明了 NET 结合袋中分子取向的影响,为单胺转运相关治疗药物的发现工作提供了宝贵的见解。
{"title":"Stereochemical optimization of <i>N</i>,2-substituted cycloalkylamines as norepinephrine reuptake inhibitors.","authors":"Majlen A Dilweg, Tamara A M Mocking, Pantelis Maragkoudakis, Gerard J P van Westen, Laura H Heitman, Adriaan P IJzerman, Willem Jespers, Daan van der Es","doi":"10.1039/d4md00521j","DOIUrl":"https://doi.org/10.1039/d4md00521j","url":null,"abstract":"<p><p>The norepinephrine transporter (NET), encoded by the SLC6A2 gene, is one of three key monoamine neurotransmitter transporters. Inhibition of NET-mediated reuptake of norepinephrine by monoamine reuptake inhibitors has been the main therapeutic strategy to treat disorders such as depression, ADHD and Parkinson's disease. Nevertheless, lack of efficacy as well as risk of adverse effects are still common for these treatments underscoring the necessity to improve drug discovery efforts for this target. In this study, we developed new inhibitors based on 4-((2-(3,4-dichlorophenyl)cyclopentyl)amino)butan-1-ol (8), a potent NET inhibitor, which emerged from earlier virtual screening efforts using a predictive proteochemometric model. Hence, we optimized the <i>N</i>,2-substituted cycloalkylamine scaffold in three regions to design twenty new derivatives. To establish structure-activity relationships for these NET inhibitors, all novel compounds were tested utilizing an impedance-based 'transporter activity through receptor activation' assay. Moreover, all stereoisomers of the most potent compound (27) were synthesized and evaluated for their inhibitory potencies. Initial screening indicated that modifications in the cyclopentylamine moiety and phenyl substitutions decreased NET inhibition compared to 8, emphasizing the importance of the five-membered ring, secondary amine and dichloro-substitution pattern in NET binding. Substituting the original butylalcohol at the <i>R</i> <sup>2</sup> position with a rigid cyclohexanol yielded lead compound 27, with potency similar to reference inhibitor nisoxetine. Pharmacological characterization of all eight stereoisomers of 27 revealed varying inhibitory potencies, favoring a <i>trans</i>-orientation of the <i>N</i>,2-substituted cyclopentyl moiety. Molecular docking highlighted key interactions and the impact of a hydrophilic region in the binding pocket. This study presents a novel set of moderate to highly potent NET inhibitors, elucidating the influence of molecular orientation in the NET binding pocket and offering valuable insights into drug discovery efforts for monoamine transport-related treatments.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11428037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A smart dendritic cell (DC)-derived whole cell cytokine (DWC) nano-regulator of TCPs was developed for tumor cytokine-immunotherapy. The DWCs were purified from activated DC-cultured media and applied as a nano-dosage form. It was found that TCPs could remodel extracellular matrices via the elimination of fibronectin and type I collagen (Col-I) in tumor tissues, as well as the inhibition of α-SMA expression in cancer associated fibroblasts (CAFs). Furthermore, after local TCP treatment, significant tumor inhibition could be achieved combined with radiotherapy.
一种用于肿瘤细胞因子免疫疗法的智能树突状细胞(DC)衍生全细胞细胞因子(DWC)纳米调节剂应运而生。DWCs 从活化的 DC 培养基中纯化,并以纳米剂型的形式应用。研究发现,TCPs 可通过消除肿瘤组织中的纤连蛋白和 I 型胶原(Col-I)重塑细胞外基质,并抑制癌症相关成纤维细胞(CAFs)中 α-SMA 的表达。此外,在局部 TCP 治疗后,结合放疗可达到显著的肿瘤抑制效果。
{"title":"DC-derived whole cell cytokine nano-regulator for remodelling extracellular matrix and synergizing tumor immunotherapy.","authors":"Jingsong Lu, Ying Li, Xiaohan Gao, Sumei Chen, Zeping Jin, Xiaoxiao Guo, Wensheng Xie, Zhenhu Guo, Yen Wei, Lingyun Zhao","doi":"10.1039/d4md00496e","DOIUrl":"https://doi.org/10.1039/d4md00496e","url":null,"abstract":"<p><p>A smart dendritic cell (DC)-derived whole cell cytokine (DWC) nano-regulator of TCPs was developed for tumor cytokine-immunotherapy. The DWCs were purified from activated DC-cultured media and applied as a nano-dosage form. It was found that TCPs could remodel extracellular matrices <i>via</i> the elimination of fibronectin and type I collagen (Col-I) in tumor tissues, as well as the inhibition of α-SMA expression in cancer associated fibroblasts (CAFs). Furthermore, after local TCP treatment, significant tumor inhibition could be achieved combined with radiotherapy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11428036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Petr Šlechta, Roman Viták, Pavel Bárta, Kateřina Koucká, Monika Berková, Diana Žďárová, Andrea Petríková, Jiří Kuneš, Vladimír Kubíček, Martin Doležal, Radek Kučera, Marta Kučerová-Chlupáčová
A new series of potential flutamide-like antiandrogens has been designed and synthesized to treat prostate cancer. This new series results from our research, which has been aimed at discovering new compounds that can be used for androgen deprivation treatment. The antiandrogens were designed and synthesized by varying the acyl part, linker, and substitution of the benzene ring in the 4-nitro-3-trifluoromethylanilide scaffold of non-steroidal androgens. In addition, the characteristic feature of the nitro group was replaced by a boronic acid functionality. Compound 9a was found to be more effective against LAPC-4 than the standard antiandrogens flutamide, hydroxyflutamide, and bicalutamide. Moreover, it exhibited lower toxicity against the non-cancerous cell line HK-2. The initial in silico study did not show evidence of covalent bonding to the androgen receptor, which was confirmed by an NMR binding experiment with arginine methyl ester. The structure-activity relationships discovered in this study could provide directions for further research on non-steroidal antiandrogens.
{"title":"Replacement of nitro function by free boronic acid in non-steroidal anti-androgens.","authors":"Petr Šlechta, Roman Viták, Pavel Bárta, Kateřina Koucká, Monika Berková, Diana Žďárová, Andrea Petríková, Jiří Kuneš, Vladimír Kubíček, Martin Doležal, Radek Kučera, Marta Kučerová-Chlupáčová","doi":"10.1039/d4md00343h","DOIUrl":"https://doi.org/10.1039/d4md00343h","url":null,"abstract":"<p><p>A new series of potential flutamide-like antiandrogens has been designed and synthesized to treat prostate cancer. This new series results from our research, which has been aimed at discovering new compounds that can be used for androgen deprivation treatment. The antiandrogens were designed and synthesized by varying the acyl part, linker, and substitution of the benzene ring in the 4-nitro-3-trifluoromethylanilide scaffold of non-steroidal androgens. In addition, the characteristic feature of the nitro group was replaced by a boronic acid functionality. Compound 9a was found to be more effective against LAPC-4 than the standard antiandrogens flutamide, hydroxyflutamide, and bicalutamide. Moreover, it exhibited lower toxicity against the non-cancerous cell line HK-2. The initial <i>in silico</i> study did not show evidence of covalent bonding to the androgen receptor, which was confirmed by an NMR binding experiment with arginine methyl ester. The structure-activity relationships discovered in this study could provide directions for further research on non-steroidal antiandrogens.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11428147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pothiyil S. Vimalkumar, Neethu Sivadas, Vishnu Priya Murali, Daisy R. Sherin, Madhukrishnan Murali, Anuja Gracy Joseph, Kokkuvayil Vasu Radhakrishnan and Kaustabh Kumar Maiti
Myristica malabarica Lam., commonly known as Malabar nutmeg or false nutmeg, is used in traditional medicine and as a spice. Our exploration focuses on malabaricones, a distinct group of secondary metabolites isolated from the fruit rind of M. malabarica. We investigated the selective cytotoxicity of malabaricones against the triple-negative breast cancer (TNBC) cell line. In particular, malabaricone A (Mal-A) displays heightened toxicity towards TNBC cells (MDA-MB-231), with an IC50 of 8.81 ± 0.03 μM. In vitro fluorimetric assays confirmed the apoptotic capability of Mal-A and its capacity to induce nuclear fragmentation. Additionally, ultrasensitive surface-enhanced Raman spectroscopy confirms DNA fragmentation during cellular apoptosis. Cell cycle analysis indicates arrest during the sub-G0 phase by downregulating key regulatory proteins involved in cell cycle progression. Increased expression levels of caspase 3, 9, and 8 suggest involvement of both extrinsic and intrinsic apoptotic pathways. Finally, assessment of protein expression patterns within apoptotic pathways reveals upregulation of key apoptotic proteins like Fas/FasL, TNF/TNFR1, and p53, coupled with downregulation of several inhibitors of apoptosis proteins such as XIAP, cIAP-2, and Livin. These findings are further verified with in silico molecular docking. Mal-A reveals a strong affinity towards apoptotic proteins, including TNF, Fas, HTRA, Smac, and XIAP, with docking scores ranging from −5.1 to −7.2 kcal mol−1. Subsequently, molecular dynamics simulation confirms the binding stability. This conclusive in vitro evaluation validates Mal-A as a potent phyto-entity against TNBC. To the best of our knowledge, this study represents the first comprehensive anticancer evaluation of Mal-A in TNBC cells.
{"title":"Exploring apoptotic induction of malabaricone A in triple-negative breast cancer cells: an acylphenol phyto-entity isolated from the fruit rind of Myristica malabarica Lam.†","authors":"Pothiyil S. Vimalkumar, Neethu Sivadas, Vishnu Priya Murali, Daisy R. Sherin, Madhukrishnan Murali, Anuja Gracy Joseph, Kokkuvayil Vasu Radhakrishnan and Kaustabh Kumar Maiti","doi":"10.1039/D4MD00391H","DOIUrl":"10.1039/D4MD00391H","url":null,"abstract":"<p > <em>Myristica malabarica</em> Lam., commonly known as Malabar nutmeg or false nutmeg, is used in traditional medicine and as a spice. Our exploration focuses on malabaricones, a distinct group of secondary metabolites isolated from the fruit rind of <em>M. malabarica</em>. We investigated the selective cytotoxicity of malabaricones against the triple-negative breast cancer (TNBC) cell line. In particular, malabaricone A (Mal-A) displays heightened toxicity towards TNBC cells (MDA-MB-231), with an IC<small><sub>50</sub></small> of 8.81 ± 0.03 μM. <em>In vitro</em> fluorimetric assays confirmed the apoptotic capability of Mal-A and its capacity to induce nuclear fragmentation. Additionally, ultrasensitive surface-enhanced Raman spectroscopy confirms DNA fragmentation during cellular apoptosis. Cell cycle analysis indicates arrest during the sub-G<small><sub>0</sub></small> phase by downregulating key regulatory proteins involved in cell cycle progression. Increased expression levels of caspase 3, 9, and 8 suggest involvement of both extrinsic and intrinsic apoptotic pathways. Finally, assessment of protein expression patterns within apoptotic pathways reveals upregulation of key apoptotic proteins like Fas/FasL, TNF/TNFR1, and p53, coupled with downregulation of several inhibitors of apoptosis proteins such as XIAP, cIAP-2, and Livin. These findings are further verified with <em>in silico</em> molecular docking. Mal-A reveals a strong affinity towards apoptotic proteins, including TNF, Fas, HTRA, Smac, and XIAP, with docking scores ranging from −5.1 to −7.2 kcal mol<small><sup>−1</sup></small>. Subsequently, molecular dynamics simulation confirms the binding stability. This conclusive <em>in vitro</em> evaluation validates Mal-A as a potent phyto-entity against TNBC. To the best of our knowledge, this study represents the first comprehensive anticancer evaluation of Mal-A in TNBC cells.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 3558-3575"},"PeriodicalIF":4.1,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sara Stocchetti, Ján Vančo, Jan Belza, Zdeněk Dvořák, Zdeněk Trávníček
Copper(ii) and zinc(ii) complexes with lapachol (HLap) of the composition [M(Lap)2(N-N)] and [Cu(Lap)(H2O)(terpy)]NO3 (4), where M = Cu (1-3) or Zn (for 5-7), and N-N stands for bathophenanthroline (1 and 5), 5-methyl-1,10-phenanthroline (2 and 6), 2,2'-bipyridine (3), 2,2';6',2''-terpyridine (terpy, 4) and 1,10-phenanthroline (7), were synthesised and characterised. Complexes 1-5 revealed strong in vitro antiproliferative effects against A2780, A2780R, MCF-7, PC-3, A549 and HOS human cancer lines and MRC-5 normal cells, with IC50 values above 0.5 μM, and reasonable selectivity index (SI), with SI > 3.8 for IC50(MRC-5)/IC50(A2780). Considerable time-dependent cytotoxicity in A2780 cells was observed for complexes 6 and 7, with IC50 > 50 μM (24 h) to ca. 4 μM (48 h). Cellular effects of complexes 1, 5 and 7 in A2780 cells were investigated by flow cytometry revealing that the most cytotoxic complexes (1 and 5) significantly perturbed the mitochondrial membrane potential and the interaction with mitochondrial metabolism followed by the triggering of the intracellular pathway of apoptosis.
{"title":"Strong <i>in vitro</i> anticancer activity of copper(ii) and zinc(ii) complexes containing naturally occurring lapachol: cellular effects in ovarian A2780 cells.","authors":"Sara Stocchetti, Ján Vančo, Jan Belza, Zdeněk Dvořák, Zdeněk Trávníček","doi":"10.1039/d4md00543k","DOIUrl":"10.1039/d4md00543k","url":null,"abstract":"<p><p>Copper(ii) and zinc(ii) complexes with lapachol (HLap) of the composition [M(Lap)<sub>2</sub>(N-N)] and [Cu(Lap)(H<sub>2</sub>O)(terpy)]NO<sub>3</sub> (4), where M = Cu (1-3) or Zn (for 5-7), and N-N stands for bathophenanthroline (1 and 5), 5-methyl-1,10-phenanthroline (2 and 6), 2,2'-bipyridine (3), 2,2';6',2''-terpyridine (terpy, 4) and 1,10-phenanthroline (7), were synthesised and characterised. Complexes 1-5 revealed strong <i>in vitro</i> antiproliferative effects against A2780, A2780R, MCF-7, PC-3, A549 and HOS human cancer lines and MRC-5 normal cells, with IC<sub>50</sub> values above 0.5 μM, and reasonable selectivity index (SI), with SI > 3.8 for IC<sub>50</sub>(MRC-5)/IC<sub>50</sub>(A2780). Considerable time-dependent cytotoxicity in A2780 cells was observed for complexes 6 and 7, with IC<sub>50</sub> > 50 μM (24 h) to <i>ca.</i> 4 μM (48 h). Cellular effects of complexes 1, 5 and 7 in A2780 cells were investigated by flow cytometry revealing that the most cytotoxic complexes (1 and 5) significantly perturbed the mitochondrial membrane potential and the interaction with mitochondrial metabolism followed by the triggering of the intracellular pathway of apoptosis.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11451940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samar I Faggal, Yara El-Dash, Amr Sonousi, Amr M Abdou, Rasha A Hassan
The development of anticancer drugs targeting both PI3K and mTOR pathways is recognized as a promising cancer therapeutic approach. In the current study, we designed and synthesized seventeen new thiazole compounds to investigate their effect on both PI3K and mTOR as well as their anti-apoptotic activity. All the synthesized thiazoles were investigated for their antiproliferative activity on a panel of 60 different cancer cell lines at the National Cancer Institute. Compounds 3b and 3e were selected for further investigation at five dose concentrations due to their effective growth inhibiting activity. Compounds 3b and 3e were further evaluated for their in vitro inhibitory activities against PI3Kα and mTOR compared to alpelisib and dactolisib, respectively as reference drugs. The inhibitory effect of compound 3b on PI3Kα was similar to alpelisib, but it showed weaker inhibitory activity on mTOR compared to dactolisib. Moreover, compound 3b exhibited significantly higher inhibitory activity compared to compound 3e against both PI3Kα and mTOR. The cell cycle analysis showed that compounds 3b and 3e induced G0-G1 phase cell cycle arrest in the leukemia HL-60(TB) cell line. Meanwhile, they significantly increased the total apoptotic activity which was supported by an increase in the level of caspase-3 in leukemia HL-60(TB) cell lines. Molecular docking experiments provided additional explanation for these results by demonstrating the ability of these derivatives to form a network of key interactions, known to be essential for PI3Kα/mTOR inhibitors. All these experimental results suggested that 3b and 3e are potential PI3Kα/mTOR dual inhibitors and could be considered promising lead compounds for the development of anticancer agents.
{"title":"Design, synthesis, and biological evaluation of novel thiazole derivatives as PI3K/mTOR dual inhibitors.","authors":"Samar I Faggal, Yara El-Dash, Amr Sonousi, Amr M Abdou, Rasha A Hassan","doi":"10.1039/d4md00462k","DOIUrl":"https://doi.org/10.1039/d4md00462k","url":null,"abstract":"<p><p>The development of anticancer drugs targeting both PI3K and mTOR pathways is recognized as a promising cancer therapeutic approach. In the current study, we designed and synthesized seventeen new thiazole compounds to investigate their effect on both PI3K and mTOR as well as their anti-apoptotic activity. All the synthesized thiazoles were investigated for their antiproliferative activity on a panel of 60 different cancer cell lines at the National Cancer Institute. Compounds 3b and 3e were selected for further investigation at five dose concentrations due to their effective growth inhibiting activity. Compounds 3b and 3e were further evaluated for their <i>in vitro</i> inhibitory activities against PI3Kα and mTOR compared to alpelisib and dactolisib, respectively as reference drugs. The inhibitory effect of compound 3b on PI3Kα was similar to alpelisib, but it showed weaker inhibitory activity on mTOR compared to dactolisib. Moreover, compound 3b exhibited significantly higher inhibitory activity compared to compound 3e against both PI3Kα and mTOR. The cell cycle analysis showed that compounds 3b and 3e induced G0-G1 phase cell cycle arrest in the leukemia HL-60(TB) cell line. Meanwhile, they significantly increased the total apoptotic activity which was supported by an increase in the level of caspase-3 in leukemia HL-60(TB) cell lines. Molecular docking experiments provided additional explanation for these results by demonstrating the ability of these derivatives to form a network of key interactions, known to be essential for PI3Kα/mTOR inhibitors. All these experimental results suggested that 3b and 3e are potential PI3Kα/mTOR dual inhibitors and could be considered promising lead compounds for the development of anticancer agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We would like to take this opportunity to thank all of RSC Medicinal Chemistry's reviewers for helping to preserve quality and integrity in chemical science literature. We would also particularly like to highlight the Outstanding Reviewers for RSC Medicinal Chemistry in 2023.
{"title":"Outstanding Reviewers for RSC Medicinal Chemistry in 2023","authors":"","doi":"10.1039/D4MD90031F","DOIUrl":"10.1039/D4MD90031F","url":null,"abstract":"<p >We would like to take this opportunity to thank all of <em>RSC Medicinal Chemistry</em>'s reviewers for helping to preserve quality and integrity in chemical science literature. We would also particularly like to highlight the Outstanding Reviewers for <em>RSC Medicinal Chemistry</em> in 2023.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 2973-2973"},"PeriodicalIF":4.1,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06eCollection Date: 2024-09-19DOI: 10.1039/d4md90031f
We would like to take this opportunity to thank all of RSC Medicinal Chemistry's reviewers for helping to preserve quality and integrity in chemical science literature. We would also particularly like to highlight the Outstanding Reviewers for RSC Medicinal Chemistry in 2023.
{"title":"Outstanding Reviewers for <i>RSC Medicinal Chemistry</i> in 2023.","authors":"","doi":"10.1039/d4md90031f","DOIUrl":"https://doi.org/10.1039/d4md90031f","url":null,"abstract":"<p><p>We would like to take this opportunity to thank all of <i>RSC Medicinal Chemistry</i>'s reviewers for helping to preserve quality and integrity in chemical science literature. We would also particularly like to highlight the Outstanding Reviewers for <i>RSC Medicinal Chemistry</i> in 2023.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":"15 9","pages":"2973"},"PeriodicalIF":4.1,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}