Medicinal Chemistry Research最新文献_第9页

A second life for the crystallographic structure of Berenil-dodecanucleotide complex: a computational revisitation thirty years after its publication 贝雷尼尔-十二核苷酸复合物晶体结构的第二次生命：发表 30 年后的计算再研究

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-09-03 DOI: 10.1007/s00044-024-03299-9

Gianluca Novello, Andrea Dodaro, Silvia Menin, Chiara Cavastracci Strascia, Mattia Sturlese, Veronica Salmaso, Stefano Moro

{"title":"A second life for the crystallographic structure of Berenil-dodecanucleotide complex: a computational revisitation thirty years after its publication","authors":"Gianluca Novello, Andrea Dodaro, Silvia Menin, Chiara Cavastracci Strascia, Mattia Sturlese, Veronica Salmaso, Stefano Moro","doi":"10.1007/s00044-024-03299-9","DOIUrl":"https://doi.org/10.1007/s00044-024-03299-9","url":null,"abstract":"<p>This study revisits the pioneering work of Professor Neidle, and co-workers, on the crystal structure of complexes formed between groove binders and DNA sequences. The original research revealed a DNA-ligand complex consisting of a dodecanucleotide bound with Berenil [1,3-bis(4′-amidinophenyl)-triazene] an anti-trypanocidal drug. This article aims to delve deeper into the structural dynamics of this system, showcasing the role played by water molecules in stabilizing the interaction between the ligand and the DNA. With this work, we reevaluate the findings from the original crystallographic study by employing modern molecular dynamics techniques, including Supervised Molecular Dynamics (SuMD) for generating binding trajectories, Thermal Titration Molecular Dynamics for assessing unbinding events, and AquaMMapS to identify regions occupied by stationary water molecules. The study addresses a minor and a major groove binding mode and assesses their strength and specificity using TTMD simulations, generating unbinding trajectories. This comprehensive approach integrates the understanding of the interaction of this DNA-ligand complex, which originated with the valuable work of Professor Neidle, resulting in an in-depth insight into the pivotal role of water molecules with this DNA, a behavior detected and extendable even to other nucleic acid complexes.</p>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"30 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181070","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}

引用次数: 0

A potent therapeutic scaffold fusing quinazolinone/melatonin for future colorectal cancer interventions: design, one-pot synthesis, biological and ADME-tox modeling studies 融合喹唑啉酮/褪黑素的强效治疗支架，用于未来的结直肠癌干预措施：设计、一锅合成、生物学和 ADME 毒理学模型研究

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-09-02 DOI: 10.1007/s00044-024-03279-z

David Preciado, Wilson Cardona-Galeano, Angie Herrera-Ramírez, Andrés F. Yepes

{"title":"A potent therapeutic scaffold fusing quinazolinone/melatonin for future colorectal cancer interventions: design, one-pot synthesis, biological and ADME-tox modeling studies","authors":"David Preciado, Wilson Cardona-Galeano, Angie Herrera-Ramírez, Andrés F. Yepes","doi":"10.1007/s00044-024-03279-z","DOIUrl":"10.1007/s00044-024-03279-z","url":null,"abstract":"<div><p>Colorectal cancer is one of the most incident and lethal cancers in the world. The search for new compounds to treat this disease is being motivated by the occurrence of side effects and the rising in the resistance to chemotherapy. We synthesized a new class of conjugates bearing quinazolinone and melatonin which were prepared in good yields (63–93%) through one-pot three-component approach. quinazolinone/melatonin conjugates were proved against SW480 human colorectal adenocarcinoma cells and non-malignant colonic cells (NCM460). The cytotoxic and antiproliferative activities were determined through the sulforhodamine B assay. Compounds <b>1f</b>, <b>1g</b> and <b>1i–l</b> displayed the best activity, being hybrids <b>1i–l</b> the most selective against malignant cells, causing either a cytostatic and/or cytotoxic effect with evident morphological changes. Moreover, a theoretical drug-like/pharmacokinetics/toxicological study suggested that the hit-promising compounds <b>1i</b> and <b>1j</b> would have a great chance to advance to further preclinical studies as anti-cancer therapeutic candidate for oral oncological management. Our study evidently identified the potency of these quinazolinone/melatonin hybrids to be a prototype drug for further investigations toward novel therapeutics treatments of colorectal cancer.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 9","pages":"1698 - 1713"},"PeriodicalIF":2.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03279-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181071","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}

引用次数: 0

Insights into computer-aided G-quadruplex prediction in the digital age 数字时代计算机辅助 G-四链路预测的启示

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-28 DOI: 10.1007/s00044-024-03302-3

Pulakesh Pramanik, Santanu Bhattacharya

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Design, synthesis and evaluation of imidazo[1,2-a]pyrazin-8(7H)-one derivatives as acetylcholinesterase inhibitors and antioxidants 咪唑并[1,2-a]吡嗪-8(7H)-酮衍生物作为乙酰胆碱酯酶抑制剂和抗氧化剂的设计、合成与评估

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-24 DOI: 10.1007/s00044-024-03298-w

Wen-Rong Du, Ben-Ben Wei, Xin-Yuan Guo, Yong Lan, Pan-Pan Shang, Yi-Xuan Wang, Xue-Wei Zhou, Xiao-Ke Wang, Zheng-Yue Ma

{"title":"Design, synthesis and evaluation of imidazo[1,2-a]pyrazin-8(7H)-one derivatives as acetylcholinesterase inhibitors and antioxidants","authors":"Wen-Rong Du, Ben-Ben Wei, Xin-Yuan Guo, Yong Lan, Pan-Pan Shang, Yi-Xuan Wang, Xue-Wei Zhou, Xiao-Ke Wang, Zheng-Yue Ma","doi":"10.1007/s00044-024-03298-w","DOIUrl":"10.1007/s00044-024-03298-w","url":null,"abstract":"<div><p>A series of 8-(piperazin-1-yl)imidazo[<i>1,2-a</i>]pyrazine derivatives were designed and synthesized as acetylcholinesterase inhibitors (AChEIs) and antioxidants for the treatment of Alzheimer’s disease (AD). Moreover, the biological evaluation results demonstrated that these synthesized compounds exhibited moderate inhibitory activities toward acetylcholinesterase (AChE) and radical scavenging activities. Among them, compound <b>17r</b> was the most potent AChE inhibitor with an IC<sub>50</sub> value of 0.47 μM and moderate inhibitory activity against butyrylcholinesterase (BuChE) (IC<sub>50</sub> = 11.02 μM). The selectivity index (SI) value of AChE over BuChE was 23.45, surpassing that of the reference drug galantamine (AChE IC<sub>50</sub> = 5.01 μM, BuChE IC<sub>50</sub> = 18.46 μM, SI = 3.68). Compound <b>17o</b> had the best antioxidant activity with an IC<sub>50</sub> value of 89.33 μM, which was lower than that of ascorbic acid (IC<sub>50</sub> value = 25.70 μM) as the control drug. Furthermore, the results of molecular docking studies indicated that <b>17r</b> could simultaneously bind to both catalytic active site and peripheral anionic site of AChE, which was consistent with the mixed inhibition pattern shown by enzyme kinetic studies. The interaction’s stability of <b>17r</b>-AChE/BuChE were also assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound <b>17r</b> in the cavity of the AChE. In addition, the molecular properties of all compounds were predicted online through the SwissADME, and the best active compound <b>17r</b> matched the properties of most orally administered drugs. Based on the biological activity and molecular properties, compound <b>17r</b> as AChEI was valuable for further development.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 10","pages":"1938 - 1953"},"PeriodicalIF":2.6,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181073","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}

引用次数: 0

Anticancer potential of delphinidin and its derivatives: therapeutic and mechanistic insights 德尔菲尼丁及其衍生物的抗癌潜力：治疗和机理见解

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-14 DOI: 10.1007/s00044-024-03296-y

Shabnoor Iqbal, Timothy Omara, Ivan Kahwa, Usman Mir Khan

{"title":"Anticancer potential of delphinidin and its derivatives: therapeutic and mechanistic insights","authors":"Shabnoor Iqbal, Timothy Omara, Ivan Kahwa, Usman Mir Khan","doi":"10.1007/s00044-024-03296-y","DOIUrl":"10.1007/s00044-024-03296-y","url":null,"abstract":"<div><p>Anthocyanins are water-soluble naturally occurring flavonoids present in fruits, flowers, leaves, and roots of fruit plants and vegetables. One of the important anthocyanidin components of red wine and berries is delphinidin (DP). This review provides an update on the potential of DP in cancer therapy, with a further understanding of the mechanisms involved. Delphinidin has been shown to elicit inhibitory effects on catabolizing enzymes of human granulocytes and parasites, TNF-induced COX-2 expression in mouse epidermal cells, and reduce oxidative stress. It also inhibited anchorage-independent growth and caused cell death in breast cancer cell lines. Delphinidin increased Nrf2 expression, increased HO-1 production, and promoted mRNA expression of mitochondrial biogenesis-related factors. Further, DP has anti-proliferative and pro-apoptotic effects in various cancer cell lines such as lung, breast, and ovarian cancer cells. The mTOR-related pathway is the most important signaling pathway in the activation of autophagy, and DP has been shown to exert its cytotoxic effects on cancer cell lines via activating protein kinases. Among DP derivatives, delphinidin-3-O-glucoside has the best anticancer activity because it is easily absorbed. However, the metabolism of DP and its bioavailability in biological systems need to be explored to fully understand its benefits.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 10","pages":"1769 - 1786"},"PeriodicalIF":2.6,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03296-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181075","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}

引用次数: 0

Terrein: Isolation, synthesis, and upscaling of a functional scaffold for multifaceted biomedical applications Terrein：用于多方面生物医学应用的功能性支架的分离、合成和放大

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-10 DOI: 10.1007/s00044-024-03294-0

Vaishali Raghuvanshi, Diksha Katiyar

引用次数: 0

Dauricine: a review of natural observation, pharmacology, and pharmacokinetics 杜冷丁：自然观察、药理学和药代动力学综述

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-09 DOI: 10.1007/s00044-024-03297-x

Tran Quang Hai, Nguyen Thi Huong, Ninh The Son

{"title":"Dauricine: a review of natural observation, pharmacology, and pharmacokinetics","authors":"Tran Quang Hai, Nguyen Thi Huong, Ninh The Son","doi":"10.1007/s00044-024-03297-x","DOIUrl":"10.1007/s00044-024-03297-x","url":null,"abstract":"<div><p><i>Menispermum dauricum</i> DC (the moonseed family Menispermaceae) was used to treat various diseases, such as inflammatory disorders, and arrhythmia. Dauricine (DRC) is the principal bisbenzylisoquinoline alkaloid found in the roots of this medicinal plant. To date, there is still a lack of documents that review natural occurrence, and pharmacological and pharmacokinetic studies regarding this molecule. The current research tends to fill this gap. References have been systematically searched from the Web’s largest databases, such as Web of Science, Google Scholar, Sci-Finder, PubMed, and others, for relevant literature. The current review has also covered the pharmacological processes and mechanisms of the studied compound in a visible arrangement. DRC has possessed a great variety of in vitro and in vivo pharmacological activities, including anticancer, anti-inflammatory, and vasorelaxant, as well as protection to the brain, bone, and lungs. The underlying mechanisms relate to various signaling pathways, in which the NF-κB (nuclear factor kappa B) can be seen as the main route. Pharmacokinetic actions of DRC may relate to the loss of proton and methyl groups, and/or the addition of hydroxyl and sugar units, whereas its absolute bioavailability is found to be less than 50%. The other pharmacological assays are expected. More studies mentioning clinical experiments, toxicology, and bioavailability are encouraged. Structural modification is such a good approach to enhance pharmacological value and reduce toxicity</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 10","pages":"1787 - 1803"},"PeriodicalIF":2.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141924652","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}

引用次数: 0

Design, synthesis and biological evaluation of potent thiazolidinedione salicylic acid inhibitors against glyoxalase-I as potential anticancer agents 作为潜在抗癌剂的强效噻唑烷二酮水杨酸抑制剂乙二醛酶-I 的设计、合成和生物学评价

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-09 DOI: 10.1007/s00044-024-03247-7

Banan O. Alomari, Lara I. Fakhouri, Nizar A. Al‑Shar’i, Qosay Albalas

{"title":"Design, synthesis and biological evaluation of potent thiazolidinedione salicylic acid inhibitors against glyoxalase-I as potential anticancer agents","authors":"Banan O. Alomari, Lara I. Fakhouri, Nizar A. Al‑Shar’i, Qosay Albalas","doi":"10.1007/s00044-024-03247-7","DOIUrl":"10.1007/s00044-024-03247-7","url":null,"abstract":"<div><p>The worldwide rise in cancer incidence and mortality rates has spurred the search for new pathways implicated in cancer development and progression. One such target is glyoxalase 1 (GLO-I), a key player in methylglyoxal detoxification and a factor in the proliferation and prognosis of numerous cancers. Recent studies led by Al-Shar’i et al. utilized computer-aided drug design to identify potential inhibitors of GLO-I. The second most potent hit, (<i>Z</i>)-5-(5-((2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)-2-hydroxybenzoic acid, (IC<sub><i>50</i></sub> = 4.24 µM), was selected as a lead for further optimization. Through molecular docking, 27 analogs were designed and evaluated for binding affinity, with 14 of the top-scorings synthesized and tested for their inhibitory activity against GLO-I. The majority of these analogs showed enhanced activities relative to the lead compound, with the most potent having an IC<sub>50</sub> of 150 nM. These findings pave the way for the continued development of highly effective GLO-I inhibitors.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 9","pages":"1526 - 1540"},"PeriodicalIF":2.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933191","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}

引用次数: 0

Novel monastrol/melatonin hybrids as a new approach for colorectal cancer intervention: design, synthesis, biological activity, and drug-likeness modeling studies 作为结直肠癌干预新方法的新型甲萘醌/褪黑素混合物：设计、合成、生物活性和药物相似性模型研究

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-08 DOI: 10.1007/s00044-024-03223-1

David Preciado-A, Andrés F. Yepes, Angie Herrera-R, Wilson Cardona-G

{"title":"Novel monastrol/melatonin hybrids as a new approach for colorectal cancer intervention: design, synthesis, biological activity, and drug-likeness modeling studies","authors":"David Preciado-A, Andrés F. Yepes, Angie Herrera-R, Wilson Cardona-G","doi":"10.1007/s00044-024-03223-1","DOIUrl":"10.1007/s00044-024-03223-1","url":null,"abstract":"<div><p>Considering the important increase in the incidence and mortality of colorectal cancer, it is necessary to develop new strategies in the search for new alternatives against this disease. Hence, we designed and synthesized a new series of monastrol/melatonin hybrids and evaluated them in vitro and in silico to determine the potential of these new chemical entities on this type of cancer. To achieve this goal, the different compounds were evaluated in human colorectal adenocarcinoma cells SW480, while establishing the selective potential of the hybrids through the nonmalignant human colon mucosal epithelial cell line (NCM460). According to the results, hybrids <b>6a</b>, <b>6c</b>, <b>6i</b>, and <b>6j</b> displayed the best response, with IC<sub>50</sub> values in the range of 5.2 and 6.3 μM, inducing important changes depending on concentration and time. In addition, these compounds were extremely active in comparison to the single molecules, and they were slightly more selective than the reference drug (5 fluorouracil, 5-FU). Besides, an optimal pharmacokinetic and toxicological profile was also estimated for hybrids <b>6a</b>, <b>6c</b>, <b>6i</b>, and <b>6j</b>. Altogether, novel hybrids of monastrol-MLT, in particular, <b>6a</b> (-H), <b>6c</b> (3-OMe), <b>6i</b> (3,4-OMe), and <b>6j</b> (3,5-OMe) could be addressed as starting points for further pharmacological studies concerning to combat colorectal cancer.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 9","pages":"1511 - 1525"},"PeriodicalIF":2.6,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-024-03223-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141926624","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}

引用次数: 0

Contrasting effect of different crowding agents on pseudoknot RNA stability 不同拥挤剂对假结 RNA 稳定性的对比效应

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-08-08 DOI: 10.1007/s00044-024-03293-1

Sagar Satpathi, T. Endoh, Naoki Sugimoto

引用次数: 0