Bioorganic Chemistry最新文献

{"title":"Synthesis and biological evaluation of a new class of azole urea compounds as Akt inhibitors with promising anticancer activity in pancreatic cancer models.","authors":"Camilla Pecoraro, Fabio Scianò, Daniela Carbone, Geng Xu, Juan Deng, Stella Cascioferro, Elisa Giovannetti, Patrizia Diana, Barbara Parrino","doi":"10.1016/j.bioorg.2024.107959","DOIUrl":"10.1016/j.bioorg.2024.107959","url":null,"abstract":"<p><p>The PI3K/Akt pathway is crucial in numerous cellular functions such as cell growth, survival proliferation and movement in both normal and cancer cells. It plays also a key role in epithelial-mesenchymal transitions and angiogenesis during the tumorigenesis processes. Since many transformative events in cancer are driven by increased PI3K/Akt pathway signaling, Akt is considered a valuable target for developing new therapies against various tumor types, including pancreatic cancer. This is because the PI3K/AKT/mTOR pathway is a key downstream effector of RAS, and RAS activation is the most prominent genetic alteration in pancreatic cancer. Herein we report the synthesis and the biological evaluation of a new series of azole urea compounds that exhibited promising antiproliferative and antimigratory activities against pancreatic cancer cells through an Akt inhibition mechanism. These effects were demonstrated using a variety of assays, including Sulforhodamine B, cell-cycle, wound-healing, and kinase activity, apotposis and ELISA assays. Additionally, the anticancer properties of the most active compound in the series were confirmed in the 3D spheroid model of PATU-T cells.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107959"},"PeriodicalIF":4.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of new 4-aminoquinoline derivatives containing an amine or hydroxamic acid terminal as multifunctional agents for the treatment of Alzheimer's disease.","authors":"Bochao Zhai, Qianyun Hao, Mingfan Wang, Zhiqiang Luo, Rui Yang, Jian Yang, Yuqing Cao","doi":"10.1016/j.bioorg.2024.107954","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107954","url":null,"abstract":"<p><p>Due to the multifactorial nature of Alzheimer's disease (AD), effective multi-targeted directed ligands (MTDLs) are urgently needed for its treatment as single-target drugs currently encounter therapeutic challenges. Two series of new 4-aminoquinoline derivatives containing an amine or hydroxamic acid terminal were designed, synthesized and evaluated for their cholinesterase inhibition, antioxidant and metal-ion chelation properties. Among them, hydroxamic acid-containing compounds 7r and 7f exhibited the best inhibitor activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), respectively, with the corresponding IC₅₀ values of 0.41 and 1.06 μM, which were superior to those of rivastigmine (IC₅₀ = 5.26, 2.02 μM, respectively). Moreover, compounds 7r and 7f presented excellent ABTS radical scavenging efficiency and selective metal-ion chelation ability such as Cu²⁺ and Fe²⁺. Both molecular docking and enzyme kinetic analysis revealed that compound 7r was a mixed-type inhibitor of AChE. Additionally, the ADME prediction indicated that compounds 7r and 7f have suitable pharmacokinetic and drug-like properties. Furthermore, they demonstrated good safety and blood-brain barrier permeability in cytotoxicity assays and in vivo experiments, respectively. These findings strongly suggest that the 4-aminoquinoline derivatives containing a hydroxamic acid terminal have great potential as promising MTDLs for the treatment of AD, opening new avenues for future therapeutic strategies.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107954"},"PeriodicalIF":4.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and structural proof of novel oxazolo[5,4-d]pyrimidine derivatives as potential VEGFR2 inhibitors. In vitro study of their anticancer activity.","authors":"Aleksandra Sochacka-Ćwikła, Andrzej Regiec, Żaneta Czyżnikowska, Urszula Śliwińska-Hill, Anna Kwiecień, Benita Wiatrak, Agnieszka Rusak, Klaudia Krawczyńska, Monika Mrozowska, Sylwia Borska, Katarzyna Ratajczak, Anna Pyra, Marcin Mączyński","doi":"10.1016/j.bioorg.2024.107958","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107958","url":null,"abstract":"<p><p>The present study aimed to design and synthesize novel 6-N-benzyloxazolo[5,4-d]pyrimidin-7(6H)-imines 3a-j as possible inhibitors of the vascular endothelial growth factor receptor 2 (VEGFR2). The structures of newly synthesized compounds were confirmed via spectral and crystallographic data. NOESY spectroscopy was very useful in distinguishing between 6-N-benzyl-7(6H)-imine 3a and isomeric 7-N-benzyl-7-amine 4a, obtained by Dimroth rearrangement. Molecular docking at the VEGFR2 active site was performed, indicating that 7(6H)-imines should have a similar binding mode as type II VEGFR2 inhibitors. All derivatives were preliminary evaluated for in vitro cytotoxic activity against four human cancer cell lines, including lung cancer (A549), colorectal cancer (HT-29), melanoma (A375), breast cancer (MCF7), using tivozanib as a reference drug, and some of them were subjected to VEGFR2 inhibition, anti-angiogenic activity, and human serum albumin (HSA) binding assays. Only 6-N-2,4-dimethoxybenzyl derivative 3h appeared to be as active as tivozanib against all tested anticancer cell lines but equally toxic to healthy normal human dermal fibroblasts (NHDF). Derivatives 3f (6-N-2-methybenzyl) and 3b (6-N-4-methylbenzyl) have revealed slightly worse activity than 3h. They were cytotoxic agents comparable to tivozanib against three anticancer lines, but only 3b showed no cytotoxicity against NHDF. Both 3b and 3h proved to be effective VEGFR2 inhibitors with IC₅₀ values comparable to that of tivozanib. Notably, 4a did not actually show an anticancer effect against the tested cancer lines, in contrast to isomeric 3a. In an angiogenesis assay, 3f and 3h significantly suppressed the tube formation ability of human dermal microvascular endothelial cells (HMEC-1), indicating their anti-angiogenic potential. The interactions between these compounds and HSA appeared to occur at two specific binding sites.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107958"},"PeriodicalIF":4.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apigenin analogs as α-glucosidase inhibitors: Molecular docking, biochemical, enzyme kinetic, and an in vivo mouse model study.","authors":"Honghui Liu, Yanxu Wei, Yan Wang, Qiu Zhao, Lan Liu, Hong Ding, Yuntian Hong","doi":"10.1016/j.bioorg.2024.107956","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107956","url":null,"abstract":"<p><p>Due to the high incidence of diabetes and its associated complications, diabetes is widely recognized as a serious global health problem. In diabetes treatment strategies, targeting α-glucosidase, a key carbohydratehydrolyzing enzyme, has emerged as a highly regarded approach. To develop novel α-glucosidase inhibitors, we successfully synthesized a series of apigenin analogs, collectively referred to as H1-H27 compounds and examined their inhibitory effects on α-glucosidase activity. H7 showed a remarkable inhibitory effect, surpassing that of the standard drug acarbose. Further analysis revealed that H7, H10, and H24 act as non-competitive inhibitors of α- glucosidase. In vivo experiments using a type 2 diabetes mouse model demonstrated the diverse therapeutic potential of H7; it effectively lowered blood sugar levels, improved glucose tolerance, and corrected lipid metabolism. In addition, H7 showed hepatoprotective effects, highlighting its ability to improve liver function. H7 also positively influenced the gut microbiota composition in diabetic mice, increasing diversity and richness. These results highlight the promising therapeutic effects of apigenin analogs, such as H7, for treating type 2 diabetes and show how they could provide numerous benefits, including effective inhibition of α-glucosidase, improved glucose control, correction of lipid metabolism, hepatoprotection, and modulation of the intestinal microbiota.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107956"},"PeriodicalIF":4.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quinazoline derivatives inhibit cell growth of prostate cancer as a WRN helicase dependent manner by regulating DNA damage repair and microsatellite instability.","authors":"Jia Yu, Yunyun Zhou, Guangyan Liang, Sha Cheng, Jiaomei Wei, Huimin Li, Xinyu Liu, Chang You, Mengsha Mao, Mashaal Ahmad, Gang Yu, Bixue Xu, Heng Luo","doi":"10.1016/j.bioorg.2024.107963","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107963","url":null,"abstract":"<p><p>WRN helicase is a crucial target of synthetic death in cancer and has a unique advantage in the treatment of microsatellite unstable cancers. Our previous studies have found that quinazoline derivatives showed the WRN-dependent antiproliferative activity. In this study, a series of new quinazoline derivatives were designed and synthesized by optimizing the structure, and evaluating the targeting and sensitivity to WRN helicase. Cell growth inhibition experiments on WRN overexpressing PC3 cells (PC3-WRN) showed that the antiproliferative activity of some compounds was significantly dependent on WRN helicase. Moreover, the antitumor activity of 9in vivo was significantly decreased in the nude mouse model constructed with WRN knockdown PC3 cells (PC3-shWRN) compare (P < 0.01) to the control group. The molecular docking and CETSA results showed that 9 directly binds to WRN protein. Mechanism studies have confirmed that 9 targeted WRN, and may affect the binding between WRN and other key regulators, to destroy the repair function and regulate genomic stability. In addition, 9 also has suitable pharmacokinetic parameters and low toxicity in vivo. This result indicates that the quinazoline derivative 9 could be a novel WRN function inhibitor for the treatment of prostate cancer.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107963"},"PeriodicalIF":4.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards antimicrobial agents: Design and antibacterial activity of a hybrid fluorophore where porphyrin and Rose Bengal moieties are linked through the hydroxyl group of a xanthene dye.","authors":"G Mamardashvili, E Kaigorodova, N Solomonova, N Mamardashvili","doi":"10.1016/j.bioorg.2024.107960","DOIUrl":"10.1016/j.bioorg.2024.107960","url":null,"abstract":"<p><p>The axial complex of Sn(IV)-tetra(4-sulfophenyl)porphyrin (SnP) with Rose Bengal (RB) was obtained where RB axial binding is realized through the hydroxyl groups of the xanthene dye [SnP(RB)₂]. The luminescent properties of the SnP(RB)₂ (fluorescence and ability to generate singlet oxygen at room temperature) in aqueous media with additives of surfactant cetylpyridinium chloride (CPC) and ε-poly-l-lysine (EPL) were studied. It was found that nature of the medium (surfactant additives of different concentrations) determines the effectiveness of the photoinduced energy transfer from the RB fragment to the SnP fragment of the hybrid fluorophore (HF). It has been established that the ability of the HF to generate singlet oxygen in D₂O and D₂O-micellar media is higher than that of its constituent fragments. The dark and photodynamic antibacterial activity of the HF against two microorganisms [Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus)] was determined and analyzed. It was shown how the antibacterial activity of the HF depends on the nature of the bacteria, the micellar environment and radiation dose.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107960"},"PeriodicalIF":4.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing potential COX-2 engagement for boosting anticancer activity of substituted 2-mercapto-4(3H)-quinazolinones with promising EGFR/VEGFR-2 inhibitory activities.","authors":"Abdelrahman Hamdi, Samar S Tawfik, Ahmed R Ali, Wafaa A Ewes, Abdullah Haikal, Adel S El-Azab, Ahmed H Bakheit, Mohamed M Hefnawy, Hazem A Ghabbour, Alaa A-M Abdel-Aziz","doi":"10.1016/j.bioorg.2024.107951","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107951","url":null,"abstract":"<p><p>We designed and synthesized new quinazolinone-tethered phenyl thiourea/thiadiazole derivatives 4-26. Based on their structural characteristics, these compounds were proposed to have a multi-target mode of action for their anticancer activities. Using the MTT assay method, antiproliferative effects were assessed against three human cancer cell lines (HEPG-2, MCF-7, and HCT-116). In vitro assessment for enzymatic inhibitory activity of the most active compounds 4, 9 and 20 was done for EGFR, VEGFR-2 and COX-2 as potential targets. The screened compounds showed low micromolar IC₅₀ inhibitory effects against the three targets. Compound 9 demonstrated similar EGFR/VEGFR-2 inhibitory effect to the control drugs and potential inhibitory activity for COX-2 enzyme. In MCF-7 cells, the most active analog 9 caused 41.02% total apoptosis, and arrested the cell cycle at the G2/M phase. Taken as a whole, the findings of this study provide significant new understandings into the relationship between COX inhibition and cancer therapy. Furthermore, the outcomes showcased the encouraging efficacy of these compounds with a multi-target mechanism, making them excellent choices for additional research and development into possible anticancer drug.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107951"},"PeriodicalIF":4.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Discovery of neuroprotective agents: Potent, brain penetrating, lipoic acid derivatives for the potential treatment of ischemic stroke by regulating oxidative stress and inflammation - A preliminary study\" [Bioorg. Chem. 147 (2024) 107339].","authors":"Chenchen Zhu, Yun Wang, Yi Li, Tingfang Wang, Fei Ye, Wei Su, Ting Chen, Chuan Zhang, Liyan Xiong","doi":"10.1016/j.bioorg.2024.107927","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107927","url":null,"abstract":"","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":" ","pages":"107927"},"PeriodicalIF":4.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro and in vivo studies of a decanuclear Ni(II) complex as a potential anti-breast cancer agent.","authors":"Haitao Zhu, Houcong Li, Yuxin Ji, Min Hou, Qingling Yang, Lili Liang, Wenge Li","doi":"10.1016/j.bioorg.2024.107949","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107949","url":null,"abstract":"<p><p>A non-platinum-metal decanuclear complex [Ni₁₀L₄(CH₃COO)₈ (C₂H₅OH)₈]·8(C₂H₅OH) (Ni₁₀ complex) has been developed with a tri-dentate 2,3-dihydroxybenzaldehyde-2-aminophenol Schiff base ligand (H₃L). Single crystal X-ray analysis reveals that the Ni₁₀ complex displays a sandwich loaf-shaped decanuclear structure and its anticancer activity was evaluated. The cell cytotoxicity results indicating that the Ni₁₀ complex is most effective to human breast cancer cells MDA-MB-231 and its mechanism were further investigated. Flow cytometry analysis showed that the Ni₁₀ complex triggered cell cycle arrest and induced apoptosis of MDA-MB-231 cells. Western blot analysis of the changes of intracellular protein expression showed that Ni₁₀ triggers MDA-MB-231 apoptosis through mitochondrial mediated apoptosis signaling pathways. In vivo experiments showed that the Ni₁₀ complex significantly suppressed breast tumor growth with low toxicity against major organs in a nude mice model. The good treatment effect, low toxicity and pharmacological mechanisms of the decanuclear Ni^II complex may provide a clue for the research and development of non-platinum multinuclear based chemotherapeutic drugs.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107949"},"PeriodicalIF":4.5,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering substrate promiscuity and specificity of indolethylamine N-methyltransferase family enzymes from amphibian toads.","authors":"An-An Zhang, Chengyu Zhou, Guo-Qiang Lin, Qing-Li He, Qunfei Zhao","doi":"10.1016/j.bioorg.2024.107950","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107950","url":null,"abstract":"<p><p>N-methylation is a crucial post-modification process in natural product biosynthesis and also contributes to the metabolism of various physiological substances, such as neurotransmitter, hormone, and trace elements. In this study, we identified seven indolethylamine N-methyltransferase (INMT) family enzymes from the amphibian toad Bufo gargarizan with distinct catalytic properties. Among these enzymes, BNMT 1, BNMT 5, BNMT 6 and BNMT 7 exhibited notable promiscuity, demonstrating the ability to methylate multiple derivatives of indolethylamine, phenylethylamine, phenylethanolamine, and nicotinamide. Conversely, BNMT 3 and BNMT 4 exhibited more specific substrate preferences, targeting particular phenylethylamine, phenylethanolamine, and nicotinamide-type substrates. Additionally, one enzyme, BNMT 11, exhibiting high specificity towards phenylethanolamines. By employing molecular docking and mutating key amino acids, we provided a rational explanation for the promiscuity and specificity mechanisms exhibited by these enzymes. This research offers valuable insights into the catalytic mechanisms of INMT family enzymes in B. gargarizans, as well as other organisms. Moreover, the identification of these broadly substrate-specific enzymes holds promise for leveraging synthetic biology in the production of a wide variety of naturally occurring N-methylated compounds.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107950"},"PeriodicalIF":4.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}