Bioorganic Chemistry最新文献

{"title":"Analysis of the effects of differently charged peptides on α-amylase and their interaction mechanisms.","authors":"Xiaoyu Yang, Chuanbo Li, Qi Yang, Jiayi Ji, Xinyue Jiang, Chunying Liu, Fubao Sun, Xiaodan Wang, Shaohua Dou","doi":"10.1016/j.bioorg.2024.107972","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107972","url":null,"abstract":"<p><p>Nowadays α-amylase is widely used in various fields. Therefore, in this study, the effects of neutral (T₀), negatively charged (T₈^-) and positively charged (T₉⁺) peptides on α-amylase activity were investigated by means of an applied protein electric field, and spectroscopy and molecular dynamics were employed to investigate this mechanism. It was found that the nature of the charge of the peptides had a strong influence on α-amylase activity, with T₈^- and T₉⁺ increasing and decreasing α-amylase activity, respectively, whereas T₀ had no effect on enzyme activity. Fluorescence spectroscopy and circular dichroism results indicated that the charged peptides changed the conformation of α-amylase. Meanwhile, the molecular dynamics results showed that the charged peptides changed the distribution of the surface charge of α-amylase mainly through electrostatic force, which not only changed the conformation of the enzyme, but also altered the microenvironment of the enzyme active centre, which caused α-amylase to become compact or loose to affect the enzyme activity.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107972"},"PeriodicalIF":4.5,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674661","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 anti-inflammatory activity and molecular docking of Peperomia pellucida (L.) Kunth extract via the NF-κB and PPAR-γ signalling in human retinal pigment epithelial cells.","authors":"Keat Lam Ho, Phaik Har Yong, Chee Woon Wang, Siew Huah Lim, Umah Rani Kuppusamy, Bavani Arumugam, Chek Tung Ngo, Zhi Xiang Ng","doi":"10.1016/j.bioorg.2024.107969","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107969","url":null,"abstract":"<p><p>This study aims to elucidate the anti-inflammatory mechanism of Peperomia pellucida (L.) Kunth in human retinal pigment epithelial cell line (ARPE-19) as stimulated by high glucose (34 mM and 68 mM), and advanced glycation end product (AGE) under different glucose (17 mM, 34 mM and 68 mM) environments via the nuclear factor kappa B (NF-κB) and peroxisome proliferator activated receptor gamma (PPAR-γ) signalling pathways. The cytotoxicity of P. pellucida in ARPE-19 cells was evaluated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The genes and proteins expression of nine pro-inflammatory, angiogenic and antioxidant markers, including glutathione peroxidase (GPx), interleukin 8, matrix metalloproteinase 2, monocyte chemoattractant protein 1, NF-κB, PPAR-γ, receptor for AGE (RAGE), soluble RAGE (sRAGE), and vascular endothelial growth factor in P. pellucida-treated ARPE-19 cells were compared to non-treated control via real-time polymerase chain reaction and western blot. Both P. pellucida methanolic extract (1.5 mg/mL and 3 mg/mL) and ethyl acetate fraction (4 mg/mL) were non-toxic to ARPE-19 cells and demonstrated cytoprotective effect against the high glucose (34 mM) and AGE (17 mM glucose)-induced cellular stress. High glucose and AGE activated the pro-inflammatory signalling in ARPE-19 cells, as evidenced by the increased NF-κB p65 phosphorylation, up-regulation of pro-inflammatory and angiogenic mediators (p<0.05) but reduced GPx, PPAR-γ and sRAGE protein expression. Both P. pellucida methanolic extract (3 mg/mL) and ethyl acetate fraction (4 mg/mL) suppressed (p<0.05) the pro-inflammatory and angiogenic markers expression under high glucose and AGE environment. The main phytochemicals identified in P. pellucida were dillapiole, 2,4,5-trimethoxystyrene, 9-octadecenoic acid, and pheophorbide A-methyl ester which displayed relatively strong binding affinity towards NF-κB p65 and PPAR-γ proteins in molecular docking analysis. This study has demonstrated that P. pellucida is a potential alternative anti-inflammatory source for managing diabetic retinopathy via NF-κB and PPAR-γ signalling.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107969"},"PeriodicalIF":4.5,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674666","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":"Sodium cromoglycate exerts anti-pulmonary fibrosis effects by targeting the Keap1 protein to activate Nrf2 signaling.","authors":"Xiaofeng Liu, Yuwei Huang, Xianchen Zhao, Yingjun Guan, Yanchun Li, Lei Yuan, Chuncheng Wang, Chao Ma, Enlong Ma","doi":"10.1016/j.bioorg.2024.107961","DOIUrl":"10.1016/j.bioorg.2024.107961","url":null,"abstract":"<p><p>Oxidative stress has been confirmed to be closely related to the occurrence and development of pulmonary fibrosis (PF). The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid-2 related factor 2 (Nrf2) pathway plays a key role in maintaining cellular redox homeostasis. Targeting the Keap1 protein to activate Nrf2 could be a promising strategy for treating PF. Virtual screening via a pharmacophore model was used to screen candidate compounds with potential Keap1 binding ability from the U.S. Food and Drug Administration (FDA) database. The results revealed that sodium cromoglycate (Cro) has the highest fit value and absolute docking score and could improve the thermal stability of the Keap1 protein in a CETSA, confirming that Cro could bind to the Keap1 protein directly. Further studies revealed that Cro promoted Nrf2 translocation into the nucleus, relieved oxidative stress, prevented the epithelial-mesenchymal transition (EMT) process and upregulated fibrosis markers in TGF-β1-induced A549 cells, indicating that Cro has anti-pulmonary fibrosis activity in an in vitro lung fibrosis model. Moreover, in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, Cro administration improved pulmonary fibrosis, activated Nrf2 signaling, and blocked the EMT process. In summary, these results demonstrated that Cro could activate Nrf2 signaling to clear reactive oxygen species (ROS) by directly binding to Keap1 and alleviate pulmonary fibrosis by blocking the progression of EMT both in vitro and in vivo.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107961"},"PeriodicalIF":4.5,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666325","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":"Development of an at-line coupling of LC-QTOF-ESI-MS/MS to steroid 5-alpha reductase inhibition assay, a fast bioactive targeting and guided purification of natural complex sample, Impatiens balsamina Linn.","authors":"Jukkarin Srivilai, Nitra Neungchamnong, Nantaka Khorana, Piyakaset Suksathan, Tammanoon Rungsang, Prapapan Temkittaworn, Ruttanaporn Chantakul, Eakkaluk Wongwad, Ranit Charoenjittichai, Kornkanok Ingkaninan","doi":"10.1016/j.bioorg.2024.107971","DOIUrl":"https://doi.org/10.1016/j.bioorg.2024.107971","url":null,"abstract":"<p><p>This study provides a rapid and accurate method for screening steroid 5-alpha reductase (S5αR) inhibitors in Impatiens balsamina Linn (IB). using at-line LC-QTOF-ESI-MS/MS coupling S5αR inhibitory assay. IB (Balsaminaceae) is an annual herbaceous plant cultivated in tropical and subtropical regions. It has been used in traditional Chinese and Thai medicine for treatment of hair loss and various skin conditions, potentially through anti-androgenic mechanisms. A combined approach of S5αR inhibitory assay and LC-QTOF-ESI-MS/MS was developed to rapidly screen for target biomarkers and guide their isolation using preparative HPLC. The toxicity of both the extract and isolated biomarkers was evaluated on skin cells, keratinocytes, and fibroblasts. Eight bioactive compounds were identified as two naphthoquinone, two fatty acid derivatives, three nitrogenous compounds and one aromatic derivative. The most potent bioactive markers, identified as 2-methoxy-1,4-naphthoquinone (2MN) and impateinol, were targeted and isolated using preparative HPLC, yielding 5.0 % and 3.5 %, respectively. These compounds exhibited S5αR inhibitory activity higher than that of finasteride drug by 10 and 2 times, respectively. Both the isolated biomarkers and the extract demonstrated a broad therapeutic index. The developed method in this study proved to be both rapid and accurate, making it suitable for screening and targeting S5αR inhibitors in herbal plants or complex matrix samples. It facilitated the fast-guided isolation of bioactive compounds, highlighting its potential for future applications in drug discovery research.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107971"},"PeriodicalIF":4.5,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674665","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":"Developing new anticancer agents: Design, synthesis, biological evaluation and in silico study of several functionalized pyrimidine-5-carbonitriles as small molecules modulators targeting breast cancer.","authors":"Waleed A Badawi, Tarek M Okda, Shrouk M Abd El Wahab, Eman S Ezz-ElDien, Omaima M AboulWafa","doi":"10.1016/j.bioorg.2024.107953","DOIUrl":"10.1016/j.bioorg.2024.107953","url":null,"abstract":"<p><p>Committed to our growing effort addressed toward the development of potent anti-breast cancer candidates, new 4-hydrazinylpyrimidine-5-carbonitriles featuring a morpholinyl or piperidinyl moiety at the position-2 and derivatized with various functionalities at the hydrazinyl group were designed through structure optimization, and their antiproliferative potency against two human breast cancer (BC) cell lines, relative to the reference drug 5-FU, was evaluated. Compounds showing remarkable cytotoxic activity versus the hormone dependent MCF-7 cell line (IC₅₀ = 1.62 ± 0.06 µM- 9.88 ± 0.38 µM) and the non-hormone dependent MDA-MB-231 cell line (IC₅₀ = 3.26 ± 0.14 µM-12.93 ± 0.55 µM) were further tested by multiple assays for clarification of their potential activity. Promising derivatives revealing low damage to healthy cells were subject to enzymatic inhibitory assessment against ARO and EGFR and their activities compared to letrozole and erlotinib respectively. Compounds 3c, 6a as well as compounds 4c, 4d proved to be good inhibitors of the ARO and EGFR enzymes respectively. Active compounds were also evaluated for their underlying mode of action by further investigation for CDK, Hsp90, PI3K inhibition and compared to normal MCF-10A cells and assessed for their enhancement of the caspase 9 levels. Additionally, cell cycle analysis and apoptotic induction were performed. They demonstrated remarkable activities in the previous assays and emanated as leads as anti-breast cancer candidates. Eventually, molecular docking analysis revealed that hit compounds 3c, 4c, 4d, and 6a could bind favorably to the proposed in silico models of various protein-ligand interactions. Therefore, our promising top candidates, by demonstrating appreciable anti-breast cancer activities, present valuable prospects for optimization, potency enhancement and future application.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107953"},"PeriodicalIF":4.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666321","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 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":"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":"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}