Pub Date : 2024-08-29DOI: 10.1016/j.bioorg.2024.107770
To find potential α-glucosidase inhibitors, a series of 2β-acetoxyferuginol derivatives containing cinnamic acid (WXC-1 ∼ 25) were synthesized and investigated their biological activity. All derivatives (WXC-1 ∼ 25) displayed better inhibitory activity (IC50 values: 7.56 ± 1.35 ∼ 25.63 ± 1.72 μM) compared to acarbose (IC50 vaule: 564.28 ± 48.68 μM). In particularly, WXC-25 with 4-hydroxycinnamic acid section showed the best inhibitory activity (IC50 vaule: 2.02 ± 0.14 μM), ∼75-fold stronger than acarbose. Kinetics results suggested WXC-25 being one reversible non-competition inhibitors. Fluorescence quenching results indicated that WXC-25 quenched the fluorescence of α-glucosidase in a static manner. 3D fluorescence spectra results indicated that WXC-25 treatment could cause the conformation changes of α-glucosidase. Moreover, molecular docking simulated the detailed interaction of WXC25 with α-glucosidase.
{"title":"2β-Acetoxyferruginol derivatives as α-glucosidase inhibitors: Synthesis and biological evaluation","authors":"","doi":"10.1016/j.bioorg.2024.107770","DOIUrl":"10.1016/j.bioorg.2024.107770","url":null,"abstract":"<div><p>To find potential α-glucosidase inhibitors, a series of 2β-acetoxyferuginol derivatives containing cinnamic acid (<strong>WXC-1 ∼ 25</strong>) were synthesized and investigated their biological activity. All derivatives (<strong>WXC-1 ∼ 25</strong>) displayed better inhibitory activity (IC<sub>50</sub> values: 7.56 ± 1.35 ∼ 25.63 ± 1.72 μM) compared to acarbose (IC<sub>50</sub> vaule: 564.28 ± 48.68 μM). In particularly, <strong>WXC-25</strong> with 4-hydroxycinnamic acid section showed the best inhibitory activity (IC<sub>50</sub> vaule: 2.02 ± 0.14 μM), ∼75-fold stronger than acarbose. Kinetics results suggested <strong>WXC-25</strong> being one reversible non-competition inhibitors. Fluorescence quenching results indicated that <strong>WXC-25</strong> quenched the fluorescence of α-glucosidase in a static manner. 3D fluorescence spectra results indicated that <strong>WXC-25</strong> treatment could cause the conformation changes of α-glucosidase. Moreover, molecular docking simulated the detailed interaction of <strong>WXC25</strong> with α-glucosidase.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117665","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}
Pub Date : 2024-08-29DOI: 10.1016/j.bioorg.2024.107757
Diseases caused by plant viruses and pathogens pose a serious threat to crop yield and quality. Traditional pesticides have gradually developed drug resistance and brought certain environmental safety issues during long-term overuse. There is an urgent need to discover new candidate compounds to address these issues. In this study, we achieved the efficient synthesis of iheyamine A and its derivatives, and discovered their excellent antiviral activities against tobacco mosaic virus (TMV). Most compounds displayed higher antiviral activities against TMV than commercial ribavirin at 500 μg/mL, with compounds 3a (Inactive effect IC50: 162 µg/mL), 3d (Inactive effect IC50: 249 µg/mL), 6p (Inactive effect IC50: 254 µg/mL), and 7a (Inactive effect IC50: 234 µg/mL) exhibiting better antiviral activities than ningnanmycin at 500 μg/mL (Inactive effect IC50: 269 µg/mL). Meanwhile, the structure–activity relationships of this type of compounds were systematically studied. We chose 3a for further antiviral mechanism research and found that it can directly act on viral coat protein (CP). The interaction of 3a and CP was further verified via molecular docking. These compounds also showed broad-spectrum fungicidal activities against 8 plant pathogenic fungi, especially for P. piricola. This study provides a reference for the role of iheyamine alkaloids in combating plant pathogenic diseases.
植物病毒和病原体引起的病害严重威胁着作物的产量和质量。传统农药在长期过度使用过程中逐渐产生了抗药性,并带来了一定的环境安全问题。目前迫切需要发现新的候选化合物来解决这些问题。在本研究中,我们实现了 iheyamine A 及其衍生物的高效合成,并发现了它们对烟草花叶病毒(TMV)的优异抗病毒活性。大多数化合物对烟草花叶病毒的抗病毒活性高于500微克/毫升的利巴韦林,其中化合物3a(非活性效应IC50:162微克/毫升)、3d(非活性效应IC50:249微克/毫升)、6p(非活性效应IC50:254微克/毫升)和7a(非活性效应IC50:234微克/毫升)的抗病毒活性优于500微克/毫升的宁南霉素(非活性效应IC50:269微克/毫升)。同时,我们还系统地研究了这类化合物的结构-活性关系。我们选择了 3a 作进一步的抗病毒机制研究,发现它能直接作用于病毒衣壳蛋白(CP)。通过分子对接进一步验证了 3a 与 CP 的相互作用。这些化合物还对 8 种植物病原真菌表现出广谱杀菌活性,尤其是对 P. piricola。这项研究为九里香生物碱在防治植物病原性疾病中的作用提供了参考。
{"title":"Synthesis, structural modification, and biological activity of a novel bisindole alkaloid iheyamine A","authors":"","doi":"10.1016/j.bioorg.2024.107757","DOIUrl":"10.1016/j.bioorg.2024.107757","url":null,"abstract":"<div><p>Diseases caused by plant viruses and pathogens pose a serious threat to crop yield and quality. Traditional pesticides have gradually developed drug resistance and brought certain environmental safety issues during long-term overuse. There is an urgent need to discover new candidate compounds to address these issues. In this study, we achieved the efficient synthesis of iheyamine A and its derivatives, and discovered their excellent antiviral activities against tobacco mosaic virus (TMV). Most compounds displayed higher antiviral activities against TMV than commercial ribavirin at 500 μg/mL, with compounds <strong>3a</strong> (Inactive effect IC<sub>50</sub>: 162 µg/mL), <strong>3d</strong> (Inactive effect IC<sub>50</sub>: 249 µg/mL), <strong>6p</strong> (Inactive effect IC<sub>50</sub>: 254 µg/mL), and <strong>7a</strong> (Inactive effect IC<sub>50</sub>: 234 µg/mL) exhibiting better antiviral activities than ningnanmycin at 500 μg/mL (Inactive effect IC<sub>50</sub>: 269 µg/mL). Meanwhile, the structure–activity relationships of this type of compounds were systematically studied. We chose <strong>3a</strong> for further antiviral mechanism research and found that it can directly act on viral coat protein (CP). The interaction of <strong>3a</strong> and CP was further verified via molecular docking. These compounds also showed broad-spectrum fungicidal activities against 8 plant pathogenic fungi, especially for <em>P. piricola</em>. This study provides a reference for the role of iheyamine alkaloids in combating plant pathogenic diseases.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122952","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}
Pub Date : 2024-08-29DOI: 10.1016/j.bioorg.2024.107756
Investigation into the interactions between photoprotective agents and skin can offer a precise understanding of their biological behaviors in vitro and in vivo, providing crucial insights for generating new substances. For this purpose, we designed and synthesized a series of naphthoxazine derivatives and examined their photoprotective properties. 1,3-naphthoxazine derivatives were synthesized through the multi-component reaction of 2-naphthol, arylamines and aromatic aldehydes in the presence of copper(II) trifluoromethanesulfonate (Cu(OTf)2) and (±)-Camphor-10-sulfonic acid ((±)-CSA) catalyst system under sonication. The potential of these synthesized 1,3-naphthoxazine derivatives as antioxidants and viable organic structural-based sunscreen ingredients has been investigated. Sun protection factor (SPF) assay results showed that especially compounds 4i, 4c, 4k, 4d, 4r, and 4h had remarkably high activity (23.65, 23.57, 23.04, 21.94, 20.80, and 20.26, respectively at 900 µg/mL concentration). Additionally, antioxidant activity of the synthesized compounds was evaluated and compounds 4h, 4e, 4b, and 4j exhibited the highest activities in DPPH scavenging activity assay (86.46 %, 82.83 %, 80.78 %, and 80.65 % respectively at 400 µg/mL concentration). The synthesized compounds exhibit promising characteristics for effective UV radiation absorption, suggesting their suitability for inclusion in sunscreen formulations. Cytotoxic activity of compound 4k against normal human fibroblast cell line (MRC-5) was determined by CVDK-8 method. The results revealed that the compound provided remarkable viability (87.55 %) of MRC-5 cells at concentration of 100 µM. The study explores their efficacy in providing broad-spectrum protection against UVA and UVB rays, degradation and photostability, ADMET profile, and other pharmacokinetic properties.
{"title":"1,3-Naphthoxazine derivatives: Synthesis, in silico pharmacokinetic studies, antioxidant and photoprotective properties","authors":"","doi":"10.1016/j.bioorg.2024.107756","DOIUrl":"10.1016/j.bioorg.2024.107756","url":null,"abstract":"<div><p>Investigation into the interactions between photoprotective agents and skin can offer a precise understanding of their biological behaviors in vitro and in vivo, providing crucial insights for generating new substances. For this purpose, we designed and synthesized a series of naphthoxazine derivatives and examined their photoprotective properties. 1,3-naphthoxazine derivatives were synthesized through the multi-component reaction of 2-naphthol, arylamines and aromatic aldehydes in the presence of copper(II) trifluoromethanesulfonate (Cu(OTf)<sub>2</sub>) and (±)-Camphor-10-sulfonic acid ((±)-CSA) catalyst system under sonication. The potential of these synthesized 1,3-naphthoxazine derivatives as antioxidants and viable organic structural-based sunscreen ingredients has been investigated. Sun protection factor (SPF) assay results showed that especially compounds 4i, 4c, 4k, 4d, 4r, and 4h had remarkably high activity (23.65, 23.57, 23.04, 21.94, 20.80, and 20.26, respectively at 900 µg/mL concentration). Additionally, antioxidant activity of the synthesized compounds was evaluated and compounds 4h, 4e, 4b, and 4j exhibited the highest activities in DPPH scavenging activity assay (86.46 %, 82.83 %, 80.78 %, and 80.65 % respectively at 400 µg/mL concentration). The synthesized compounds exhibit promising characteristics for effective UV radiation absorption, suggesting their suitability for inclusion in sunscreen formulations. Cytotoxic activity of compound 4k against normal human fibroblast cell line (MRC-5) was determined by CVDK-8 method. The results revealed that the compound provided remarkable viability (87.55 %) of MRC-5 cells at concentration of 100 µM. The study explores their efficacy in providing broad-spectrum protection against UVA and UVB rays, degradation and photostability, ADMET profile, and other pharmacokinetic properties.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144558","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}
Pub Date : 2024-08-28DOI: 10.1016/j.bioorg.2024.107768
Alzheimer’s disease is associated both with imbalances in Al3+ production and changes in viscosity in cells. Their simultaneous measurement could therefore provide valuable insights into Alzheimer’s disease pathology. Their simultaneous measurement would therefore be of great value in investigating the pathological mechanism of Alzheimer’s disease. We designed a fluorescent probe YM2T with AIE effect that is capable of selectively responding to Al3+ by fluorescence colormetrics and to viscosity by fluorescence “turn on” modes. Additionally, Al3+ and viscosity were simultaneously detected in PC12 cells using the low cytotoxic probe YM2T via blue and green fluorescence channels. More importantly, the YM2T probe was used to image mice with AD. Hence, the YM2T probe shows potential as a useful molecular instrument for studying the pathological impact of Al3+ and viscosity.
{"title":"Development of an AIE-active fluorescent probe for the simultaneous detection of Al3+ and viscosity and imaging in Alzheimer’s disease model","authors":"","doi":"10.1016/j.bioorg.2024.107768","DOIUrl":"10.1016/j.bioorg.2024.107768","url":null,"abstract":"<div><p>Alzheimer’s disease is associated both with imbalances in Al<sup>3+</sup> production and changes in viscosity in cells. Their simultaneous measurement could therefore provide valuable insights into Alzheimer’s disease pathology. Their simultaneous measurement would therefore be of great value in investigating the pathological mechanism of Alzheimer’s disease. We designed a fluorescent probe <strong>YM2T</strong> with AIE effect that is capable of selectively responding to Al<sup>3+</sup> by fluorescence colormetrics and to viscosity by fluorescence “turn on” modes. Additionally, Al<sup>3+</sup> and viscosity were simultaneously detected in PC12 cells using the low cytotoxic probe <strong>YM2T</strong> via blue and green fluorescence channels. More importantly, the <strong>YM2T</strong> probe was used to image mice with AD. Hence, the <strong>YM2T</strong> probe shows potential as a useful molecular instrument for studying the pathological impact of Al<sup>3+</sup> and viscosity.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095833","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}
Pub Date : 2024-08-28DOI: 10.1016/j.bioorg.2024.107736
Novel anticancer strategies reduce side effects on healthy tissues by elevating the lethal abilities of cancer cells. The development of effective particles with good bioavailability and selectivity remains problematic. For undesirable features, green chemistry is used to synthesize the best compounds, or natural-based particles are improved. Photodynamic therapy (PDT), modelled on phthalocyanines (Pcs), still delivers second-generation sensitizers which are complemented with metal ions, such as Zn2+, Al3+, or Ga3+. Gallium octacarboxyphthalocyanine hydroxide (Ga(OH)PcOC), was designed for skin cancer treatment, and was used as a pro-apoptotic and pro-oxidative agent on normal skin cell lines, fibroblasts (NHDF), and keratinocytes (HaCaT), with promising selectivity against melanoma cancer cells (Me45) in vitro. Compared to the previous reported findings, where the ZnPcOC acted on the skin cell lines at higher doses, the sensitivities to the Ga(OH)PcOC allows for an effective reduction of the sensitizer dose. The effective dose, for a novel Ga(OH)PcOC particle, was significantly reduced from 30 µM to 6 µM on Me45 cancer cells, tested using 24 h MTT viability, as well as cytometric pro-oxidative and pro-apoptotic assays. The promising photosensitizer did not reduce viability in normal fibroblasts and keratinocytes without reactive oxygen species (ROS) elevation or apoptosis induction. The improvement to the previous findings is better Ga-based photosensitizer selectivity against the cancer Me45 cells, then observed in Zn-based compounds.
{"title":"Gallium octacarboxyphthalocyanine hydroxide as a potential pro-apoptotic drug against cancer skin cells","authors":"","doi":"10.1016/j.bioorg.2024.107736","DOIUrl":"10.1016/j.bioorg.2024.107736","url":null,"abstract":"<div><p>Novel anticancer strategies reduce side effects on healthy tissues by elevating the lethal abilities of cancer cells. The development of effective particles with good bioavailability and selectivity remains problematic. For undesirable features, green chemistry is used to synthesize the best compounds, or natural-based particles are improved. Photodynamic therapy (PDT), modelled on phthalocyanines (Pcs), still delivers second-generation sensitizers which are complemented with metal ions, such as Zn<sup>2+</sup>, Al<sup>3+</sup>, or Ga<sup>3+</sup>. Gallium octacarboxyphthalocyanine hydroxide (Ga(OH)PcOC), was designed for skin cancer treatment, and was used as a pro-apoptotic and pro-oxidative agent on normal skin cell lines, fibroblasts (NHDF), and keratinocytes (HaCaT), with promising selectivity against melanoma cancer cells (Me45) <em>in vitro</em>. Compared to the previous reported findings, where the ZnPcOC acted on the skin cell lines at higher doses, the sensitivities to the Ga(OH)PcOC allows for an effective reduction of the sensitizer dose. The effective dose, for a novel Ga(OH)PcOC particle, was significantly reduced from 30 µM to 6 µM on Me45 cancer cells, tested using 24 h MTT viability, as well as cytometric pro-oxidative and pro-apoptotic assays. The promising photosensitizer did not reduce viability in normal fibroblasts and keratinocytes without reactive oxygen species (ROS) elevation or apoptosis induction. The improvement to the previous findings is better Ga-based photosensitizer selectivity against the cancer Me45 cells, then observed in Zn-based compounds.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0045206824006412/pdfft?md5=fc519ce4c8a9337f0eb802d49abf26cd&pid=1-s2.0-S0045206824006412-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142089545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.bioorg.2024.107745
The diagnosis and treatment of triple negative breast cancer (TNBC) are huge challenges due to the lack of identifiable molecular targets. The high expression of Nectin4 in a variety of tumors, including TNBC, is associated with the occurrence, invasion, progression and poor prognosis of tumors. Therefore, Nectin4 is an emerging biomarker for the diagnosis and treatment of TNBC. A PET imaging method to non-invasively quantify Nectin4 expression levels may aid in TNBC diagnosis and classification. In this study, a novel bicyclic peptide molecular probe [68Ga]Ga-DN68 was used to evaluate the expression of Nectin4 in tumors. The radiolabeling rate of [68Ga]Ga-DN68 was over 97 %, while maintaining more than 99 % radiochemical purity. In vitro experiments showed that [68Ga]Ga-DN68 could effectively target Nectin4 in tumor cells, and the cellular uptake of MC38-Nectin4 cells (Nectin4+) was significantly higher than that of MC38 cells (Nectin4-). Biodistribution and PET imaging studies consistently showed that [68Ga]Ga-DN68 was specifically accumulated in MC38-Nectin4 and MDA-MB-468 tumors, which was significantly higher than that of MC38. When co-injected with cold DN68, the specific accumulation could block the tumor uptake of MDA-MB-468. Notably, the signal-to-noise ratio at the tumor site gradually increased over time, reaching a peak at 1 h. These results strongly suggest that [68Ga]Ga-DN68 has broad application prospects as a PET tracer in TNBC imaging.
由于缺乏可识别的分子靶点,三阴性乳腺癌(TNBC)的诊断和治疗面临巨大挑战。Nectin4在包括TNBC在内的多种肿瘤中的高表达与肿瘤的发生、侵袭、进展和不良预后有关。因此,Nectin4是诊断和治疗TNBC的新兴生物标志物。一种无创量化Nectin4表达水平的PET成像方法可能有助于TNBC的诊断和分类。本研究采用了一种新型双环肽分子探针[68Ga]Ga-DN68来评估肿瘤中Nectin4的表达。68Ga]Ga-DN68的放射标记率超过97%,放射化学纯度保持在99%以上。体外实验表明,[68Ga]Ga-DN68能有效靶向肿瘤细胞中的Nectin4,MC38-Nectin4细胞(Nectin4+)的细胞摄取率明显高于MC38细胞(Nectin4-)。生物分布和 PET 成像研究一致表明,[68Ga]Ga-DN68 在 MC38-Nectin4 和 MDA-MB-468 肿瘤中特异性蓄积,明显高于 MC38。当与冷DN68联合注射时,特异性蓄积可阻断MDA-MB-468的肿瘤摄取。这些结果有力地表明,[68Ga]Ga-DN68作为PET示踪剂在TNBC成像中具有广阔的应用前景。
{"title":"A cutting-edge 68Ga-labeled bicyclic peptide PET molecular probe for noninvasive assessment of Nectin4 expression","authors":"","doi":"10.1016/j.bioorg.2024.107745","DOIUrl":"10.1016/j.bioorg.2024.107745","url":null,"abstract":"<div><p>The diagnosis and treatment of triple negative breast cancer (TNBC) are huge challenges due to the lack of identifiable molecular targets. The high expression of Nectin4 in a variety of tumors, including TNBC, is associated with the occurrence, invasion, progression and poor prognosis of tumors. Therefore, Nectin4 is an emerging biomarker for the diagnosis and treatment of TNBC. A PET imaging method to non-invasively quantify Nectin4 expression levels may aid in TNBC diagnosis and classification. In this study, a novel bicyclic peptide molecular probe [<sup>68</sup>Ga]Ga-DN68 was used to evaluate the expression of Nectin4 in tumors. The radiolabeling rate of [<sup>68</sup>Ga]Ga-DN68 was over 97 %, while maintaining more than 99 % radiochemical purity. In vitro experiments showed that [<sup>68</sup>Ga]Ga-DN68 could effectively target Nectin4 in tumor cells, and the cellular uptake of MC38-Nectin4 cells (Nectin4+) was significantly higher than that of MC38 cells (Nectin4-). Biodistribution and PET imaging studies consistently showed that [<sup>68</sup>Ga]Ga-DN68 was specifically accumulated in MC38-Nectin4 and MDA-MB-468 tumors, which was significantly higher than that of MC38. When co-injected with cold DN68, the specific accumulation could block the tumor uptake of MDA-MB-468. Notably, the signal-to-noise ratio at the tumor site gradually increased over time, reaching a peak at 1 h. These results strongly suggest that [<sup>68</sup>Ga]Ga-DN68 has broad application prospects as a PET tracer in TNBC imaging.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095838","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}
Pub Date : 2024-08-28DOI: 10.1016/j.bioorg.2024.107766
LSM-83177, a phenoxy acetic acid derivative, is a small molecule reported for its promising anti-tumor properties. Via inhibiting the interaction between MDM2 and p53, LSM-83177 can elevate the active p53 levels within cells, thereby promoting apoptosis and inhibiting tumor growth. Also, LSM-83177 has been shown to inhibit GST activity in colorectal cancer HT29 cells. In the current work, novel LSM-83177 hydrazone analogs 5a-f, 7a-b, 10a-e, and 13a-b have been designed according to the structure features of LSM-83177 and their binding mode in the active site of MDM2. The anti-cancer activity of the newly synthesized analogs is evaluated against the HT29 cell line. The most potent compounds, 7a and 10a, showed IC50= 12.48 and 10.44 µg/ml, respectively, when compared with Cisplatin (IC50= 11.32 µg/ml) as a reference drug. Compounds 7a and 10a were introduced for further inspection for p53-MDM2 protein–protein interaction, where they displayed IC50 values of 3.65 and 11.08 µg/ml, respectively. Furthermore, hydrazones 7a and 10a increased the p-53 expression levels by 3.22– and 4.25-fold, respectively; in addition, they effectively reduced the GST expression levels in HT29 cancer cells with 0.56- and 0.30-fold increments in comparison to the untreated control.
{"title":"Development of new LSM-83177 analogues as anti-tumor agents against colorectal cancer targeting p53-MDM2 interaction","authors":"","doi":"10.1016/j.bioorg.2024.107766","DOIUrl":"10.1016/j.bioorg.2024.107766","url":null,"abstract":"<div><p><strong>LSM-83177</strong>, a phenoxy acetic acid derivative, is a small molecule reported for its promising anti-tumor properties. Via inhibiting the interaction between MDM2 and p53, <strong>LSM-83177</strong> can elevate the active p53 levels within cells, thereby promoting apoptosis and inhibiting tumor growth. Also, <strong>LSM-83177</strong> has been shown to inhibit GST activity in colorectal cancer HT29 cells. In the current work, novel <strong>LSM-83177</strong> hydrazone analogs <strong>5a-f</strong>, <strong>7a-b</strong>, <strong>10a-e</strong>, and <strong>13a-b</strong> have been designed according to the structure features of <strong>LSM-83177</strong> and their binding mode in the active site of MDM2. The anti-cancer activity of the newly synthesized analogs is evaluated against the HT29 cell line. The most potent compounds, <strong>7a</strong> and <strong>10a</strong>, showed IC<sub>50</sub> <strong>=</strong> 12.48 and 10.44 µg/ml, respectively, when compared with <strong>Cisplatin</strong> (IC<sub>50</sub> <strong>=</strong> 11.32 µg/ml) as a reference drug. Compounds <strong>7a</strong> and <strong>10a</strong> were introduced for further inspection for p53-MDM2 protein–protein interaction, where they displayed IC<sub>50</sub> values of 3.65 and 11.08 µg/ml, respectively. Furthermore, hydrazones <strong>7a</strong> and <strong>10a</strong> increased the p-53 expression levels by 3.22– and 4.25-fold, respectively; in addition, they effectively reduced the GST expression levels in HT29 cancer cells with 0.56- and 0.30-fold increments in comparison to the untreated control.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142149804","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}
Pub Date : 2024-08-28DOI: 10.1016/j.bioorg.2024.107764
Chemotherapy drug efflux, toxic side effects, and low efficacy against drug-resistant cells have plagued safe and efficient cancer theranostics. However, the materials or methods that resolve these defects all-in-one are scarce. Here, a new cancer theranostics strategy is proposed by utilizing changes in lysosomal acidity in cancer cells to activate the membranolytic model to overcome these obstacles together. Therefore, a simple fluorescent anthracene derivative Lyso-Mito is developed, which has a perfect pKa (4.62) value that falls between the pH of lysosomes in cancer and normal cells. Lyso-Mito itself can precisely target and convert the pH perturbation of lysosomes in cancer cells to fluorescent response and membranolytic module activity to accomplish the low drug efflux, weak toxic side effects, and low drug-resistant cancer diagnosis and treatment without linking other functional units or any additional assistance. Hereby, a new cancer theranostics strategy of integrating organelle microenvironment and the membranolytic model is realized.
{"title":"Unlocking lysosomal acidity to activate membranolytic module for accurately cancer theranostics","authors":"","doi":"10.1016/j.bioorg.2024.107764","DOIUrl":"10.1016/j.bioorg.2024.107764","url":null,"abstract":"<div><p>Chemotherapy drug efflux, toxic side effects, and low efficacy against drug-resistant cells have plagued safe and efficient cancer theranostics. However, the materials or methods that resolve these defects all-in-one are scarce. Here, a new cancer theranostics strategy is proposed by utilizing changes in lysosomal acidity in cancer cells to activate the membranolytic model to overcome these obstacles together. Therefore, a simple fluorescent anthracene derivative <strong>Lyso-Mito</strong> is developed, which has a perfect p<em>K</em><sub>a</sub> (4.62) value that falls between the pH of lysosomes in cancer and normal cells. <strong>Lyso-Mito</strong> itself can precisely target and convert the pH perturbation of lysosomes in cancer cells to fluorescent response and membranolytic module activity to accomplish the low drug efflux, weak toxic side effects, and low drug-resistant cancer diagnosis and treatment without linking other functional units or any additional assistance. Hereby, a new cancer theranostics strategy of integrating organelle microenvironment and the membranolytic model is realized.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142128460","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}
Pub Date : 2024-08-26DOI: 10.1016/j.bioorg.2024.107759
In the present study, the design and synthesis of novel coumarin derivatives 8a-h, 11a-d and 16a-c as potential selective inhibitors for the tumor associated human carbonic anhydrase isoforms (hCA IX and XII) was reported. All the newly synthesized derivatives showed potent to mild activity against the targeted CA IX (KI = 0.08–9.57 µM), with selectivity indices over CA I (SI = 2.0–21.9) and over CA II (SI = 1.1–15.7). They showed similar activities against CA XII (KI = 0.06–9.48 µM) with selectivity indices over CA I (SI = 1.4–21.2) and CA II (SI = 0.9–15.5). Compound 16b featuring sulfonamide function possessed promising inhibitory activities against the targeted isoforms CA IX and XII with KI values of 0.08 and 0.06 µM, respectively. Interestingly, it was found that using compound 16b at a nontoxic concentration as an adjuvant with Doxorubicin against MCF-7 cells enhanced the cytotoxicity under hypoxia by almost 3.5 folds; IC50 decreased from 25.74 to 7.43 µM. Therefore, compound 16b restored the cytotoxicity of Doxorubicin against MCF-7 cells under hypoxia, almost as normoxia. Furthermore, flow cytometry analysis of a combination treatment of compound 16b and Doxorubicin to the MCF7 cell line revealed an increase in cell cycle arrest at the G2/M phase and a more efficient apoptotic effect than Doxorubicin alone. Furthermore, compound 16b showed no cytotoxicity against normal breast MCF-10A cell line (IC50 = 296.25 µM).
据报道,本研究设计并合成了新型香豆素衍生物 8a-h、11a-d 和 16a-c,作为与肿瘤相关的人类碳酸酐酶同工酶(hCA IX 和 XII)的潜在选择性抑制剂。所有新合成的衍生物都对目标 CA IX(KI = 0.08-9.57 µM)表现出强效至温和的活性,对 CA I(SI = 2.0-21.9)和 CA II(SI = 1.1-15.7)具有选择性指数。它们对 CA XII(KI = 0.06-9.48 µM)显示出相似的活性,对 CA I(SI = 1.4-21.2 )和 CA II(SI = 0.9-15.5 )具有选择性指数。具有磺酰胺功能的化合物 16b 对目标同工酶 CA IX 和 XII 具有良好的抑制活性,KI 值分别为 0.08 和 0.06 µM。有趣的是,研究发现将无毒浓度的化合物 16b 作为多柔比星的辅助剂,可使 MCF-7 细胞在缺氧条件下的细胞毒性增强近 3.5 倍;IC50 从 25.74 µM 降至 7.43 µM。因此,化合物 16b 恢复了多柔比星在缺氧条件下对 MCF-7 细胞的细胞毒性,几乎与正常缺氧时相同。此外,对 MCF7 细胞系进行的化合物 16b 和多柔比星联合处理的流式细胞术分析表明,细胞周期在 G2/M 期的停滞时间延长,凋亡效果比单独使用多柔比星更有效。此外,化合物 16b 对正常乳腺 MCF-10A 细胞株没有细胞毒性(IC50 = 296.25 µM)。
{"title":"Mitigating the resistance of MCF-7 cancer cells to Doxorubicin under hypoxic conditions with novel coumarin based carbonic anhydrase IX and XII inhibitors","authors":"","doi":"10.1016/j.bioorg.2024.107759","DOIUrl":"10.1016/j.bioorg.2024.107759","url":null,"abstract":"<div><p>In the present study, the design and synthesis of novel coumarin derivatives <strong>8a-h</strong>, <strong>11a-d</strong> and <strong>16a-c</strong> as potential selective inhibitors for the tumor associated human carbonic anhydrase isoforms (hCA IX and XII) was reported. All the newly synthesized derivatives showed potent to mild activity against the targeted CA IX (K<sub>I</sub> = 0.08–9.57 µM), with selectivity indices over CA I (SI = 2.0–21.9) and over CA II (SI = 1.1–15.7). They showed similar activities against CA XII (K<sub>I</sub> = 0.06–9.48 µM) with selectivity indices over CA I (SI = 1.4–21.2) and CA II (SI = 0.9–15.5). Compound <strong>16b</strong> featuring sulfonamide function possessed promising inhibitory activities against the targeted isoforms CA IX and XII with K<sub>I</sub> values of 0.08 and 0.06 µM, respectively. Interestingly, it was found that using compound <strong>16b</strong> at a nontoxic concentration as an adjuvant with Doxorubicin against MCF-7 cells enhanced the cytotoxicity under hypoxia by almost 3.5 folds; IC<sub>50</sub> decreased from 25.74 to 7.43 µM. Therefore, compound <strong>16b</strong> restored the cytotoxicity of Doxorubicin against MCF-7 cells under hypoxia, almost as normoxia. Furthermore, flow cytometry analysis of a combination treatment of compound <strong>16b</strong> and Doxorubicin to the MCF7 cell line revealed an increase in cell cycle arrest at the G2/M phase and a more efficient apoptotic effect than Doxorubicin alone. Furthermore, compound <strong>16b</strong> showed no cytotoxicity against normal breast MCF-10A cell line (IC<sub>50</sub> = 296.25 µM).</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095441","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}