Pub Date : 2024-11-02DOI: 10.1016/j.ejmech.2024.117027
Ziting Feng , Duoli Xie , Fang Qiu , Jie Huang , Zhuqian Wang , Chao Liang
Tumors and angiogenesis are connected through a complex interplay. VEGF165, generated from both tumor and vascular endothelial cells, serves as a mutual benefit for both cell types. Therapeutic approaches modulating VEGF165 have been proposed as promising antitumor therapies. PROTACs are bifunctional molecules that exploit the intracellular ubiquitin-proteasome system to degrade specific proteins. To date, there are no targeted PROTACs designed to degrade VEGF165 in both tumor and vascular endothelial cells. The aptamer AS1411 is notable for its ability to selectively recognize and enter both tumor and vascular endothelial cells by targeting the cell surface nucleolin (NCL). Moreover, AS1411 has also been repurposed as an intracellular recruiter of E3 ligase MDM2 via leveraging NCL as a molecular bridge. In this study, we conjugated AS1411 with a VEGF165-specific aptamer V7t1, creating hybrid aptamers-engineered PROTACs. The PROTACs demonstrate remarkable selectivity for both tumor and vascular endothelial cells and facilitate the ubiquitination and proteasomal degradation of VEGF165. The PROTACs inhibit the growth of tumor cells and also impede angiogenesis, without causing toxicity to normal tissues. The hybrid aptamers-engineered PROTACs provide an avenue for disrupting the tumor-angiogenesis interplay through modulation of VEGF165 in both tumor and vascular endothelial cells.
{"title":"Development of hybrid aptamers-engineered PROTACs for degrading VEGF165 in both tumor- and vascular endothelial cells","authors":"Ziting Feng , Duoli Xie , Fang Qiu , Jie Huang , Zhuqian Wang , Chao Liang","doi":"10.1016/j.ejmech.2024.117027","DOIUrl":"10.1016/j.ejmech.2024.117027","url":null,"abstract":"<div><div>Tumors and angiogenesis are connected through a complex interplay. VEGF165, generated from both tumor and vascular endothelial cells, serves as a mutual benefit for both cell types. Therapeutic approaches modulating VEGF165 have been proposed as promising antitumor therapies. PROTACs are bifunctional molecules that exploit the intracellular ubiquitin-proteasome system to degrade specific proteins. To date, there are no targeted PROTACs designed to degrade VEGF165 in both tumor and vascular endothelial cells. The aptamer AS1411 is notable for its ability to selectively recognize and enter both tumor and vascular endothelial cells by targeting the cell surface nucleolin (NCL). Moreover, AS1411 has also been repurposed as an intracellular recruiter of E3 ligase MDM2 via leveraging NCL as a molecular bridge. In this study, we conjugated AS1411 with a VEGF165-specific aptamer V7t1, creating hybrid aptamers-engineered PROTACs. The PROTACs demonstrate remarkable selectivity for both tumor and vascular endothelial cells and facilitate the ubiquitination and proteasomal degradation of VEGF165. The PROTACs inhibit the growth of tumor cells and also impede angiogenesis, without causing toxicity to normal tissues. The hybrid aptamers-engineered PROTACs provide an avenue for disrupting the tumor-angiogenesis interplay through modulation of VEGF165 in both tumor and vascular endothelial cells.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117027"},"PeriodicalIF":6.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566096","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 : 2024-11-01DOI: 10.1016/j.ejmech.2024.117017
Asmita Singh , Charu Bhutani , Pankaj Khanna , Sangeeta Talwar , Sandeep Kumar Singh , Leena Khanna
In recent years, viral infections such as COVID-19, Zika virus, Nipah virus, Ebola, Influenza, Monkeypox, and Dengue have substantially impacted global health. These outbreaks have led to heightened global health initiatives and collaborative efforts to address and mitigate these significant threats effectively. Thus, developing antiviral treatments and research in this field has become highly important. Heterocycles, particularly indole motifs, have been a valuable resource in drug discovery, as they can be used as treatments or inspire the synthesis of new potent candidates. Indole-containing drugs, such as enfuvirtide (T-20), arbidol, and delavirdine, have demonstrated significant efficacy in treating viral diseases. This review aims to comprehensively assess the latest research and developments in novel indoles as potential scaffolds for antiviral activity. We have compiled detailed information about indoles as potential antivirals by conducting a thorough literature survey from the past ten years. The review includes discussions on synthetic protocols, inhibitory concentrations, SAR study, and computational study. This review shall identify new antiviral indoles that may help to combat new viral threats in the future.
{"title":"Recent report on indoles as a privileged anti-viral scaffold in drug discovery","authors":"Asmita Singh , Charu Bhutani , Pankaj Khanna , Sangeeta Talwar , Sandeep Kumar Singh , Leena Khanna","doi":"10.1016/j.ejmech.2024.117017","DOIUrl":"10.1016/j.ejmech.2024.117017","url":null,"abstract":"<div><div>In recent years, viral infections such as COVID-19, Zika virus, Nipah virus, Ebola, Influenza, Monkeypox, and Dengue have substantially impacted global health. These outbreaks have led to heightened global health initiatives and collaborative efforts to address and mitigate these significant threats effectively. Thus, developing antiviral treatments and research in this field has become highly important. Heterocycles, particularly indole motifs, have been a valuable resource in drug discovery, as they can be used as treatments or inspire the synthesis of new potent candidates. Indole-containing drugs, such as enfuvirtide (T-20), arbidol, and delavirdine, have demonstrated significant efficacy in treating viral diseases. This review aims to comprehensively assess the latest research and developments in novel indoles as potential scaffolds for antiviral activity. We have compiled detailed information about indoles as potential antivirals by conducting a thorough literature survey from the past ten years. The review includes discussions on synthetic protocols, inhibitory concentrations, SAR study, and computational study. This review shall identify new antiviral indoles that may help to combat new viral threats in the future.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117017"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562207","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 : 2024-11-01DOI: 10.1016/j.ejmech.2024.117022
Zhen Zhang , Rui Su , Junao Liu , Keyu Chen , Chengjun Wu , Pinghua Sun , Tiemin Sun
Microtubules, one of the cytoskeletons in eukaryotic cells, maintain the proper operation of several cellular functions. Additionally, they are regulated by the acetylation of HDAC6 and SIRT2 which affects microtubule dynamics. Given the fact that tubulin and HDAC inhibitors play a synergistic effect in the treatment of many cancers, the development of tubulin/HDAC dual-target inhibitors is conducive to addressing multiple limitations including drug resistance, dose toxicity, and unpredictable pharmacokinetic properties. At present, tubulin/HDAC dual-target inhibitors have been obtained in three main ways: uncleavable linked pharmacophores, cleavable linked pharmacophores, and modification of single-target drugs. Their therapeutic efficacy has been verified in vivo and in vitro assays. In this article, we reviewed the research progress of tubulin/HDAC dual inhibitors from design strategies, SARs, and biological activities, which may provide help for the discovery of novel tubulin/HDAC dual inhibitors.
{"title":"Tubulin/HDAC dual-target inhibitors: Insights from design strategies, SARs, and therapeutic potential","authors":"Zhen Zhang , Rui Su , Junao Liu , Keyu Chen , Chengjun Wu , Pinghua Sun , Tiemin Sun","doi":"10.1016/j.ejmech.2024.117022","DOIUrl":"10.1016/j.ejmech.2024.117022","url":null,"abstract":"<div><div>Microtubules, one of the cytoskeletons in eukaryotic cells, maintain the proper operation of several cellular functions. Additionally, they are regulated by the acetylation of HDAC6 and SIRT2 which affects microtubule dynamics. Given the fact that tubulin and HDAC inhibitors play a synergistic effect in the treatment of many cancers, the development of tubulin/HDAC dual-target inhibitors is conducive to addressing multiple limitations including drug resistance, dose toxicity, and unpredictable pharmacokinetic properties. At present, tubulin/HDAC dual-target inhibitors have been obtained in three main ways: uncleavable linked pharmacophores, cleavable linked pharmacophores, and modification of single-target drugs. Their therapeutic efficacy has been verified in <em>vivo</em> and in <em>vitro</em> assays. In this article, we reviewed the research progress of tubulin/HDAC dual inhibitors from design strategies, SARs, and biological activities, which may provide help for the discovery of novel tubulin/HDAC dual inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117022"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562205","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 : 2024-11-01DOI: 10.1016/j.ejmech.2024.117020
Yudi Wang , Xinrong Geng , Song Qin , Tuanjie Che , Libo Yan , Biao Yuan , Wenjun Li
The development of inflammation has an indispensable importance in the self-protection of the human body. However, over-inflammation may damage human health, and inflammatory pathways and inflammasomes have a significant impact on the onset of inflammation. Therefore, how to constrain the development of inflammation through inflammatory pathways or inflammasomes becomes a hot research issue. Carotenoids are a natural pigment and an active substance in algae, with anti-inflammatory and antioxidant effects. Many studies have shown that carotenoids have inhibitory effects on the inflammatory pathways and inflammasomes. In this review, we discussed the mechanism of carotenoids targeting those important inflammatory pathways and their effects on common inflammasome NLRP3 and inflammation-related diseases from the perspective of several inflammatory pathways, including p38 MAPK, IL-6/JAK/STAT3, and PI3K, with a focus on the targets and targeting effects of carotenoids on different inflammatory signaling pathways, and at last proposed possible anti-inflammatory targets.
{"title":"Advance on the effects of algal carotenoids on inflammatory signaling pathways","authors":"Yudi Wang , Xinrong Geng , Song Qin , Tuanjie Che , Libo Yan , Biao Yuan , Wenjun Li","doi":"10.1016/j.ejmech.2024.117020","DOIUrl":"10.1016/j.ejmech.2024.117020","url":null,"abstract":"<div><div>The development of inflammation has an indispensable importance in the self-protection of the human body. However, over-inflammation may damage human health, and inflammatory pathways and inflammasomes have a significant impact on the onset of inflammation. Therefore, how to constrain the development of inflammation through inflammatory pathways or inflammasomes becomes a hot research issue. Carotenoids are a natural pigment and an active substance in algae, with anti-inflammatory and antioxidant effects. Many studies have shown that carotenoids have inhibitory effects on the inflammatory pathways and inflammasomes. In this review, we discussed the mechanism of carotenoids targeting those important inflammatory pathways and their effects on common inflammasome NLRP3 and inflammation-related diseases from the perspective of several inflammatory pathways, including p38 MAPK, IL-6/JAK/STAT3, and PI3K, with a focus on the targets and targeting effects of carotenoids on different inflammatory signaling pathways, and at last proposed possible anti-inflammatory targets.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117020"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563217","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 : 2024-11-01DOI: 10.1016/j.ejmech.2024.117019
Qingqing Zhou , Zhenxin Wu , Feixia Qin , Pan He , Zhuoran Wang , Fangyi Zhu , Ying Gao , Wei Xiong , Chenyang Li , Haiqiang Wu
Upregulated glutaminyl cyclase isoenzyme (isoQC) contributes to cancer development by catalyzing pE-CD47 generation and thus enhancing CD47-SIRPα binding and subsequent “don't eat me” signals. We thus consider that isoQC could represent a novel target for cancer therapy. We previously prepared a series of diphenyl conjugated imidazole derivatives (DPCIs) and evaluated their use as glutaminyl cyclase (QC) inhibitors. Here, a new series of DPCIs was rationally designed and synthesized. As anticipated, the analogues exhibited considerably improved inhibitory potency against both QC and isoQC. Crucially, these chemicals exhibited marked selectivity toward isoQC. Further assessments established that one selected compound (27) did not affect the viability of A549, H1299, PC9, or HEK293T cells or the body weight of mice. This compound did, however, reduce pE-CD47 levels in infected A549 cells (isoQC_OE and isoQC_KD) and exhibited apparent anti-cancer effects in vivo by downregulating the level of pE-CD47 via the inhibition of isoQC activity. Taken together, these findings indicated that the compounds synthesized in this study could represent potential QC/isoQC inhibitors for the treatment of cancers.
{"title":"Design, synthesis, and evaluation of 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine derivatives as potential glutaminyl cyclase isoenzyme inhibitors for the treatment of cancer","authors":"Qingqing Zhou , Zhenxin Wu , Feixia Qin , Pan He , Zhuoran Wang , Fangyi Zhu , Ying Gao , Wei Xiong , Chenyang Li , Haiqiang Wu","doi":"10.1016/j.ejmech.2024.117019","DOIUrl":"10.1016/j.ejmech.2024.117019","url":null,"abstract":"<div><div>Upregulated glutaminyl cyclase isoenzyme (isoQC) contributes to cancer development by catalyzing pE-CD47 generation and thus enhancing CD47-SIRPα binding and subsequent “don't eat me” signals. We thus consider that isoQC could represent a novel target for cancer therapy. We previously prepared a series of diphenyl conjugated imidazole derivatives (DPCIs) and evaluated their use as glutaminyl cyclase (QC) inhibitors. Here, a new series of DPCIs was rationally designed and synthesized. As anticipated, the analogues exhibited considerably improved inhibitory potency against both QC and isoQC. Crucially, these chemicals exhibited marked selectivity toward isoQC. Further assessments established that one selected compound (<strong>27</strong>) did not affect the viability of A549, H1299, PC9, or HEK293T cells or the body weight of mice. This compound did, however, reduce pE-CD47 levels in infected A549 cells (isoQC_OE and isoQC_KD) and exhibited apparent anti-cancer effects <em>in vivo</em> by downregulating the level of pE-CD47 via the inhibition of isoQC activity. Taken together, these findings indicated that the compounds synthesized in this study could represent potential QC/isoQC inhibitors for the treatment of cancers.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117019"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562206","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 : 2024-11-01DOI: 10.1016/j.ejmech.2024.117016
Chaowei Wen , Prathibha R. Gajjala , Yihan Liu , Bingzhong Chen , Mehtab S. Bal , Payal Sutaria , Qiao Yuanyuan , Yang Zheng , Yang Zhou , Jinwei Zhang , Weixue Huang , Xiaomei Ren , Zhen Wang , Ke Ding , Arul M. Chinnaiyan , Fengtao Zhou
Pseudokinase TRIB2, a member of the CAMK Ser/Thr protein kinase family, regulates various cellular processes through phosphorylation-independent mechanisms. Dysregulation of TRIB2 has been implicated in promoting tumor growth, metastasis, and therapy resistance, making it a promising target for cancer treatment. In this study, we designed and synthesized a series of TRIB2 PROTAC degraders by conjugating a TRIB2 binder 1 with VHL or CRBN ligands via linkers of varying lengths and compositions. Among these compounds, 5k demonstrated potent TRIB2 degradation with a DC50 value of 16.84 nM (95 % CI: 13.66–20.64 nM) in prostate cancer PC3 cells. Mechanistic studies revealed that 5k directly interacted with TRIB2, selectively inducing its degradation through a CRBN-dependent ubiquitin-proteasomal pathway. Moreover, 5k outperformed the TRIB2 binder alone in inhibiting cell proliferation and inducing apoptosis, confirming that TRIB2 protein degradation could be a promising therapeutic strategy for TRIB2-associated cancers. Additionally, compound 5k also serves as an effective tool for probing TRIB2 biology.
{"title":"Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2","authors":"Chaowei Wen , Prathibha R. Gajjala , Yihan Liu , Bingzhong Chen , Mehtab S. Bal , Payal Sutaria , Qiao Yuanyuan , Yang Zheng , Yang Zhou , Jinwei Zhang , Weixue Huang , Xiaomei Ren , Zhen Wang , Ke Ding , Arul M. Chinnaiyan , Fengtao Zhou","doi":"10.1016/j.ejmech.2024.117016","DOIUrl":"10.1016/j.ejmech.2024.117016","url":null,"abstract":"<div><div>Pseudokinase TRIB2, a member of the CAMK Ser/Thr protein kinase family, regulates various cellular processes through phosphorylation-independent mechanisms. Dysregulation of TRIB2 has been implicated in promoting tumor growth, metastasis, and therapy resistance, making it a promising target for cancer treatment. In this study, we designed and synthesized a series of TRIB2 PROTAC degraders by conjugating a TRIB2 binder <strong>1</strong> with VHL or CRBN ligands via linkers of varying lengths and compositions. Among these compounds, <strong>5k</strong> demonstrated potent TRIB2 degradation with a DC<sub>50</sub> value of 16.84 nM (95 % CI: 13.66–20.64 nM) in prostate cancer PC3 cells. Mechanistic studies revealed that <strong>5k</strong> directly interacted with TRIB2, selectively inducing its degradation through a CRBN-dependent ubiquitin-proteasomal pathway. Moreover, <strong>5k</strong> outperformed the TRIB2 binder alone in inhibiting cell proliferation and inducing apoptosis, confirming that TRIB2 protein degradation could be a promising therapeutic strategy for TRIB2-associated cancers. Additionally, compound <strong>5k</strong> also serves as an effective tool for probing TRIB2 biology.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117016"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562190","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 : 2024-10-31DOI: 10.1016/j.ejmech.2024.117021
Marialuigia Fantacuzzi, Simone Carradori, Letizia Giampietro, Cristina Maccallini, Barbara De Filippis, Rosa Amoroso, Alessandra Ammazzalorso
Since their discovery from natural sources, the potent cytotoxic effects of combretastatins were widely studied for the application in antitumor therapy. However, major pharmacokinetic issues as low water solubility and chemical instability of the double bond configuration prevented their use in therapy. A lot of efforts have been directed towards the search of novel strategies, allowing a safer use of combretastatins as anticancer agents. This review analyses the recent landscape in combretastatin research, characterized by the identification of hybrids, prodrugs, and novel combination treatments. Interestingly, the potent cytotoxic agent combretastatin A4 (CA4) was recently proposed as payload in the construction of novel antibody-drug conjugates (ADCs), allowing an efficient targeting of the cytotoxic agent to specific tumors.
{"title":"A novel life for antitumor combretastatins: Recent developments of hybrids, prodrugs, combination therapies, and antibody-drug conjugates","authors":"Marialuigia Fantacuzzi, Simone Carradori, Letizia Giampietro, Cristina Maccallini, Barbara De Filippis, Rosa Amoroso, Alessandra Ammazzalorso","doi":"10.1016/j.ejmech.2024.117021","DOIUrl":"10.1016/j.ejmech.2024.117021","url":null,"abstract":"<div><div>Since their discovery from natural sources, the potent cytotoxic effects of combretastatins were widely studied for the application in antitumor therapy. However, major pharmacokinetic issues as low water solubility and chemical instability of the double bond configuration prevented their use in therapy. A lot of efforts have been directed towards the search of novel strategies, allowing a safer use of combretastatins as anticancer agents. This review analyses the recent landscape in combretastatin research, characterized by the identification of hybrids, prodrugs, and novel combination treatments. Interestingly, the potent cytotoxic agent combretastatin A4 (CA4) was recently proposed as payload in the construction of novel antibody-drug conjugates (ADCs), allowing an efficient targeting of the cytotoxic agent to specific tumors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117021"},"PeriodicalIF":6.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555815","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 : 2024-10-30DOI: 10.1016/j.ejmech.2024.117013
Valeria A. Litvinova , Vladimir B. Tsvetkov , Yulia L. Volodina , Lyubov G. Dezhenkova , Alina A. Markova , Minh Tuan Nguyen , Alexander S. Tikhomirov , Andrey E. Shchekotikhin
The acquisition of multidrug resistance (MDR) to chemotherapy is a major obstacle to successful cancer treatment. Aiming to improve the potency of anthraquinone-derived antitumor compounds against MDR cancer cells, we employed a rational design approach to develop new heteroarene-fused anthraquinones. Shifting the carboxamide group in the naphtho[2,3-f]indole scaffold from the 3-position to 2 increased the lipophilicity and P-glycoprotein (P-gp) binding of the derivatives, potentially enhancing their ability to circumvent P-gp-mediated MDR. To validate the computations, we developed a scheme for heterocyclization into esters of naphtho[2,3-f]indole-2-carboxylic acid, based on the 5-endo-dig cyclization of 2-alkynyl-3-amino-1,4-dimethoxyanthraquinone under mild basic conditions using tetra-n-butylammonium fluoride (TBAF). The synthesized naphthoindole-2-carboxamides, particularly compound 1a bearing (S)-3-aminopyrrolidine in the carboxamide fragment, demonstrated the highest antiproliferative activity. Most importantly, 1a suppressed the growth of the P-gp-positive K562/4 leukemia tumor cell line (resistance index = 2.4), while its 3-isomer LCTA-2640 and Dox did not (RI = 125 and 140, respectively). Studies of intracellular uptake and distribution showed that 1a, unlike its 3-substituted isomer, effectively accumulated in resistant tumor cells, confirming the correlation between in silico and experimental data. The lead compound 1a interacts with DNA duplex and inhibits topoisomerase 1 but does not induce oxidative stress. Treatment with 1a increases the population of apoptotic cells in both K562 and K562/4 sublines, regardless of the cell cycle phase. Taken together, this work provides an interesting example of how a little modification in chemical structure can lead to striking differences in antitumor properties. In conclusion, we have identified a potent class of compounds that offer distinct advantages in combating resistant tumor cells.
{"title":"Naphthoindole-2-carboxamides as a lipophilic chemotype of hetarene-anthraquinones potent against P-gp resistant tumor cells","authors":"Valeria A. Litvinova , Vladimir B. Tsvetkov , Yulia L. Volodina , Lyubov G. Dezhenkova , Alina A. Markova , Minh Tuan Nguyen , Alexander S. Tikhomirov , Andrey E. Shchekotikhin","doi":"10.1016/j.ejmech.2024.117013","DOIUrl":"10.1016/j.ejmech.2024.117013","url":null,"abstract":"<div><div>The acquisition of multidrug resistance (MDR) to chemotherapy is a major obstacle to successful cancer treatment. Aiming to improve the potency of anthraquinone-derived antitumor compounds against MDR cancer cells, we employed a rational design approach to develop new heteroarene-fused anthraquinones. Shifting the carboxamide group in the naphtho[2,3-<em>f</em>]indole scaffold from the 3-position to 2 increased the lipophilicity and P-glycoprotein (P-gp) binding of the derivatives, potentially enhancing their ability to circumvent P-gp-mediated MDR. To validate the computations, we developed a scheme for heterocyclization into esters of naphtho[2,3-<em>f</em>]indole-2-carboxylic acid, based on the 5-<em>endo</em>-dig cyclization of 2-alkynyl-3-amino-1,4-dimethoxyanthraquinone under mild basic conditions using tetra-<em>n</em>-butylammonium fluoride (TBAF). The synthesized naphthoindole-2-carboxamides, particularly compound <strong>1a</strong> bearing (<em>S</em>)-3-aminopyrrolidine in the carboxamide fragment, demonstrated the highest antiproliferative activity. Most importantly, <strong>1a</strong> suppressed the growth of the P-gp-positive K562/4 leukemia tumor cell line (resistance index = 2.4), while its 3-isomer <strong>LCTA-2640</strong> and <strong>Dox</strong> did not (RI = 125 and 140, respectively). Studies of intracellular uptake and distribution showed that <strong>1a</strong>, unlike its 3-substituted isomer, effectively accumulated in resistant tumor cells, confirming the correlation between <em>in silico</em> and experimental data. The lead compound <strong>1a</strong> interacts with DNA duplex and inhibits topoisomerase 1 but does not induce oxidative stress. Treatment with <strong>1a</strong> increases the population of apoptotic cells in both K562 and K562/4 sublines, regardless of the cell cycle phase. Taken together, this work provides an interesting example of how a little modification in chemical structure can lead to striking differences in antitumor properties. In conclusion, we have identified a potent class of compounds that offer distinct advantages in combating resistant tumor cells.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117013"},"PeriodicalIF":6.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541958","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 : 2024-10-30DOI: 10.1016/j.ejmech.2024.117018
Qian Xu , Hao Deng , Xing Huang , Guo-Qing Chen , Yin-Sheng Quan , Ya-Lan Wang , Jin-Ying Liu , Rui Yan , Wen-Zhe Nie , Qing-Kun Shen , Zhe-Shan Quan , Hong-Yan Guo
Natural products play a pivotal role in drug development, including their direct use as pharmaceuticals and their structural modification, yielding molecules with enhanced therapeutic potential. The discovery of bioactive molecules, lead compounds, and novel drugs is intrinsically linked to the structural optimization of natural products. In this study, forty-one derivatives of dihydroartemisinin (DHA) were synthesized by incorporating fragments with anti-tumour activity via molecular hybridization, and assessed for their anti-proliferative activity against human cancer cell lines (A549, Bel-7402, HCT-116, and SW620) and normal human liver cells (LO2). Most derivatives exhibited superior anti-proliferative activity compared to DHA. Notably, compound A3, featuring a 4-Cl phenyl carbamate moiety, demonstrated significant anti-proliferative activity against HCT-116 cells with an IC50 of 0.31 μM, making it 16-fold more potent than DHA (IC50 = 5.10 μM). The anti-proliferative mechanism did not involve cytotoxicity (SI = 54.13), indicating its superior safety profile compared to DHA (SI = 1.65).
Further mechanistic studies revealed that compound A3 inhibits HCT-116 cell proliferation by modulating the expression of PI3K/AKT/mTOR and STAT3 proteins. STAT3 downregulation represses the expression of the critical ferroptosis protein glutathione peroxidase 4 (GPX4), aggravating the accumulation of reactive oxygen species (ROS) and depletion of glutathione (GSH). This redox imbalance triggers and accelerates ferroptosis. Additionally, A3 also induces apoptosis by damaging mitochondria and influencing MAPK signaling. Compound A3 arrested cells in the G2/M phase by regulating p53 expression. In an HCT-116 xenograft mouse model, compound A3 exhibited significant anti-cancer efficacy, with a tumor growth inhibition rate of 58.7 %. Therefore, compound A3 thus has the potential to serve as a lead compound for the development of new anti-tumor drugs.
{"title":"Design, synthesis, and in vitro and in vivo biological evaluation of dihydroartemisinin derivatives as potent anti-cancer agents with ferroptosis-inducing and apoptosis-activating properties","authors":"Qian Xu , Hao Deng , Xing Huang , Guo-Qing Chen , Yin-Sheng Quan , Ya-Lan Wang , Jin-Ying Liu , Rui Yan , Wen-Zhe Nie , Qing-Kun Shen , Zhe-Shan Quan , Hong-Yan Guo","doi":"10.1016/j.ejmech.2024.117018","DOIUrl":"10.1016/j.ejmech.2024.117018","url":null,"abstract":"<div><div>Natural products play a pivotal role in drug development, including their direct use as pharmaceuticals and their structural modification, yielding molecules with enhanced therapeutic potential. The discovery of bioactive molecules, lead compounds, and novel drugs is intrinsically linked to the structural optimization of natural products. In this study, forty-one derivatives of dihydroartemisinin (DHA) were synthesized by incorporating fragments with anti-tumour activity via molecular hybridization, and assessed for their anti-proliferative activity against human cancer cell lines (A549, Bel-7402, HCT-116, and SW620) and normal human liver cells (LO2). Most derivatives exhibited superior anti-proliferative activity compared to DHA. Notably, compound <strong>A3</strong>, featuring a 4-Cl phenyl carbamate moiety, demonstrated significant anti-proliferative activity against HCT-116 cells with an IC<sub>50</sub> of 0.31 μM, making it 16-fold more potent than DHA (IC<sub>50</sub> = 5.10 μM). The anti-proliferative mechanism did not involve cytotoxicity (SI = 54.13), indicating its superior safety profile compared to DHA (SI = 1.65).</div><div>Further mechanistic studies revealed that compound <strong>A3</strong> inhibits HCT-116 cell proliferation by modulating the expression of PI3K/AKT/mTOR and STAT3 proteins. STAT3 downregulation represses the expression of the critical ferroptosis protein glutathione peroxidase 4 (GPX4), aggravating the accumulation of reactive oxygen species (ROS) and depletion of glutathione (GSH). This redox imbalance triggers and accelerates ferroptosis. Additionally, <strong>A3</strong> also induces apoptosis by damaging mitochondria and influencing MAPK signaling. Compound <strong>A3</strong> arrested cells in the G2/M phase by regulating p53 expression. In an HCT-116 xenograft mouse model, compound <strong>A3</strong> exhibited significant anti-cancer efficacy, with a tumor growth inhibition rate of 58.7 %. Therefore, compound <strong>A3</strong> thus has the potential to serve as a lead compound for the development of new anti-tumor drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117018"},"PeriodicalIF":6.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541952","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 : 2024-10-30DOI: 10.1016/j.ejmech.2024.117007
T. Srinivasa Reddy , Steven H. Privér , Ruchika Ojha , Nedaossadat Mirzadeh , Ganga Reddy Velma , Ranjithkumar Jakku , Tayebeh Hosseinnejad , Rodney Luwor , Sistla Ramakrishna , Donald Wlodkowic , Magdalena Plebanski , Suresh K. Bhargava
Four new mononuclear gold (I) compounds of the type [AuL{κC-2-C6H4P(S)Ph2}] {L = PTA (1), PPh3 (2), PPh2(C6H4-3-SO3Na) (3), and PPh2(2-py) (4)} were prepared by scission of the dinuclear compound [Au2{μ-2-C6H4P(S)Ph2}2] by L or via a transmetalation reaction using the organotin reagent 2-Me3SnC6H4P(S)Ph2 and a suitable gold halide precursor. The cytotoxic potential of complexes 1–4 was evaluated against four human cancer cell lines of diverse cellular origin: cervical (HeLa), prostate (PC-3), non-small cell lung adenocarcinoma (A549), and fibrosarcoma (HT-1080). The in vitro cytotoxicity results showed that 1 demonstrated exceptional anticancer activity with IC50 values ranging from 0.08 to 3.5 μM. Complex 3, which contains a sulfonated triphenyl phosphine ligand, displayed the weakest anticancer activity with IC50 values ranging from 3.1 to >50 μM. When compared to the standard chemotherapeutic drug cisplatin, 1 displayed approximately 27-fold greater cytotoxic activity against cervical cancer cells and 3.5- and 7.5-fold greater activities against prostate and fibrosarcoma cancer cells, respectively. Additionally, 1 exhibited 3-fold selectivity for cervical cancer cells compared to non-cancerous HEK-293 cells. Mechanistic investigations revealed that 1 induced apoptosis, which was associated with elevated reactive oxygen species (ROS) and inhibition of the intracellular enzyme thioredoxin reductase. Furthermore, 1 exhibited notable antiangiogenic characteristics in an in vivo model using transgenic zebrafish Tg(fli1a:EGFP). In vivo studies using mouse xenograft models showed that complex 1 displayed superior inhibition of tumour growth (82 %) compared to the clinical drug cisplatin (29 %). Overall, these results highlight the potential of gold (I) compounds as novel antitumour agents.
{"title":"Gold(I) somplexes of the type [AuL{κC-2-C6H4P(S)Ph2}] [L = PTA, PPh3, PPh2(C6H4-3-SO3Na) and PPh2(2-py)]: Synthesis, characterisation, crystal structures, and In Vitro and In Vivo anticancer properties.","authors":"T. Srinivasa Reddy , Steven H. Privér , Ruchika Ojha , Nedaossadat Mirzadeh , Ganga Reddy Velma , Ranjithkumar Jakku , Tayebeh Hosseinnejad , Rodney Luwor , Sistla Ramakrishna , Donald Wlodkowic , Magdalena Plebanski , Suresh K. Bhargava","doi":"10.1016/j.ejmech.2024.117007","DOIUrl":"10.1016/j.ejmech.2024.117007","url":null,"abstract":"<div><div>Four new mononuclear gold (I) compounds of the type [AuL{κ<em>C</em>-2-C<sub>6</sub>H<sub>4</sub>P(S)Ph<sub>2</sub>}] {L = PTA (<strong>1</strong>), PPh<sub>3</sub> (<strong>2</strong>), PPh<sub>2</sub>(C<sub>6</sub>H<sub>4</sub>-3-SO<sub>3</sub>Na) (<strong>3</strong>), and PPh<sub>2</sub>(2-py) (<strong>4</strong>)} were prepared by scission of the dinuclear compound [Au<sub>2</sub>{μ-2-C<sub>6</sub>H<sub>4</sub>P(S)Ph<sub>2</sub>}<sub>2</sub>] by L or via a transmetalation reaction using the organotin reagent 2-Me<sub>3</sub>SnC<sub>6</sub>H<sub>4</sub>P(S)Ph<sub>2</sub> and a suitable gold halide precursor. The cytotoxic potential of complexes <strong>1</strong>–<strong>4</strong> was evaluated against four human cancer cell lines of diverse cellular origin: cervical (HeLa), prostate (PC-3), non-small cell lung adenocarcinoma (A549), and fibrosarcoma (HT-1080). The <em>in vitro</em> cytotoxicity results showed that <strong>1</strong> demonstrated exceptional anticancer activity with IC<sub>50</sub> values ranging from 0.08 to 3.5 μM. Complex <strong>3</strong>, which contains a sulfonated triphenyl phosphine ligand, displayed the weakest anticancer activity with IC<sub>50</sub> values ranging from 3.1 to >50 μM. When compared to the standard chemotherapeutic drug cisplatin, <strong>1</strong> displayed approximately 27-fold greater cytotoxic activity against cervical cancer cells and 3.5- and 7.5-fold greater activities against prostate and fibrosarcoma cancer cells, respectively. Additionally, <strong>1</strong> exhibited 3-fold selectivity for cervical cancer cells compared to non-cancerous HEK-293 cells. Mechanistic investigations revealed that <strong>1</strong> induced apoptosis, which was associated with elevated reactive oxygen species (ROS) and inhibition of the intracellular enzyme thioredoxin reductase. Furthermore, <strong>1</strong> exhibited notable antiangiogenic characteristics in an <em>in vivo</em> model using transgenic zebrafish Tg(fli1a:EGFP). <em>In vivo</em> studies using mouse xenograft models showed that complex <strong>1</strong> displayed superior inhibition of tumour growth (82 %) compared to the clinical drug cisplatin (29 %). Overall, these results highlight the potential of gold (I) compounds as novel antitumour agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117007"},"PeriodicalIF":6.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541954","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}
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