Nanoparticles are being developed to enhance drug delivery to cancer tumors, leveraging advantages such as the enhanced permeability and retention (EPR) effect. However, traditional nanoparticles often face challenges with low specificity for cancer cells, leading to inefficient delivery and unwanted side effects. Esterase-responsive nanoparticles offer a maximum targeted approach to tumor cells because they release their therapeutic payload at the tumor site under the influence of esterase activity. This review explores the role of esterase-responsive nanoparticles in drug and gene delivery, examines esterase prodrug therapy, and discusses prostate-specific membrane antigen (PSMA) targets esterase-responsive nanoparticles in prostate cancer treatment. Additionally, we reviewed the current research progress and future potential of esterase-responsive nanoparticles in enhancing drug and gene delivery.
{"title":"Esterase-responsive nanoparticles (ERN): A targeted approach for drug/gene delivery exploits","authors":"Ashok Kumar Madikonda , Amritha Ajayakumar , Sudeena Nadendla , Janardhan Banothu , Venkanna Muripiti","doi":"10.1016/j.bmc.2024.118001","DOIUrl":"10.1016/j.bmc.2024.118001","url":null,"abstract":"<div><div>Nanoparticles are being developed to enhance drug delivery to cancer tumors, leveraging advantages such as the enhanced permeability and retention (EPR) effect. However, traditional nanoparticles often face challenges with low specificity for cancer cells, leading to inefficient delivery and unwanted side effects. Esterase-responsive nanoparticles offer a maximum targeted approach to tumor cells because they release their therapeutic payload at the tumor site under the influence of esterase activity. This review explores the role of esterase-responsive nanoparticles in drug and gene delivery, examines esterase prodrug therapy, and discusses prostate-specific membrane antigen (PSMA) targets esterase-responsive nanoparticles in prostate cancer treatment. Additionally, we reviewed the current research progress and future potential of esterase-responsive nanoparticles in enhancing drug and gene delivery.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 118001"},"PeriodicalIF":3.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142651884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-10DOI: 10.1016/j.bmc.2024.117999
Yali Kong , Michael C. Edler , Ernest Hamel , Asa R. Britton-Jenkins , Omar Gillan , Susan L. Mooberry , David Mu , Milton L. Brown
The boronic acid group plays an important role in drug discovery. Following our discovery of a boronic acid analog of combretastatin A-4 (CA-4), a series of analogs featuring a boronic acid group on the C phenyl ring of CA-4 was synthesized and evaluated for cytotoxicity, as well as for their ability to inhibit tubulin polymerization, inhibit the binding of [3H]colchicine to tubulin and cause depolymerization of cellular microtubules. Modifications on the C ring of CA-4, either eliminating the methoxy group or replacing the C phenyl ring with a pyridine ring, resulted in a reduced potency for inhibiting tubulin polymerization, colchicine binding and cytotoxic activities as compared to CA-4. Replacing the phenol group with a boronic acid group on the C ring of phenstatin led to a slight increase in cytotoxic potency but a decreased potency for inhibition of tubulin assembly and colchicine binding. Moreover, there was a significant decrease in activity by replacing the C phenyl ring with a pyridine ring. Our results indicate the critical importance of the methoxy group on the C ring as well as the importance of the C phenyl ring compared to a pyridine ring, despite the latter providing a nitrogen atom as a hydrogen bond donor/acceptor, which was predicted by molecular modeling to enhance interaction with the target. The decreased activities of our modified CA-4 boronic analogs may be attributed to weakened hydrogen bonding in our docking model based on the crystal structure of colchicine bound to αβ-tubulin. Notably, even though their effectiveness in inhibiting tubulin polymerization and colchicine binding and causing microtubule depolymerization in cells, the majority of these boronic acid analogs exhibited substantial cytotoxicity. This suggests that they may have additional cellular targets that contribute to their cytotoxicity, and this warrants further evaluation of these unique boronic acid compounds as potential anticancer agents.
硼酸基团在药物发现中发挥着重要作用。在我们发现考布他丁 A-4（CA-4）的硼酸类似物之后，我们合成了一系列在 CA-4 的 C 苯环上带有硼酸基团的类似物，并对它们的细胞毒性以及抑制微管蛋白聚合、抑制[3H]秋水仙碱与微管蛋白结合和导致细胞微管解聚的能力进行了评估。与 CA-4 相比，对 CA-4 的 C 环进行改性（消除甲氧基或用吡啶环取代 C 苯环）会降低其抑制小管蛋白聚合、秋水仙碱结合和细胞毒性活性的效力。用硼酸基团取代苯司他丁 C 环上的苯酚基团后，细胞毒性效力略有提高，但抑制小管蛋白组装和秋水仙碱结合的效力有所降低。此外，用吡啶环取代 C 苯环也会显著降低活性。我们的研究结果表明，C 环上的甲氧基以及 C 苯环与吡啶环相比至关重要，尽管后者提供了一个氮原子作为氢键供体/受体，而分子建模预测后者能增强与靶标的相互作用。我们根据秋水仙素与 αβ-tubulin 结合的晶体结构建立的对接模型中，氢键作用被削弱，这可能是改良的 CA-4 硼酸类似物活性降低的原因。值得注意的是，尽管这些硼酸类似物能有效抑制细胞中微管蛋白的聚合和秋水仙碱的结合，并导致微管解聚，但它们中的大多数都表现出很大的细胞毒性。这表明它们可能还有其他的细胞靶点，这些靶点有助于它们的细胞毒性，因此有必要进一步评估这些独特的硼酸化合物，将其作为潜在的抗癌药物。
{"title":"Synthesis and structure-activity relationship of boronic acid bioisosteres of combretastatin A-4 as anticancer agents","authors":"Yali Kong , Michael C. Edler , Ernest Hamel , Asa R. Britton-Jenkins , Omar Gillan , Susan L. Mooberry , David Mu , Milton L. Brown","doi":"10.1016/j.bmc.2024.117999","DOIUrl":"10.1016/j.bmc.2024.117999","url":null,"abstract":"<div><div>The boronic acid group plays an important role in drug discovery. Following our discovery of a boronic acid analog of combretastatin A-4 (CA-4), a series of analogs featuring a boronic acid group on the C phenyl ring of CA-4 was synthesized and evaluated for cytotoxicity, as well as for their ability to inhibit tubulin polymerization, inhibit the binding of [<sup>3</sup>H]colchicine to tubulin and cause depolymerization of cellular microtubules. Modifications on the C ring of CA-4, either eliminating the methoxy group or replacing the C phenyl ring with a pyridine ring, resulted in a reduced potency for inhibiting tubulin polymerization, colchicine binding and cytotoxic activities as compared to CA-4. Replacing the phenol group with a boronic acid group on the C ring of phenstatin led to a slight increase in cytotoxic potency but a decreased potency for inhibition of tubulin assembly and colchicine binding. Moreover, there was a significant decrease in activity by replacing the C phenyl ring with a pyridine ring. Our results indicate the critical importance of the methoxy group on the C ring as well as the importance of the C phenyl ring compared to a pyridine ring, despite the latter providing a nitrogen atom as a hydrogen bond donor/acceptor, which was predicted by molecular modeling to enhance interaction with the target. The decreased activities of our modified CA-4 boronic analogs may be attributed to weakened hydrogen bonding in our docking model based on the crystal structure of colchicine bound to αβ-tubulin. Notably, even though their effectiveness in inhibiting tubulin polymerization and colchicine binding and causing microtubule depolymerization in cells, the majority of these boronic acid analogs exhibited substantial cytotoxicity. This suggests that they may have additional cellular targets that contribute to their cytotoxicity, and this warrants further evaluation of these unique boronic acid compounds as potential anticancer agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117999"},"PeriodicalIF":3.3,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-09DOI: 10.1016/j.bmc.2024.117990
Ahmed A. Elbatrawy , Taiwo A. Ademoye , Heba Alnakhala , Arati Tripathi , Germán Plascencia-Villa , Xiongwei Zhu , George Perry , Ulf Dettmer , Jessica S. Fortin
Tau and α-synuclein (α-syn) are prone-to-aggregate proteins that can be responsible for pathological lesions found in the brains of Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease (PD) patients. The early-stage oligomers and protofibrils of tau are believed to be strongly linked to human cognitive impairment while the toxic α-syn oligomers are associated with behavioral motor deficits. Therefore, concurrent targeting of both proteinaceous aggregates and oligomers are very challenging. Herein, rhodanine-based compounds were designed and synthesized to target the fibrils and oligomers of tau and α-syn proteins. In particular, the indole-containing rhodanines 5l and 5r displayed significantly high anti-aggregation activity towards α-syn fibrils by reducing of the thioflavin-T (ThT) fluorescence to less than 5 %. Moreover, 5r showed a remarkable decrease in the fluorescence of thioflavin-S (ThS) when incubated with the non-phosphorylated tau 0N4R and 2N4R, as well as the hyperphosphorylated tau isoform 1N4R. Transmission electron microscopy (TEM) analyses validated the powerful anti-fibrillar activity of 5l and 5r towards both protein aggregates. In addition, both 5l and 5r highly suppressed 0N4R tau and α-syn oligomer formation using the photo-induced cross-linking of unmodified protein (PICUP) assay. The fluorescence emission intensity of 5l was quenched to almost half in the presence of both protein fibrils at 510 nm. 5r showed a similar fluorescence response upon binding to 2N4R fibrils while no quenching effect was observed with α-syn aggregates. Ex vivo disaggregation assay using extracted human Aβ plaques was employed to confirm the ability of 5l and 5r to disaggregate the dense fibrils. Both inhibitors reduced the Aβ fibrils isolated from AD brains. 5l and 5r failed to show activity toward the cell-based α-syn inclusion formation. However, another indolyl derivative 5j prevented the α-syn inclusion at 5 µM. Collectively, the indolyl-rhodanine scaffold could act as a building block for further structural optimization to obtain dual targeting disease-modifying candidates for AD, LBD, and PD.
{"title":"Exploring the rhodanine universe: Design and synthesis of fluorescent rhodanine-based derivatives as anti-fibrillar and anti-oligomer agents against α-synuclein and 2N4R tau","authors":"Ahmed A. Elbatrawy , Taiwo A. Ademoye , Heba Alnakhala , Arati Tripathi , Germán Plascencia-Villa , Xiongwei Zhu , George Perry , Ulf Dettmer , Jessica S. Fortin","doi":"10.1016/j.bmc.2024.117990","DOIUrl":"10.1016/j.bmc.2024.117990","url":null,"abstract":"<div><div>Tau and α-synuclein (α-syn) are prone-to-aggregate proteins that can be responsible for pathological lesions found in the brains of Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease (PD) patients. The early-stage oligomers and protofibrils of tau are believed to be strongly linked to human cognitive impairment while the toxic α-syn oligomers are associated with behavioral motor deficits. Therefore, concurrent targeting of both proteinaceous aggregates and oligomers are very challenging. Herein, rhodanine-based compounds were designed and synthesized to target the fibrils and oligomers of tau and α-syn proteins. In particular, the indole-containing rhodanines <strong>5l</strong> and <strong>5r</strong> displayed significantly high anti-aggregation activity towards α-syn fibrils by reducing of the thioflavin-T (ThT) fluorescence to less than 5 %. Moreover, <strong>5r</strong> showed a remarkable decrease in the fluorescence of thioflavin-S (ThS) when incubated with the non-phosphorylated tau 0N4R and 2N4R, as well as the hyperphosphorylated tau isoform 1N4R. Transmission electron microscopy (TEM) analyses validated the powerful anti-fibrillar activity of <strong>5l</strong> and <strong>5r</strong> towards both protein aggregates. In addition, both <strong>5l</strong> and <strong>5r</strong> highly suppressed 0N4R tau and α-syn oligomer formation using the photo-induced cross-linking of unmodified protein (PICUP) assay. The fluorescence emission intensity of <strong>5l</strong> was quenched to almost half in the presence of both protein fibrils at 510 nm. <strong>5r</strong> showed a similar fluorescence response upon binding to 2N4R fibrils while no quenching effect was observed with α-syn aggregates. <em>Ex vivo</em> disaggregation assay using extracted human A<em>β</em> plaques was employed to confirm the ability of <strong>5l</strong> and <strong>5r</strong> to disaggregate the dense fibrils. Both inhibitors reduced the A<em>β</em> fibrils isolated from AD brains. <strong>5l</strong> and <strong>5r</strong> failed to show activity toward the cell-based α-syn inclusion formation. However, another indolyl derivative <strong>5j</strong> prevented the α-syn inclusion at 5 µM. Collectively, the indolyl-rhodanine scaffold could act as a building block for further structural optimization to obtain dual targeting disease-modifying candidates for AD, LBD, and PD.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117990"},"PeriodicalIF":3.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cardiac inflammation, a pathological cornerstone in cardiac dysfunction, triggers diastolic impairment, leading to profound myocardial hypoxia. This hypoxic state serves as a potent stimulus for the amplification of inflammatory mediator release, ultimately limiting the therapeutic potential of monotherapies. To address this challenge, compounds that integrate non-steroidal anti-inflammatory drugs (NSAIDs) with nitric oxide (NO) donors was synthesized. The in vitro screening unveiled the remarkable anti-hypoxic inflammatory injury activity of a sulindac derivative, despite its suboptimal COX-2 inhibition when comparing with other NSAIDs derivatives. This revelation propelled us to delve deeper into the intricate synergistic relationship between sulindac and NO. Employing two-way ANOVA and high-throughput screening technique, we incontrovertibly confirmed their synergism. Further, the underlying mechanism was unmasked through the detection of signal molecule release levels and western blot analysis. In a definitive step, we evaluated the therapeutic effects of sulindac and its derivatives in vivo, leveraging a rat model that recapitulates cardiac inflammation coupled with hypoxia. Our findings herald a promising drug candidate and establish a foundation for the expanded utilization of NSAIDs in the intricate landscape of cardiovascular diseases.
心脏炎症是心脏功能障碍的病理基石，会引发舒张功能障碍，导致心肌严重缺氧。这种缺氧状态是扩大炎症介质释放的有效刺激，最终限制了单一疗法的治疗潜力。为了应对这一挑战，我们合成了将非甾体抗炎药（NSAID）与一氧化氮（NO）供体结合在一起的化合物。体外筛选揭示出一种舒林酸衍生物具有显著的抗缺氧性炎症损伤活性，尽管与其他非甾体抗炎药物衍生物相比，它对 COX-2 的抑制效果并不理想。这一发现促使我们深入研究舒林酸与 NO 之间错综复杂的协同作用关系。利用双向方差分析和高通量筛选技术，我们无可争议地证实了它们之间的协同作用。此外，我们还通过检测信号分子释放水平和 Western 印迹分析揭示了其潜在机制。最后，我们利用再现心脏炎症和缺氧的大鼠模型，评估了舒林酸及其衍生物在体内的治疗效果。我们的研究结果预示着一种很有前景的候选药物，并为在错综复杂的心血管疾病中扩大非甾体抗炎药的应用奠定了基础。
{"title":"Discovery of the synergy between sulindac and NO expands the application of NSAIDs in cardiac complications","authors":"Wen Zhou , Ping Jiang , Chunping Wang , Shaohua Gou","doi":"10.1016/j.bmc.2024.117991","DOIUrl":"10.1016/j.bmc.2024.117991","url":null,"abstract":"<div><div>Cardiac inflammation, a pathological cornerstone in cardiac dysfunction, triggers diastolic impairment, leading to profound myocardial hypoxia. This hypoxic state serves as a potent stimulus for the amplification of inflammatory mediator release, ultimately limiting the therapeutic potential of monotherapies. To address this challenge, compounds that integrate non-steroidal anti-inflammatory drugs (NSAIDs) with nitric oxide (NO) donors was synthesized. The <em>in vitro</em> screening unveiled the remarkable anti-hypoxic inflammatory injury activity of a sulindac derivative, despite its suboptimal COX-2 inhibition when comparing with other NSAIDs derivatives. This revelation propelled us to delve deeper into the intricate synergistic relationship between sulindac and NO. Employing two-way ANOVA and high-throughput screening technique, we incontrovertibly confirmed their synergism. Further, the underlying mechanism was unmasked through the detection of signal molecule release levels and western blot analysis. In a definitive step, we evaluated the therapeutic effects of sulindac and its derivatives <em>in vivo</em>, leveraging a rat model that recapitulates cardiac inflammation coupled with hypoxia. Our findings herald a promising drug candidate and establish a foundation for the expanded utilization of NSAIDs in the intricate landscape of cardiovascular diseases.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117991"},"PeriodicalIF":3.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.bmc.2024.117989
Mukul Mahanti , Sofi Gummesson , Anders Sundin , Hakon Leffler , Fredrik Zetterberg , Ulf J Nilsson
Four directional and positional variants of sulfonamide-derivatized galactopyranosides were synthesized and evaluated against human galectin-1, -3, -4C (C-terminal), -7, -8N (N-terminal), -8C (C-terminal), -9N (N-terminal), and -9C (C-terminal), which revealed that one of the sulfonamide positions and directionalities (methyl 3-{4-[2-(phenylsulfonylamino)-phenyl]-triazolyl}-3-deoxy-α-d-galactopyranosides) bound with 6–15 fold higher affinity than the corresponding phenyltriazole (lacking the phenylsulfonamide moiety) for galectin-9N. Molecular dynamic simulations suggested that inhibitor adopted a conformation that is complementary to the galectin-9N binding site and where the sulfonamide moiety protrudes into an unexplored and non-conserved binding site perpendicular to and below the A–B subsite to interact with a His61 NH proton. This resulted in the discovery of galectin-9N inhibitors with unprecedented selectivity over other galectins, thus constituting valuable tools for studies of the biological functions of galectin-9.
{"title":"Sulfonamide-derivatized galactosides selectively target an unexplored binding site in the galectin-9N-terminal domain","authors":"Mukul Mahanti , Sofi Gummesson , Anders Sundin , Hakon Leffler , Fredrik Zetterberg , Ulf J Nilsson","doi":"10.1016/j.bmc.2024.117989","DOIUrl":"10.1016/j.bmc.2024.117989","url":null,"abstract":"<div><div>Four directional and positional variants of sulfonamide-derivatized galactopyranosides were synthesized and evaluated against human galectin-1, -3, -4C (C-terminal), -7, -8N (N-terminal), -8C (C-terminal), -9N (N-terminal), and -9C (C-terminal), which revealed that one of the sulfonamide positions and directionalities (methyl 3-{4-[2-(phenylsulfonylamino)-phenyl]-triazolyl}-3-deoxy-α-<span>d</span>-galactopyranosides) bound with 6–15 fold higher affinity than the corresponding phenyltriazole (lacking the phenylsulfonamide moiety) for galectin-9N. Molecular dynamic simulations suggested that inhibitor adopted a conformation that is complementary to the galectin-9N binding site and where the sulfonamide moiety protrudes into an unexplored and non-conserved binding site perpendicular to and below the A–B subsite to interact with a His61 N<img>H proton. This resulted in the discovery of galectin-9N inhibitors with unprecedented selectivity over other galectins, thus constituting valuable tools for studies of the biological functions of galectin-9.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117989"},"PeriodicalIF":3.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1016/j.bmc.2024.117980
Sahani Sandalima Uthumange , Angie Jun Hui Liew , Xavier Wezen Chee , Keng Yoon Yeong
Scaffold-based drug design has become increasingly prominent in the pharmaceutical field due to the systematic and effective approach through which it facilitates the development of novel drugs. The identification of key scaffolds provides medicinal chemists with a fundamental framework for subsequent research. With mounting evidence suggesting that increased aromaticity could impede the chances of developmental success for oral drug candidates, there is an imperative need for a more thorough exploration of alternative ring systems to mitigate attrition risks. The unique characteristics exhibited by three-membered rings have led to their application in medicinal chemistry. This review explores the use of cyclopropane-, aziridine-, thiirane-, and epoxide-containing compounds in drug discovery, focusing on their roles in approved medicines and drug candidates. Specifically, the importance of the three-membered ring systems in rending biological activity for each drug molecule was highlighted. The undeniable therapeutic value and intriguing features presented by these compounds suggest significant pharmacological potential, providing justification for their incorporation into the design of novel drug candidates.
{"title":"Ringing medicinal chemistry: The importance of 3-membered rings in drug discovery","authors":"Sahani Sandalima Uthumange , Angie Jun Hui Liew , Xavier Wezen Chee , Keng Yoon Yeong","doi":"10.1016/j.bmc.2024.117980","DOIUrl":"10.1016/j.bmc.2024.117980","url":null,"abstract":"<div><div>Scaffold-based drug design has become increasingly prominent in the pharmaceutical field due to the systematic and effective approach through which it facilitates the development of novel drugs. The identification of key scaffolds provides medicinal chemists with a fundamental framework for subsequent research. With mounting evidence suggesting that increased aromaticity could impede the chances of developmental success for oral drug candidates, there is an imperative need for a more thorough exploration of alternative ring systems to mitigate attrition risks. The unique characteristics exhibited by three-membered rings have led to their application in medicinal chemistry. This review explores the use of cyclopropane-, aziridine-, thiirane-, and epoxide-containing compounds in drug discovery, focusing on their roles in approved medicines and drug candidates. Specifically, the importance of the three-membered ring systems in rending biological activity for each drug molecule was highlighted. The undeniable therapeutic value and intriguing features presented by these compounds suggest significant pharmacological potential, providing justification for their incorporation into the design of novel drug candidates.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117980"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1016/j.bmc.2024.117982
Hao Yang , Haoran Xu , Xinxin Lin , Zengxuan Cai , Yong Xia , Yu Wang , Zejie Chen , Koutian Zhang , Yanling Wu , Jianwei Wang , Annoor Awadasseid , Wen Zhang
Transmembrane Serine Protease 2 (TMPRSS2) plays a critical role in tumorigenesis and progression, making its degradation a promising therapeutic strategy. In this study, we designed and synthesized TMPRSS2-PROTACs, including VPOT64 and VPOT76, based on camostat. Both compounds exhibited superior inhibitory effects on HT-29 colorectal and Calu-3 lung cancer cells compared to paclitaxel. Notably, VPOT76 effectively degraded TMPRSS2, significantly inhibiting the proliferation of TMPRSS2-positive HT-29 cells and inducing apoptosis with an IC50 of 0.39 ± 0.01 μM. Flow cytometry analysis demonstrated that VPOT76 increased early apoptotic cells in a dose-dependent manner and caused G2 phase arrest at 0.8 μM. Colony formation assays showed that VPOT76 inhibited HT-29 colony formation, even at low concentrations, further confirming its anti-proliferative effect. Additionally, wound healing assays indicated that VPOT76 reduced the migration of HT-29 cells after 48 h, suggesting its potential to impair tumor cell invasion and metastasis. These findings highlight the multifaceted anticancer activities of VPOT76, including apoptosis induction, cell cycle arrest, colony formation inhibition, and migration suppression. Overall, this study establishes VPOT76 as a potent TMPRSS2-degrading PROTAC with strong therapeutic potential, laying the groundwork for further development of TMPRSS2-targeting treatments for colorectal and other cancers.
{"title":"Design, synthesis and biological evaluation of novel TMPRSS2-PROTACs with florosubstituted 4-guanidino-N-phenylbenzamide derivative ligands","authors":"Hao Yang , Haoran Xu , Xinxin Lin , Zengxuan Cai , Yong Xia , Yu Wang , Zejie Chen , Koutian Zhang , Yanling Wu , Jianwei Wang , Annoor Awadasseid , Wen Zhang","doi":"10.1016/j.bmc.2024.117982","DOIUrl":"10.1016/j.bmc.2024.117982","url":null,"abstract":"<div><div>Transmembrane Serine Protease 2 (TMPRSS2) plays a critical role in tumorigenesis and progression, making its degradation a promising therapeutic strategy. In this study, we designed and synthesized TMPRSS2-PROTACs, including <strong>VPOT64</strong> and <strong>VPOT76</strong>, based on camostat. Both compounds exhibited superior inhibitory effects on HT-29 colorectal and Calu-3 lung cancer cells compared to paclitaxel. Notably, <strong>VPOT76</strong> effectively degraded TMPRSS2, significantly inhibiting the proliferation of TMPRSS2-positive HT-29 cells and inducing apoptosis with an IC<sub>50</sub> of 0.39 ± 0.01 μM. Flow cytometry analysis demonstrated that <strong>VPOT76</strong> increased early apoptotic cells in a dose-dependent manner and caused G2 phase arrest at 0.8 μM. Colony formation assays showed that <strong>VPOT76</strong> inhibited HT-29 colony formation, even at low concentrations, further confirming its anti-proliferative effect. Additionally, wound healing assays indicated that <strong>VPOT76</strong> reduced the migration of HT-29 cells after 48 h, suggesting its potential to impair tumor cell invasion and metastasis. These findings highlight the multifaceted anticancer activities of <strong>VPOT76</strong>, including apoptosis induction, cell cycle arrest, colony formation inhibition, and migration suppression. Overall, this study establishes <strong>VPOT76</strong> as a potent TMPRSS2-degrading PROTAC with strong therapeutic potential, laying the groundwork for further development of TMPRSS2-targeting treatments for colorectal and other cancers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117982"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-11DOI: 10.1016/j.bmc.2023.117531
Heng Zhang , Jing Li , Karoly Toth , Ann E. Tollefson , Lanlan Jing , Shenghua Gao , Xinyong Liu , Peng Zhan
The main protease (Mpro) represents one of the most effective and attractive targets for designing anti-SARS-CoV-2 drugs. In this study, we designed and synthesized a novel series of Ebselen derivatives by incorporating privileged fragments from different pockets of the Mpro active site. Among these compounds, 11 compounds showed submicromolar activity in the FRET-based SARS-CoV-2 Mpro inhibition assay, with IC50 values ranging from 233 nM to 550 nM. Notably, compound 3a displayed submicromolar Mpro activity (IC50 = 364 nM) and low micromolar antiviral activity (EC50 = 8.01 µM), comparable to that of Ebselen (IC50 = 339 nM, EC50 = 3.78 µM). Time-dependent inhibition assay confirmed that these compounds acted as covalent inhibitors. Taken together, our optimization campaigns thoroughly explored the structural diversity of Ebselen and verified the impact of specific modifications on potency against Mpro.
{"title":"Identification of Ebselen derivatives as novel SARS-CoV-2 main protease inhibitors: Design, synthesis, biological evaluation, and structure-activity relationships exploration","authors":"Heng Zhang , Jing Li , Karoly Toth , Ann E. Tollefson , Lanlan Jing , Shenghua Gao , Xinyong Liu , Peng Zhan","doi":"10.1016/j.bmc.2023.117531","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117531","url":null,"abstract":"<div><p>The main protease (M<sup>pro</sup>) represents one of the most effective and attractive targets for designing anti-SARS-CoV-2 drugs. In this study, we designed and synthesized a novel series of Ebselen derivatives by incorporating privileged fragments from different pockets of the M<sup>pro</sup> active site. Among these compounds, 11 compounds showed submicromolar activity in the FRET-based SARS-CoV-2 M<sup>pro</sup> inhibition assay, with IC<sub>50</sub> values ranging from 233 nM to 550 nM. Notably, compound <strong>3a</strong> displayed submicromolar M<sup>pro</sup> activity (IC<sub>50</sub> = 364 nM) and low micromolar antiviral activity (EC<sub>50</sub> = 8.01 µM), comparable to that of Ebselen (IC<sub>50</sub> = 339 nM, EC<sub>50</sub> = 3.78 µM). Time-dependent inhibition assay confirmed that these compounds acted as covalent inhibitors. Taken together, our optimization campaigns thoroughly explored the structural diversity of Ebselen and verified the impact of specific modifications on potency against M<sup>pro</sup>.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"96 ","pages":"Article 117531"},"PeriodicalIF":3.5,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134657861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-10DOI: 10.1016/j.bmc.2023.117530
Guiying Wu , Hui Zhong , Ying Wang, Li Chen, Jianbo Sun
A number of NO-releasing quinoline derivatives have been designed and synthesized by introducing NO donor to quinoline carboxylic acid fragment. The anti-proliferation of all target compounds was evaluated against human cancer cell lines (HCT-116, MCF-7, and A549), MCF-7/ADR and normal cell (MCF-10A). Most compounds showed cytotoxic activity on cancer cells and drug-resistant cells with IC50 values in the range of 0.62–5.51 μM. Importantly, these compounds showed low toxicity to normal cells (4.21–34.08 μM). Further mechanism studies showed that the most potent compound 9 could release high concentration of NO and inhibit the activity of topoisomerase I. In addition, 9 regulated apoptosis-related proteins, generated ROS and blocked MCF-7 cells in G2/M phase to induce cell apoptosis. Furthermore, the P-gp-mediated transport was also influenced by 9. And 9 could significantly inhibit the growth of tumor in vivo without observable organ-related toxicities. Overall, as a novel NO-releasing quinoline derivative, 9 was worthy for further in-depth study.
{"title":"Development of novel quinoline-NO donor hybrids inducing human breast cancer cells apoptosis via inhibition of topoisomerase I","authors":"Guiying Wu , Hui Zhong , Ying Wang, Li Chen, Jianbo Sun","doi":"10.1016/j.bmc.2023.117530","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117530","url":null,"abstract":"<div><p>A number of NO-releasing quinoline derivatives have been designed and synthesized by introducing NO donor to quinoline carboxylic acid fragment. The anti-proliferation of all target compounds was evaluated against human cancer cell lines (HCT-116, MCF-7, and A549), MCF-7/ADR and normal cell (MCF-10A). Most compounds showed cytotoxic activity on cancer cells and drug-resistant cells with IC<sub>50</sub> values in the range of 0.62–5.51 μM. Importantly, these compounds showed low toxicity to normal cells (4.21–34.08 μM). Further mechanism studies showed that the most potent compound <strong>9</strong> could release high concentration of NO and inhibit the activity of topoisomerase I. In addition, <strong>9</strong> regulated apoptosis-related proteins, generated ROS and blocked MCF-7 cells in G2/M phase to induce cell apoptosis. Furthermore, the P-gp-mediated transport was also influenced by <strong>9</strong>. And <strong>9</strong> could significantly inhibit the growth of tumor <em>in vivo</em> without observable organ-related toxicities. Overall, as a novel NO-releasing quinoline derivative, <strong>9</strong> was worthy for further in-depth study.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"96 ","pages":"Article 117530"},"PeriodicalIF":3.5,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92108593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-10DOI: 10.1016/j.bmc.2023.117534
Mengmeng Fan , Liping Hu , Shengmin Shi , Xiaomeng Song , Huan He , Baohui Qi
Acquired drug resistance occurred in the treatment of non-small-cell lung cancer is a persistent challenge, especially in EGFR mutant type. In this study, we present design, synthesis and biological evaluation of novel quinazoline and pyrrolopyrimidine derivatives that simultaneously occupy the orthosteric and allosteric sites of EGFR. Among them, compound A-7 was confirmed as a potential EGFRL858R/T790M/C797S and EGFRDel19/T790M/C797S inhibitor. Docking study indicated that compound A-7 could simultaneously occupy two binding sites of EGFR and form three key H-bonds with the residues Met793, Lys745 and Met766 in two regions.
{"title":"Design, synthesis and biological evaluation of EGFR kinase inhibitors that spans the orthosteric and allosteric sites","authors":"Mengmeng Fan , Liping Hu , Shengmin Shi , Xiaomeng Song , Huan He , Baohui Qi","doi":"10.1016/j.bmc.2023.117534","DOIUrl":"10.1016/j.bmc.2023.117534","url":null,"abstract":"<div><p>Acquired drug resistance occurred in the treatment of non-small-cell lung cancer is a persistent challenge, especially in EGFR mutant type. In this study, we present design, synthesis and biological evaluation of novel quinazoline and pyrrolopyrimidine derivatives that simultaneously occupy the orthosteric and allosteric sites of EGFR. Among them, compound A-7 was confirmed as a potential EGFR<sup>L858R/T790M/C797S</sup> and EGFR<sup>Del19/T790M/C797S</sup> inhibitor. Docking study indicated that compound A-7 could simultaneously occupy two binding sites of EGFR and form three key H-bonds with the residues Met793, Lys745 and Met766 in two regions.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"96 ","pages":"Article 117534"},"PeriodicalIF":3.5,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89716265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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