Pub Date : 2024-10-01DOI: 10.1016/j.ejmech.2024.116933
For clinically prevalent traumatic optic neuropathy (TON) and other retinal and optic nerve injuries lacking effective therapeutic agents, there is an urgent clinical demand for developing highly efficient and safe neuroprotective agents. Here, we have integrated naturally sourced chalcone with isatin through a catalyst-free green synthesis method, reporting a series of spirocyclic chalcone derivatives with significantly lower cytotoxicity than chalcone itself. Following in vitro cell protection assays in models of hydrogen peroxide and glutamic acid-induced damage, multiple active compounds capable of combating both forms of damage were identified. Among these, candidate compound X38 demonstrated promising neuroprotective prospects: in vitro, it attenuated glutamate-induced cell apoptosis, while in vivo, it effectively ameliorated retinal thinning and loss of optic nerve electrophysiological function induced by optic nerve injury. Preliminary mechanistic studies suggest that X38 exerts its neuroprotective effects by mitigating intracellular ROS accumulation, inhibiting JNK phosphorylation, and alleviating oxidative stress. Additionally, acute toxicity studies (intraperitoneal injection, 500 mg/kg) underscored the favorable in vivo safety profile of X38. Taken together, this study has designed a class of safe, neuroprotective spirocyclic chalcone derivatives that can be synthesized using green methods, offering an attractive candidate for treating retinal and optic nerve injuries.
{"title":"Green synthesis of neuroprotective spirocyclic chalcone derivatives and their role in protecting against traumatic optic nerve injury","authors":"","doi":"10.1016/j.ejmech.2024.116933","DOIUrl":"10.1016/j.ejmech.2024.116933","url":null,"abstract":"<div><div>For clinically prevalent traumatic optic neuropathy (TON) and other retinal and optic nerve injuries lacking effective therapeutic agents, there is an urgent clinical demand for developing highly efficient and safe neuroprotective agents. Here, we have integrated naturally sourced chalcone with isatin through a catalyst-free green synthesis method, reporting a series of spirocyclic chalcone derivatives with significantly lower cytotoxicity than chalcone itself. Following <em>in vitro</em> cell protection assays in models of hydrogen peroxide and glutamic acid-induced damage, multiple active compounds capable of combating both forms of damage were identified. Among these, candidate compound <strong>X38</strong> demonstrated promising neuroprotective prospects: <em>in vitro</em>, it attenuated glutamate-induced cell apoptosis, while <em>in vivo</em>, it effectively ameliorated retinal thinning and loss of optic nerve electrophysiological function induced by optic nerve injury. Preliminary mechanistic studies suggest that <strong>X38</strong> exerts its neuroprotective effects by mitigating intracellular ROS accumulation, inhibiting JNK phosphorylation, and alleviating oxidative stress. Additionally, acute toxicity studies (intraperitoneal injection, 500 mg/kg) underscored the favorable <em>in vivo</em> safety profile of <strong>X38</strong>. Taken together, this study has designed a class of safe, neuroprotective spirocyclic chalcone derivatives that can be synthesized using green methods, offering an attractive candidate for treating retinal and optic nerve injuries.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369804","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 : 2024-10-01DOI: 10.1016/j.ejmech.2024.116931
Carbon dots (CDs) exhibit great potential in medicinal chemistry due to its excellent optical properties, biocompatibility and scalability, which have attracted significant interest. Based on their specific synthesis and modification, this review provided an overview of the evolution of the synthesis of CDs and reviewed the discovery and development of their optical properties. This review examines recent advances of CDs in medicinal chemistry, with a particular focus on the use of CDs as drugs and carriers for photodynamic and photothermal therapies in the field of neurological disorders, cancer, bacterial, viral, and further in combination with imaging for diagnostic and therapeutic integration. Finally, this review addresses the challenges and limitations of CDs in medicinal chemistry. This review provides a comprehensive overview of the development process of CDs and their applications in various aspects of medicinal chemistry, thereby offers insights to the development of CDs in the field of medicinal chemistry.
碳点（CD）因其优异的光学特性、生物相容性和可扩展性，在药物化学中展现出巨大的潜力，引起了人们的极大兴趣。根据碳点的具体合成和修饰方法，本综述概述了碳点合成的演变过程，并回顾了碳点光学特性的发现和发展。本综述探讨了 CD 在药物化学方面的最新进展，尤其关注将 CD 作为药物和载体用于神经系统疾病、癌症、细菌和病毒领域的光动力和光热疗法，并进一步结合成像技术实现诊断和治疗一体化。最后，本综述探讨了 CD 在药物化学中面临的挑战和局限性。本综述全面概述了 CD 的开发过程及其在药物化学各方面的应用，从而为 CD 在药物化学领域的发展提供了见解。
{"title":"Advancements of carbon dots: From the perspective of medicinal chemistry","authors":"","doi":"10.1016/j.ejmech.2024.116931","DOIUrl":"10.1016/j.ejmech.2024.116931","url":null,"abstract":"<div><div>Carbon dots (CDs) exhibit great potential in medicinal chemistry due to its excellent optical properties, biocompatibility and scalability, which have attracted significant interest. Based on their specific synthesis and modification, this review provided an overview of the evolution of the synthesis of CDs and reviewed the discovery and development of their optical properties. This review examines recent advances of CDs in medicinal chemistry, with a particular focus on the use of CDs as drugs and carriers for photodynamic and photothermal therapies in the field of neurological disorders, cancer, bacterial, viral, and further in combination with imaging for diagnostic and therapeutic integration. Finally, this review addresses the challenges and limitations of CDs in medicinal chemistry. This review provides a comprehensive overview of the development process of CDs and their applications in various aspects of medicinal chemistry, thereby offers insights to the development of CDs in the field of medicinal chemistry.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369805","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 : 2024-10-01DOI: 10.1016/j.ejmech.2024.116910
There is growing interest in developing monotherapy drugs that treat inflammation caused by microbial infections, focusing on dual antimicrobial and anti-inflammatory agents with minimal side effects and high safety margins. This study synthesized and characterized a library of novel cis-4-ferrocenylazetidin-2-ones, evaluating their antimicrobial and anti-inflammatory activities. These organometallic monocyclic β-lactams showed moderate in vitro antimicrobial activity against various standard microbial strains, including yeasts and Gram-negative and Gram-positive bacteria. Some compounds overcame the resistance of clinical Staphylococcus aureus isolates. Traditionally, monocyclic β-lactams target Gram-negative bacilli, but adding a ferrocene moiety and substituting the COOH group near the N-1 position with a non-ionizable ester group (COOR) extended their activity spectrum. The anti-inflammatory properties were assessed in macrophage-based models, revealing non-cytotoxicity below 10 μM. Two compounds were shown to be strong and selective arginase inhibitors, while five others effectively suppressed excessive NO formation without affecting basal NO production. The presence of a phenoxy group at C-3 of the β-lactam ring appeared to be crucial for selective NO inhibition. These hybrids did not scavenge NO but inhibited NO synthesis by suppressing iNOS expression. Overall, two novel hybrids were identified as promising hit candidates for treating infection-induced inflammatory reactions.
人们对开发治疗微生物感染引起的炎症的单一疗法药物越来越感兴趣，重点关注副作用小、安全系数高的双重抗菌消炎药物。本研究合成并表征了一个新型顺式-4-二茂铁氮杂环丁烷-2-酮库，评估了它们的抗菌和抗炎活性。这些有机金属单环 β-内酰胺类化合物对各种标准微生物菌株（包括酵母菌、革兰氏阴性菌和革兰氏阳性菌）显示出中等程度的体外抗菌活性。一些化合物克服了临床金黄色葡萄球菌分离株的耐药性。传统上，单环β-内酰胺类药物主要针对革兰氏阴性杆菌，但加入二茂铁分子并用非离子化酯基（COOR）取代靠近 N-1 位的 COOH 基团后，它们的活性谱得到了扩展。在基于巨噬细胞的模型中对其抗炎特性进行了评估，结果表明其毒性低于 10 μM。有两种化合物被证明是强效的选择性精氨酸酶抑制剂，另外五种化合物则有效抑制了过量 NO 的形成，而不影响基础 NO 的产生。β-内酰胺环 C-3 上的苯氧基似乎是选择性抑制 NO 的关键。这些杂交化合物不会清除 NO，但会通过抑制 iNOS 的表达来抑制 NO 的合成。总之，两种新型杂交化合物被确定为治疗感染引起的炎症反应的有希望的候选药物。
{"title":"Repurposing of monocyclic β-lactams as anti-inflammatory agents – The case of new ferrocene-azetidin-2-one hybrids","authors":"","doi":"10.1016/j.ejmech.2024.116910","DOIUrl":"10.1016/j.ejmech.2024.116910","url":null,"abstract":"<div><div>There is growing interest in developing monotherapy drugs that treat inflammation caused by microbial infections, focusing on dual antimicrobial and anti-inflammatory agents with minimal side effects and high safety margins. This study synthesized and characterized a library of novel <em>cis</em>-4-ferrocenylazetidin-2-ones, evaluating their antimicrobial and anti-inflammatory activities. These organometallic monocyclic β-lactams showed moderate <em>in vitro</em> antimicrobial activity against various standard microbial strains, including yeasts and Gram-negative and Gram-positive bacteria. Some compounds overcame the resistance of clinical <em>Staphylococcus aureus</em> isolates. Traditionally, monocyclic β-lactams target Gram-negative bacilli, but adding a ferrocene moiety and substituting the COOH group near the N-1 position with a non-ionizable ester group (COOR) extended their activity spectrum. The anti-inflammatory properties were assessed in macrophage-based models, revealing non-cytotoxicity below 10 μM. Two compounds were shown to be strong and selective arginase inhibitors, while five others effectively suppressed excessive NO formation without affecting basal NO production. The presence of a phenoxy group at C-3 of the β-lactam ring appeared to be crucial for selective NO inhibition. These hybrids did not scavenge NO but inhibited NO synthesis by suppressing iNOS expression. Overall, two novel hybrids were identified as promising hit candidates for treating infection-induced inflammatory reactions.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369803","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 : 2024-10-01DOI: 10.1016/j.ejmech.2024.116929
Hepatocellular carcinoma (HCC) is the most common type of liver solid tumor and the second leading cause of cancer-related deaths worldwide. Although new treatment options have been recently approved, the development of tumor resistance and the poor prognosis for advanced HCC make the current standard of care unsatisfying. In this scenario, the non-receptor tyrosine kinase (TK) c-Src emerged as a promising target for developing new anti-HCC agents. Our group reported a large library of pyrazolo[3,4-d]pyrimidines active as potent c-Src inhibitors. Starting from these data, we applied a molecular hybridization approach to combine the in-house pyrazolo[3,4-d]pyrimidine SI192 with the approved TK inhibitor (TKI) dasatinib, with the aim of identifying a new generation of Src inhibitors. Enzymatic results prompted us to design second-generation compounds with a better binding profile based on a hit optimization protocol comprised of molecular modeling and on-paper rational design. This investigation led to the identification of a few nanomolar Src inhibitors active toward two HCC cell lines (HepG2 and HUH-7) selected according to their high and low c-Src expression, respectively. In particular, 7e showed an IC50 value of 0.7 nM toward Src and a relevant antiproliferative efficacy on HepG2 cells after 72h (IC50 = 2.47 μM). Furthermore, 7e exhibited a cytotoxic profile better than dasatinib. The ADME profile suggested that 7e deserves further investigation as a promising TKI in cancer therapies. Finally, 7e′s ability to inhibit HepG2 cell proliferation, elicit an irreversible cytotoxic effect, arrest cellular migration, and induce apoptotic-mediated cell death was assessed.
{"title":"Applying molecular hybridization to design a new class of pyrazolo[3,4-d]pyrimidines as Src inhibitors active in hepatocellular carcinoma","authors":"","doi":"10.1016/j.ejmech.2024.116929","DOIUrl":"10.1016/j.ejmech.2024.116929","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is the most common type of liver solid tumor and the second leading cause of cancer-related deaths worldwide. Although new treatment options have been recently approved, the development of tumor resistance and the poor prognosis for advanced HCC make the current standard of care unsatisfying. In this scenario, the non-receptor tyrosine kinase (TK) c-Src emerged as a promising target for developing new anti-HCC agents. Our group reported a large library of pyrazolo[3,4-<em>d</em>]pyrimidines active as potent c-Src inhibitors. Starting from these data, we applied a molecular hybridization approach to combine the <em>in-house</em> pyrazolo[3,4-<em>d</em>]pyrimidine SI192 with the approved TK inhibitor (TKI) dasatinib, with the aim of identifying a new generation of Src inhibitors. Enzymatic results prompted us to design second-generation compounds with a better binding profile based on a hit optimization protocol comprised of molecular modeling and on-paper rational design. This investigation led to the identification of a few nanomolar Src inhibitors active toward two HCC cell lines (HepG2 and HUH-7) selected according to their high and low c-Src expression, respectively. In particular, <strong>7e</strong> showed an IC<sub>50</sub> value of 0.7 nM toward Src and a relevant antiproliferative efficacy on HepG2 cells after 72h (IC<sub>50</sub> = 2.47 μM). Furthermore, <strong>7e</strong> exhibited a cytotoxic profile better than dasatinib. The ADME profile suggested that <strong>7e</strong> deserves further investigation as a promising TKI in cancer therapies. Finally, <strong>7e</strong>′s ability to inhibit HepG2 cell proliferation, elicit an irreversible cytotoxic effect, arrest cellular migration, and induce apoptotic-mediated cell death was assessed.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369771","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 : 2024-09-30DOI: 10.1016/j.ejmech.2024.116928
Self-immolative prodrugs have gained significant attention as an innovative approach for targeted cancer therapy. These prodrugs are engineered to release the active anticancer agents in response to specific triggers within the tumor microenvironment, thereby improving therapeutic precision while reducing systemic toxicity. This review focuses on the molecular architecture and design principles of self-immolative prodrugs, emphasizing the role of stimuli-responsive linkers and activation mechanisms that enable controlled drug release. Recent advancements in this field include the development of prodrugs that incorporate targeting moieties for enhanced site-specificity. Moreover, the review discusses the incorporation of targeting moieties to achieve site-specific drug delivery, thereby improving the selectivity of treatment. By summarizing key research from the past five years, this review highlights the potential of self-immolative prodrugs to revolutionize cancer treatment strategies and pave the way for their integration into clinical practice.
{"title":"Stimuli-responsive prodrugs with self-immolative linker for improved cancer therapy","authors":"","doi":"10.1016/j.ejmech.2024.116928","DOIUrl":"10.1016/j.ejmech.2024.116928","url":null,"abstract":"<div><div>Self-immolative prodrugs have gained significant attention as an innovative approach for targeted cancer therapy. These prodrugs are engineered to release the active anticancer agents in response to specific triggers within the tumor microenvironment, thereby improving therapeutic precision while reducing systemic toxicity. This review focuses on the molecular architecture and design principles of self-immolative prodrugs, emphasizing the role of stimuli-responsive linkers and activation mechanisms that enable controlled drug release. Recent advancements in this field include the development of prodrugs that incorporate targeting moieties for enhanced site-specificity. Moreover, the review discusses the incorporation of targeting moieties to achieve site-specific drug delivery, thereby improving the selectivity of treatment. By summarizing key research from the past five years, this review highlights the potential of self-immolative prodrugs to revolutionize cancer treatment strategies and pave the way for their integration into clinical practice.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369815","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 : 2024-09-30DOI: 10.1016/j.ejmech.2024.116926
Inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) by small-molecules is being eagerly investigated for the treatment of various autoimmune diseases and in the field of immuno-oncology after its active involvement in antigen presentation and processing. Currently, ERAP1 inhibitors are at different stages of clinical development, which highlights its significance as a promising drug target. In the present work, we describe the first-ever successful identification of several ERAP1 inhibitors derived from a fragment-based screening approach. We applied an enzymatic activity assay to a large library of ∼3000 fragment entries in order to retrieve 32 hits. After a multi-faceted selection process, we prioritized 3 chemotypes for SAR optimization and strategic modifications provided 2 series (2-thienylacetic acid and rhodanine scaffolds) with improved analogues at the low micromolar range of ERAP1 inhibition. We report also evidence of selectivity against homologous aminopeptidase IRAP, combined with complementary in silico docking studies to predict the binding mode and site of inhibition. Our compounds can be the starting point for future fragment growing and rational drug development, incorporating new chemical modalities.
{"title":"First fragment-based screening identifies new chemotypes inhibiting ERAP1-metalloprotease","authors":"","doi":"10.1016/j.ejmech.2024.116926","DOIUrl":"10.1016/j.ejmech.2024.116926","url":null,"abstract":"<div><div>Inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) by small-molecules is being eagerly investigated for the treatment of various autoimmune diseases and in the field of immuno-oncology after its active involvement in antigen presentation and processing. Currently, ERAP1 inhibitors are at different stages of clinical development, which highlights its significance as a promising drug target. In the present work, we describe the first-ever successful identification of several ERAP1 inhibitors derived from a fragment-based screening approach. We applied an enzymatic activity assay to a large library of ∼3000 fragment entries in order to retrieve 32 hits. After a multi-faceted selection process, we prioritized 3 chemotypes for SAR optimization and strategic modifications provided 2 series (2-thienylacetic acid and rhodanine scaffolds) with improved analogues at the low micromolar range of ERAP1 inhibition. We report also evidence of selectivity against homologous aminopeptidase IRAP, combined with complementary <em>in silico</em> docking studies to predict the binding mode and site of inhibition. Our compounds can be the starting point for future fragment growing and rational drug development, incorporating new chemical modalities.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369806","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 : 2024-09-30DOI: 10.1016/j.ejmech.2024.116918
The interaction between menin and MLL1 protein plays an important role in AML with MLL rearrangement and NPM1 mutation. Blocking the formation of menin-MLL complex can inhibit proliferation and induce differentiation in these cancer subtypes. In development of anticancer drugs, irreversible inhibitors are gaining spotlight as they may have better activities than the reversible analogs. Therefore, we designed and developed a novel series of covalent menin inhibitors. Among these compounds, 37 emerges as a selective and potent inhibitor of MLL fusion protein-expressing leukemic cells. The cellular study indicates 37 has a distinct mechanism of action, in both reducing menin protein levels and downregulating MEN1 transcription. This effect of 37 is not involved in proteasomal degradation, and may directly affect the synthesis of menin protein, which offers a significant advantage in addressing acquired resistance to menin inhibitors. Further study showed that compound 37 has prolonged anti-leukemic action and exhibits promising in vivo efficacy, making it a valuable probe for further menin-MLL interaction studies.
{"title":"Design and development of a series of 4-(piperazin-1-yl)pyrimidines as irreversible menin inhibitors","authors":"","doi":"10.1016/j.ejmech.2024.116918","DOIUrl":"10.1016/j.ejmech.2024.116918","url":null,"abstract":"<div><div>The interaction between menin and MLL1 protein plays an important role in AML with MLL rearrangement and NPM1 mutation. Blocking the formation of menin-MLL complex can inhibit proliferation and induce differentiation in these cancer subtypes. In development of anticancer drugs, irreversible inhibitors are gaining spotlight as they may have better activities than the reversible analogs. Therefore, we designed and developed a novel series of covalent menin inhibitors. Among these compounds, <strong>37</strong> emerges as a selective and potent inhibitor of MLL fusion protein-expressing leukemic cells. The cellular study indicates <strong>37</strong> has a distinct mechanism of action, in both reducing menin protein levels and downregulating <em>MEN1</em> transcription. This effect of <strong>37</strong> is not involved in proteasomal degradation, and may directly affect the synthesis of menin protein, which offers a significant advantage in addressing acquired resistance to menin inhibitors. Further study showed that compound <strong>37</strong> has prolonged anti-leukemic action and exhibits promising <em>in vivo</em> efficacy, making it a valuable probe for further menin-MLL interaction studies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369807","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 : 2024-09-30DOI: 10.1016/j.ejmech.2024.116915
Plants are rich in steroidal and triterpenoid saponins. Diosgenin is an important sapogenin obtained from various steroidal saponins and specially from dioscin. It possesses diverse pharmacological activities as it is capable of modulating various endogenous pathways. Diosgenin is the molecule of choice for the industrial synthesis of the steroid based clinical drugs namely progesterone, testosterone, dexamethasone, dehydroepiandrosterone, vitamin D3, steroidal contraceptive pills, norethindrone, norgestrel etc. Diosgenin has been a molecule of discussion due to its high demand in industry as well as for future research applications. Present review describes its chemistry and detailed pharmacological profile.
{"title":"Plant based steroidal and triterpenoid sapogenins: Chemistry on diosgenin and biological aspects","authors":"","doi":"10.1016/j.ejmech.2024.116915","DOIUrl":"10.1016/j.ejmech.2024.116915","url":null,"abstract":"<div><div>Plants are rich in steroidal and triterpenoid saponins. Diosgenin is an important sapogenin obtained from various steroidal saponins and specially from dioscin. It possesses diverse pharmacological activities as it is capable of modulating various endogenous pathways. Diosgenin is the molecule of choice for the industrial synthesis of the steroid based clinical drugs namely progesterone, testosterone, dexamethasone, dehydroepiandrosterone, vitamin D<sub>3</sub>, steroidal contraceptive pills, norethindrone, norgestrel etc. Diosgenin has been a molecule of discussion due to its high demand in industry as well as for future research applications. Present review describes its chemistry and detailed pharmacological profile.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369810","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 : 2024-09-30DOI: 10.1016/j.ejmech.2024.116927
Antibody radionuclide conjugates are an emerging modality for targeted imaging and potent therapy of disseminated disease. Coupling of radionuclides to monoclonal antibodies (mAbs) is typically achieved by applying non-site-specific labelling techniques. With the ambition of reducing variability, increasing labelling efficacy and stability, several site-specific conjugation strategies have been developed in recent years for toxin- and fluorophore-mAb conjugates. In this study, we studied two site-specific labelling strategies for the conjugation of the macrocyclic chelating agent, DOTA, to the anti-Leucine Rich Repeat Containing 15 (LRRC15) mAb DUNP19. Specifically, one approach utilized a DOTA-bearing peptide (FcIII) with a strong affinity for the fragment crystallizable (Fc) domain of the human IgG1 of DUNP19 (DUNP19LF-FcIII-DOTASS), while the other leveraged a chemo-enzymatic technique to substitute the N-linked bi-antennary oligosaccharides in the human IgG1 Fc domain with DOTA (DUNP19LF-gly-DOTASS). To assess if these methods impact the antibody's binding properties and targeting efficacy, comparative in vitro and in vivo studies of the generated DUNP19-conjugates were performed. While the LRRC15 binding of both radioimmunoconjugates remained intact, the conjugation methods had different impacts on their abilities to interact with FcRn and FcγRs. In vitro assessments of DUNP19LF-FcIII-DOTASS and DUNP19LF-gly-DOTASS demonstrated markedly decreased affinity for FcRn and FcγRIIIa (CD16), respectively. DUNP19LF-FcIII-DOTASS demonstrated increased blood and tissue kinetics in vivo, confirming loss of FcRn binding. While the ablated FcγR interaction of DUNP19LF-gly-DOTASS had no immediate impact on in vivo biodistribution, reduced immunotherapeutic effect can be expected in future studies as a result of reduced NK-cells interaction. In conclusion, our findings underscore the necessity for meticulous consideration and evaluation of mAb labelling strategies, extending beyond mere conjugation efficiency and radiolabeling yields. Notably, site-specific labelling methods were found to significantly influence the immunological impact of Fc interactions. Therefore, it is of paramount importance to consider the intended diagnostic or therapeutic application of the construct and to adopt conjugation strategies that ensure the preservation of critical pharmacological properties and functionality of the antibody in use.
{"title":"Impact of site-specific conjugation strategies on the pharmacokinetics of antibody conjugated radiotherapeutics","authors":"","doi":"10.1016/j.ejmech.2024.116927","DOIUrl":"10.1016/j.ejmech.2024.116927","url":null,"abstract":"<div><div>Antibody radionuclide conjugates are an emerging modality for targeted imaging and potent therapy of disseminated disease. Coupling of radionuclides to monoclonal antibodies (mAbs) is typically achieved by applying non-site-specific labelling techniques. With the ambition of reducing variability, increasing labelling efficacy and stability, several site-specific conjugation strategies have been developed in recent years for toxin- and fluorophore-mAb conjugates. In this study, we studied two site-specific labelling strategies for the conjugation of the macrocyclic chelating agent, DOTA, to the anti-Leucine Rich Repeat Containing 15 (LRRC15) mAb DUNP19. Specifically, one approach utilized a DOTA-bearing peptide (FcIII) with a strong affinity for the fragment crystallizable (Fc) domain of the human IgG<sub>1</sub> of DUNP19 (DUNP19<sup>LF</sup>-FcIII-DOTA<sup>SS</sup>), while the other leveraged a chemo-enzymatic technique to substitute the N-linked bi-antennary oligosaccharides in the human IgG<sub>1</sub> Fc domain with DOTA (DUNP19<sup>LF</sup>-gly-DOTA<sup>SS</sup>). To assess if these methods impact the antibody's binding properties and targeting efficacy, comparative <em>in vitro</em> and <em>in vivo</em> studies of the generated DUNP19-conjugates were performed. While the LRRC15 binding of both radioimmunoconjugates remained intact, the conjugation methods had different impacts on their abilities to interact with FcRn and FcγRs. <em>In vitro</em> assessments of DUNP19<sup>LF</sup>-FcIII-DOTA<sup>SS</sup> and DUNP19<sup>LF</sup>-gly-DOTA<sup>SS</sup> demonstrated markedly decreased affinity for FcRn and FcγRIIIa (CD16), respectively. DUNP19<sup>LF</sup>-FcIII-DOTA<sup>SS</sup> demonstrated increased blood and tissue kinetics <em>in vivo</em>, confirming loss of FcRn binding. While the ablated FcγR interaction of DUNP19<sup>LF</sup>-gly-DOTA<sup>SS</sup> had no immediate impact on <em>in vivo</em> biodistribution, reduced immunotherapeutic effect can be expected in future studies as a result of reduced NK-cells interaction. In conclusion, our findings underscore the necessity for meticulous consideration and evaluation of mAb labelling strategies, extending beyond mere conjugation efficiency and radiolabeling yields. Notably, site-specific labelling methods were found to significantly influence the immunological impact of Fc interactions. Therefore, it is of paramount importance to consider the intended diagnostic or therapeutic application of the construct and to adopt conjugation strategies that ensure the preservation of critical pharmacological properties and functionality of the antibody in use.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369808","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 : 2024-09-29DOI: 10.1016/j.ejmech.2024.116912
Deep learning has gained increasing attention in recent years, yielding promising results in hit screening and molecular optimization. Herein, we employed an efficient strategy based on multiple deep learning techniques to optimize Wee1 inhibitors, which involves activity interpretation, scaffold-based molecular generation, and activity prediction. Starting from our in-house Wee1 inhibitor GLX0198 (IC50 = 157.9 nM), we obtained three optimized compounds (IC50 = 13.5 nM, 33.7 nM, and 47.1 nM) out of five picked molecules. Further minor modifications on these compounds led to the identification of potent Wee1 inhibitors with desirable inhibitory effects on multiple cancer cell lines. Notably, the best compound 13 exhibited superior cancer cell inhibition, with IC50 values below 100 nM in all tested cancer cells. These results suggest that deep learning can greatly facilitate decision-making at the stage of molecular optimization.
{"title":"Wee1 inhibitor optimization through deep-learning-driven decision making","authors":"","doi":"10.1016/j.ejmech.2024.116912","DOIUrl":"10.1016/j.ejmech.2024.116912","url":null,"abstract":"<div><div>Deep learning has gained increasing attention in recent years, yielding promising results in hit screening and molecular optimization. Herein, we employed an efficient strategy based on multiple deep learning techniques to optimize Wee1 inhibitors, which involves activity interpretation, scaffold-based molecular generation, and activity prediction. Starting from our in-house Wee1 inhibitor <strong>GLX0198</strong> (IC<sub>50</sub> = 157.9 nM), we obtained three optimized compounds (IC<sub>50</sub> = 13.5 nM, 33.7 nM, and 47.1 nM) out of five picked molecules. Further minor modifications on these compounds led to the identification of potent Wee1 inhibitors with desirable inhibitory effects on multiple cancer cell lines. Notably, the best compound <strong>13</strong> exhibited superior cancer cell inhibition, with IC<sub>50</sub> values below 100 nM in all tested cancer cells. These results suggest that deep learning can greatly facilitate decision-making at the stage of molecular optimization.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369811","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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