Medicinal Chemistry Research最新文献

{"title":"Synthesis of novel benzothieno-[3,2’-f][1,3] oxazepines and their isomeric 2-oxo-2H-spiro[benzothiophene-3,3’-pyrrolines] via 1,4-dipolar cycloaddition reaction and their evaluation as cytotoxic anticancer leads","authors":"Mohammed M. Al-Mahadeen,&nbsp;Areej M. Jaber,&nbsp;Jalal A. Zahra,&nbsp;Mustafa M. El-Abadelah,&nbsp;Walhan Alshaer,&nbsp;Mutasem O. Taha","doi":"10.1007/s00044-024-03229-9","DOIUrl":"10.1007/s00044-024-03229-9","url":null,"abstract":"<div><p>This study introduces a novel class of hybrid compounds, namely, benzothieno[3,2’-<i>f</i>][1,3]oxazepines and their isomeric 2-oxo-2<i>H</i>-spiro[benzothiophene-3,3’-pyrrolines]. The synthetic strategy employs a three-component reaction and 1,4-Dipolar cycloaddition, yielding spiro and oxazepine compounds. Structural elucidation <i>via</i> NMR and MS analyses is complemented by X-ray crystallography and a proposed mechanistic pathway. Biological evaluation against HEK-293 and HT-29 cells reveals potent and selective cytotoxicity against HEK-293 without cytotoxic effects against HT-29 cells. Compound <b>16c</b> exhibited the highest cytotoxic properties with IC₅₀ = 4.30 μM against HEK-293 cells. Accordingly, the new compounds can be considered as promising leads for possible optimization into novel selective cytotoxic treatments.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 6","pages":"918 - 929"},"PeriodicalIF":2.6,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140930975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Folate-conjugated organic CO prodrugs: Synthesis and CO release kinetic studies","authors":"Shameer M. Kondengadan, Shubham Bansal, Xiaoxiao Yang, Binghe Wang","doi":"10.1007/s00044-024-03232-0","DOIUrl":"https://doi.org/10.1007/s00044-024-03232-0","url":null,"abstract":"<p>Carbon monoxide (CO) is an endogenously produced molecule and has shown efficacy in animal models of inflammation, organ injury, colitis and cancer metastasis. Because of its gaseous nature, there is a need for developing efficient CO delivery approaches, especially those capable of targeted delivery. In this study, we aim to take advantage of a previously reported approach of enrichment-triggered prodrug activation to achieve targeted delivery by targeting the folate receptor. The general idea is to exploit folate receptor-mediated enrichment as a way to accelerate a bimolecular Diels-Alder reaction for prodrug activation. In doing so, we first need to find ways to tune the reaction kinetics in order to ensure minimal reaction without enrichment and optimal activation upon enrichment. In this feasibility study, we synthesized two diene-dienophile pairs and studied their reaction kinetics and ability to target the folate receptor. We found that folate conjugation significantly affects the reaction kinetics of the original diene-dienophile pairs. Such information will be very useful in future designs of similar targeted approaches of CO delivery.</p>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"40 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140931408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-activity relationships and pharmacokinetic evaluation of L-cystine diamides as L-cystine crystallization inhibitors for cystinuria","authors":"Longqin Hu, Haifa Albanyan, Jeffrey Yang, Xiangduan Tan, Yiling Wang, Min Yang, Xiaodi Zhong, Michael D. Ward, Amrik Sahota","doi":"10.1007/s00044-024-03228-w","DOIUrl":"https://doi.org/10.1007/s00044-024-03228-w","url":null,"abstract":"<p>Cystinuria is a rare genetic disorder characterized by defective <span>l</span>-cystine reabsorption from the renal proximal tubule, resulting in abnormally high concentrations of L-cystine and subsequent <span>l</span>-cystine crystallization and stone formation in urine. <span>l</span>-Cystine diamides have shown great promise as inhibitors of <span>l</span>-cystine crystallization. The free α-amino groups in <span>l</span>-cystine diamides have previously been shown to be necessary for <span>l</span>-cystine crystallization inhibitory activity. In this study, three additional series of <span>l</span>-cystine diamide analogs were designed to explore further the structure-activity relationships for <span>l</span>-cystine crystallization inhibition. It has been demonstrated that the middle disulfide bond is required for optimal <span>l</span>-cystine crystallization inhibitory activity, and the only regions that can be modified are the two terminal amides. The presence of another basic amine 2–3 atoms away from the amide nitrogen is also critical for optimal activity. Disulfide exchange was found to be the main metabolic pathway resulting in the formation of two molecules of the active mixed disulfide metabolite from a single <span>l</span>-cystine diamide. <span>l</span>-Cystine diamides have the potential to be developed into a much-needed therapy for cystinuria.</p>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"112 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140882771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular hybridization method for obtaining paeonol-based fibrate derivatives with potent lipid-lowering and hepatoprotective activity","authors":"Lina Quan,&nbsp;Ying Guo,&nbsp;Siyao Wang,&nbsp;Mengfei Sun,&nbsp;Yan Pang,&nbsp;Chunli Cui,&nbsp;Jinrui Wang,&nbsp;Jinlian Wei,&nbsp;Peifeng Wei,&nbsp;Yundong Xie","doi":"10.1007/s00044-024-03214-2","DOIUrl":"10.1007/s00044-024-03214-2","url":null,"abstract":"<div><p>Molecular hybridization method was applied to design and synthesize a series of target compounds paeonol-based fibrate derivatives. The target compound was screened using a Triton WR-1339 induced hyperlipidemia mouse model, and compound T9 was found to have good lipid-lowering activity. The dose-dependent study of its lipid-lowering activity was also conducted. To further evaluate the lipid-lowering activity of compound T9, a hyperlipidemic mouse model induced by high fat emulsion can be used. The findings of the research illustrate that T9 is capable of significantly decreasing blood lipid levels, including TG, TC, LDL-C, and increasing HDL-C. The results of liver tissue oil red O staining and HE staining demonstrated that T9 improved the hepatic lipid accumulation, thus decreasing AST and ALT levels and protecting against hyperlipidemic liver injury. Studies into the lipid-lowering effect of T9 have indicated that it can upregulate PPAR-α protein expression in liver tissue, while simultaneously decreasing the expression of HMG-CoA protein. T9 was further demonstrated to possess antioxidant properties, as evidenced by an increase in SOD and a decrease in MDA, as well as anti-inflammatory effects, demonstrated by a decrease in TNF-α, IL-1β, and IL-6, thus confirming its potential as a hypolipidemia and hepatoprotective agent.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 5","pages":"796 - 810"},"PeriodicalIF":2.6,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140882773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of natural secondary metabolites as HIF-1 inhibitors in cancer therapy","authors":"Prem Shankar Mishra,&nbsp;Rakhi Mishra,&nbsp;Vaishali Manikrao Patil,&nbsp;Samiksha Dewangan","doi":"10.1007/s00044-024-03219-x","DOIUrl":"10.1007/s00044-024-03219-x","url":null,"abstract":"<div><p>Hypoxia-inducible Factor 1 (HIF-1) is a transcriptional activator that intervenes in versatile reactions to hypoxia. Natural drugs, widely distributed in plants, comprise many metabolites, possessing their potential as anti-cancer agents. Studies have highlighted HIF-1 as a potential pharmacological target for cancer therapy. Secondary metabolites derived from natural products (plant-derived or marine organisms) with unique chemical structures have demonstrated HIF-1 inhibition. Ganetespib, topotecan, PX-478, aminoflavone, fluorine-19-fluoroded xyglucose, etc. have entered clinical phases of evaluation for different types of cancer. The present work describes role of HIF-1 in tumor progression, summarizes plant based inhibitors such as berberine, rohitukine, harringtonine, acronycin, nuciferine, evodiamine, matrine, etc. Some of the major categories with HIF-1 inhibitory potential are alkaloids, flavonoids, steroids, etc. The manuscript aims to benefit the discovery and development of anti-cancer therapeutics from natural compounds.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 5","pages":"721 - 734"},"PeriodicalIF":2.6,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140883026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the CO release properties of a common CO donor, CORM-401, in the context of its application in studying CO biology","authors":"Nicola Bauer, Qiyue Mao, Xiaoxiao Yang, Binghe Wang","doi":"10.1007/s00044-024-03221-3","DOIUrl":"https://doi.org/10.1007/s00044-024-03221-3","url":null,"abstract":"<p>In studying CO for its pathophysiological roles, four metal/borane-carbonyl complexes have been widely used as CO-releasing molecules (CORMs) because of their commercial availability. The CO-release properties of CORM-2, CORM-3, and CORM-A1 have been rigorously characterized. In this study, we characterize CORM-401 for its CO-donating ability under various conditions relevant to studying CO biology. First, with regard to the “intrinsic” CO-release ability of CORM-401 and factors that could influence such ability, we found significant effects of added reagents such as thiol, peroxide, and dithionite on CO-release yields and rate. The variable nature of CO release from CORM-401 indicates the need for predetermining CO production yield and rate under the same conditions before biology experiments. Second, because of the commercial availability of CORM-401 in DMSO stock solution, we characterized its stability in such a preparation and found significantly diminished CO-release capacity of CORM-401 after exposing to DMSO or aqueous solution. Third, because carboxyhemoglobin (COHb) is an important indicator of the ability for a CO donor to supply CO in animal model work, we characterized the property for CORM-401 to elevate COHb. Fourth, quality assurance of such a metal complex is important to ensure consistency in results. Our findings indicate that the unstable nature of CORM-401 presents a quality assurance issue for end users. All these combined with the previously reported chemical reactivity of CORM-401could lead to intractable scenarios in obtaining meaningful results using CORM-401 that can be reasonably attributed to CO in biology experiments.</p>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"114 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140630978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antitumor studies on celastrol and its derivatives as RORα agonists and RORγ inhibitors based on Alphafold reverse docking strategy","authors":"Bangwen Yue,&nbsp;Xiuli Wu","doi":"10.1007/s00044-024-03213-3","DOIUrl":"10.1007/s00044-024-03213-3","url":null,"abstract":"<div><p>Celastrol (CSL), an active compound extracted from the root bark of <i>Tripterygium wilfordii</i>, has been studied for its outstanding efficacy in anti-cancer and cerebral neurology. We have obtained a series of derivatives with reduced toxicity through biotransformation. Here, 23391 proteins of homo sapiens from AlphaFold DB and Schrödinger’s Glide were used for reverse docking with the basic scaffold of CSL to discover the pharmacological activity of its derivatives. Based on the drug target database, the targets selected for the study were the RORα and RORγ of the Retinoic Acid Related-Orphan Receptors family (RORs). The series of compounds were filtered through QikProp, docked for dynamics stimulation and molecular mechanics-generalized born surface area (MMGBSA) binding energy calculations. We also performed fluorescence polarization assay (FP assay), luciferase reporter gene assay, and the CCK8 assay. In summary, we performed reverse docking of CSLs to find its key targets RORα and RORγ to explain its anti-inflammatory and anti-tumor effects, found binding sites Gln19, Arg97, Arg100 for RORα-Ligand binding domain (LBD) and Gln25, Leu26, Arg103, Arg106 for RORγ-LBD, screened for the highest affinity derivatives. The luciferase reporter gene assay showed that 2 μM 18-OH-CSL and 28-OH-CSL had the strongest agonistic effect on RORα-LBD, while CSLs had the weak inhibitory effect on RORγ-LBD, and these compounds also demonstrated a good apoptotic effect on the KG-1a tumor cell.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 5","pages":"779 - 795"},"PeriodicalIF":2.6,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140584048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenoxyalkyl cyclic and acyclic amine derivatives: what do they teach us about scaffold-based drug design?","authors":"Mohammad Mahdi Rezaeifar,&nbsp;Ardavan Abiri,&nbsp;Hojjat Rezaiezadeh,&nbsp;Marziye Ranjbar Tavakoli,&nbsp;Mohammad Amin Langarizadeh,&nbsp;Yaghoub Pourshojaei","doi":"10.1007/s00044-024-03215-1","DOIUrl":"10.1007/s00044-024-03215-1","url":null,"abstract":"<div><p>Fragment-based drug design of new bioactive scaffolds is a recent aspect of medicinal chemistry that provides a faster and more efficient road in drug discovery. Phenoxyethyl piperidine and morpholine derivatives have various pharmacological activities, from antitussive to anticancer properties. They are also widely used in selective estrogen receptor modulator (SERM) drugs and can be used to prevent osteoporosis in postmenopausal women. Also, other recent findings suggest that these compounds exhibit high anticholinergic and H₃ inverse agonistic activities. We outlined the process of developing novel medications for Alzheimer’s disease, malaria, cancer, and various other illnesses, which could entail modifying or incorporating these structures into a different biologically active framework. Pharmacokinetic assessment and organic pathways for synthesizing these scaffolds are also indicated. This review will discuss the recent pharmaceutical advances of phenoxyethyl cyclic amine derivatives in experimental, investigational, and FDA-approved drugs to draw an apparent viewpoint for future drug research and discovery.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 5","pages":"703 - 720"},"PeriodicalIF":2.6,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140583875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and anticancer activity of novel coumarin-stilbene hybrids with different hydrocarbon chains as linkers","authors":"Lamya A. Al-lehaib,&nbsp;Ehab M. M. Ali,&nbsp;Khalid O. Al-Footy,&nbsp;Reda M. El-Shishtawy","doi":"10.1007/s00044-024-03212-4","DOIUrl":"10.1007/s00044-024-03212-4","url":null,"abstract":"<div><p>Stilbene derivatives (pterostilbene and resveratrol) and 4-methylumbelliferone occur naturally in plants. These compounds and coumarin-stilbene hybrids have a variety of biological activities. It was envisioned that the molecular hybridization strategy would produce new bioactive molecules. Thus, six new coumarin-stilbene hybrids (<b>3a-b, 4a-b, and 5a-b)</b> with different hydrocarbon chains as linkers were synthesized by the <i>O</i>-alkylation reaction and characterized using FTIR, ¹H NMR, ¹³C NMR, DEPT-135, and HRMS (ESI+) spectral analysis. An MTT assay was used to test the synthesized hybrids against breast cancer (<b>MCF-7</b> and <b>T47D</b>) and liver cancer (<b>HepG2</b>) cell lines. The results showed that the synthesis of coumarin-stilbene hybrids via the <i>O</i>-alkylation reaction requires the presence of KI in addition to K₂CO₃ as a base to complete the reaction. On the other hand, the synthesis of coumarin-pterostilbene hybrids (<b>3a-b</b>) via the <i>O</i>-alkylation reaction with DMF as a solvent and an excess of base (K₂CO₃) and catalyst (KI) improved the yield significantly (65.43 and 73.71%, respectively). The biological results exhibited that all hybrids showed moderate to weak anticancer activities, much lower than the medication (cisplatin). However, most compounds showed superior activities than parent compounds against three different human cell lines. Among them, compounds <b>4a</b> and <b>4b</b> exhibited the best cytotoxic activity against <b>T47D</b> and <b>MCF-7</b>, with IC₅₀ values of 102.05 and 23.12 µM, respectively. Compound (<b>3a</b>) showed the most cytotoxic activity against <b>HepG2</b>, with an IC₅₀ value of 80.09 µM. To conclude, due to the simplicity of synthesis, hybridization is a promising strategy for producing new hybrid compounds with hydrocarbon chains as linkers and improving biological activity compared with their parent compounds.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 5","pages":"764 - 778"},"PeriodicalIF":2.6,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140583853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vital residues-orientated rational design of butenolide inhibitors targeting Of ChtI","authors":"Qing Han,&nbsp;Yun-Jiang Zi,&nbsp;Tian-Yu Feng,&nbsp;Nan Wu,&nbsp;Ren-Xuan Zou,&nbsp;Jing-Yu Zhang,&nbsp;Ru-Lei Zhang,&nbsp;Qing Yang,&nbsp;Hong-Xia Duan","doi":"10.1007/s00044-024-03211-5","DOIUrl":"10.1007/s00044-024-03211-5","url":null,"abstract":"<div><p>An effective approach for discovering small molecular inhibitors is the residues-oriented strategy based on enzyme analysis. In this study, we employed a rational approach to design and synthesize a library of butenolide analogues (<b>Ia-f</b> and <b>IIa-f</b>) targeting Trp107, utilizing reported piperonyl butenolide as lead compound. Notably, the most compounds <b>IIa-f</b> (R² = NO₂) exhibited slightly higher inhibitory potency against <i>Of</i> ChtI compared to compounds <b>Ia-f</b> (R² = Br). Molecular mechanism studies unveiled a crucial hydrogen bond interaction between the NO₂ group and Trp107, explaining the enhanced binding affinities. Compounds <b>IIe</b> and <b>IIf</b>, both bearing NO₂ on the benzene ring at the R² position, displayed the highest inhibitory activity, with <i>K</i>_i values of 0.87 and 0.68 <i>μ</i>M, respectively. Our findings highlight the potential of designing inhibitors with high enzymatic activity by structurally optimizing compounds based on the distinct interaction modes with crucial residues in the binding cavity of <i>Of</i> ChtI.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 5","pages":"740 - 747"},"PeriodicalIF":2.6,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140583881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}