Bioorganic & Medicinal Chemistry Letters最新文献_第2页

Design, synthesis, and biological evaluation of novel potent dual Mer/c-Met inhibitors based on structural optimization 基于结构优化的新型高效双Mer/c-met抑制剂的设计、合成和生物学评价。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-20 DOI: 10.1016/j.bmcl.2025.130415

Lihong Duan , Xiaoyu Meng , Fang Li , Chen Wang , Ying Wu , Daowei Huang , Zhiwei Li

{"title":"Design, synthesis, and biological evaluation of novel potent dual Mer/c-Met inhibitors based on structural optimization","authors":"Lihong Duan , Xiaoyu Meng , Fang Li , Chen Wang , Ying Wu , Daowei Huang , Zhiwei Li","doi":"10.1016/j.bmcl.2025.130415","DOIUrl":"10.1016/j.bmcl.2025.130415","url":null,"abstract":"<div><div>Mer and c-Met kinases are frequently co-overexpressed in diverse malignancies, where their concurrent inhibition offers potential for synergetic antitumor efficacy while mitigating toxicity risks associated with single-target therapy. Building upon our previously identified lead compound, we designed and synthesized novel derivatives targeting dual Mer/c-Met inhibition. Among these, compound <strong>17j</strong> emerged as a potent dual inhibitor, demonstrating IC<sub>50</sub> values of 1.00 ± 0.14 nM (Mer) and 19.00 ± 3.23 nM (c-Met). This agent exhibited robust antiproliferative activity against HCT116, A2780, and PC-3 cancer cell lines, coupled with favorable safety profiles including hERG liability. Notably, <strong>17j</strong> displayed exceptional metabolic stability in human liver microsomes (t<sub><em>1/2</em></sub> = 72.6 min) over compound <strong>17c</strong>. Mechanistic studies confirmed its dose-dependent cytotoxicity and significant suppression of HCT116 cell migration. Collectively, these findings position <strong>17j</strong> as a promising therapeutic candidate for Mer/c-Met driven cancers.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130415"},"PeriodicalIF":2.2,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124130","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}

引用次数: 0

Design, synthesis, and biological evaluation of novel 1,5-diarylpyrazole carboxamides with dual inhibition of EGFR and COX-2 for the treatment of cancer and inflammatory diseases 具有双重抑制EGFR和COX-2治疗癌症和炎症性疾病的新型1,5-二芳基吡唑类羧酰胺的设计、合成和生物学评价

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-20 DOI: 10.1016/j.bmcl.2025.130416

Osama M. Soltan , Salah A. Abdel-Aziz , Kamal S. Abdelrahman , Atsushi Narumi , Mohamed Abdel-Aziz , Mai E. Shoman , Hiroyuki Konno

{"title":"Design, synthesis, and biological evaluation of novel 1,5-diarylpyrazole carboxamides with dual inhibition of EGFR and COX-2 for the treatment of cancer and inflammatory diseases","authors":"Osama M. Soltan , Salah A. Abdel-Aziz , Kamal S. Abdelrahman , Atsushi Narumi , Mohamed Abdel-Aziz , Mai E. Shoman , Hiroyuki Konno","doi":"10.1016/j.bmcl.2025.130416","DOIUrl":"10.1016/j.bmcl.2025.130416","url":null,"abstract":"<div><div>This study presents a series of dual-target epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) inhibitors developed as anticancer and anti-inflammatory agents. These novel inhibitors were designed based on key pharmacophoric features of known selective EGFR/COX-2 inhibitors with distinct chemical structures, and various substituents were selected according to rational criteria. Many of the novel compounds exhibited excellent antiproliferative activities and EGFR/COX-2 inhibitory activity. Among them, <strong>10a</strong> exhibited the highest potency against cancer cell lines, with IC<sub>50</sub> values of 6.7, 9.0, and 13.0 μM against leukemia, cervical cancer, and pancreatic cancer cell lines, respectively. Moreover, the optimal compound <strong>10a</strong> was tested in a cell viability assay using human PC12 normal cell line and exhibited low cytotoxicity (IC<sub>50</sub> = 77.4 μM, SI = 8.6, 11.5, 5.9) and it might be used as a potent, selective and safe antitumor agent. It also exhibited high inhibitory activity against EGFR (IC<sub>50</sub> = 6.0 μM) and COX-2 (IC<sub>50</sub> = 50 μM, SI = 3.8). Mechanistic studies revealed that <strong>10a</strong> increased the cell population in the S phase and induced cell cycle arrest mainly in this phase. Moreover, an increase in apoptotic HeLa cells was observed following treatment with <strong>10a</strong>. In addition, <strong>8d</strong> was identified as the most potent and selective COX-2 inhibitor, with an IC<sub>50</sub> value of 12.5 μM and SI of 16. Molecular docking studies demonstrated that <strong>10a</strong> and <strong>8d</strong> adopted orientations in the EGFR and COX-2 binding sites are oriented and fit in a similar manner to those of ligand inhibitors, supporting the experimental results.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130416"},"PeriodicalIF":2.2,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119590","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}

引用次数: 0

The Pyrimidinyl Hydrazones: Selective for anti-Cancer cytotoxicity 嘧啶酰腙：选择性抗癌细胞毒性。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-17 DOI: 10.1016/j.bmcl.2025.130405

Rohina Alim, Scott D. Andrew, Christopher J. Parkinson

{"title":"The Pyrimidinyl Hydrazones: Selective for anti-Cancer cytotoxicity","authors":"Rohina Alim, Scott D. Andrew, Christopher J. Parkinson","doi":"10.1016/j.bmcl.2025.130405","DOIUrl":"10.1016/j.bmcl.2025.130405","url":null,"abstract":"<div><div>Pyrimidinyl hydrazones (PH) can be prepared using simple procedures beginning with dichloropyrimidine. A total of 9 PH were synthesised and these compounds associated strongly with copper, iron and zinc ions both at physiological and mildly acidic pH. The PH were cytotoxic <em>in vitro</em> against cancer cell lines (compound <strong>15</strong> having IC<sub>50</sub> values of 0.37, 0.11 and 1.09 μM against melanoma, ovarian cancer and pancreatic cancer cell lines respectively – these values being superior to known agents such as doxorubicin) and displayed only minimal toxicity against non-cancer cell lines (no toxicity at 25 μM against the non-cancer MRC-5 fibroblast). Copper complexes of the PH formed <em>in situ</em> showed cytotoxicity against cancer lines similar to that of the PH alone – albeit with substantial increases in toxicity against non-cancer cells. Association of PH with iron or zinc ions <em>in situ</em> did not generally result in enhanced potency – unlike related thiosemicarbazones. The cytotoxic potency of PH was comparable to that observed for thiosemicarbazones. The PH are likely to exert their cytotoxic action through a combination of metal mobilisation and reactive oxygen generation. The PH should be more extensively studied as a class of metal-chelating anti-cancer agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130405"},"PeriodicalIF":2.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090740","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}

引用次数: 0

Polymethoxy-/polyacetyl-flavones cytotoxicity towards colorectal and prostate cancer cell lines: SAR, mechanisms of action and evaluation as potential adjuvants in chemotherapy 多甲氧基/多乙酰黄酮对结直肠癌和前列腺癌细胞系的细胞毒性：化疗中潜在佐剂的SAR、作用机制和评价

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-14 DOI: 10.1016/j.bmcl.2025.130404

Roxane Tenta , Katerina Gioti , Vincent Dumontet , Laurent Picot , Raphael Grougnet

{"title":"Polymethoxy-/polyacetyl-flavones cytotoxicity towards colorectal and prostate cancer cell lines: SAR, mechanisms of action and evaluation as potential adjuvants in chemotherapy","authors":"Roxane Tenta , Katerina Gioti , Vincent Dumontet , Laurent Picot , Raphael Grougnet","doi":"10.1016/j.bmcl.2025.130404","DOIUrl":"10.1016/j.bmcl.2025.130404","url":null,"abstract":"<div><div>A set of natural and semi-synthetic polymethoxy- and polyacetyl-flavones (PMFs/PAFs) was evaluated towards colorectal (HCT116) and prostate (PC-3) cancer cells. The most active compounds were then combined with 5-fluorouracil (5-FU) or with adriamycin (ADR) in order to determine a potential synergism, focusing on contingent changes in cell cycle and apoptosis. Two derivatives were strongly cytotoxic. They also induced G0/G1 cell cycle arrest, but differently behaved when combined to the reference drugs 5-FU or ADR. The induction of apoptosis was stronger towards HCT116, noticeably increasing the activity of 5-FU, suggesting a potential additive effect. Besides, the results of soluble caspase-cleaved K18 showed that another phenomenon such as autophagy may be involved towards PC-3 cells and should be deciphered. Consequently, these two PMFs are considered as suitable candidates for further studies in hit-to‑lead approach, in a context of a therapeutic protocol involving natural products as chemosensitizers, aiming to increase the potency and to reduce the side effects of antitumor drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130404"},"PeriodicalIF":2.2,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074337","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}

引用次数: 0

Synthesis and functional evaluation of tetrahydroisoquinoline and polysubstituted benzylamine derivatives as sigma-2 receptor-targeted small-molecule probes 四氢异喹啉和多取代苄胺衍生物作为sigma-2受体靶向小分子探针的合成及功能评价。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-13 DOI: 10.1016/j.bmcl.2025.130403

Ai-Fang Chen , Xiao-Yang Xie , Wei-Shuai Xu , Ya-Xin Wang , Hua-Lun Liang

{"title":"Synthesis and functional evaluation of tetrahydroisoquinoline and polysubstituted benzylamine derivatives as sigma-2 receptor-targeted small-molecule probes","authors":"Ai-Fang Chen , Xiao-Yang Xie , Wei-Shuai Xu , Ya-Xin Wang , Hua-Lun Liang","doi":"10.1016/j.bmcl.2025.130403","DOIUrl":"10.1016/j.bmcl.2025.130403","url":null,"abstract":"<div><div>The sigma-2 receptor has been identified as a marker of abnormal tumor proliferation. Novel sigma-2 small molecule probes have been developed to assist in localizing tumor sites, tracking in vivo tumor cell proliferation and migration, and facilitating cancer diagnosis and treatment. A series of tetrahydroisoquinoline- and polysubstituted benzylamine-based sigma-2 small molecule probes were synthesized, and compounds <strong>6</strong>–<strong>8</strong> were found to exhibit moderate to high affinity and selectivity for sigma-2 receptors, with Ki values ranging from 7.8 to 53.2 nM. Functional analysis confirmed that the three active compounds act as sigma-2 receptor antagonists. Lower cytotoxicity was observed for compounds <strong>6</strong>–<strong>8</strong>, with no significant or only weak cytotoxic effects detected in the MCF-7 cell line. In the tumor cell fluorescence imaging experiment, it could be clearly observed from the merged images that fluorescence was localized within MCF-7 cells, and target compounds <strong>6</strong>–<strong>8</strong> were able to enter target cells and exhibit obvious fluorescence. Among them, the fluorescence of compound <strong>6</strong> was the most distinct.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130403"},"PeriodicalIF":2.2,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068788","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}

引用次数: 0

Stanolone-1,2,3-Triazole derivatives: Synthesis, DNA damage in tumor cells and anti-prostate Cancer activity study 斯坦诺酮-1,2,3-三唑衍生物：合成、肿瘤细胞DNA损伤及抗前列腺癌活性研究。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-13 DOI: 10.1016/j.bmcl.2025.130402

Xixi Hou , Shuxiang Xu , Longfei Mao , Yue-Ming Li , Jianji Wang

{"title":"Stanolone-1,2,3-Triazole derivatives: Synthesis, DNA damage in tumor cells and anti-prostate Cancer activity study","authors":"Xixi Hou , Shuxiang Xu , Longfei Mao , Yue-Ming Li , Jianji Wang","doi":"10.1016/j.bmcl.2025.130402","DOIUrl":"10.1016/j.bmcl.2025.130402","url":null,"abstract":"<div><div>1,2,3-Triazole skeleton may act as both a hydrogen bond acceptor and a linker connecting different structures, and androgens bearing 1,2,3-triazole structures exhibit interesting biological activities against prostate cancer. Based on this rationale, various substituted 1,2,3-triazole groups were introduced to stanolone via click chemistry, and a total of 32 stanolone derivatives (<strong>13a</strong> - <strong>13r</strong> and <strong>14a</strong>–<strong>14n</strong>) were obtained under mild conditions. Their in vitro inhibitory activities against two prostate cancer cell lines, PC3 and DU145, were evaluated, and a preliminary structure-activity relationship (SAR) was established. Compounds <strong>14e</strong>, <strong>14f</strong>, and <strong>14 k</strong> exhibited significant inhibitory effects, with IC<sub>50</sub> values of 12.33 μM, 6.69 μM, and 13.83 μM, respectively, against PC3 cells, and 18.55 μM, 5.67 μM, and 5.08 μM, respectively, against DU145 cells. These compounds were found to induce mitochondrial apoptosis in PC3 and DU145 cells. Further investigation revealed the activation of the γ-H2AX signaling pathway, leading to DNA damage in tumor cells. Notably, compound <strong>14 k</strong> also demonstrated promising antitumor efficacy in a DU145 xenograft mouse model, and showing no cytotoxicity to normal human renal epithelial cells (HK−2), human liver cells (LO2), or human lung epithelial cells (BESA-2b) in vitro, indicating its potential as a lead compound for future antitumor drug study.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130402"},"PeriodicalIF":2.2,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068706","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}

引用次数: 0

Design, synthesis and biological evaluation of novel histone deacetylase 6 inhibitors containing indole-based cap groups 含有吲哚基帽基的新型组蛋白去乙酰化酶6抑制剂的设计、合成和生物学评价

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-10 DOI: 10.1016/j.bmcl.2025.130399

Xinhui Zhang , Haiqian Nie , Junru Zhao , Mengkai Feng , Yulin Liu , Huiqin Kang , Yuanfan Liu , Shiyu Li , Hongmin Liu , Ya Gao , Liying Ma

{"title":"Design, synthesis and biological evaluation of novel histone deacetylase 6 inhibitors containing indole-based cap groups","authors":"Xinhui Zhang , Haiqian Nie , Junru Zhao , Mengkai Feng , Yulin Liu , Huiqin Kang , Yuanfan Liu , Shiyu Li , Hongmin Liu , Ya Gao , Liying Ma","doi":"10.1016/j.bmcl.2025.130399","DOIUrl":"10.1016/j.bmcl.2025.130399","url":null,"abstract":"<div><div>Based on our previous report, this study systematically elucidated the development process of a novel class of HDAC6 inhibitors containing indole-based cap groups. Starting from lead compound <strong>L9</strong> identified <em>via</em> an in-house compound library screening, systematic structural optimization was performed, and a series of derivatives were designed and synthesized. Structure-activity relationship (SAR) studies demonstrated the advantages of cap groups derived from indole ring and the preference of different modification sites. We finally identified compound <strong>10n</strong>, substituted with a cyclopropyl-methyl group in the N-1 position of its indole ring, as the most potent HDAC6 inhibitor (IC<sub>50</sub> = 3.11 ± 0.09 nM), with selectivity ratios of 27.8- to 622.2-fold over HDAC1/2/3/8 and >3000-fold over other isoforms. <em>In vitro</em> evaluations further demonstrated its potential anti-proliferative and apoptosis-inducing ability in gastric cancer, as well as good <em>in vivo</em> pharmacokinetic properties. Docking analysis revealed its strong binding affinity to the HDAC6 catalytic pocket: including spatial complementarity in conformation and the formation of strong interactions with nearby amino acid residues. These findings highlight <strong>10n</strong> as a promising scaffold for developing HDAC6-selective inhibitors, with structural insights guiding future optimizations.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130399"},"PeriodicalIF":2.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045209","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}

引用次数: 0

Design, synthesis and biological evaluation of novel quinazolinedione derivatives as non-covalent SARS-CoV-2 3CL protease inhibitors 新型非共价sars -cov - 23cl蛋白酶抑制剂喹唑啉二酮衍生物的设计、合成及生物学评价

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-10 DOI: 10.1016/j.bmcl.2025.130400

Yoshiyuki Taoda, Akihiro Hori, Genta Tadano, Shuichi Sugiyama, Sota Masakado, Satoru Tanaka, Riku Ogasahara, Kenji Nakahara, Shomitsu Maeno, Yuto Unoh, Yuki Tachibana, Shota Uehara, Yusuke Sako, Shiho Yamamoto, Sho Kawashima, Haruki Nobori, Teruhisa Kato

{"title":"Design, synthesis and biological evaluation of novel quinazolinedione derivatives as non-covalent SARS-CoV-2 3CL protease inhibitors","authors":"Yoshiyuki Taoda, Akihiro Hori, Genta Tadano, Shuichi Sugiyama, Sota Masakado, Satoru Tanaka, Riku Ogasahara, Kenji Nakahara, Shomitsu Maeno, Yuto Unoh, Yuki Tachibana, Shota Uehara, Yusuke Sako, Shiho Yamamoto, Sho Kawashima, Haruki Nobori, Teruhisa Kato","doi":"10.1016/j.bmcl.2025.130400","DOIUrl":"10.1016/j.bmcl.2025.130400","url":null,"abstract":"<div><div>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has spread around the world since 2020, affecting many people and placing a heavy burden on medical facilities and the economy. The 3C-like protease (3CL<sup>pro</sup>) of SARS-CoV-2 is an essential enzyme for viral replication, and has been therefore attracting attention as a drug target. With the aim of creating novel non-covalent 3CL<sup>pro</sup> inhibitors, we planned a scaffold hopping transformation starting with ensitrelvir, which was discovered by Shionogi. Optimization of the substituents at the 5- and 7-positions of the newly designed quinazolinedione scaffold led to the discovery of compound <strong>16</strong>, which exceeds ensitrelvir in enzyme inhibitory and antiviral activities. We solved the X-ray co-crystal structure of our synthesized inhibitor and 3CL<sup>pro</sup>, and clarified the interaction that contributes to its high activity. The newly discovered compound has shown good results in terms of metabolic stability and oral absorption in rat PK studies. It is expected to be a good lead compound for finding superior 3CL<sup>pro</sup> inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130400"},"PeriodicalIF":2.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045208","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}

引用次数: 0

Design, synthesis, and anticancer evaluation of benzimidazole and benzothiazole derivatives targeting Hsp70 and FoxM1 靶向Hsp70和FoxM1的苯并咪唑和苯并噻唑衍生物的设计、合成及抗癌评价

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-10 DOI: 10.1016/j.bmcl.2025.130401

Zahra Alimardan , Khosrow Kashfi , Maryam Abbasi , Ghadamali Khodarahmi

{"title":"Design, synthesis, and anticancer evaluation of benzimidazole and benzothiazole derivatives targeting Hsp70 and FoxM1","authors":"Zahra Alimardan , Khosrow Kashfi , Maryam Abbasi , Ghadamali Khodarahmi","doi":"10.1016/j.bmcl.2025.130401","DOIUrl":"10.1016/j.bmcl.2025.130401","url":null,"abstract":"<div><div>A series of novel benzimidazole and benzothiazole derivatives was designed based on the scaffolds of known Hsp70 (VER-155008) and FoxM1 (FDI-6) inhibitors. Molecular docking studies indicated favorable binding affinities to both targets, with several compounds showing strong interactions within the ATPase domain of Hsp70 and the DNA-binding region of FoxM1. The most promising candidates, as identified by docking scores, were synthesized and structurally confirmed using FT-IR, <sup>1</sup>H NMR, and <sup>13</sup>C NMR spectroscopy. Their cytotoxicity was evaluated against MCF-7, HeLa, and HUVEC cell lines using the MTT assay. Benzothiazole derivatives exhibited greater cytotoxic activity than benzimidazole counterparts. Among them, compound <strong>7d</strong> demonstrated the most potent antiproliferative effect, with IC₅₀ values of 10.83 μM (MCF-7), 12.68 μM (HeLa), and 106.75 μM (HUVEC). Molecular dynamics simulations further confirmed the stability of <strong>7d</strong> within the FoxM1 binding pocket, supporting its role as a potential FoxM1 inhibitor. While experimental confirmation of dual-target inhibition in cell-based assays is pending, the computational findings suggest that <strong>7d</strong> may function as a dual modulator of Hsp70 and FoxM1, warranting further mechanistic investigation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130401"},"PeriodicalIF":2.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051552","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}

引用次数: 0

Structure activity relationship exploration of imidazo[1,2-a]pyridine series to reverse isoform selectivity and identify potent SIK1 selective inhibitors 咪唑[1,2-a]吡啶系列的构效关系探索以逆转同工异构体选择性并鉴定有效的SIK1选择性抑制剂。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-08 DOI: 10.1016/j.bmcl.2025.130397

Christophe Peixoto , Elsa De Lemos , Laëtitia Cherel , Gregory Newsome , Aurelie Dos Santos , Irena Ćaleta , Thomas Coudrat , Kenneth Goossens , Mia Jans , Reginald Brys , Steve De Vos , David Amantini , Juan-Miguel Jimenez , Nicolas Desroy

{"title":"Structure activity relationship exploration of imidazo[1,2-a]pyridine series to reverse isoform selectivity and identify potent SIK1 selective inhibitors","authors":"Christophe Peixoto , Elsa De Lemos , Laëtitia Cherel , Gregory Newsome , Aurelie Dos Santos , Irena Ćaleta , Thomas Coudrat , Kenneth Goossens , Mia Jans , Reginald Brys , Steve De Vos , David Amantini , Juan-Miguel Jimenez , Nicolas Desroy","doi":"10.1016/j.bmcl.2025.130397","DOIUrl":"10.1016/j.bmcl.2025.130397","url":null,"abstract":"<div><div>The salt-inducible kinase (SIK) family encompasses three isoforms, SIK1, SIK2, and SIK3, which are members of the AMP-activated protein kinase (AMPK) family of serine/threonine protein kinases. SIK inhibition has emerged as a potential therapeutic approach across multiple indications, as SIKs regulate a diverse set of physiological processes such as metabolism, bone remodeling, immune response, malignancies, skin pigmentation, and circadian rhythm. Within isoform-specific SIK inhibitors there is a need to understand the distinct role of each protein, and here we describe the first SIK1 selective inhibitors. Beginning with a high-throughput screening (HTS) hit that exhibited pan-SIK inhibition, structure-activity relationship (SAR) investigation led to the identification of a substitution pattern on a phenyl ring that increased both potency on SIK1 and selectivity against SIK2 and SIK3. Further optimization of isoform selectivity led to compound <strong>27</strong>, a subnanomolar inhibitor of SIK1 in biochemical assays that exhibited more than 100-fold selectivity against SIK2 and SIK3. Isoform selectivity of <strong>27</strong> was confirmed in a cellular context. Identification of compound <strong>27</strong> provided a SIK1-selective compound to investigate the role of SIK1 in biological processes mediated by SIKs; however, activity of <strong>27</strong> on other kinases, in particular tyrosine kinases, should not be neglected upon data interpretation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130397"},"PeriodicalIF":2.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032428","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}

引用次数: 0