Bioorganic & Medicinal Chemistry Letters最新文献

英文中文

Cytosine mimic azophenoxazine tC^O_Azo quenches FAM fluorescence and provides concentration-dependent Raman quenching upon molecular beacon hybridization.

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-07 DOI: 10.1016/j.bmcl.2025.130131

Dmitriy Y Ryazantsev, Nadezda F Meshcheryakova, Vera A Alferova, Polina N Kamzeeva, Ekaterina V Ryabukhina, Timofei S Zatsepin, Elena G Zavyalova, Andrey V Aralov

The molecular beacon (MB) strategy finds diverse applications in bioimaging, biosensing and disorders diagnostics. Classical MBs are loop-stem hairpin oligonucleotides modified with a reporter and a quencher at the 5'- and 3'- ends. Hybridization with a specific target leads to spatial separation of the quencher and the reporter with subsequent changes in spectral signal, for example, an increase in reporter fluorescence emission. However, hydrophobic interactions between a convenient bulky quencher and the reporter might influence hybridization properties and limit stem length in MB design. In this work, we studied the synthetic nucleobase analog tC^o_Azo mimicking cytosine, capable of quenching reporter (FAM) fluorescence in folded MBs while minimally affecting their stability compared to MBs with classical FAM/BHQ1 labels. In addition, we conducted a preliminary assessment of the applicability of FAM/tC^o_Azo-modified MBs for SERS-based techniques using short single-stranded and long double-stranded DNA fragments from Fusarium avenaceum elongation factor 1a DNA as matrices. SERS intensity was decreased in the presence of matrix DNA compared to the scrambled sequence; and the MB modified with three tC^o_Azo residues provided concentration-dependent signal. The results indicate that tC^o_Azo is a promising tool for fine tuning MB properties for fluorescent- and SERS-based diagnostic applications.

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引用次数: 0

Corrigendum to “Synthesis and biological evaluations of new nitric oxide-anti-inflammatory drug hybrids” [Bioorg. Med. Chem. Lett. 27(18) (2017) 4358–4369]

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-03 DOI: 10.1016/j.bmcl.2025.130119

Eman K.A. Abdelall , Abdou O. Abdelhamid , Amany A. Azouz

引用次数: 0

Synthesis, cytotoxic evaluation, and molecular docking of novel zerumbone oxime esters and azazerumbone derivatives

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-01 DOI: 10.1016/j.bmcl.2025.130120

Pham The Chinh , Pham Thi Tham , Hoang Thi Thanh , Vu Thi Lien , Le Thi Thuy Loan , Kim Thi Phuong Oanh , Vu Tuan Kien , Phan Thanh Phuong , Dinh Thuy Van , Cao Thanh Hai

Available online A series of thirteen novel zerumbone oxime esters and five new azazerumbone derivatives were successfully synthesized. Most of these derivatives exhibited significant cytotoxic activity against four human tumor cell lines (HepG2, A549, HL-60, and AGS). Among them, three derivatives (3i, 3j, and 3k) demonstrated strong cytotoxic effects against all tested cell lines, with IC₅₀ values ranging from 0.41 ± 0.05 to 3.88 ± 0.19 μg/mL, displaying potency comparable to that of zerumbone and ellipticine. Docking results revealed that one compound (3i) showed the highest binding affinity for NF-κB p65.

引用次数: 0

Synthesis and Structure-Activity Relationship of Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease with Antiviral Potency 具有抗病毒效力的 SARS-CoV-2 木瓜蛋白酶类共价抑制剂的合成及结构-活性关系。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-01 DOI: 10.1016/j.bmcl.2024.130034

Catherine C. Rouch , Arnab K. Chatterjee , Connor McCarty , Lirui Song , Alan Chu , Kristen Johnson , Mina Heacock , Laura Riva , Case W. McNamara , Karen C. Wolff , Rebecca Greene-Cramer , Anna De Falco , Gaetano T. Montelione , Gennadii A. Grabovyi

The papain-like protease (PLpro) is a highly conserved domain encoded by the coronavirus (CoV) genome and it plays an essential role in the replication and maturation of the virus in addition to weakening host immune response. Due to the virus’s reliance on PLpro for survival and propagation, small-molecule inhibitors of PLpro serve as an attractive model for direct-acting antiviral therapeutic agents against SARS-CoV-2. Building upon existing work aimed at designing covalent inhibitors against PLpro, we report the synthesis and structure–activity relationship of analogs based on the known covalent inhibitor 1 (Sanders, et al.2023). To evaluate the efficacy of synthesized derivatives, we conducted enzymatic inhibition assays, SARS-CoV-2/HeLa-ACE2 cellular potency and toxicity assays, and profiled the most promising analogs via in vitro ADME and in vivo pharmacokinetic studies. Additionally, we describe computational docking of profiled compounds bound to PLpro to elucidate the structure–activity relationship of compounds based on 1 and offer suggestions for optimizing the potency and selectivity of the electrophilic warhead and improving ADME and PK properties for this chemotype. Relative to the parent compound, new designs demonstrate comparable potency and target selectivity for PLpro. The accomplished SAR campaign provides novel insight for future development of antivirals against SARS-CoV-2.

木瓜蛋白酶（PLpro）是冠状病毒（CoV）基因组编码的一个高度保守的结构域，它在病毒的复制和成熟过程中起着至关重要的作用，此外还能削弱宿主的免疫反应。由于病毒的生存和繁殖依赖 PLpro，PLpro 的小分子抑制剂成为一种有吸引力的针对 SARS-CoV-2 的直接作用抗病毒治疗剂模型。在现有的旨在设计 PLpro 共价抑制剂的工作基础上，我们报告了基于已知共价抑制剂 1（Sanders 等，2023 年）的类似物的合成和结构-活性关系。为了评估合成衍生物的功效，我们进行了酶抑制试验、SARS-CoV-2/HeLa-ACE2 细胞效力和毒性试验，并通过体外 ADME 和体内药代动力学研究分析了最有前景的类似物。此外，我们还描述了与 PLpro 结合的特征化合物的计算对接，以阐明基于 1 的化合物的结构-活性关系，并为优化亲电弹头的效力和选择性以及改善该化学型的 ADME 和 PK 特性提供建议。与母体化合物相比，新设计的 PLpro 具有相当的效力和目标选择性。已完成的 SAR 研究为今后开发 SARS-CoV-2 抗病毒药物提供了新的思路。

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引用次数: 0

Synthesis, X-ray studies and antiproliferative activity of novel lasalocid amides 新型 lasalocid 酰胺的合成、X 射线研究和抗增殖活性。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-01 DOI: 10.1016/j.bmcl.2024.130041

Michał Sulik , Zbigniew Kubis , Dagmara Kłopotowska , Jan Janczak , Joanna Wietrzyk , Adam Huczyński

Seeking new drug candidates among compounds of natural origin is an effective and widely used method of fighting various diseases, especially cancer. Lasalocid acid is one of the naturally occurring polyether ionophore antibiotics, which also exhibits interesting anticancer activity. Therefore, to expand the knowledge about the anticancer properties of lasalocid derivatives, a series of its new amides were synthesized and their antiproliferative activity against cancer cell lines was studied. Amides 7–9 with an aromatic substituent, displayed potent antiproliferative activity (IC₅₀: 0.84–5.18 μM) and demonstrated a good selectivity index (SI: 1.4–15.3). Furthermore, almost all of lasalocid amides overcame the drug resistance of the doxorubicin-resistant cancer cell line (LoVo/DX). Because the biological activity of ionophores is strictly connected with their ability to transport the Na⁺ cation through lipid bilayers, the crystal structure of the complex of compound 8 with the Na⁺ cation was resolved. Lasalocid amides exhibit a pseudocyclic structure and are able to coordinate the Na⁺ cation.

从天然来源的化合物中寻找新的候选药物，是抗击各种疾病（尤其是癌症）的有效且广泛使用的方法。Lasalocid 酸是天然存在的聚醚离子体抗生素之一，也具有有趣的抗癌活性。因此，为了进一步了解 Lasalocid 衍生物的抗癌特性，我们合成了一系列新的酰胺类化合物，并研究了它们对癌细胞株的抗增殖活性。带有芳香取代基的酰胺 7-9 显示出了强效的抗增殖活性（IC50：0.84-5.18 μM），并表现出了良好的选择性指数（SI：1.4-15.3）。此外，几乎所有的 lasalocid 酰胺都能克服多柔比星耐药癌细胞株（LoVo/DX）的耐药性。由于离子导体的生物活性与其通过脂质双分子层转运 Na+ 阳离子的能力密切相关，因此研究人员解析了化合物 8 与 Na+ 阳离子复合物的晶体结构。Lasalocid 酰胺呈现伪环结构，能够配位 Na+ 阳离子。

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引用次数: 0

Synthesis, antibacterial and anticancer activity of azo-based and aminomethylene derivatives of cyclic β-keto sulfones

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-30 DOI: 10.1016/j.bmcl.2025.130115

Demyd S. Milokhov , Mykola O. Balabushko , Anna Y. Kolomiets , Sofiia D. Rabotnikova , Pavlo A. Virych , Anton O. Poliudov , Svitlana V. Shishkina , Yulian M. Volovenko , Alexey V. Dobrydnev

Herein we describe efficient and cost-effective synthesis of azo-based and aminomethylene derivatives of cyclic β-keto sulfones, specifically, 4,4-disubstituted (E)-2-(2-phenylhydrazineylidene)dihydrothiophen-3(2H)-one 1,1-dioxides and 4,4-disubstituted (E)-2-((methylamino)methylene)dihydrothiophen-3(2H)-one 1,1-dioxides. The azo-based derivatives were prepared through the azo coupling of cyclic β-keto sulfones with aromatic diazonium acetates, in situ prepared by diazotization of appropriate substituted amino benzenes. The aminomethylene derivatives were synthesized through the condensation of cyclic β-keto sulfones with DMF-DMA followed by a transamination reaction with primary amines. The target products were obtained in good yields and their structure was unambiguously established based on NMR spectra data, X-ray diffraction study, and DFT calculations. These compounds were designed as cost-effective and multitarget biologically active compounds. Further in vitro study showed antibacterial activity against Staphylococcus aureus and cytotoxicity against the MDA-MB-231 breast cancer cell line without affecting non-malignant cells MAEC. The molecular docking study confirmed good binding affinity of the studied compounds for DHPS, crucial for the bacterial life cycle and for CLK4 and IDO1, which are the therapeutic targets in cancer treatment.

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引用次数: 0

Solid-phase supported direct 18F-radiofluorination of peptides 多肽的固相直接 18F 放射氟化。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-30 DOI: 10.1016/j.bmcl.2025.130118

Eduardo F.A. Fernandes , Line B.S. Knudsen , Andreas Kjaer , Kristian Strømgaard , Matthias M. Herth

The absence of universal and expedient labeling procedures hampers the widespread application of peptides as molecular tracers for positron emission tomography (PET). In this work, we have developed a proof-of-concept direct radiofluorination procedure for peptides using conventional solid-phase peptide synthesis. The method is compatible with all standard amino acids and enables the generation of a range of peptide-based radiopharmaceuticals archieving radiochemical yields of up to 30 % and radiochemical purities above 95 %.

引用次数: 0

Discovery of dual PARP/NAMPT inhibitors for the treatment of BRCA wild-type triple-negative breast cancer

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-30 DOI: 10.1016/j.bmcl.2025.130117

Jie Mao , Kaizhen Wang , Jun Tong , Wanheng Zhang, Guoqing Shen, Dexiang Wang, Zepeng Liao, Zhiyi Zhang, Qi Miao, Sheng Jiang, Kuojun Zhang

Simultaneous inhibition of poly(ADP-ribose) polymerase (PARP) and nicotinamide phosphoribosyltransferase (NAMPT) has been shown to be synergistically effective against breast cancer susceptibility (BRCA) wild-type triple-negative breast cancer (TNBC) through synthetic lethality, which may be explored to broaden the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/NAMPT inhibitors through a pharmacophore linking approach. The lead compound 13j with potent inhibitory activity against both PARP1 and NAMPT (IC₅₀ = 0.8 and 18 nM, respectively) effectively inhibited the proliferation of TNBC MDA-MB-231 cells with wild-type BRCA at submicromolar level. Mechanically, 13j disrupted the homologous recombination repair (HRR) pathway, caused the accumulation of DNA double-strand breaks (DSBs) and ultimately induced apoptotic cell death. In addition, this compound exhibited potent inhibitory potency on the migration of MDA-MB-231 cells. This study demonstrates that compound 13j is a promising lead compound for the development of better PARP/NAMPT inhibitors to treat TNBC with wild-type BRCA.

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引用次数: 0

Optimization of clofibrate by carvacrol results in a new hypolipidemic compound with low hepatic injury

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-29 DOI: 10.1016/j.bmcl.2025.130116

Xinyi Shi , Yumiao Song , Xinyu Zhang , Ling Ding , Huizi Shangguan , Xin Wang , Jiping Liu , Yongheng Shi , Xinya Xu , Yundong Xie

The hepatic injury caused by clofibrate (CF) is strongly associated with oxidative stress and inflammation. This study aims to develop a hypolipidemic compound that possesses antioxidant, anti-inflammatory properties and reduces liver injury. Carvacrol-clofibrate (CF-Carvacrol) was synthesized by optimizing the structure of CF by carvacrol. CF-Carvacrol showed significant lipid-lowering effects in hyperlipidemic mouse models induced by Triton WR 1339. The molecular docking results showed that CF-Carvacrol has a good affinity for PPAR-α. The liver injury study showed that CF-Carvacrol had significantly lower liver injury compared to CF. Manifested as a significant decrease in liver weight and liver coefficient (P < 0.01), as well as a significant decrease in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) (P < 0.01). Histopathology of liver tissue showed that the necrosis of liver cells, cytoplasmic looseness, nuclear degeneration, and infiltration of inflammatory cells were significantly reduced in the CF-Carvacrol group. CF-Carvacrol can significantly up-regulate the expression of Nrf2 and HO-1 in liver (P < 0.05, P < 0.01). The expression of inflammatory factors TNF-α and IL-6 in the liver was significantly down-regulation (P < 0.05, P < 0.01). The levels of superoxide dismutase (SOD) and glutathione (GSH) significantly increased (P < 0.05, P < 0.01), while the content of malondialdehyde (MDA) in lipid peroxidation significantly decreased (P < 0.01). These results revealed that CF-Carvacrol has significant hypolipidemic activity and mild liver injury, and may exert antioxidant and anti-inflammatory activity by activating the Nrf2/HO-1 signaling pathway to reduce liver injury.

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引用次数: 0

Synthesis and evaluation of KX-01 analogs with an exploration of linker attachment points for antibody-drug conjugates

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130114

Yeju Oh , Da Eun An , Jaebeom Park , Byumseok Koh , Kyung-Jin Cho , Hongjun Jeon

KX-01 (tirbanibulin, Klisyri®) is a recently FDA-approved drug for treating actinic keratosis, with a distinct dual mechanism of action combining microtubule disruption and non-ATP-competitive Src inhibition. This unique mechanism and novel chemotype highlight KX-01′s potential as a payload for antibody-drug conjugates. In this study, we synthesized and evaluated KX-01 derivatives to enhance anticancer potency and explore functional groups suitable for antibody conjugation. Notably, replacing the morpholine group with an N-benzoylpiperazine scaffold resulted in an analog with significantly improved in vitro antiproliferative activity, attributed to enhanced microtubule disruption and Src inhibition. Furthermore, introducing a phenol or aniline functionality as a common linker attachment point preserved substantial cytotoxicity. These results suggest the potential of KX-01 derivatives for future use as ADC payloads.

引用次数: 0

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