Bioorganic & Medicinal Chemistry最新文献_第10页

Targeting glioma with heteroaromatic alkaloids: A review of potential therapeutics

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-12-25 DOI: 10.1016/j.bmc.2024.118051

Karen Ichikawa , Hannah M. Johnson , Maurice A. Curtis , Nandita Biswas , Snigdha Singh , Hasmik N. Khachatryan , Anastasia E. Gater , Simon X. Lin , Jonathan Sperry

Glioblastoma multiforme (GBM), classified as a grade IV astrocytoma, is the most aggressive and deadly form of glioma, characterized by rapid progression, extensive genetic heterogeneity, and resistance to conventional therapies. Despite advancements in surgical techniques, radiation therapy, and the frontline chemotherapeutic agent temozolomide, the prognosis for GBM patients remains poor, with a median survival of 15 months and a 5-year survival rate of approximately 7 %. The absence of effective long-term treatments underscores the urgent, unmet clinical need for novel therapeutic strategies to improve patient outcomes. Natural products, particularly alkaloids, have garnered attention as a rich source of bioactive compounds with diverse pharmacological properties. Alkaloids, a structurally diverse group of natural products, are renowned for their chemotherapeutic properties and ability to cross the blood–brain barrier (BBB), making them promising candidates for glioma therapy.

This review systematically examines all reported heteroaromatic alkaloids with documented anti-glioma activities, highlighting their mechanisms of action where available. By providing a comprehensive resource, it aims to facilitate the identification and optimisation of alkaloid-based compounds for glioma-targeted drug discovery. Additionally, this review emphasizes the importance of incorporating natural products into the drug development pipeline to address the pressing challenges associated with glioma, particularly GBM treatment.

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引用次数: 0

Chemical dissection of bacterial virulence 细菌毒力的化学解剖。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-12-20 DOI: 10.1016/j.bmc.2024.118047

Xinglin Yang , Howard C. Hang

The emergence of antibiotic-resistant bacteria has intensified the need for novel therapeutic strategies targeting bacterial virulence rather than growth or survival. Bacterial virulence involves complex processes that enable pathogens to invade and survive within host cells. Chemical biology has become a powerful tool for dissecting these virulence mechanisms at the molecular level. This review highlights key chemical biology approaches for studying bacterial virulence, focusing on four areas: 1) regulation of virulence, where chemoproteomics has identified small molecule-protein interactions that modulate virulence gene expression; 2) identification of virulence proteins, using techniques like unnatural amino acid incorporation and activity-based protein profiling (ABPP) to uncover proteins involved in infection; 3) post-translational modifications of host proteins, where chemical probes have revealed how bacterial effectors alter host cell processes; and 4) effector-host protein interactions, with methods such as bifunctional unnatural amino acid incorporation facilitating the discovery of key host targets manipulated by bacterial effectors. Collectively, these chemical tools are providing new insights into pathogen-host interactions, offering potential therapeutic avenues that aim to disarm pathogens and combat antibiotic resistance.

抗生素耐药细菌的出现加强了对针对细菌毒力而不是生长或生存的新治疗策略的需求。细菌的毒力涉及复杂的过程，使病原体能够入侵并在宿主细胞内存活。化学生物学已经成为在分子水平上剖析这些毒力机制的有力工具。本文综述了研究细菌毒力的关键化学生物学方法，主要集中在四个方面：1)毒力调控，其中化学蛋白质组学已经确定了调节毒力基因表达的小分子-蛋白质相互作用；2)鉴定毒力蛋白，使用非天然氨基酸掺入和基于活性的蛋白质谱（ABPP）等技术来发现与感染有关的蛋白质；3)宿主蛋白的翻译后修饰，其中化学探针揭示了细菌效应物如何改变宿主细胞过程；4)效应物与宿主蛋白的相互作用，通过双功能非天然氨基酸掺入等方法，促进发现由细菌效应物操纵的关键宿主靶点。总的来说，这些化学工具为病原体-宿主相互作用提供了新的见解，提供了旨在解除病原体和对抗抗生素耐药性的潜在治疗途径。

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引用次数: 0

Structural toxicity relationship (STR) of linezolid to mitigate myelosuppression and serotonergic toxicity 利奈唑胺减轻骨髓抑制和血清素能毒性的结构毒性关系

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-11-29 DOI: 10.1016/j.bmc.2024.118025

Matin Shaikh , Harun Patel

Tuberculosis (TB) remains a significant global health challenge, with multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains posing severe threats to treatment efficacy. Linezolid, a key component of the BPaL (Bedaquiline, Pretomanid and Linezolid) regimen, has demonstrated substantial efficacy against MDR-TB and XDR-TB. However, its clinical utility is often limited by side effects such as myelosuppression and monoamine oxidase (MAO) inhibition, linked to its mechanism of action. This perspective centres on the structural toxicity relationship (STR) of Linezolid and its analogues, exploring modifications to the C-ring and C-5 position that aim to reduce these toxicities while maintaining or enhancing antibacterial activity. Several promising analogues have been identified that exhibit reduced myelosuppression and MAO inhibition, highlighting the potential for developing safer Linezolid derivatives. The findings underscore the importance of continued research into the structure toxicity relationships of oxazolidinones to improve the therapeutic profiles of these essential drugs in combating drug-resistant TB.

结核病（TB）仍然是一个重大的全球卫生挑战，耐多药（MDR-TB）和广泛耐药（XDR-TB）菌株对治疗效果构成严重威胁。利奈唑胺是BPaL（贝达喹啉、普雷托马尼和利奈唑胺）方案的关键组成部分，已证明对耐多药结核病和广泛耐药结核病具有显著疗效。然而，它的临床应用往往受到副作用的限制，如骨髓抑制和单胺氧化酶（MAO）抑制，这与它的作用机制有关。这一观点集中在利奈唑胺及其类似物的结构毒性关系（STR）上，探索对c环和C-5位置的修饰，旨在降低这些毒性，同时保持或增强抗菌活性。已经确定了几种有前途的类似物，它们表现出减少骨髓抑制和MAO抑制，突出了开发更安全的利奈唑胺衍生物的潜力。这些发现强调了继续研究恶唑烷酮的结构毒性关系以改善这些基本药物在对抗耐药结核病中的治疗概况的重要性。

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引用次数: 0

Synthesis and anti-tumor activity of menthylamine derivatives: Focusing on the potent inhibitory effect of compound W8 on glioma growth 甲胺衍生物的合成及抗肿瘤活性：重点研究化合物W8对胶质瘤生长的抑制作用

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-11-28 DOI: 10.1016/j.bmc.2024.118024

Xiaoran Wu , Yanhang Zhuo , Jiangjian Liu , Ziming He , Meiling Wang , Wenjun Lei , Qiong Liang , Aidong Wang , Zhiyi Shen , Sunhui Chen , Shihao Zheng , Huihui Huang

In this work, we successfully synthesized eight distinct compounds, comprising four chiral menthylamines and related derivatives. We evaluated their cytotoxic potential against a panel of human cancer cell lines, including human colon cancer HCT-116 cells, human esophageal squamous KYSE-150 cells, human breast cancer MCF-7 cells, and human glioma U87 cells. The U87 cells were chosen for a more in-depth investigation of their anti-tumor efficacy. Further exploration of the cytotoxicity mechanisms was conducted, complemented by in vivo studies using mice bearing tumors. These analyses unveiled the possible mechanisms by which menthylamide derivatives exert their anti-tumor effects. Notably, compound W8 demonstrated a potent inhibitory action against the proliferation of brain glioma cells. The findings from this research provide valuable insights that pave the way for the future application of menthylamides in cancer therapeutics.

在这项工作中，我们成功地合成了八种不同的化合物，包括四种手性甲胺及其衍生物。我们评估了它们对一组人类癌细胞系的细胞毒性潜力，包括人类结肠癌HCT-116细胞、人类食管鳞状细胞KYSE-150细胞、人类乳腺癌MCF-7细胞和人类胶质瘤U87细胞。选择U87细胞进行更深入的抗肿瘤效果研究。进一步探索细胞毒性机制，并辅以小鼠体内肿瘤研究。这些分析揭示了甲基酰胺衍生物发挥其抗肿瘤作用的可能机制。值得注意的是，化合物W8显示出对脑胶质瘤细胞增殖的有效抑制作用。这项研究的发现提供了有价值的见解，为未来甲基胺在癌症治疗中的应用铺平了道路。

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引用次数: 0

De novo discovery of cyclic peptide inhibitors of IL-11 signaling IL-11信号通路环肽抑制剂的新发现。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-11-27 DOI: 10.1016/j.bmc.2024.118017

Sam Lear , Rosalba Tafi , Valentina A. Di Biasio , Petro Halkowycz , Ruhi Kamran , Joanne Miura , Tony S. Gibson , Jing Li , Bertram Bleck , Claudia Dall’Armi , Anna Demartis , Antoine Henninot

Interleukin-11 (IL-11), a member of the IL-6 cytokine family, has potential pro-inflammatory and pro-fibrotic roles in pulmonary, hepatic, cardiovascular, renal and intestinal disease pathogenesis, including oncogenesis. The potential for therapeutic intervention in these disease spaces has therefore made the IL-11 signaling axis an attractive target in drug discovery, and antibody inhibitors of IL-11 signaling are currently under evaluation in Phase I/II clinical trials. While lower molecular weight small molecule and peptide inhibitors may offer the potential for improved tissue penetration, developability and manufacturing cost compared with a protein therapeutic, reports of such chemical matter in the literature are limited. In this work, a series of cyclic peptides derived from phage display biopanning campaigns against both IL-11 and its cognate receptor IL-11Rα are presented. The most active IL-11 binder (peptide 4, K_D 140 nM) exhibited inhibition of IL-11/IL-11Rα dimerization in a biochemical AlphaLISA assay (K_i 300 nM), and alanine scanning was carried out on this sequence to identify residues important for target binding and inhibitory activity. Further structural optimization yielded lead peptide 15 (K_i 180 nM), which exhibited at least 70-fold greater activity than IL-11 inhibitors previously reported in the literature. The de novo peptide macrocycles presented serve as a robust starting point for development of therapeutic inhibitors of the IL-11/IL-11Rα interaction.

白细胞介素-11 （IL-11）是IL-6细胞因子家族的一员，在肺、肝、心血管、肾和肠道疾病的发病包括肿瘤发生中具有潜在的促炎和促纤维化作用。因此，对这些疾病空间进行治疗干预的潜力使IL-11信号轴成为药物发现的一个有吸引力的靶点，IL-11信号的抗体抑制剂目前正在I/II期临床试验中进行评估。虽然与蛋白质治疗药物相比，低分子量小分子和肽抑制剂可能提供改善组织渗透、可开发性和制造成本的潜力，但文献中关于此类化学物质的报道有限。在这项工作中，提出了一系列从噬菌体展示生物筛选运动中获得的环肽，这些运动可以对抗IL-11及其同源受体IL-11Rα。在生化AlphaLISA实验（Ki 300 nM）中，最活跃的IL-11结合物（肽4，KD 140 nM）显示出对IL-11/IL-11Rα二聚化的抑制作用，并对该序列进行丙氨酸扫描，以确定对目标结合和抑制活性重要的残基。进一步的结构优化得到导联肽15 (Ki 180 nM)，其活性比先前文献报道的IL-11抑制剂至少高70倍。新发现的肽大环为开发IL-11/IL-11Rα相互作用的治疗性抑制剂提供了强有力的起点。

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引用次数: 0

Discovery of a potent and selective TRPC3 antagonist with neuroprotective effects 发现具有神经保护作用的强效选择性 TRPC3 拮抗剂

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-11-26 DOI: 10.1016/j.bmc.2024.118021

Jiaxing Wang , Sicheng Zhang , Vijay K. Boda , Hao Chen , Hyunseo Park , Keyur Parmar , Dejian Ma , Duane D. Miller , Bernd Meibohm , Jianyang Du , Francesca-Fang Liao , Zhongzhi Wu , Wei Li

The TRPC3 protein plays a pivotal role in calcium signaling, influencing cell function. Aberrant TRPC3 expression is implicated in various pathologies, including cardiovascular diseases, tumors, and neurodegeneration. Despite its functional similarities with TRPC6 and TRPC7, TRPC3 exhibits distinct roles in disease contexts. Therefore, it is of paramount importance to develop a potent and selective TRPC3 antagonist with favorable drug-like properties. We employed extensive medicinal chemistry synthesis and structure–activity relationships (SARs) study. Thirty-one novel TRPC3 antagonists were designed and synthesized using the lead compound JW-65 as the scaffold. Compound 60a exhibits a 4-fold improvement in potency and displays exceptional selectivity. With favorable drug-like properties, this compound shows a heightened in vitro neuronal protective effect. Molecular modeling suggests possible modes of action between the TRPC3 protein and its antagonists. In summary, 60a holds significant promise for clinical development in conditions associated with TRPC3 dysregulation.

TRPC3 蛋白在钙信号转导中发挥着关键作用，影响着细胞功能。TRPC3 的异常表达与心血管疾病、肿瘤和神经变性等多种病症有关。尽管 TRPC3 与 TRPC6 和 TRPC7 在功能上相似，但在疾病中却表现出不同的作用。因此，开发一种具有药物特性的强效、选择性 TRPC3 拮抗剂至关重要。我们采用了大量的药物化学合成和结构-活性关系（SARs）研究。以先导化合物 JW-65 为支架，设计并合成了 31 种新型 TRPC3 拮抗剂。化合物 60a 的药效提高了 4 倍，并显示出卓越的选择性。该化合物具有良好的类药物特性，体外神经元保护效果更强。分子建模显示了 TRPC3 蛋白与其拮抗剂之间可能的作用模式。总之，60a 在与 TRPC3 失调有关的疾病的临床开发方面前景广阔。

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引用次数: 0

Synthesis of aromatic glycoconjugates as anti-fungal agents against Candida spp. and assessment of their covalent crosslinking capabilities 芳香糖缀合物抗念珠菌的合成及其共价交联性能的评价

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-11-26 DOI: 10.1016/j.bmc.2024.118020

Kyle Doherty , Keela Kessie , Harlei Martin , Jordan Loughlin , Oliwier Dulawa , Kaja Kasements , Trinidad Velasco-Torrijos

Covalent drugs are becoming increasingly attractive in drug discovery, as they can enhance potency and selectivity for their molecular targets. Covalent inhibitors have been investigated for several therapeutic applications, including anti-cancer and anti-infection agents. However, there are only a few examples of covalent inhibitors targeting fungal pathogens. We have previously reported aromatic glycoconjugates (AGCs) capable of inhibiting the adhesion of Candida albicans to buccal epithelial cells. In this work, we synthesize novel derivatives of the AGCs to which we have added reactive functional groups, such as acryloyl and vinyl sulfones, and investigated their antifungal efficacy against Candida spp. Although the compounds were ineffective at clinically relevant concentrations, we found that some of the galactose derivatives featuring reactive groups were amongst the most active, so their ability to crosslink nucleophilic side chains was assessed in model reactions.

共价药物在药物发现中越来越有吸引力，因为它们可以增强其分子靶点的效力和选择性。共价抑制剂已被研究用于多种治疗应用，包括抗癌和抗感染药物。然而，针对真菌病原体的共价抑制剂只有少数例子。我们以前报道过芳香糖缀合物（AGCs）能够抑制白色念珠菌对口腔上皮细胞的粘附。在这项工作中，我们合成了添加活性官能团（如丙烯酰和乙烯基砜）的AGCs的新衍生物，并研究了它们对念珠菌的抗真菌功效。尽管这些化合物在临床相关浓度下无效，但我们发现一些具有活性基团的半乳糖衍生物是最活跃的，因此在模型反应中评估了它们交联亲核侧链的能力。

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引用次数: 0

A bleomycin-mimicking manganese-porphyrin-conjugated mitochondria-targeting peptoid for cancer therapy 一种用于癌症治疗的博莱霉素模拟锰卟啉共轭线粒体靶向蛋白胨

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-11-24 DOI: 10.1016/j.bmc.2024.118023

Minjae Jun , Veena Vijayan , Seungheon Shin , Ho Yeon Nam , Dasom Song , Jieun Choi , Shyam Vasvani , Steve K. Cho , In-Kyu Park , Jiwon Seo

Bleomycin (BLM) is a natural product with established anticancer activity, attributed to its ability to cleave intracellular DNA. BLM complexes with iron (BLM-Fe³⁺) exhibit peroxidase-like activity, generate reactive oxygen species (ROS), and cause DNA cleavage. Inspired by the mechanism of BLM, we synthesized a novel conjugate of manganese tetraphenylporphyrin (MnTPP) with a biomimetic peptoid (i.e., oligo-N-substituted glycines); this conjugate harnesses the oxidative capabilities of manganese porphyrins combined with the cell-penetrating ability of a previously reported mitochondria-targeting peptoid (MTP). UV–vis spectroscopy showed the formation of Mn(V)-oxo porphyrin, a potent oxidative species, in the presence of hydrogen peroxide, simulating metallobleomycin reactivity. Biological assays demonstrated that MnTPP-MTP significantly boosted ROS production and induced cytotoxicity toward cancer cells, while sparing normal fibroblasts. Tetramethylrhodamine ethyl ester (TMRE) assay revealed reversible, dose-dependent impairment of the mitochondrial membrane potential by MnTPP-MTP treatment. DNA cleavage assays showed that MnTPP-MTP, specifically in the presence of hydrogen peroxide, could elicit substantial DNA damage, in a similar way to BLM. In vivo studies using liposome-encapsulated MnTPP-MTP (lipo-peptoid) indicated superior tumor suppression, without systemic toxicity, when administered locally. Immunofluorescence staining for Ki67 and TUNEL confirmed reduced cell proliferation and increased apoptosis, respectively, validating the anticancer efficacy of lipo-peptoid. These results suggest that MnTPP-MTP, particularly in a liposomal formulation, is a promising new chemotherapeutic agent with robust oxidative mechanisms, poised for further development and application against diverse cancers.

博莱霉素（Bleomycin，BLM）是一种天然产物，具有公认的抗癌活性，这归功于它能够裂解细胞内的 DNA。BLM 与铁的复合物（BLM-Fe3+）具有过氧化物酶样活性，能产生活性氧（ROS）并导致 DNA 断裂。受 BLM 机理的启发，我们合成了一种新型的四苯基卟啉锰（MnTPP）与仿生拟肽类化合物（即低聚-N-取代甘氨酸）的共轭物；这种共轭物利用了卟啉锰的氧化能力以及之前报道的线粒体靶向拟肽类化合物（MTP）的细胞穿透能力。紫外-可见光谱显示，在过氧化氢存在的情况下，会形成锰（V）-氧代卟啉，这是一种强氧化性物质，模拟了金属博来霉素的反应性。生物学实验表明，MnTPP-MTP 能显著促进 ROS 的产生，并诱导癌细胞产生细胞毒性，而正常成纤维细胞则不受影响。四甲基罗丹明乙酯（TMRE）测定显示，MnTPP-MTP 处理对线粒体膜电位的损害具有可逆性和剂量依赖性。DNA 裂解试验表明，MnTPP-MTP，特别是在存在过氧化氢的情况下，能引起大量 DNA 损伤，其方式与 BLM 相似。使用脂质体包裹的 MnTPP-MTP（类脂胨）进行的体内研究表明，局部用药可有效抑制肿瘤，且无全身毒性。Ki67 和 TUNEL 免疫荧光染色分别证实细胞增殖减少和凋亡增加，验证了类脂胨的抗癌功效。这些结果表明，MnTPP-MTP（尤其是脂质体制剂）是一种很有前途的新型化疗药物，具有强大的氧化机制，有望进一步开发和应用于多种癌症的治疗。

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引用次数: 0

Stereoisomers of cannabidiols and their pharmacological activities – A potentially novel direction for cannabinoids 大麻二酚的立体异构体及其药理活性--大麻素的潜在新方向

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-11-23 DOI: 10.1016/j.bmc.2024.118019

Vajja Krishna Rao , Melissa M. Lewis-Bakker , Ewa Wasilewski , Hance A. Clarke , Lakshmi P. Kotra

Cannabidiol (CBD), a bicyclic non-psychoactive cannabinoid biosynthesized by Cannabis spp. of plants, has attracted significant interest in the past decade due to its therapeutic properties. In 2018, the US FDA approved Epidiolex®, a CBD-based drug for the treatment of two rare epileptic seizure disorders.

CBD possesses two chiral centers at C3 and C4 on its terpenoid moiety and exhibits cis–trans stereoisomerism along the C3–C4 bond axis. (−)-trans-(3R,4R)-CBD, the natural CBD, is biosynthesized by the cannabis plant, while the unnatural (+)-trans-(3S,4S)-CBD is obtained via chemical synthesis. Both trans isomers exhibit broad in vitro and in vivo biological activities; typically, the unnatural stereoisomer (+)-trans-CBD and its derivatives exhibited more potent activities in comparison to the corresponding (−)-trans isomers. On the other hand, cis-CBD isomers have only been reported recently and can undergo epimerization into trans isomers.

There is a significant opportunity to explore unique synthetic methods and biological activities of stereoisomers of CBD that may pave the path for the development of novel therapeutics. Herein, as a novel direction in cannabinoids, we review the chemistry of CBD stereoisomers, their structure–activity relationships, target selectivity and efficacy in animal models.

大麻二酚（CBD）是一种由大麻属植物生物合成的双环非精神活性大麻素，因其治疗特性在过去十年中引起了人们的极大兴趣。2018 年，美国 FDA 批准了一种基于 CBD 的药物 Epidiolex®，用于治疗两种罕见的癫痫发作性疾病。CBD 在其萜类分子的 C3 和 C4 上具有两个手性中心，并沿着 C3-C4 键轴呈现顺反立体异构。(-)-反式-(3R,4R)-CBD（天然 CBD）由大麻植物生物合成，而非天然的(+)-反式-(3S,4S)-CBD 则通过化学合成获得。这两种反式异构体都具有广泛的体外和体内生物活性；与相应的(-)-反式异构体相比，非天然立体异构体(+)-反式-CBD及其衍生物通常具有更强的活性。另一方面，顺式-CBD异构体最近才有报道，而且会发生外嵌合反应变成反式异构体。探索CBD立体异构体的独特合成方法和生物活性是一个重要机会，这可能为开发新型疗法铺平道路。在这里，作为大麻素的一个新方向，我们回顾了 CBD 立体异构体的化学性质、它们的结构-活性关系、靶点选择性和在动物模型中的疗效。

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引用次数: 0

Alkaloids from Mackinlaya species and synthetic mackinazolinone derivatives: An overview 来自麦金拉雅物种的生物碱和合成的麦金唑啉酮衍生物：概述

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-11-23 DOI: 10.1016/j.bmc.2024.118018

Julie Jaouen , Christian Bailly

Mackinazolinone is the main alkaloid isolated from plants of the genus Mackinlaya, essentially distributed in tropical Asia and Australia. There are five Mackinlaya species all containing bioactive alkaloids with a tetrahydropyridoquinazolinone core such as mackinazoline (1) and mackinazolinone (2). The present review retraces the origin of mackinazolinone and compares the different chemical routes to synthesize the natural product, through different methods including classical batch synthesis, solid-phase supported synthesis, microwaved irradiation and photochemistry. A panel of about 70 mackinazolinone analogues and derivatives is presented to illustrate the diversity of chemical approaches and structures. The pharmacology of mackinazolinone has been little investigated but derivatives with antibacterial or anticancer properties have been identified. The molecular targets for these compounds are essentially unknown, but a few proteins of interest have been evoked occasionally, such as the EGFR kinase. The natural product mackinazolinone has largely inspired chemists to develop novel products and chemical processes. Hopefully, the review will now encourage pharmacologists to further explore the properties of these quinazolinones as potential anti-infectious, anticancer and/or neuroprotective agents.

麦金唑啉酮是从麦金拉雅属植物中分离出来的主要生物碱，主要分布在亚洲热带地区和澳大利亚。马钱子属植物共有五个品种，均含有以四氢吡啶喹唑啉酮为核心的生物活性生物碱，如马钱子啉（1）和马钱子啉酮（2）。本综述追溯了麦金唑啉酮的起源，并比较了通过经典批量合成、固相支持合成、微波辐照和光化学等不同方法合成这种天然产物的不同化学途径。书中介绍了约 70 种麦金唑啉酮类似物和衍生物，以说明化学方法和结构的多样性。对麦金唑啉酮的药理学研究很少，但已发现了具有抗菌或抗癌特性的衍生物。这些化合物的分子靶标基本上是未知的，但偶尔会唤起一些感兴趣的蛋白质，如表皮生长因子受体激酶。天然产物麦金唑啉酮在很大程度上激发了化学家开发新产品和化学工艺的热情。希望这篇综述能鼓励药理学家进一步探索这些喹唑啉酮作为潜在抗感染、抗癌和/或神经保护剂的特性。

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引用次数: 0