Unraveling the Potential of Amino-, Acylamino-, and Ureido-Substituted 3H-1,2-Benzoxaphosphepine 2-Oxides toward Nanomolar Inhibitors of Tumor-Associated Carbonic Anhydrases IX and XII

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-05-13 DOI:10.1021/acsmedchemlett.5c0009910.1021/acsmedchemlett.5c00099

Anastasija Balašova, Aleksandrs Pustenko, Andrea Angeli, Elena Andreucci, Alessio Biagioni, Alessio Nocentini, Fabrizio Carta, Claudiu T. Supuran and Raivis Žalubovskis*,

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引用次数: 0

Abstract

3H-1,2-Benzoxaphosphepine 2-oxides were recently identified as a novel class of carbonic anhydrase (CA) inhibitors. In this study, which aims to broaden the chemical space around this scaffold and improve inhibition potency against cancer-related isoforms (CA IX and CA XII), we report the synthesis and biochemical evaluation of amino-, acylamino-, and ureido-substituted benzoxaphosphepine oxides 2–4. All members of these series showed no off-target inhibition of cytosolic CA I and CA II activity, while the inhibition of the target isoforms was strongly dependent on the substitution pattern. To our delight, several compounds managed to inhibit tumor-associated CA isoforms at the nanomolar level, which is equal to or even surpasses that of the reference drugs. The results of the current study bolster and extend previous research, demonstrating the capability of the benzoxaphosphepine oxide chemotype to serve as a platform for the future development of new therapeutic agents.

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揭示氨基、酰基氨基和脲基取代的3h -1,2-苯并膦酸2-氧化物对肿瘤相关碳酸酐酶IX和XII纳米摩尔抑制剂的潜力

3h -1,2-苯并膦酸2-氧化物是近年来发现的一类新型碳酸酐酶抑制剂。在本研究中，旨在拓宽该支架周围的化学空间并提高对癌症相关异构体（CA IX和CA XII）的抑制能力，我们报道了氨基，酰基氨基和脲基取代的苯并磷磷脂氧化物的合成和生化评价2-4。这些系列的所有成员对细胞质CA I和CA II活性都没有脱靶抑制，而对目标亚型的抑制则强烈依赖于取代模式。令我们高兴的是，一些化合物能够在纳摩尔水平上抑制肿瘤相关的CA亚型，这等于甚至超过了参考药物。目前的研究结果支持并扩展了先前的研究，证明了氧化苯并膦平化学型的能力，可以作为未来开发新治疗剂的平台。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.