糖-异恶唑e偶联物铂族金属半夹心配合物的合成及其抗肿瘤和抗菌活性的评价。

IF 4.7 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Rahaf Akel, István Kacsir, Éva Kerekes, Csongor Freytag, Evelin Szoták, Dóra Boros-Pál, Eszter Anna Janka, Attila Bényei, Gábor Kardos, Éva Bokor, László Somsák, Péter Bai, Adrienn Sipos, Sándor Kun
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引用次数: 0

摘要

铂族金属半夹心配合物被认为是临床上广泛使用的铂类药物的潜在替代品。在我们之前的工作中,我们使用了一系列2-吡啶取代的N-和c -糖基杂环作为N,N螯合配体来制备钌(II),锇(II),铱(III)和铑(III)聚hapto芳烃/芳烃半夹层配合物。其中一些复合物,特别是与o -过苯甲酰形式的c -葡萄糖吡喃基异恶唑衍生配体的复合物,表现出比顺铂更高的抗癌效率,对非转化成纤维细胞的影响很小或可以忽略不计。此外,这些细胞抑制化合物对多重耐药革兰氏阳性细菌表现出微摩尔的抗菌活性。在本工作中,研究了糖和异恶唑基团之间的新偶联模式。具体而言,合成了糖基吡啶-螺-异恶唑啉和聚羟基烷基异恶唑支架,并将其用于复杂的生成反应。以吡啶-2-碳醛肟为原料,由外甘醛和腈氧化物经1,3-偶极环加成得到螺-异恶唑啉。旋螺-异恶唑啉在碱或过渡金属介导的条件下开环生成多羟基烷基异恶唑。然后将这些化合物转化为o -过乙酰化,o -过苯甲酰化和o -未保护的变体,用于与上述铂族金属离子形成配合物。该复合物在卵巢癌和胰腺腺癌细胞模型中诱导细胞抑制;最佳化合物的IC50值为亚微摩尔(0.4 ~ 0.5µM)。一部分细胞抑制剂复合物对顺铂耐药卵巢癌细胞保持活性。此外,当复合物在原代人成纤维细胞上进行评估时,检测到合理的治疗指数,指出复合物的潜在适用性。出乎意料的是,没有一种复合物对革兰氏阳性细菌如金黄色葡萄球菌或肠球菌产生抑菌作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Platinum-group metal half-sandwich complexes of sugar-isoxazol(in)e conjugates - synthesis and evaluation of their antineoplastic and antimicrobial activities.

Platinum-group metal half-sandwich complexes are considered to be potential replacements of the clinically widely used platins which have several side effects and tend to cause resistance to develop. In our previous works, we used a range of 2-pyridyl-substituted N- and C-glycosyl heterocycles as N,N-chelating ligands to prepare ruthenium(II), osmium(II), iridium(III) and rhodium(III) polyhapto arene/arenyl half-sandwich complexes. Some of these complexes, particularly with the C-glucopyranosyl isoxazole derived ligand in its O-perbenzoylated form, exhibited greater anticancer efficiency than cisplatin and had minimal or negligible effects on non-transformed fibroblasts. Additionally, these cytostatic compounds exhibited micromolar antibacterial activity against multiresistant Gram-positive bacteria. In the present work, novel modes of conjugation between the sugar and the isoxazole moieties have been studied. Specifically, glycosylidene-spiro-isoxazoline and polyhydroxyalkylisoxazole scaffolds were synthesised and utilised in complex formation reactions. The spiro-isoxazolines were obtained in 1,3-dipolar cycloadditions of exo-glycals and nitrile oxides generated from pyridine-2-carbaldoximes. Ring opening of the spiro-isoxazolines under basic or transition-metal-mediated conditions produced polyhydroxyalkylisoxazoles. These compounds were then transformed into their O-peracetylated, O-perbenzoylated and O-unprotected variants, which were used for complex formation with the above-mentioned platinum-group metal ions. The complexes induced cytostasis in cellular models of ovarian cancer and pancreatic adenocarcinoma; the best compounds had submicromolar IC50 values (0.4-0.5 µM). A subset of the cytostatic complexes retained their activity on cisplatin resistant ovarian cancer cells. Furthermore, a reasonable therapeutic index was detected when complexes were assessed on primary human fibroblasts pointing towards a potential applicability of the complexes. Unexpectedly, none of the complexes induced bacteriostasis in Gram-positive bacteria as Staphylococcus aureus or Enterococcus species.

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来源期刊
CiteScore
9.60
自引率
2.20%
发文量
248
审稿时长
50 days
期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
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