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Synthesis, structure and bioactivity of primary sulfamate-containing natural products
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2018-04-16 , DOI: 10.1016/j.bmcl.2018.04.038
Prashant Mujumdar , Silvia Bua , Claudiu T. Supuran , Thomas S. Peat , Sally-Ann Poulsen

Here we report the synthesis of natural products (NPs) 5′-O-sulfamoyl adenosine 1 and 5′-O-sulfamoyl-2-chloroadenosine 2. As primary sulfamates these compounds represent an uncommon class of NPs, furthermore there are few NPs known that contain a NS bond. Compounds 1 and 2 were evaluated for inhibition of carbonic anhydrases (CA), a metalloenzyme family where the primary sulfamate is known to coordinate to the active site zinc and form key hydrogen bonds with adjacent CA active site residues. Both NPs were good to moderate CA inhibitors, with compound 2 a 20–50-fold stronger CA inhibitor (Ki values 65–234 nM) than compound 1. The protein X-ray crystal structures of 1 and 2 in complex with CA II show that it is not the halogen-hydrophobic interactions that give compound 2 a greater binding energy but a slight movement in orientation of the ribose ring that allows better hydrogen bonds to CA residues. Compounds 1 and 2 were further investigated for antimicrobial activity against a panel of microbes relevant to human health, including Gram-negative bacteria (4 strains), Gram-positive bacteria (1 strain) and yeast (2 strains). Antimicrobial activity and selectivity was observed. The minimum inhibitory concentration (MIC) of NP 1 was 10 µM against Gram-positive Staphylococcus aureus and NP 2 was 5 µM against Gram-negative Escherichia coli. This is the first time that NP primary sulfamates have been assessed for inhibition and binding to CAs, with systematic antimicrobial activity studies also reported.



中文翻译:

含氨基磺酸初级产物的天然产物的合成,结构和生物活性

在这里,我们报告的天然产物(NPS)5'的合成Ø -氨磺酰基腺苷1和5'- Ø -氨磺酰-2-氯2。由于伯氨基磺酸盐,这些化合物代表不常见的NP类,此外,几乎没有包含N S键的NP 。评价了化合物12对碳酸酐酶(CA)的抑制作用,该酶是金属酶家族,其中已知的氨基磺酸伯胺与活性位点锌配位并与相邻的CA活性位点残基形成关键氢键。两种NP都是良好的中度CA抑制剂,而化合物2则是20-50倍强的CA抑制剂(K i值65-234纳米)比化合物1。与CA II结合的12的蛋白质X射线晶体结构表明,不是卤素-疏水相互作用使化合物2具有更大的结合能,而是核糖环取向的轻微移动允许与之形成更好的氢键。 CA残基。进一步研究了化合物12对与人类健康相关的一组微生物的抗菌活性,这些微生物包括革兰氏阴性菌(4株),革兰氏阳性菌(1株)和酵母菌(2株)。观察到抗菌活性和选择性。NP 1的最小抑菌浓度(MIC)对革兰氏阳性金黄色葡萄球菌为10 µM,对革兰氏阴性大肠杆菌的NP 2为5 µM 。这是首次评估NP伯氨基磺酸盐对CA的抑制和结合,同时还报道了系统的抗菌活性研究。

更新日期:2018-04-16
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