Abstract：
Diabetes mellitus is a metabolic disease characterized by hyperglycemia, which can be counteracted by the inhibition of α-glucosidase (α-Glu) and α-amylase (α-Amy), enzymes responsible for the hydrolysis of carbohydrates. In recent decades, many natural compounds and their bioinspired analogues have been studied as α-Glu and α-Amy inhibitors. However, no studies have been devoted to the evaluation of α-Glu and α-Amy inhibition by the neolignan obovatol (1). In this work, we report the synthesis of 1 and a library of new analogues. The synthesis of these compounds was achieved by implementing methodologies based on: phenol allylation, Claisen/Cope rearrangements, methylation, Ullmann coupling, demethylation, phenol oxidation and Michael-type addition. Obovatol (1) and ten analogues were evaluated for their in vitro inhibitory activity towards α-Glu and α-Amy. Our investigation highlighted that the naturally occurring 1 and four neolignan analogues (11, 22, 26 and 27) were more effective inhibitors than the hypoglycemic drug acarbose (α-Amy: 34.6 µM; α-Glu: 248.3 µM) with IC5O value of 6.2-23.6 µM toward α-Amy and 39.8-124.6 µM toward α-Glu. Docking investigations validated the inhibition outcomes, highlighting optimal compatibility between synthesized neolignans and both the enzymes. Concurrently circular dichroism spectroscopy detected the conformational changes in α-Glu induced by its interaction with the studied neolignans. Detailed studies through fluorescence measurements and kinetics of α-Glu and α-Amy inhibition also indicated that 1, 11, 22, 26 and 27 have the greatest affinity for α-Glu and 1, 11 and 27 for α-Amy. Surface plasmon resonance imaging (SPRI) measurements confirmed that among the compounds studied, the neolignan 27 has the greater affinity for both enzymes, thus corroborating the results obtained by kinetics and fluorescence quenching. Finally, in vitro cytotoxicity of the investigated compounds was tested on human colon cancer cell line (HCT-116). All these results demonstrate that these obovatol-based neolignan analogues constitute promising candidates in the pursuit of developing novel hypoglycemic drugs.
摘要：
糖尿病是一种以高血糖为特征的代谢性疾病，可以通过抑制α-葡萄糖苷酶（α-Glu）和α-淀粉酶（α-Amy）来抵消，负责碳水化合物水解的酶。近几十年来,已经研究了许多天然化合物及其生物启发类似物作为α-Glu和α-Amy抑制剂。然而,尚未有研究致力于评估新木脂聚糖对α-Glu和α-Amy的抑制作用(1)。在这项工作中,我们报告了1的合成和新类似物库。这些化合物的合成是通过以下方法实现的：苯酚烯丙基化，Claisen/应对重新安排，甲基化,Ullmann耦合,去甲基化,苯酚氧化和迈克尔型加成。评估了Obovatol（1）和十种类似物对α-Glu和α-Amy的体外抑制活性。我们的研究强调，天然存在的1种和4种新木脂聚糖类似物（11、22、26和27）比降血糖药物阿卡波糖（α-Amy：34.6µM；α-Glu：248.3µM）更有效，IC50值为6.2-23.6µM的α-Amy和39.8-124.6µM的α-Glu。对接调查验证了抑制结果，强调合成的新木霉聚糖和两种酶之间的最佳相容性。同时圆二色性光谱法检测到α-Glu与所研究的新木脂素相互作用引起的构象变化。通过荧光测量和α-Glu和α-Amy抑制的动力学的详细研究还表明,1、11、22、26和27对α-Glu具有最大的亲和力,而1、11和27对α-Amy具有最大的亲和力。表面等离子体共振成像（SPRI）测量证实，在所研究的化合物中，Neolignan27对这两种酶都有更大的亲和力，从而证实了通过动力学和荧光猝灭获得的结果。最后,在人结肠癌细胞系(HCT-116)上测试所研究化合物的体外细胞毒性。所有这些结果表明，这些基于obovatol的Neolignan类似物在开发新型降血糖药物方面构成了有希望的候选人。
