Bellarmine University, 2001 Newburg Rd., Louisville, KY 40205, United States.
University of Louisville, 2320 South Brook St., Louisville, KY 40292, United States.
Bioorg Med Chem Lett. 2023 Oct 15;95:129467. doi: 10.1016/j.bmcl.2023.129467. Epub 2023 Sep 4.
Chalcones and their derivatives are a privileged scaffold in medicinal chemistry, demonstrating numerous biological activities. These molecules have shown significant potential toward the development of novel cancer therapies. While much is known about modification to the chalcone aryl rings, little is known about conformations of the bridge between the aryl rings. Here we report the synthesis and biological evaluation of a series of molecules with flexible and rigid bridge conformations. Crystal structures of a select group of molecules were determined. Flexibility in the chalcone bridge containing the enone moiety was determined to be important for activity. Screening in three distinct cancer cell lines showed significant differences in the activity between the flexible and rigid conformations. Crystal structures suggest an increase in bond rotation and weakened π-bonding in the flexible chalcone bridge, which may contribute to the stronger anti-proliferative activity.
查耳酮及其衍生物是药物化学中的一个重要结构单元，具有多种生物活性。这些分子在开发新型癌症治疗方法方面显示出了巨大的潜力。虽然人们对查耳酮芳基环的修饰有了很多了解，但对芳基环之间桥接的构象知之甚少。在这里，我们报告了一系列具有柔性和刚性桥接构象的分子的合成和生物学评价。确定了一组选定分子的晶体结构。含有烯酮部分的查尔酮桥的柔性被确定对活性很重要。在三种不同的癌细胞系中的筛选显示出柔性和刚性构象之间的活性有显著差异。晶体结构表明，柔性查尔酮桥中的键旋转增加，π键结合减弱，这可能有助于增强抗增殖活性。
