Allosteric Regulation of Aptamer Affinity through Mechano-Chemical Coupling.

The capacity to precisely modulate aptamer affinity is important for a wide variety of applications. However, most such engineering strategies entail laborious trial-and-error testing or require prior knowledge of an aptamer's structure and ligand-binding domain. We describe here a simple and generalizable strategy for allosteric modulation of aptamer affinity by employing a double-stranded molecular clamp that destabilizes aptamer secondary structure through mechanical tension. We demonstrate the effectiveness of the approach with a thrombin-binding aptamer and show that we can alter its affinity by as much as 65-fold. We also show that this modulation can be rendered reversible by introducing a restriction enzyme cleavage site into the molecular clamp domain and describe a design strategy for achieving even more finely-tuned affinity modulation. This strategy requires no prior knowledge of the aptamer's structure and binding mechanism and should thus be generalizable across aptamers.

Structure-based design, structure-activity relationship analysis, and antitumor activity of diaryl ether derivatives.

To identify novel therapeutic agents to treat cancer, we synthesized a series of diaryl ether derivatives. Structure-activity relationship studies revealed that the presence of a chlorine or hydroxyl at the para-position on the phenyl ring (5h or 5k) significantly enhanced antitumor activity. Compound 5h had stronger growth inhibitory activity in HepG2, A549, and HT-29 cells than compound 5k, with IC50 values of 2.57, 5.48, and 30.04 µM, respectively. Compound 5h also inhibited the growth of other cells lines, including Hep3B, PLC/PRF5, SMMC-7721, HeLa, and A375, with IC50 values of 2.76, 4.26, 29.66, 18.86, and 10.21 µM, respectively. The antitumor activity of compound 5h was confirmed by a colony forming assay. Further, our results indicated that the antitumor activity of compound 5h may be mediated by enhancing expression of p21 and cl-caspase3, and leading to apoptosis of cancer cells.

Evaluation of Novel N-(piperidine-4-yl)benzamide Derivatives as Potential Cell Cycle Inhibitors in HepG2 Cells.

In this study, a series of novel N-(piperidine-4-yl)benzamide derivatives was designed, synthesized, and evaluated for antitumor activity. Some compounds were found to have potent antitumor activity. In particular, compound 47 showed the most potent biological activity against HepG2 cells, with an IC50 value of 0.25 µm. Western blot analysis demonstrated that compound 47 inhibited the expression of cyclin B1 and p-Rb and enhanced the expression of p21, p53, Rb, and phospho-adenosine monophosphate-activated protein kinase (p-AMPK). Further, cell cycle arrest was observed by flow cytometry (FCM). In summary, compound 47 was screened to have potential activity for the treatment of hepatocarcinoma via the induction of cell cycle arrest by a p53/p21-dependent pathway.