New modification strategy of matrine as Hsp90 inhibitors based on its specific L conformation for cancer treatment.

The similarity of spatial structure between radicicol and matrine urged us to perform conformation modification of matrine, followed by L-shaped matrine derivatives, 6, 12, 21a-h and 22a-h were originally designed, synthesized and evaluated for Hsp90N inhibitors as anticancer agents. TSA (Thermal Shift Assay) results indicated that 21e, 22a-c and 22e-g exhibited strong binding force against Hsp90N with∣ΔTm∣ > 3, meanwhile, MTT assay also revealed these compounds displayed potent anticancer activity with IC50 values below 25 µM against HepG2, HeLa and MDA-MB-231 cells lines. Then, compound 22g with a high ΔTm = 10.92 was chosen as a representative to perform further mechanism study. It can induce cell apoptosis, arrest the cell cycle at the S phase and decrease the expression level of Hsp90 in Hela cell. These results originally provided targeted modification strategy for matrine derivatives to serve as Hsp90 inhibitors for cancer therapy.

Novel indolo-sophoridinic scaffold as Topo I inhibitors: Design, synthesis and biological evaluation as anticancer agents.

Based on the mechanism of action, novel scaffolds as Topo I inhibitors bearing indole and sophoridinine were designed. Preliminary docking study revealed that some molecules among the designed series possessed promising Topo I inhibitor properties. Subsequently, thirty new compounds were synthesized and characterized by 1H NMR, 13C NMR, and Mass spectral analyses. The compounds were then screened for their antiproliferative and enzymatic inhibitory activities. The results affirmed the consistency between docking and activities and the rationality of the design strategy. Furthermore, compound 10b was chosen as a representative compound to test its anticancer effects in vitro and in vivo. The results showed that 10b caused prominent S phase cell cycle arrest and significantly suppressed tumor growth in HepG2 cell derived mouse model. These findings present a promising series of lead molecules which can serve as potential Topo I inhibitors for the treatment of cancer and a theoretical basis for structural modifications.

Design, synthesis and evaluation of novel sophoridinic imine derivatives containing conjugated planar structure as potent anticancer agents.

Based on our previous study and the binding mode of camptothecin with Topo I, a series of novel sophoridine imine derivatives containing conjugated planar structure were designed, synthesized and tested for their in vitro anticancer activity. The results showed that most of the derivatives displayed potent activity. In particular, compounds 10b exhibited excellent anti-proliferative activities with IC50 5.7 µM and 8.5 µM against HepG-2 and HeLa cell lines, respectively. Molecular docking studies revealed that the introduction of conjugated planar structure could form π-π stacking interaction with DNA, leading to the improvement of biological activity. Its mode of action was to inhibit the activity of DNA Topo I, followed by the G0/G1 phase arrest. This work provides a theoretical basis for structural optimizations and exploring anticancer pathways of this kind of compound and 10b could emerge as promising lead compounds for the development of novel Topo I inhibitors.