Chalcones, inhibitors for topoisomerase I and cathepsin B and L, as potential anti-cancer agents.

In order to diversify the pharmacological activity of chalcones and extend the scaffold of topoisomerase and cathepsins B and L inhibitors, we have designed and synthesized total 18 chalcone compounds and tested their biological activity. In the topoisomerase inhibition test, most analogues in group III and IV except compound 11 exhibited more efficient topoisomerase I inhibitory activity than camptothecin at 20 µM. Compounds 15, 16 and 18 in group IV showed significant cathepsin B and L inhibitory activity. Among the compounds, compound 15 was most active with IC50 values of 1.81±0.05 µM on cathepsin B and 3.15±0.07 µM on cathepsin L, respectively. Compound 15 also showed most potent cytotoxic activity against T47D and SNU638 cells with IC50 values of 1.37±0.05 µM and 0.62±0.01 µM, respectively. Overall, although more compounds should be tested and analyzed for clear SAR against topoisomerase I and cathepsin B and L, compound 15 showed consistent inhibitory ability on the tested assays, which can implicate the cytotoxic activity of compound 15 on topoisomerase I and cathepsin B and L inhibitory pathways.

A series of novel terpyridine-skeleton molecule derivants inhibit tumor growth and metastasis by targeting topoisomerases.

A series of novel terpyridine-skeleton molecules containing conformational rigidity, 14 containing benzo[4,5]furo[3,2-b]pyridine core and 15 comprising chromeno[4,3-b]pyridine core, were synthesized, and their biological activities were evaluated. 3-(4-Phenylbenzo[4,5]furo[3,2-b]pyridin-2-yl)phenol (8) was determined to be a nonintercalative topo I and II dual catalytic inhibitor and 3-(4-phenylchromeno[4,3-b]pyridine-2-yl)phenol (22) was determined to be a nonintercalative topo IIα specific catalytic inhibitor by various assays. These two catalytic inhibitors induced apoptosis in addition to G1 arrest in T47D human breast cancer cells with much less DNA toxicity than etoposide. Compounds 8 and 22 significantly inhibited tumor growth in HCT15 subcutaneously implanted xenografted mice. The modification of compounds 8 and 22 with the introduction of a methoxy instead of a hydroxy group enhanced endogenous topo inhibitory activity, metabolic stability in diverse types of liver microsomes and improved pharmacokinetic parameters in rat plasma such as augmentation of bioavailability (41.3% and 33.2% for 2-(3-methoxyphenyl)-4-phenylbenzofuro[3,2-b]pyridine (8-M) and 3-(4-phenylchromeno[4,3-b]pyridine-2-yl)methoxybenzene (22-M), respectively).

Design, synthesis, and antitumor evaluation of 2,4,6-triaryl pyridines containing chlorophenyl and phenolic moiety.

We have designed and synthesized a series of 2,4,6-triaryl pyridine derivatives containing chlorophenyl and phenolic moeity at 2- and 4- position of the central pyridine, respectively, resulting in a total of 42 compounds. They were evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Most compounds showed better topoisomerase II inhibitory activity compared to topoisomerase I inhibitory activity. Compounds 19, 20, 26-28, and 47-50 especially showed stronger topo II inhibitory activity than etoposide.