Younghwa Na

Recent cancer drug development with xanthone structures.

Objectives Xanthones are simple three‐membered ring compounds that are mainly found as secondary metabolites in higher plants and microorganisms. Xanthones have very diverse biological profiles, including antihypertensive, antioxidative, antithrombotic and anticancer activity, depending on their diverse structures, which are modified by substituents on the ring system. Although several reviews have already been published on xanthone compounds, few of them have focused on the anticancer activity of xanthone derivatives. In this review we briefly summarize natural and synthetic xanthone compounds which have potential as anticancer drugs.

2-Thienyl-4-furyl-6-aryl pyridine derivatives: Synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship study

Designed and synthesized 60 2-thienyl-4-furyl-6-aryl pyridine derivatives were evaluated for their topoisomerase I and II inhibitory activities at 20 microM and 100 microM and cytotoxicity against several human cancer cell lines. Compounds 8, 9, 11-29 showed significant topoisomerase II inhibitory activity and compounds 10 and 11 showed significant topoisomerase I inhibitory activity. Most of the compounds (7-21) possessing 2-(5-chlorothiophen-2-yl)-4-(furan-3-yl) moiety showed higher or similar cytotoxicity against HCT15 cell line as compared to standards. Most of the selected compounds displayed moderate cytotoxicity against MCF-7, HeLa, DU145, and K562 cell lines. Structure-activity relationship study revealed that 2-(5-chlorothiophen-2-yl)-4-(furan-3-yl) moiety has an important role in displaying biological activities.

New insight for fluoroquinophenoxazine derivatives as possibly new potent topoisomerase I inhibitor.

Fluoroquinolones, represented by ciproxacin and norfloxacin, are well-known clinical antimicrobial agents, and their phenyl ring expanded quinophenoxazines are reported as possible antitumor active compounds. These quinophenoxazines are known to inhibit DNA topoisomerase II essential for cell replication cycle. But there were no reports for topoisomerase I inhibition study for these compounds. In this report, we have prepared a few quinophenoxazine analogues and tested their topoisomerases I and II inhibitory activities and cytotoxicity. From the result, we found that quinophenoxazine analogues possessed strong topoisomerase I inhibitory capacity as well as topoisomerase II inhibition. Among the compounds prepared, A-62176 analogues showed strong topoisomerases I and II inhibitory activities. Interestingly, compound 8 missing the 3-aminopyrrolidine moiety at C2 position has similar potent inhibitory capacity against topoisomerases I and II at higher concentrations (20 and 10 microM, respectively). But compound 8 inhibited topoisomerase I function more selectively at lower concentration, 2 microM. Our observation might strongly implicate that fluoroquinophenoxazines can be developed as efficient topoisomerase I inhibitor with the elaborate modification.

2,6-Dithienyl-4-furyl pyridines: Synthesis, topoisomerase I and II inhibition, cytotoxicity, structure–activity relationship, and docking study

For the development of novel antitumor agents, 2,6-dithienyl-4-furyl pyridine derivatives were prepared and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against several human cancer cell lines. Among the 21 prepared compounds, compound 24 exhibited strong topoisomerase I inhibitory activity. In addition, a docking study with topoisomerase I and compound 24 was performed.

Synthesis of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives and evaluation of their topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship

A series of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives were designed, synthesized, and evaluated for their topoisomerase I and II inhibition and cytotoxic activity against several human cancer cell lines. Compounds 10-19 showed moderate topoisomerase I and II inhibitory activity and 20-29 showed significant topoisomerase II inhibitory activity. Structure-activity relationship study revealed that 4-(5-chlorofuran-2-yl)-2-(thiophen-3-yl) moiety has an important role in displaying topoisomerase II inhibition.

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.

Synthesis of 2,4-diaryl chromenopyridines and evaluation of their topoisomerase I and II inhibitory activity, cytotoxicity, and structure—activity relationship

Designed and synthesized were a series of 5H-chromeno[4,3-b]pyridines with substitution at 2- and 4-positions with various 5- or 6-membered heteroaromatics as antitumor agents. They were evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Structure-activity relationship study showed that 2-furyl or 2-thienyl at 2- or 4-position of central pyridine is crucial in displaying topo I or II inhibitory activity and cytotoxicity.

Licochalcone E has an antidiabetic effect

Licochalcone E (lico E) is a retrochalcone isolated from the root of Glycyrrhiza inflata. Retrochalcone compounds evidence a variety of pharmacological profiles, including anticancer, antiparasitic, antibacterial, antioxidative and superoxide-scavenging properties. In this study, we evaluated the biological effects of lico E on adipocyte differentiation in vitro and obesity-related diabetes in vivo. We employed 3T3-L1 preadipocyte and C3H10T1/2 stem cells for in vitro adipocyte differentiation study and diet-induced diabetic mice for in vivo study. The presence of lico E during adipogenesis induced adipocyte differentiation to a significant degree, particularly at the early induction stage. Licochalcone E evidenced weak, but significant, peroxisome proliferator-activated receptor gamma (PPARγ) ligand-binding activity. Two weeks of lico E treatment lowered blood glucose levels and serum triglyceride levels in the diabetic mice. Additionally, treatment with lico E resulted in marked reductions in adipocyte size and increases in the mRNA expression levels of PPARγ in white adipose tissue (WAT). Licochalcone E was also shown to significantly stimulate Akt signaling in epididymal WAT. In conclusion, lico E increases the levels of PPARγ expression, at least in part, via the stimulation of Akt signals and functions as a PPARγ partial agonist, and this increased PPARγ expression enhances adipocyte differentiation and increases the population of small adipocytes, resulting in improvements in hyperglycemia and hyperlipidemia under diabetic conditions.

Oxiranylmethyloxy or thiiranylmethyloxy-azaxanthones and -acridone analogues as potential topoisomerase I inhibitors.

A total of seven new oxyranylmethyloxy or thiiranylmethyloxy group substituted 5-azaxanthones and -acridones analogues were synthesized and tested for their biological activities for cancer cell lines and topoisomerases. Among the compounds, compound 5, 3-thiiranylmethyloxy-1-hydroxy-5-azaxanthone, showed effective topoisomerase I inhibitory activity, 50% and 27% inhibition ratio at 100 and 20muM, respectively. This result is the first finding of the function of 5-azaxanthone compounds for topoisomerase I inhibition and can provide a novel skeleton for the anticancer drug development process.

2,4-Diaryl-5,6-dihydro-1,10-phenanthroline and 2,4-diaryl-5,6-dihydrothieno[2,3-h] quinoline derivatives for topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship study

Designed and synthesized thirty-two 2,4-diaryl-5,6-dihydro-1,10-phenanthroline and 2,4-diaryl-5,6-dihydrothieno[2,3-h] quinoline derivatives as rigid analogs of 2,4,6-trisubstituted pyridines were evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Structure-activity relationship study showed that [2,2;6,2]-terpyridine skeleton is important for the cytotoxicity against several human cancer cell lines.