Seojeong Park

Effect of chlorine substituent on cytotoxic activities: Design and synthesis of systematically modified 2,4-diphenyl-5H-indeno[1,2-b]pyridines

In continuation of our previous work, six hydroxylated 2,4-diphenyl-5H-indeno[1,2-b]pyridine analogs were modified by introducing one chlorine functionality at ortho, meta or para position of the 2- or 4-phenyl ring. Eighteen new chlorinated compounds were thus prepared and assessed for topoisomerase inhibitory activity and cytotoxicity against HCT15, T47D, and HeLa cancer cell lines. All of the chlorinated compounds displayed significant cytotoxic effect, revealing potent anticancer activity against T47D breast cancer cells. This functional group modification allowed us to explore the importance of chlorine group substitution for the cytotoxic properties. The information reported here provides valuable insight for further study to develop new anticancer agents using related scaffolds.

Dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines: Topoisomerase I and IIα dual inhibitors with DNA non-intercalative catalytic activity

With the aim to develop novel antiproliferative agents, a new series of eighteen dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines were systematically designed, prepared, and investigated for their topoisomerase (topo) I and IIα inhibitory properties and antiproliferative effect in three different human cancer cell lines (HCT15, T47D, and HeLa). Compounds 22-30 which possess a meta- or para-phenol on 2-, or 6-position of central pyridine ring showed significant dual topo I and topo IIα inhibitory activities with strong antiproliferative activities against all the tested human cancer cell lines. However, compounds 13-21 which possess an ortho-phenol on 2-, or 6-position of central pyridine ring did not show significant topo I and topo IIα inhibitory activities but displayed moderate antiproliferative activities against all the tested human cancer cell lines. Compound 23 exhibited the highest antiproliferative potency as much as 348.5 and 105 times compared to etoposide and camptothecin, respectively, in T47D cancer cell line. The structure-activity relationship study revealed that the para position of a hydroxyl group at 2-and 6-phenyl ring and chlorine atom at the para position of 4-phenyl ring of the central pyridine exhibited the most significant topo I and topo IIα inhibition, which might indicate introduction of the chlorine atom at the phenyl ring of 4-pyridine have an important role as dual inhibitors of topo I and topo IIα. Compound 30 which showed the most potent dual topo I and topo IIα inhibition with strong antiproliferative activity in T47D cell line was selected to perform further study on the mechanism of action, which revealed that compound 30 functions as a potent DNA non-intercalative catalytic topo I and IIα dual inhibitor.

2-Chlorophenyl-substituted benzofuro[3,2-b]pyridines with enhanced topoisomerase inhibitory activity: The role of the chlorine substituent

A new series of 2-chloropheny-substituted benzofuro[3,2-b]pyridines were designed, synthesized, and evaluated for topoisomerase I and II inhibition and antiproliferative activity. Compounds 17-19, 23, 24, 26, and 27 exhibited excellent topo II inhibitory activity. A systematic structure-activity relationship study revealed the important role of chlorine substitution in the strong topoisomerase inhibitory activity.

Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as topoisomerase II inhibitors and cytotoxic agents

A new series of 2-phenol-4-chlorophenyl-6-aryl pyridines were designed, synthesized, and evaluated for topoisomerase (topo) I and II inhibitory activities as well as cytotoxic activity against four different human cancer cell lines such as HCT15, T47D, DU145, and Hela. Most of the tested compounds exhibited stronger topo II inhibitory activity at 100μM as compared to etoposide. All the compounds, except 39, did not show topo I inhibitory activity. Interestingly, compounds that showed better topo II inhibition than etoposide have ortho- or para-chlorophenyl at 4-position of central pyridine, and none of the compounds possess meta-chlorophenyl. SAR study revealed the importance of ortho- or para-chlorophenyl at 4-position of the central pyridine for selective topo II inhibitory activity. Similarly, all compounds possessing meta- or para-hydroxyphenyl moieties showed moderate to significant cytotoxic effects. Particularly, compounds 27-37, and 39 which showed excellent cytotoxicity (IC50=0.68-1.25μM) against T47D breast cancer cells suggest the importance of meta- or para-hydroxyphenyl moiety at 2-position of the central pyridine for the design of anticancer agents with related scaffolds.

Design, synthesis, biological evaluation, structure-activity relationship study, and mode of action of 2-phenol-4,6-dichlorophenyl-pyridines

Human DNA topoisomerases (Topos) are essential nuclear enzyme whose level of expression is potential indicator for prediction of responsive result of chemotherapy. Topos has become a key cellular target for most of the anticancer agents that regulates topological problems of DNA during cellular metabolic processes such as replication, transcription, and recombination. Inspired by previous studies of 2,4,6-trisubstituted pyridines to find out safer and effective topoisomerase targeted anticancer agent, twenty-seven 2-phenol-4,6-dichlorophenyl-pyridines were designed, synthesized, and tested for their topo I and IIα inhibitory and anti-proliferative activity. Most of the dichlorinated meta- and para-phenolic series compounds (1-18) exhibited potent and selective topo IIα inhibition along with significant anti-proliferative activity in the HCT-15 and T47D cell lines compared to the positive control, etoposide. Interestingly, dichlorinated ortho-phenolic series compounds (19-27) exhibited potent and dual topo inhibition but very weak anti-proliferative activity in the tested cancer cell lines. Structure-activity relationship with previously synthesized compounds revealed the importance of chlorine moiety to improve the potency of topo inhibitory activity. Further mechanistic study confirmed that compounds 2 and 12 acted as non-intercalative specific topo IIα catalytic inhibitor with less DNA damage, and induced G1 arrest and apoptosis in HCT-15 and T47D cell lines, respectively.

A new phenolic series of indenopyridinone as topoisomerase inhibitors: Design, synthesis, and structure-activity relationships

DNA Topoisomerase IIα (topo IIα) is one of the most effective therapeutic targets to control cancer. In an effort to develop novel and effective topo IIα targeting anti-proliferative agent, a phenolic series of indenopyridinone and indenopyridinol were designed and prepared using efficient multi-component one pot synthetic method. Total twenty-two synthesized compounds were assessed for topo I and IIα inhibition, and anti-proliferation in three different human cancer cell lines. Overall structure-activity relationship study explored the significance of meta-phenolic group at 4-position and para-phenolic group at 2- and/or 4-position of indenopyridinone skeleton for strong topo IIα-selective inhibition and anti-proliferative activity against human cervix (HeLa) and colorectal (HCT15) cell lines. Compound 12 with excellent topo IIα inhibition (93.7%) was confirmed as a DNA intercalator that could be a new promising lead to develop effective topo IIα-targeted anticancer agents.