Di-indenopyridines as topoisomerase II-selective anticancer agents: Design, synthesis, and structure-activity relationships.

Topoisomerases are key molecular enzymes responsible for altering DNA topology, thus they have long been considered as attractive targets for novel chemotherapeutic agents. Topoisomerase type II (Topo II) catalytic inhibitors embrace a fresh perspective meant to get beyond drawbacks caused by topo II poisons, such as cardiotoxicity and secondary malignancies. Based on previously reported 5H-indeno[1,2-b]pyridines, here we presented new twenty-three hybrid di-indenopyridines along with their topo I/IIα inhibitory and antiproliferative activity. Most of the prepared 11-phenyl-diindenopyridines showed negligible topo I inhibitory activity, showing selectivity over topo II. Among the series, we finally selected compound 17, which displayed 100 % topo IIα inhibition at 20 µM concentration and comparable antiproliferative activity against the tested cell lines. Through competitive EtBr displacement assay, cleavable complex assay, and comet assay, compound 17 was finally determined as a non-intercalative catalytic topo IIα inhibitor. The findings in this study highlight the significance of phenolic, halophenyl, thienyl, and furyl groups at the 4-position of the indane ring in the design and synthesis of di-indenopyridines as potent catalytic topo IIα inhibitors with remarkable anticancer effects.

Potent inhibitory activity of hydroxylated 2-benzylidene-3,4-dihydronaphthalen-1(2H)-ones on LPS-stimulated reactive oxygen species production in RAW 264.7 macrophages.

This study attempted to discover tetralone-derived potent ROS inhibitors by synthesizing sixty-six hydroxylated and halogenated 2-benzylidene-3,4-dihydronaphthalen-1(2H)-ones via Claisen-Schmidt condensation reaction. The majority of the synthesized and investigated compounds significantly inhibited ROS in LPS-stimulated RAW 264.7 macrophages. When compared to malvidin (IC50 = 9.00 µM), compound 28 (IC50 = 0.18 µM) possessing 6­hydroxyl and 2­trifluoromethylphenyl moiety showed the most potent ROS inhibition. In addition, the compounds 20, 31, 39, 45, 47-48, 52, 55-56, 58-60, and 62 also displayed ten folds greater ROS inhibitory activity relative to the reference compound. Based on the structure-activity relationship study, incorporating hydroxyl groups at the 6- and 7-positions of tetralone scaffold along with different halogen functionalities in phenyl ring B is crucial for potent ROS suppression. This study contributes to a better understanding of the effect of halogen and phenolic groups in ROS suppression, and further investigations on 2-benzylidene-3,4-dihydronaphthalen-1(2H)-ones will potentially lead to the discovery of effective anti-inflammatory agents.

Topoisomerase IIα inhibitory and antiproliferative activity of dihydroxylated 2,6-diphenyl-4-fluorophenylpyridines: Design, synthesis, and structure-activity relationships.

A new series of fifty-four 2-phenol-4-aryl-6-hydroxyphenylpyridines containing fluorophenyl, trifluoromethylphenyl, and trifluoromethoxy phenyl groups were synthesized and tested for topoisomerase IIα inhibitory and antiproliferative activity against different cancer cell lines in an attempt to look into topoisomerase IIα-targeted prospective anticancer agents to counter the limitations of available treatment options. When compared to positive controls, several compounds 11-12, 37, 50, and 51 showed high antiproliferative activity, while several 4-fluorophenyl substituted compounds 13-14 and 18 showed strong topoisomerase IIα inhibition. Surprisingly, most of the compounds had a significant antiproliferative effect on the HCT15 colorectal adenocarcinoma and T47D breast cancer cell lines. Moreover, compound 12 with para-fluorophenyl at the 4-position and meta-phenolic groups at the 2- and 6-positions inhibited proliferating HeLa cervix adenocarcinoma cells with an IC50 value of 1.28 µM. Based on biological results, the structure-activity relationships of the synthesized derivatives emphasized the significance of 4-trifluoromethoxyphenyl groups for strong antiproliferative activity and 4-fluorophenyl groups for strong topo IIα inhibition. Furthermore, meta- and para-phenolic groups at the 2- and 4-positions are favorable for strong topo IIα inhibitory and antiproliferative activity. The research findings provide insight into the effect of different fluorine functionalities in the discovery of novel topoisomerase IIα-targeted anticancer agents.

Identification of new halogen-containing 2,4-diphenyl indenopyridin-5-one derivative as a boosting agent for the anticancer responses of clinically available topoisomerase inhibitors.

Based on previous reports on the significance of halogen moieties and the indenopyridin-5-one skeleton, we designed and synthesized a novel series of halogen (F-, Cl-, Br-, CF3- and OCF3-)-containing 2,4-diphenyl indenopyridin-5-ones and their corresponding -5-ols. Unlike indenopyridin-5-ols, most of the prepared indenopyridin-5-ones with Cl-, Br-, and CF3- groups at the 2-phenyl ring conferred a strong dual topoisomerase I/IIα inhibitory effect. Among the series, para-bromophenyl substituted compound 9 exhibited the most potent topoisomerase inhibition and antiproliferative effects, which showed dependency upon the topoisomerase gene expression level of diverse cancer cells. In particular, as a DNA minor groove-binding non-intercalative topoisomerase I/IIα catalytic inhibitor, compound 9 synergistically promoted the anticancer efficacy of clinically applied topoisomerase I/IIα poisons both in vitro and in vivo, having the great advantage of alleviating poison-related toxicities.

Discovery of a 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amine derivative as a novel DNA intercalating topoisomerase IIα poison.

Several anticancer agents have been developed and innovative approaches have been made toward cancer type-specific medicines for cancer treatment. As a continuous effort to develop potential chemotherapeutic agents, a novel series of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines containing amino groups, hydroxyphenyl and fluorine functionalities were designed and synthesized. The compounds were evaluated for topo IIα inhibitory and cytotoxicity against HCT15, and HeLa human cancer cell lines. Among synthesized thirty compounds, the majority exhibited strong topo IIα inhibition and anti-proliferation against HCT15 colorectal adenocarcinoma cell line. The structure-activity relationship study revealed that compounds with -CF3 and -OCF3 substituents at 4- position and 3' or 4'-hydroxyphenyl at 2-position attached to the central pyridine ring displayed potent topo IIα and anti-proliferative activity in colorectal and cervix cancer cell line. In vitro studies provided the evidence that compounds 16, 19, 22, and 28 possess excellent topo IIα inhibition and antiproliferative activity. For a better understanding, topo IIα cleavage complex, EtBr displacement, KI quenching assays and molecular docking of compound 19 was performed and the results revealed the mode of action as a DNA intercalative topo IIα poison inhibitor. The results obtained from this study provide insight into the DNA binding mechanism of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines and alteration in topo IIα inhibitory and antiproliferative activity with modifications in the rigid structure.

4-Flourophenyl-substituted 5H-indeno[1,2-b]pyridinols with enhanced topoisomerase IIα inhibitory activity: Synthesis, biological evaluation, and structure-activity relationships.

A series of fluorinated and hydroxylated 2,4-diphenyl indenopyridinols were designed and synthesized using l-proline-catalyzed and microwave-assisted synthetic methods for the development of new anticancer agents. Adriamycin and etoposide were used as reference compounds for the evaluation of topo IIα inhibitory and anti-proliferative activity of the synthesized compounds. Exploring the structure-activity relationships of 36 prepared compounds and biological results, most of the compounds with ortho- and para-fluorophenyl at 4-position of indenopyridinol ring displayed strong topo IIα inhibition. In addition, the majority of the ortho- and meta-fluorophenyl substituted compounds 1-24 displayed strong anti-proliferative activity against DU145 prostate cancer cell line compared to the positive controls. Interestingly, compound 4 possessing ortho-phenolic and ortho-fluorophenyl group at 2- and 4-position, respectively of the central pyridine ring showed high anti-proliferative activity (IC50 = 0.82 µM) against T47D human breast cancer cell line, while para-phenolic and para-fluorophenyl substituted compound 36 exhibited potent topo IIα inhibitory activity with 94.7% and 88.6% inhibition at 100 µM and 20 µM concentration, respectively. A systematic comparison between the results of this study and the previous study indicated that minor changes in the position of functional groups in the structure affect the topo IIα inhibitory activity and anti-proliferative activity of the compounds. The findings from this study will provide valuable information to the researchers working on the medicinal chemistry of topoisomerase IIα-targeted anticancer agents.

Synthesis and structure-activity relationships of hydroxylated and halogenated 2,4-diaryl benzofuro[3,2-b]pyridin-7-ols as selective topoisomerase IIα inhibitors.

The objective of this study was to discover potential topoisomerase (topo) targeting anticancer agents. Novel series of hydroxylated and halogenated(-F, -Cl, and -CF3) 2,4-diaryl benzofuro[3,2-b]pyridin-7-ols were systematically designed and synthesized by faster, economic, and environmentally friendly l-proline catalyzed and microwave-assisted one pot reaction method. The synthesized compounds were assessed for topo I and IIα inhibitory and anti-proliferative activities. The in vitroevaluation displayed that most of the compounds have selective topo IIα inhibitoryactivity as well as selectivity towards T47D human cancer cell line. Structure-activity relationship study suggested that the introduction of additional hydroxyl functionality at 7-positon of benzofuro[3,2-b]pyridine skeleton is crucial for selective topo IIα inhibitory activity. Placement of phenolic moiety on the 4-position of the tricyclic system imparts better topo IIα inhibitory and anti-proliferative activity.