Anticancer efficacy of unique pyridine-based tetraindoles.

Abstract

Results of previous studies demonstrated that the tetraindole, SK228, which has a high lipid but low water solubility, displayed moderate anticancer efficacy in a xenograft model of breast cancer. This finding led to the proposal that new, pyridine based tetraindole (PBT) analogs of SK228, containing tetraindole moieties distributed about central protonated pyridine cores, would have enhanced bioavailabilities and anticancer efficacies. Among the PBTs prepared and subjected to biological studies, 3f (FCW81) was observed to display the highest antiproliferative activity against the two triple negative breast cancer (TNBCs) cell lines, MDA-MB-231 and BT549. In addition, its mode of action was shown to involve G2/M arrest of the cell cycle along with the promotion of increased levels of cyclin B1 and p-chk2 and a decreased level of p-cdc2. DNA damage and induction of apoptosis caused by FCW81 was found to be associated with a decrease in DNA repair. Significantly, FCW81 displays therapeutic efficacy in a xenograft model of human breast cancer by not only serving to inhibit markedly the growth of cancer cells but also to block effectively cancer cell metastasis. Collectively, the results of these studies have led to the identification of novel pyridine-tetraindole based anticancer agents with potential use in TNBC therapy.

• Authors: Chih-Wei Fu, Yun-Jung Hsieh, Tzu Ting Chang, Chia-Ling Chen, Cheng-Yu Yang, Anne Liao, Pei-Wen Hsiao, Wen-Shan Li
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 104 Pg. 165-76 (Nov 02 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 26457743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• 1,4-bis(di(5-hydroxy-1H-indol-3-yl)methyl)benzene
• Antineoplastic Agents
• Indoles
• Pyridines
• Xylenes
• pyridine

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Female
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Mammary Neoplasms, Experimental (drug therapy, pathology)
• Mice
• Mice, Nude
• Pyridines (chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Xylenes (chemical synthesis, chemistry, pharmacology)