Development of Novel Tetracyclic and Heterocyclic Dual Topoisomerases Inhibitors as Anticancer Agents( I )

Project: A - Government Institutionb - National Science and Technology Council

Project Details


Background: During the pathogenesis of cancer, the topoisomerase, telomerase, relevant kinases and cytotoxicity play key roles in tumor angiogenesis, tumor growth, metastasis and drugs resistance. A wide variety of cellular events, including cell growth, differentiation, apoptosis, mobility and angiogenesis are modulated by topoisomerases. The ability to interact with a variety of intracellular targets, including nucleic acids, topoisomerases (Top1 and Top2), telomerase, protein kinases, receptors etc., makes the anthraquinone moiety an important pharmacophore for rational drug design. Furthermore, topoisomerase inhibitors are important and clinically effective drugs, while DNA, DNA-topoisomerase complex and/or topoisomerase-interactive compounds that disrupt DNA duplication mechanisms have yet to be proven useful in the clinic. In recent years, several compounds which entered Phase II or III clinical trials were mainly found their tetracyclic core pharmacophore may be better than traditional tricyclic structure. Rational design, lead optimization and evaluate a series of tetracyclic heterocyclic derivative for the core small molecular structure as anti-cancer drugs is a tendency to development. Purpose: In order to find stronger DNA binding, a series of tetracyclic and heterocyclic small molecules will be design and evaluate their biological activity. In this three years study, we plan to further investigate whether the target small molecules exhibit an anti-cancer effect through cell growth, differentiation, apoptosis, mobility and angiogenesis. Method: Studies include the preparation of starting materials, design and synthesis target compounds, moreover the underlying mechanisms involved and SARs and their polypharmacology activities are also investigated. Progresses of the studies are planned as: 1st year: (1) To design and synthesize various analogues of tetracyclic azathioxanthone and identify the basic anti-cancer activity in cell based assays or NCI-60 cell line assay. (2) To primary evaluate the anti-cancer activities of these synthetic compounds by MTT assay in vitro. (3) Effects of these potential anti-cancer compounds on alongside cytotoxicity tests with matched pairs of enzyme resistant, sensitive cells and cell lines are also investigated. 2nd year: (1) To evaluate of these potential small molecules on DNA binding, telomerase activities and hTERT expression between G-quadruplex stabilization and telomerase inhibition. (2) To further evaluate the topoisomerase and anti-cancer activities of these potential compounds in vitro. 3rd year: To study the effects of novel derivatives on DNA binding, topoisomerase, telomerase, relevant kinases and cytotoxicity. By comparing profiles of biological assay including the NCI-60 cell line assay, we will identify targets for small molecules development and lead optimization, which provide a rational basis for the SARs and pharmacological studies. Anticipated results: The study will lead to obtain potential target small molecules for development of more efficient and safer anti-cancer drugs.
Effective start/end date8/1/157/31/16


  • thiochromoquinoline
  • MTT assay
  • topoisomerase
  • telomerase
  • NCI-60 cell line assay


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