New norindenoisoquinolines, indenoisoquinolinium salts, and 5,11-diketoindenoisoquinolines: Design and synthesis of topoisomerase I inhibitors as anticancer agents
Abstract
Camptothecin, a natural alkaloid isolated from Camptotheca acuminata, acts as a topoisomerase I poison and, as a result, it displays high cytotoxicity in a number of malignant cell lines. The biological properties of camptothecin demonstrate the validity of topoisomerase I as a target for anticancer therapy. This alkaloid is not suitable to be used in the clinic due to its toxicity and its chemical instability. Efforts to address these limitations include the design of other camptothecins as well as the synthesis of structurally unrelated compounds that inhibit topoisomerase I. The indenoisoquinolines pertain to the second group. The present study describes the preparation and anticancer activity of three types of indenoisoquinolines: norindenoisoquinolines, indenoisoquinolinium salts, and 5,11-diketoindenoisoquinolines. All three subgroups were designed to act as topoisomerase I poisons. For novel compounds, cytotoxicity tests were conducted at the National Cancer Institute along with topoisomerase I-mediated DNA cleavage assays. A series of norindenoisoquinolines containing oxygenated substituents was prepared using a Pomeranz-Fritsch-related approach. Recently, the structure of norindenoisoquinoline 1 in complex with topoisomerase I and DNA has been solved, providing insight into the mechanism of action for this subclass. The reduced bulk of compounds 1(MGM 50.5 nM) and 31 (MGM 0.27 μM) is essential in allowing the compounds to bind in the active site of the enzyme. Indenoisoquinolinium salts are likely to interact strongly with DNA and target DNA in addition to topoisomerase I. The aminopropyl derivative 9 displayed the highest cytotoxicity from the series (MGM 0.31 μM), yet it poisoned topoisomerase I only to a modest extent. Based on the crystallographic data available from topoisomerase I ternary complexes, an energy minimization method was identified that allows topoisomerase I to accommodate the ligand in silico much in the same way the enzyme was found to accomplish this in real life, as reflected by the available crystal structures. The complexes prepared in Sybyl® 6.9 and 7.0 successfully account for the trends observed in structure activity relationships. In the series of 5,11-diketoindenoisoquinolines, potency in topoisomerase I inhibition assays was found to increase with the hydrophilicity of the N-6 substituent.
Degree
Ph.D.
Advisors
Cushman, Purdue University.
Subject Area
Organic chemistry|Pharmacology
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