Topoisomerase I (TOP1) is an enzyme that alters the topology of DNA by transiently breaking one DNA strand. TOP1-targeting anticancer agents exert their cytotoxic activity by trapping an abortive enzyme-DNA cleavable complex, converting TOP1 into a cellular poison. Camptothecin (CPT) was the first TOP1 poison identified. The poor solubility of this alkaloid, the metabolic instability of its lactone moiety and the high binding affinity to human serum albumin of its hydrolysis product are among the obstacles that hampered clinical development of this first generation of TOP1-targeting anticancer agents. Despite these shortcomings, there are two derivatives of CPT (Irinotecan, and Topotecan) in clinical use. The focus of this proposal is to advance the development of benzo[i]phenanthridines and related compounds as a novel class TOP1-targeting anticancer agents. It is our hypothesis that within this class of noncamptothecin TOP1-targeting agents, there are compounds that 1) have enhanced chemical and metabolic stability and 2) are able to overcome known mechanisms of resistance that do affect the cytotoxic activity of CPT analogues. Such attributes within a second generation of TOP1-targeting anticancer agents may provide the basis for broader clinical utility as well as improved efficacy.
The specific aims of this proposal are 1) Evaluate select benzo[i]phenanthridines, azabenzo[i]phenanthridines, and azadibenzo[c,h]cinnolines as novel TOP1-targeting agents capable of overcoming multidrug resistance associated with efflux transporters such as BCRP, as well as MDR1 (P-glycoprotein), MRP1, and LRP; 2) to assess in vivo efficacy using various human tumor cell lines, including those that express MDR1 and BCRP and 3) characterize the metabolism and bioavailability of ARC-111 (azabenzo[i]phenanthridine analogue) and ARC-31 (an azadibenzo[c,h]cinnoline). While ARC-111 and ARC-31 possess potent TOP1-targeting activity and cytotoxicity, these compounds differ in regard to their relative efficacy in vivo. Our laboratory has identified several compounds structurally-related to benzo[i]phenanthridines with similar potency to CPT in TOP1-targeting activity and cytotoxicity. The exceptional in vitro and in vivo biological activities of benzo[i]phenanthridines, azabenzo[i]phenanthridines and azadibenzo[c,h]cinnolines observed in our laboratory form the basis for the studies proposed to advance our understanding of these potentially clinically-useful agents. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA098127-01A1
Application #
6774195
Study Section
Special Emphasis Panel (ZRG1-DT (01))
Program Officer
Fu, Yali
Project Start
2004-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$244,913
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Feng, Wei; Satyanarayana, Mavurapu; Tsai, Yuan-Chin et al. (2009) 12-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridines as novel topoisomerase I-targeting antitumor agents. Bioorg Med Chem 17:2877-85
Feng, Wei; Satyanarayana, Mavurapu; Tsai, Yuan-Chin et al. (2009) Novel topoisomerase I-targeting antitumor agents synthesized from the N,N,N-trimethylammonium derivative of ARC-111, 5H-2,3-dimethoxy-8,9-methylenedioxy-5-[(2-N,N,N-trimethylammonium)ethyl]dibenzo[c,h][1,6]naphthyridin-6-one iodide. Eur J Med Chem 44:3433-8
Sharma, Lisa; Tsai, Yuan-Chin; Liu, Angela A et al. (2009) Cytotoxicity and TOP1-targeting activity of 8- and 9-amino derivatives of 5-butyl- and 5-(2-N,N-dimethylamino)ethyl-5H-dibenzo[c,h][1,6]naphthyridin-6-ones. Eur J Med Chem 44:1471-6
Feng, Wei; Satyanarayana, Mavurapu; Cheng, Liang et al. (2008) Synthesis of N-substituted 5-[2-(N-alkylamino)ethyl]dibenzo[c,h][1,6]naphthyridines as novel topoisomerase I-targeting antitumor agents. Bioorg Med Chem 16:9295-301
Pilch, Daniel S; Barbieri, Christopher M; Rzuczek, Suzanne G et al. (2008) Targeting human telomeric G-quadruplex DNA with oxazole-containing macrocyclic compounds. Biochimie 90:1233-49
Satyanarayana, Mavurapu; Rzuczek, Suzanne G; Lavoie, Edmond J et al. (2008) Ring-closing metathesis for the synthesis of a highly G-quadruplex selective macrocyclic hexaoxazole having enhanced cytotoxic potency. Bioorg Med Chem Lett 18:3802-4
Feng, Wei; Satyanarayana, Mavurapu; Tsai, Yuan-Chin et al. (2008) 11-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine derivatives as novel topoisomerase I-targeting agents. Bioorg Med Chem 16:8598-606
Satyanarayana, Mavurapu; Feng, Wei; Cheng, Liang et al. (2008) Syntheses and biological evaluation of topoisomerase I-targeting agents related to 11-[2-(N,N-dimethylamino)ethyl]-2,3-dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-c]cinnolin-12-one (ARC-31). Bioorg Med Chem 16:7824-31
Rzuczek, Suzanne G; Pilch, Daniel S; LaVoie, Edmond J et al. (2008) Lysinyl macrocyclic hexaoxazoles: synthesis and selective G-quadruplex stabilizing properties. Bioorg Med Chem Lett 18:913-7
Feng, Wei; Satyanarayana, Mavurapu; Tsai, Yuan-Chin et al. (2008) Facile formation of hydrophilic derivatives of 5H-8,9-dimethoxy-5-[2-(N,N-dimethylamino)ethyl]-2,3-methylenedioxydibenzo[c,h] [1,6]naphthyridin-6-one (ARC-111) and its 12-aza analog via quaternary ammonium intermediates. Bioorg Med Chem Lett 18:3570-2

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