Topoisomerase I-targeting Agents Research Articles

Synthesis of N-substituted 5-[2-( N-alkylamino)ethyl]dibenzo[ c, h][1,6]naphthyridines as novel topoisomerase I-targeting antitumor agents

Several N-alkyl and N, N-dialkyl 5 H-8,9-dimethoxy-5-(2-aminoethyl)-2,3-methylenedioxydibenzo[ c, h][1,6]naphthyridin-6-ones have been identified as topoisomerase I-targeting agents with potent antitumor activity. In the present study, the impact on biological activity of substitution of a trifluoromethyl, cyano, aminocarbonyl, or ethynyl group on a N-methyl substituent of N, N-dimethyl-, N-methyl- N-ethyl-, and N-methyl- N-isopropyl 5 H-8,9-dimethoxy-5-(2-aminoethyl)-2,3-methylenedioxydibenzo[ c, h][1,6]naphthyridin-6-ones was assessed.

11-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[ i]phenanthridine derivatives as novel topoisomerase I-targeting agents

Several 11-substituted benzo[ i]phenanthridine derivatives were synthesized, and their TOP1-targeting activity and cytotoxicity were assessed. Comparative data indicate that TOP1-targeting was often the primary molecular target associated with their cytotoxicity. Several 11-aminoalkyl derivatives, 11-aminocarboxy derivatives as well as the 11-[(2-dimethylamino)ethyl]carboxamide of 2,3-dimethoxy-8,9-methylenedioxybenzo[ i]phenanthridine were synthesized and did exhibit considerable cytotoxicity with IC 50 values ranging from 20 to 120 nM in the human lymphoblast tumor cell line RPMI8402.

Syntheses and biological evaluation of topoisomerase I-targeting agents related to 11-[2-( N, N-dimethylamino)ethyl]-2,3-dimethoxy-8,9-methylenedioxy-11 H-isoquino[4,3- c]cinnolin-12-one (ARC-31)

Several 11-ethyl-2,3-dimethoxy-8,9-methylenedioxy-11 H-isoquino[4,3- c]cinnolin-12-ones with varied functionality on the ethyl substituent have exhibited potent topoisomerase I (TOP1) targeting activity and antitumor activity. The influence of various polar substituents at the 2-position of the 11-ethyl substituent, including N-methylamine, N-isopropylamine, hydroxyl, and hydroxylamino groups, on TOP1-targeting activity and cytotoxicity was assessed. The N-methylamine and N-isopropylamine derivatives were also evaluated as antitumor agents in athymic nude mice with MDA-MB-435 human tumor xenografts. Both compounds were active as antitumor agents upon either parenteral or oral administration.

11 H-Isoquino[4,3- c]cinnolin-12-ones : novel anticancer agents with potent topoisomerase I-targeting activity and cytotoxicity

Recent studies have identified 2,3-dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)ethyl]-11 H-isoquino[4,3- c]cinnolin-12-one ( 1a) as a novel topoisomerase I-targeting agent with potent cytotoxic activity. The effect of varied substituents at the 11-position of 2,3-dimethoxy-8,9-methylenedioxy-11 H-isoquino[4,3- c]cinnolin-12-ones on topoisomerase I-targeting activity and cytotoxicity was evaluated. Potent TOP1-targeting activity was observed when the 11-position was substituted with either a 2-( N, N-dimethylamino)ethyl, a 2-( N, N-diethylamino)ethyl, a n-butyl, or a 2-(pyrrolidin-1-yl)ethyl group. The addition of a β-methyl group to 1a provided an analogue with dramatically reduced TOP1-targeting activity and cytotoxicity. Analogues of 1a wherein the 2-( N, N-dimethylamino)ethyl group was replaced with a (2-tetrahydrofuranyl)methyl, a 2-(piperidin-1-yl)ethyl, or a 2-(4-methylpiperazin-1-yl)ethyl substituent exhibited decreased activity as TOP1-targeting agents. Replacement of the dimethoxy groups of 1a with hydrogen atoms resulted in an analogue with significantly decreased TOP1-targeting activity and cytotoxicity. Removal of both the vicinal dimethoxyl groups and the methylenedioxy moiety resulted in a complete loss of TOP1-targeting activity. The presence of a 9-nitro substituent in place of the 8,9-methylenedioxy group of 1a resulted in a decrease in relative TOP1-targeting activity and cytotoxicity. Compounds 1a and the 11- n-butyl analogue 1d were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line MDA-MB-435 was used in these assays. At dose levels that approached its maximum tolerated dose, 1a proved to be effective in inhibiting tumor growth in vivo when administered orally or by ip injection.

8,9-Methylenedioxybenzo[ i]phenanthridines : Topoisomerase I-Targeting activity and cytotoxicity

Substituted benzo[ i]phenanthridines that have incorporated within their structure an 8,9-methylenedioxy group can exhibit topoisomerase I-targeting activity. Structure–activity studies were performed to examine the influence of saturation at the 11,12-positions of several substituted 8,9-methylenedioxybenzo[ i]phenanthridines. The activities of these dihydro analogues were compared to those of their unsaturated analogues. In addition, the influence of varying substituents at the 2- and 3-positions within the A-ring of these 8,9-methylenedioxybenzo[ i]phenanthridines on their relative potency as topoisomerase I-targeting agents and cell proliferation as determined using the MTT assay was investigated. 2,3-Dimethoxy-8,9-methylenedioxybenzo[ i]phenanthridine and its 11,12-dihydro derivative were among the more potent analogues evaluated with regard to topoisomerase I-targeting activity and cytotoxicity.

Substituted benzo[ i]phenanthridines as mammalian topoisomerase-Targeting agents

Several benzo[ c]phenanthridine and protoberberine alkaloids, such as nitidine and berberrubine, are known to induce DNA cleavage in the presence of either topoisomerase I or II. Structure–activity studies performed on various analogues related to benzo[ c]phenanthridine and protoberberine alkaloids have provided insights into structural features that influence this topoisomerase-targeting activity. Modifications within the A-ring of benzo[ c]phenanthridine and protoberberine alkaloids can significantly alter their ability to enhance the cleavable complex formation that occurs between DNA and topoisomerases. Select benzo[ i]phenanthridines were synthesized as potential bioisosteres of nitidine and its analogues. In the present study, 2,3-methylenedioxy-8,9-dimethoxybenzo[ i]phenanthridine, 2,3-methylenedioxy-8,9-dimethoxy-5-methylbenzo[ i]phenanthridine, 2,3,8,9-tetramethoxybenzo[ i]phenanthridine and 5-methyl-2,3,8,9-tetramethoxybenzo[ i]phenanthridine were synthesized. These benzo[ i]phenanthridine derivatives were evaluated for their ability to enhance cleavable complex formation in the presence of topoisomerases and DNA as well as for their cytotoxicity against the human lymphoblastoma cell line, RPMI8402. 2,3-Methylenedioxy-8,9-dimethoxybenzo[ i]phenanthridine ( 4a) and its 5-methyl derivative ( 4b) are active as topoisomerase I-targeting agents. In contrast to nitidine, the presence of the 5-methyl substituent in the case of 4b is not associated with enhanced activity. Consistent with previous structure–activity studies on nitidine and protoberberine alkaloids, 2,3,8,9-teramethoxybenzo[ i]phenanthridine, 5a, and its 5-methyl derivative, 5b, are inactive as topoisomerase I-targeting agents. These studies were extended to an evaluation of the relative pharmacological activities of 2,8,9-trimethoxybenzo[ i]phenanthridine, 3,8,9-trimethoxybenzo[ i]phenanthridine, and 2,3-methylenedioxy-8,9-methylenedioxybenzo[ i]phenanthridine.

2,3-Dimethoxybenzo[ i]phenanthridines: topoisomerase I-targeting anticancer agents

Appropriately substituted benzo[ i]phenanthridines structurally related to nitidine, a benzo[ c]phenanthridine alkaloid with antitumor activity, are active as topoisomerase I-targeting agents. Studies on benzo[ i]phenanthridines have indicated analogues that possess a 2,3-methylenedioxy moiety and at least one and preferably two methoxyl groups at the 8- and 9-positions, such as 8,9-dimethoxy-2,3-methylenedioxybenzo[ i]phenanthridine, 2, are active as topoisomerase I-targeting agents. Tetramethoxylated benzo[ i]phenanthridines, wherein the 2,3-methylenedioxy moiety is replaced with methoxyl groups at the 2- and 3-position, are inactive as a topoisomerase I-targeting agent. These results initially suggested that the 2,3-methylenedioxy moiety was critical to the retention of potent activity. Further studies revealed that 2,3-dimethoxy-8,9-methylenedioxybenzo[ i]phenanthridine, 7a, is more potent than 2 as a topoisomerase I-targeting agent. The observation that 2,3-dimethoxylated benzo[ i]phenanthridines can actually exhibit enhanced activity prompted the present study in which several 8-substituted 2,3-dimethoxybenzo[ i]phenanthridines were prepared and their pharmacological activities evaluated. The influence of NH 2, CN, CH 2OH, OBn, OCH 3, OH, and NHCOCH 3 substituents at the 8-position on the relative activity of these 2,3-dimethoxybenzo[ i]phenanthridines was examined. Relative to these derivatives, 7a was the most potent topoisomerase I-targeting agent, possessing similar cytotoxicity to that of nitidine in the human lymphoblast tumor cell line, RPMI8402.

The clinical development of 9-aminocamptothecin.

9-Aminocamptothecin (9-AC) is a topoisomerase I-targeting agent first synthesized by Wani and Wall in 1986. Because of its potent in vitro effects and promising preclinical activity in colorectal cancer animal models, it was designated a high-priority compound for further drug development by the NCI. In 1993, 9-AC first entered clinical trials as a 72-hour intravenous (i.v.) infusion. Predictable myelosuppression was the major dose-limiting toxicity, and pharmacokinetic studies showed a relatively short plasma half-life and unstable lactone ring. Unfortunately, phase II studies using this schedule showed minimal or no activity in tumors such as colorectal and lung cancer. Modest activity was observed in ovarian cancer and in refractory lymphomas. Efforts to improve systemic drug exposure by utilizing alternative schedules of administration of 9-AC such as prolonged, continuous intravenous infusions have also been tested. However, phase II studies of 120-hour weekly infusions of 9-AC have not shown improved activity against solid tumors such as colorectal cancer. More recently, a daily times 5 days i.v. administration schedule has been tested. Currently, further development of intravenously administered 9-AC for the treatment of colorectal cancer is not promising. Thus, topotecan and irinotecan remain the only two successfully developed topoisomerase I-targeting drugs in the United States. This experience with 9-AC raises important questions regarding how to best select new topoisomerase I-targeting drugs for future clinical development.

DNA topoisomerase-targeting antitumor agents and drug resistance.

A review of the chemotherapeutic agents which have been developed by targeting DNA topoisomerase I and II is presented. Camptothecins as topoisomerase I-targeting agents and newly developed topoisomerase II-targeting agents with unique properties are expected to be promising anticancer agents in the near future. An important issue is how cellular sensitivity to these agents is controlled. One approach is to establish and characterize drug-resistant human cancer cell lines, which would provide powerful tools to understand their intracellular target sites and also the mechanisms for acquirement of drug resistance to topoisomerase inhibitors. Drug resistance to topoisomerase-targeting agents appears to be closely correlated with two events, namely decreased expression and point mutation of topoisomerase genes.