Synthesis and Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Substituted with Nitrogen Heterocycles

Nagarajan, Muthukaman; Morrell, Andrew; Ioanoviciu, Alexandra; Antony, Smitha; Kohlhagen, Glenda; Agama, Keli; Hollingshead, Melinda G.; Pommier, ﻿Yves; Cushman, Mary

doi:10.1021/jm060564z

Cited by 94 publications

(110 citation statements)

References 18 publications

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“…In the 60-cell-line National Cancer Institute anticancer drug screen, indenoisoquinolines demonstrated a cell-line-specific cytotoxicity profile consistent with topoisomerase IB poisons, and they can trap topoisomerase IB-DNA covalent complexes (19,20,36). Some of the indenoisoquinolines have the ability to bind and intercalate into DNA in the absence of the enzyme (30,35,36), and others may even interact directly with the mammalian topoisomerase IB protein at high drug concentrations (29). We have evaluated a battery of indenoisoquinolines (26)(27)(28)30) against T. brucei and we find that they have potent antitrypanosomal activities in vitro, inhibit nucleic acid synthesis in the parasite, act as topoisomerase poisons within the cell, and show preliminary evidence of efficacy in mice challenged with trypanosomes.…”

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Activity of Indenoisoquinolines against African Trypanosomes

Bakshi

Sang

Morrell

et al. 2009

Antimicrob Agents Chemother

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African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.

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Activity of Indenoisoquinolines against African Trypanosomes

Bakshi

Sang

Morrell

et al. 2009

Antimicrob Agents Chemother

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“…23, 24 The amines 15 – 17 were selected because they contributed to the synthesis of very active carbohydrate-substituted indenoisoquinolines, 25 while 18 , 19 , and 20 were chosen because they would lead to compounds with side chains present in the indotecan (LMP400), indimitecan (LMP776), and MJ-III-65 (LMP744). 7, 11, 13 …”

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confidence: 99%

Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons

Beck

Abdelmalak

et al. 2016

Bioorganic & Medicinal Chemistry

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Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds’ activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogues were discovered through testing in human cancer cell cultures. A hydroxyethylaminopropyl side chain on the lactam nitrogen of two halogenated indenoisoquinoline Top1 inhibitors was found to also impart inhibitory activity against tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes that participate in the repair of DNA damage induced by Top1 poisons.

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“…The non-CPT Top I inhibitors include indenoisoquinolines, [13][14][15] indolocarbazones, 16) saintopin, 17) benzophenazines, 18) terpyridines, 19) and 3-arylisoquinolines.…”

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“…The non-CPT Top I inhibitors include indenoisoquinolines, [13][14][15] indolocarbazones, 16) saintopin, 17) benzophenazines, 18) terpyridines, 19) and 3-arylisoquinolines. 20) The successful clinical cases of the non-CPT derivatives were attributed to the better chemical stability at longer lifetimes of the trapped cleavage complex of the non-CPT Top I inhibitors at the absence of a lactone ring in their skeleton.…”

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Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Quinolone Derivatives as Potential Antitumor Topoisomerase I Inhibitors

Shou

Jin

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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A novel series of quinolone derivatives (6a-n) were designed and synthesized, and their biological activities were evaluated as potential antitumor topoisomerase I (Top I) inhibitors. Among these compounds, 6j exhibited the most potent antitumor activities against multiple cancer cell lines. Docking simulation was performed to insert compound 6j into the crystal structure of DNA-Top I to determine the probable binding model. Key words quinolone derivative; antitumor; topoisomerase I; molecular docking DNA-topoisomerase I (Top I) is an important enzyme to relax supercoiled DNA for transcription, replication, and mitosis.1) Top I relaxes DNA by producing reversible single-strand DNA breaks. The generally accepted mechanism of Top I action involves a nucleophilic attack by the catalytic tyrosine 723 residue of Top I on the phosphate group at 3′-end of the broken DNA strand, which leads to the break of the DNA phosphodiester bond and the formation of a binary Top I-DNA covalent complex (Top I-DNAcc). The rotation of the 5′-end around the intact strand allows for relaxation of the supercoil.1,2) As it plays a pivotal role in cellular proliferation, Top I is often overexpressed in human tumors. Thus, DNA-Top I has been identified as a promising cancer therapeutic target. 3)Camptothecin (CPT) (1) 4) and its clinically used analogues, topotecan (2) and irinotecan (3) 5,6) ( Fig. 1), were found to inhibit Top I activity by intercalating into the cleavage complex and preventing the relegation step of the catalytic cycle. As a result, the covalent Top I-DNA adduct produces collisions with advancing replication forks and transcription complexes, which triggers irreversible DNA damage and apoptosis. 7,8) Although the camptothecins possess potent antitumor activity, they also suffer from well-identified drawbacks, including solubility and bioactivity, dose-limiting toxicity.7-10) Additionally, the E-ring lactone of camptothecin is readily opened to its hydroxycarboxylate form in vivo.11) This form is less active and binds strongly to human blood proteins. 12) Thus, these problems recommended further development of other non-CPT Top I inhibitors with better pharmacokinetic features.The non-CPT Top I inhibitors include indenoisoquinolines, [13][14][15] indolocarbazones, 16) saintopin, 17) benzophenazines, 18) terpyridines, 19) and 3-arylisoquinolines.20) The successful clinical cases of the non-CPT derivatives were attributed to the better chemical stability at longer lifetimes of the trapped cleavage complex of the non-CPT Top I inhibitors at the absence of a lactone ring in their skeleton. 21) Quinolones are among the most common frameworks present in bioactive molecules and hence represent an attractive starting point for the design of combinatorial libraries.22) Recently, You and co-workers 23) discovered series of quinolone derivatives as potential Top I inhibitors by scaffold modification. In addition, Al-Trawneh et al. 24) also reported that tetracyclic fluoroquinolones exhibited high antiproliferative activity against b...

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Synthesis and Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Substituted with Nitrogen Heterocycles

Cited by 94 publications

References 18 publications

Activity of Indenoisoquinolines against African Trypanosomes

Activity of Indenoisoquinolines against African Trypanosomes

Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons

Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Quinolone Derivatives as Potential Antitumor Topoisomerase I Inhibitors

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