Nitrated Indenoisoquinolines as Topoisomerase I Inhibitors:  A Systematic Study and Optimization

Morrell, Andrew; Placzek, Michael S.; Parmley, Seth; Antony, Smitha; Dexheimer, Thomas S.; Pommier, and Yves; Cushman, Mary

doi:10.1021/jm070361q

Cited by 62 publications

(77 citation statements)

References 37 publications

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“…57,61−63,65−68 However, there is very limited study on the modification of the A ring of indenoisoquinoline, especially on the 2-position. To date, the methoxy group is the only substituent that has been placed at the 2-position.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of O-2-Modified Indenoisoquinolines as Dual Topoisomerase I–Tyrosyl-DNA Phosphodiesterase I Inhibitors

Agama²,

Marchand³

et al. 2014

J. Med. Chem.

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Tyrosyl-DNA phosphodiesterase I (TDP1) repairs stalled topoisomerase I (Top1)–DNA covalent complexes and has been proposed to be a promising and attractive target for cancer treatment. Inhibitors of TDP1 could conceivably act synergistically with Top1 inhibitors and thereby potentiate the effects of Top1 poisons. This study describes the successful design and synthesis of 2-position-modified indenoisoquinolines as dual Top1–TDP1 inhibitors using a structure-based drug design approach. Enzyme inhibition studies indicate that indenoisoquinolines modified at the 2-position with three-carbon side chains ending with amino substituents show both promising Top1 and TDP1 inhibitory activity. Molecular modeling of selected target compounds bound to Top1 and TDP1 was used to rationalize the enzyme inhibition results and structure–activity relationship analysis.

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Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of O-2-Modified Indenoisoquinolines as Dual Topoisomerase I–Tyrosyl-DNA Phosphodiesterase I Inhibitors

Agama²,

Marchand³

et al. 2014

J. Med. Chem.

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“…Indenoisoquinoline derivatives have previously shown antiproliferative properties in various human cancer cell lines and have been considered to be topoisomerase 1 inhibitors. [27][28][29] Herein, we present the design, synthesis, and biophysical and primary biological evaluation of 6-substituted indenoisoquinolines as a new class of G-quadruplex stabilizing ligands. We have synthesized indenoisoquinolines 1a-e from commercially available indeno[1,2-c]isochromene-5,11-dione (2) with excellent yields (Scheme 1) (generally >90%, see the Supporting Information for details).…”

mentioning

confidence: 99%

Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines

Bejugam

Gunaratnam

Müller

et al. 2010

ACS Med. Chem. Lett.

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Herein, we demonstrate the design, synthesis, biophysical properties, and preliminary biological evaluation of 6-substituted indenoisoquinolines as a new class of G-quadruplex stabilizing small molecule ligands. We have synthesized 6-substituted indenoisoquinolines 1a-e in two steps from commercially available starting materials with excellent yields. The G-quadruplex stabilization potential of indenoisoquinolines 1a-e was evaluated by fluorescence resonance energy transfer-melting analysis, which showed that indenoisoquinolines show a high level of stabilization of various G-quadruplex DNA structures. Indenoisoquinolines demonstrated potent inhibition of cell growth in the GIST882 patient-derived gastrointestinal stromal tumor cell line, accompanied by inhibition of both c-Kit transcription and KIT oncoprotein levels.KEYWORDS DNA, quadruplex, c-kit regulation, inhibition, ligand G -quadruplexes constitute a structural form of DNA that is distinct from the double helix. 1 They are formed from particular guanine-rich nucleic acid sequences in which guanines form planar quartets stabilized using the Watson-Crick and Hoogsteen edges to form hydrogen bonds. Their occurrence has been demonstrated within ciliate telomeres. 2,3 In addition, G-quadruplex sequence motifs (G 3þ N 1-7 G 3þ N 1-7 G 3þ N 1-7 G 3þ ) are found at many positions within genomes, 4,5 with a notable increase in density in close vicinity to transcriptional start sites, highly suggestive of a biological function in gene regulation. 5,6 NMR spectroscopy and X-ray crystallographical studies have shown that these guanine-rich sequences can fold into G-quadruplex structures in vitro. 7,8 Their unique structural features and possible biological functions make them attractive targets for drug design. 9,10 Genomic locations that are known to possess quadruplex structures include the immunoglobulin switch region and the promoters of numerous proto-oncogenes, such as c-MYC, 11 VEGF, 12 BCL-2, 13 and K-RAS. 14 Two quadruplex-forming motifs have been identified in the c-Kit promoter (c-Kit 1 15,16 and c-Kit 2 17,18 ). Here, we present a new class of quadruplex stabilizing compounds that have been used to explore relationships between quadruplexes and their biological functions.c-Kit is a proto-oncogene that codes for a 145-160 kDa protein belonging to the receptor tyrosine kinase (RTK) family. The KIT protein regulates signal transduction cascades that control cell growth and differentiation. 19 c-Kit expression has been shown to control the growth of various cell lines, including gastrointestinal stromal tumors (GIST), hematopoietic cells, small cell lung cancer, and colorectal cancer. [20][21][22][23] Gain-of-function mutations in the KIT protein are found in various highly malignant human cancers, especially GIST. Gleevec (imatinib mesylate), a small molecule antagonist originally developed to treat chronic myelogenous leukemia (CML), acts by maintaining the bcr-abl kinase in an inactive conformation. Gleevec is also the mainstay of target therapy ...

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“…The effect of installation of this group on indenoisoquinoline Top1 poisoning activity was not consistent with observations from previous studies, which have shown that the group can increase activity moderately. 20, 29 …”

Section: Resultsmentioning

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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Nitrated Indenoisoquinolines as Topoisomerase I Inhibitors: A Systematic Study and Optimization

Cited by 62 publications

References 37 publications

Design, Synthesis, and Biological Evaluation of O-2-Modified Indenoisoquinolines as Dual Topoisomerase I–Tyrosyl-DNA Phosphodiesterase I Inhibitors

Design, Synthesis, and Biological Evaluation of O-2-Modified Indenoisoquinolines as Dual Topoisomerase I–Tyrosyl-DNA Phosphodiesterase I Inhibitors

Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines

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

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