Alcohol-, Diol-, and Carbohydrate-substituted Indenoisoquinolines As Topoisomerase I Inhibitors: Investigating the Relationships Involving Stereochemistry, Hydrogen Bonding, and Biological Activity

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2011 Jun 30

PMID 21710981

Citations 10

Authors

Katherine E Peterson

Maris A Cinelli

Andrew E Morrell

Akhil Mehta

Thomas S Dexheimer

Keli Agama

Smitha Antony

Yves Pommier

Mark Cushman

Affiliations

Soon will be listed here.

Abstract

The DNA-relaxing enzyme topoisomerase I (Top1) can be inhibited by heterocyclic compounds such as indolocarbazoles and indenoisoquinolines. Carbohydrate and hydroxyl-containing side chains are essential for the biological activity of indolocarbazoles. The current study investigated how similar functionalities could be "translated" to the indenoisoquinoline system and how stereochemistry and hydrogen bonding affect biological activity. Herein is described the preparation and assay of indenoisoquinolines substituted with short-chain alcohols, diols, and carbohydrates. Several compounds (including those derived from sugars) display potent Top1 poisoning and antiproliferative activities. The Top1 poisoning activity of diol-substituted indenoisoquinolines is dependent upon stereochemistry. Although the effect is striking, molecular modeling and docking studies do not indicate any reason for the difference in activity due to similar calculated interactions between the ligand and Top1-DNA complex and ambiguity about the binding mode. A stereochemical dependence was also observed for carbohydrate-derived indenoisoquinolines. Although similar trends were observed in other classes of Top1 inhibitors, the exact nature of this effect has yet to be elucidated.

Citing Articles

Chronic exposure to the gibberellin derivative GA-13315 sensitizes breast cancer MCF-7 cells but not colon cancer HCT116 cells to irinotecan.

Cheng X, Wang G, Liao Y, Mo J, Qing C Oncol Lett. 2020; 20(6):281.

PMID: 33014159 PMC: 7520751. DOI: 10.3892/ol.2020.12144.

Novel Mannitol-Based Small Molecules for Inhibiting Aggregation of α-Synuclein Amyloids in Parkinson's Disease.

Paul A, Zhang B, Mohapatra S, Li G, Li Y, Gazit E Front Mol Biosci. 2019; 6:16.

PMID: 30968030 PMC: 6438916. DOI: 10.3389/fmolb.2019.00016.

A practical and efficient approach to imidazo[1,2-]pyridine-fused isoquinolines through the post-GBB transformation strategy.

Shao T, Gong Z, Su T, Hao W, Che C Beilstein J Org Chem. 2017; 13:817-824.

PMID: 28546839 PMC: 5433183. DOI: 10.3762/bjoc.13.82.

A robust synthesis of 7,8-didemethyl-8-hydroxy-5-deazariboflavin.

Bender M, Mouritsen H, Christoffers J Beilstein J Org Chem. 2016; 12:912-7.

PMID: 27340481 PMC: 4901869. DOI: 10.3762/bjoc.12.89.

Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons.

Beck D, Reddy P, Lv W, Abdelmalak M, Tender G, Lopez S J Med Chem. 2016; 59(8):3840-53.

PMID: 27070999 PMC: 5317104. DOI: 10.1021/acs.jmedchem.6b00003.

References

Pommier Y . Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006; 6(10):789-802. DOI: 10.1038/nrc1977. View

Xiao X, Antony S, Pommier Y, Cushman M . On the binding of indeno[1,2-c]isoquinolines in the DNA-topoisomerase I cleavage complex. J Med Chem. 2005; 48(9):3231-8. DOI: 10.1021/jm050017y. View

Wang J . Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002; 3(6):430-40. DOI: 10.1038/nrm831. View

Saif M, Sellers S, Diasio R, Douillard J . A phase I dose-escalation study of edotecarin (J-107088) combined with infusional 5-fluorouracil and leucovorin in patients with advanced/metastatic solid tumors. Anticancer Drugs. 2010; 21(7):716-23. PMC: 2931818. DOI: 10.1097/CAD.0b013e32833cb658. View

Morrell A, Placzek M, Steffen J, Antony S, Agama K, Pommier Y . Investigation of the lactam side chain length necessary for optimal indenoisoquinoline topoisomerase I inhibition and cytotoxicity in human cancer cell cultures. J Med Chem. 2007; 50(9):2040-8. PMC: 2519145. DOI: 10.1021/jm0613119. View

Luzzio M, Besterman J, Emerson D, Evans M, Lackey K, Leitner P . Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem. 1995; 38(3):395-401. DOI: 10.1021/jm00003a001. View

Carrasco C, Facompre M, Chisholm J, Van Vranken D, Wilson W, Bailly C . DNA sequence recognition by the indolocarbazole antitumor antibiotic AT2433-B1 and its diastereoisomer. Nucleic Acids Res. 2002; 30(8):1774-81. PMC: 113207. DOI: 10.1093/nar/30.8.1774. View

Cinelli M, Morrell A, Dexheimer T, Agama K, Agrawal S, Pommier Y . The structure-activity relationships of A-ring-substituted aromathecin topoisomerase I inhibitors strongly support a camptothecin-like binding mode. Bioorg Med Chem. 2010; 18(15):5535-52. PMC: 2911012. DOI: 10.1016/j.bmc.2010.06.040. View

Delcros J, Tomasi S, Carrington S, Martin B, Renault J, Blagbrough I . Effect of spermine conjugation on the cytotoxicity and cellular transport of acridine. J Med Chem. 2002; 45(23):5098-111. DOI: 10.1021/jm020843w. View

10.

Teicher B . Next generation topoisomerase I inhibitors: Rationale and biomarker strategies. Biochem Pharmacol. 2007; 75(6):1262-71. DOI: 10.1016/j.bcp.2007.10.016. View

11.

Kaluzhny D, Tatarskiy Jr V, Dezhenkova L, Plikhtyak I, Miniker T, Shchyolkina A . Novel antitumor L-arabinose derivative of indolocarbazole with high affinity to DNA. ChemMedChem. 2009; 4(10):1641-8. DOI: 10.1002/cmdc.200900227. View

12.

Erickson J, Jalaie M, Robertson D, Lewis R, Vieth M . Lessons in molecular recognition: the effects of ligand and protein flexibility on molecular docking accuracy. J Med Chem. 2003; 47(1):45-55. DOI: 10.1021/jm030209y. View

13.

Dallavalle S, Giannini G, Alloatti D, Casati A, Marastoni E, Musso L . Synthesis and cytotoxic activity of polyamine analogues of camptothecin. J Med Chem. 2006; 49(17):5177-86. DOI: 10.1021/jm060285b. View

14.

Antony S, Jayaraman M, Laco G, Kohlhagen G, Kohn K, Cushman M . Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I. Cancer Res. 2003; 63(21):7428-35. View

15.

Pommier Y, Leo E, Zhang H, Marchand C . DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol. 2010; 17(5):421-33. PMC: 7316379. DOI: 10.1016/j.chembiol.2010.04.012. View

16.

SCHAEPPI U, FLEISCHMAN R, Cooney D . Toxicity of camptothecin (NSC-100880). Cancer Chemother Rep 3. 1974; 5(1):25-36. View

17.

Dexheimer T, Pommier Y . DNA cleavage assay for the identification of topoisomerase I inhibitors. Nat Protoc. 2008; 3(11):1736-50. PMC: 10758284. DOI: 10.1038/nprot.2008.174. View

18.

Brand J, Huhn T, Groth U, Jochims J . Nitrosation of sugar oximes: preparation of 2-glycosyl-1-hydroxydiazene-2-oxides. Chemistry. 2005; 12(2):499-509. DOI: 10.1002/chem.200500325. View

19.

Long B, Rose W, Vyas D, Matson J, Forenza S . Discovery of antitumor indolocarbazoles: rebeccamycin, NSC 655649, and fluoroindolocarbazoles. Curr Med Chem Anticancer Agents. 2003; 2(2):255-66. DOI: 10.2174/1568011023354218. View

20.

Bailly C, Qu X, Graves D, Prudhomme M, Chaires J . Calories from carbohydrates: energetic contribution of the carbohydrate moiety of rebeccamycin to DNA binding and the effect of its orientation on topoisomerase I inhibition. Chem Biol. 1999; 6(5):277-86. DOI: 10.1016/S1074-5521(99)80073-8. View