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Synthesis of new indeno[1,2-c]isoquinolines: cytotoxic non-camptothecin topoisomerase I inhibitors.
J Med Chem. 2000 Oct 05; 43(20):3688-98.JM

Abstract

In an attempt to design and synthesize potential anticancer agents acting by inhibition of topoisomerase I (top1), a new series of indenoisoquinolines was prepared and tested for cytotoxicity in human cancer cell cultures and for activity against top1. The synthesis relied on the condensation of substituted Schiff bases with homophthalic anhydrides to produce cis-3-aryl-4-carboxyisoquinolones that were cyclized to indenoisoquinolines in the presence of thionyl chloride. Both top1 inhibitory activity and cytotoxicity maximized in a single compound, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline hydrochloride (19a), which proved to be a very potent top1 inhibitor having a 110 nM mean graph midpoint (MGM) when tested for cytotoxicity in 55 human cancer cell cultures. A number of structurally related indenoisoquinolines were also obtained that had both potent cytotoxicity as well as top1 inhibitory activity. The key feature of the more potent compounds was the presence of an aminoalkyl side chain on the indenoisoquinoline nitrogen atom. The DNA cleavage patterns induced by top1 in the presence of the indenoisoquinolines were different from those seen with camptothecin. Some of the cleavage sites induced by the indenoisoquinolines were different from those seen with camptothecin, and conversely, camptothecin induced unique cleavage sites not apparent with the indenoisoquinolines. However, both camptothecin and the indenoisoquinolines also induced DNA cleavage sites that were the same in both series but varied in intensity. In addition, some of the DNA cleavages seen with the free base of 19a (compound 18c) in the presence of top1 were inhibited at higher drug concentrations, suggesting either a direct inhibition of the enzyme or an alternative mechanism involving DNA intercalation. Consistent with intercalation, compound 18c did unwind DNA.

Authors+Show Affiliations

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA. cushman@pharmacy.purdue.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11020283

Citation

Cushman, M, et al. "Synthesis of New Indeno[1,2-c]isoquinolines: Cytotoxic Non-camptothecin Topoisomerase I Inhibitors." Journal of Medicinal Chemistry, vol. 43, no. 20, 2000, pp. 3688-98.
Cushman M, Jayaraman M, Vroman JA, et al. Synthesis of new indeno[1,2-c]isoquinolines: cytotoxic non-camptothecin topoisomerase I inhibitors. J Med Chem. 2000;43(20):3688-98.
Cushman, M., Jayaraman, M., Vroman, J. A., Fukunaga, A. K., Fox, B. M., Kohlhagen, G., Strumberg, D., & Pommier, Y. (2000). Synthesis of new indeno[1,2-c]isoquinolines: cytotoxic non-camptothecin topoisomerase I inhibitors. Journal of Medicinal Chemistry, 43(20), 3688-98.
Cushman M, et al. Synthesis of New Indeno[1,2-c]isoquinolines: Cytotoxic Non-camptothecin Topoisomerase I Inhibitors. J Med Chem. 2000 Oct 5;43(20):3688-98. PubMed PMID: 11020283.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis of new indeno[1,2-c]isoquinolines: cytotoxic non-camptothecin topoisomerase I inhibitors. AU - Cushman,M, AU - Jayaraman,M, AU - Vroman,J A, AU - Fukunaga,A K, AU - Fox,B M, AU - Kohlhagen,G, AU - Strumberg,D, AU - Pommier,Y, PY - 2000/10/6/pubmed PY - 2001/2/28/medline PY - 2000/10/6/entrez SP - 3688 EP - 98 JF - Journal of medicinal chemistry JO - J Med Chem VL - 43 IS - 20 N2 - In an attempt to design and synthesize potential anticancer agents acting by inhibition of topoisomerase I (top1), a new series of indenoisoquinolines was prepared and tested for cytotoxicity in human cancer cell cultures and for activity against top1. The synthesis relied on the condensation of substituted Schiff bases with homophthalic anhydrides to produce cis-3-aryl-4-carboxyisoquinolones that were cyclized to indenoisoquinolines in the presence of thionyl chloride. Both top1 inhibitory activity and cytotoxicity maximized in a single compound, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline hydrochloride (19a), which proved to be a very potent top1 inhibitor having a 110 nM mean graph midpoint (MGM) when tested for cytotoxicity in 55 human cancer cell cultures. A number of structurally related indenoisoquinolines were also obtained that had both potent cytotoxicity as well as top1 inhibitory activity. The key feature of the more potent compounds was the presence of an aminoalkyl side chain on the indenoisoquinoline nitrogen atom. The DNA cleavage patterns induced by top1 in the presence of the indenoisoquinolines were different from those seen with camptothecin. Some of the cleavage sites induced by the indenoisoquinolines were different from those seen with camptothecin, and conversely, camptothecin induced unique cleavage sites not apparent with the indenoisoquinolines. However, both camptothecin and the indenoisoquinolines also induced DNA cleavage sites that were the same in both series but varied in intensity. In addition, some of the DNA cleavages seen with the free base of 19a (compound 18c) in the presence of top1 were inhibited at higher drug concentrations, suggesting either a direct inhibition of the enzyme or an alternative mechanism involving DNA intercalation. Consistent with intercalation, compound 18c did unwind DNA. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/11020283/Synthesis_of_new_indeno[12_c]isoquinolines:_cytotoxic_non_camptothecin_topoisomerase_I_inhibitors_ L2 - https://doi.org/10.1021/jm000029d DB - PRIME DP - Unbound Medicine ER -