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Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons.
J Med Chem. 1999 Feb 11; 42(3):446-57.JM

Abstract

A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs topoisomerase 1 (top1). The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (21) and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (22), both of which displayed submicromolar mean graph midpoints when tested in 55 human cancer cell cultures. Two of the most potent top1 inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5, 11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2, 3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27), both of which also inhibited top2, unwound DNA, and are assumed to be DNA intercalators. However, two additional potent top1 inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect top2. Some of the DNA cleavage sites detected in the presence of the indenoisoquinolines were different from those seen with the camptothecins. The cleavage sites induced by the indenoisoquinolines were reversed by salt treatment, which is consistent with the reversible trapping of top1 cleavable complexes by the indenoisoquinolines. In general, the potencies of the indenoisoquinolines as top1 inhibitors did not correlate with their potencies as cytotoxic agents, as some of the most cytotoxic agents had little if any effect on top1. On the other hand, the most potent of the indenoisoquinolines vs top1 were not the most cytotoxic. In several cases, moderate activity was observed for both cytotoxicity and activity vs top1.

Authors+Show Affiliations

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, Purdue University, West Lafayette, Indiana 47906, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

9986716

Citation

Strumberg, D, et al. "Synthesis of Cytotoxic Indenoisoquinoline Topoisomerase I Poisons." Journal of Medicinal Chemistry, vol. 42, no. 3, 1999, pp. 446-57.
Strumberg D, Pommier Y, Paull K, et al. Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons. J Med Chem. 1999;42(3):446-57.
Strumberg, D., Pommier, Y., Paull, K., Jayaraman, M., Nagafuji, P., & Cushman, M. (1999). Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons. Journal of Medicinal Chemistry, 42(3), 446-57.
Strumberg D, et al. Synthesis of Cytotoxic Indenoisoquinoline Topoisomerase I Poisons. J Med Chem. 1999 Feb 11;42(3):446-57. PubMed PMID: 9986716.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons. AU - Strumberg,D, AU - Pommier,Y, AU - Paull,K, AU - Jayaraman,M, AU - Nagafuji,P, AU - Cushman,M, PY - 1999/2/13/pubmed PY - 1999/2/13/medline PY - 1999/2/13/entrez SP - 446 EP - 57 JF - Journal of medicinal chemistry JO - J Med Chem VL - 42 IS - 3 N2 - A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs topoisomerase 1 (top1). The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (21) and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (22), both of which displayed submicromolar mean graph midpoints when tested in 55 human cancer cell cultures. Two of the most potent top1 inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5, 11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2, 3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27), both of which also inhibited top2, unwound DNA, and are assumed to be DNA intercalators. However, two additional potent top1 inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect top2. Some of the DNA cleavage sites detected in the presence of the indenoisoquinolines were different from those seen with the camptothecins. The cleavage sites induced by the indenoisoquinolines were reversed by salt treatment, which is consistent with the reversible trapping of top1 cleavable complexes by the indenoisoquinolines. In general, the potencies of the indenoisoquinolines as top1 inhibitors did not correlate with their potencies as cytotoxic agents, as some of the most cytotoxic agents had little if any effect on top1. On the other hand, the most potent of the indenoisoquinolines vs top1 were not the most cytotoxic. In several cases, moderate activity was observed for both cytotoxicity and activity vs top1. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9986716/Synthesis_of_cytotoxic_indenoisoquinoline_topoisomerase_I_poisons_ L2 - https://doi.org/10.1021/jm9803323 DB - PRIME DP - Unbound Medicine ER -