Synthesis and anticancer activity of simplified indenoisoquinoline topoisomerase I inhibitors lacking substituents on the aromatic rings

Journal of Medicinal Chemistry

Volumn 47, Issue 23, 2004, Pages 5651-5661

  Nagarajan, Muthukaman ^a   Morrell, Andrew ^a   Fort, Brian C ^a   Meckley, Marintha Rae ^a   Antony, Smitha ^b   Kohlhagen, Glenda ^b   Pommier, Yves ^b   Cushman, Mark ^a  

^a PURDUE UNIVERSITY   (United States)

^b NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5,6 DIHYDRO 5,11 DIOXO 6(2 N PIPERAZINE 1 ETHYL) 11H INDENO[1,2 C]ISOQUINOLINE; 5,6 DIHYDRO 6 (2 N MORPHOLINYL 1 ETHYL) 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE; 5,6 DIHYDRO 6 (3 (DIMETHYLAMINO) 1 PROPYL) 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE; 5,6 DIHYDRO 6 (3 IMIDAZOLYL 1 PROPYL) 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE HYDROCHLORIDE; 5,6 DIHYDRO 6 [3 (3 IMIDAZOLYLPROPYL)AMINO 1 PROPYL] 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE DI(HYDROCHLORIDE); 5,6 DIHYDRO 8,9 METHYLENEDIOXY 5,11 DIOXO 6 PROPYL 11H INDENO[1,2 C]ISOQUINOLINE; 6 (2 AMINOETHYL) 5,6 DIHYDRO 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE HYDROCHLORIDE; 6 (3 AMINOPROPYL) 5,6 DIHYDRO 5,11 DIOXO 11H INDENO [1,2 C]ISOQUINOLINE HYDROCHLORIDE; 6 (3 AMINOPROPYL) 5,6 DIHYDRO 8,9 METHYLENEDIOXY 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE HYDROCHLORIDE SALT; 6 (3 AZIDOPROPYL) 5,6 DIHYDRO 8,9 METHYLENEDIOXY 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE; 6 (3 BROMOPROPYL) 5,6 DIHYDRO 8,9 METHYLENEDIOXY 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE; 6 (3 ETHYL) 5,6 DIHYDRO 8,9 METHYLENEDIOXY 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE; 6 (3 GUANIDINYL 1 PROPYL) 5,6 DIHYDRO 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE TRIFLUOROACETATE; 6 (3' TERT BOC AMINOPROPYL) 5,6 DIHYDRO 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE; 6 (4 1MINO 1 BUTYL) 5,6 DIHYDRO 5,11 DIOXO 11H INDENO [1,2 C]ISOQUINOLINE HYDROCHLORIDE; 6 [(4 TERT BOC AMINO) 5,6 DIHYDRO 1 BUTYL] 5,11 DIOXO 11H INDENO[1,2 C]ISOQUINOLINE; ARGININE DERIVATIVE; AROMATIC AMINE; CAMPTOTHECIN; CIS 4 CARBOXY N ETHYL 3,4 DIHYDRO 3(3,4 METHYLENE DIOXYPHENYL) 1 (2,H) ISOQUINOLONE; CIS 4 CARBOXY N PROPYL 3,4 DIHYDRO 3(3,4 METHYLENE DIOXYPHENYL) 1 (2,H) ISOQUINOLINE; CIS N (3 BROMOPROPYL) 4 CARBOXY 3,4 DIHYDRO 3 (3,4 METHYLENEDIOXYPHENYL) 1(2H) ISOQUINOLONE; DNA TOPOISOMERASE; DNA TOPOISOMERASE INHIBITOR; GUANIDINE; INDENOISOQUINOLINE; ISOQUINOLINE DERIVATIVE; LACTAM; NITROGEN; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL CULTURE; CANCER INHIBITION; CHEMICAL STRUCTURE; CONTROLLED STUDY; CYTOTOXICITY; DNA CLEAVAGE; DRUG ACTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; ENZYME STABILITY; GENOME; HUMAN; HUMAN CELL; HYDROGEN BOND; MOLECULAR MODEL; STRUCTURE ACTIVITY RELATION;

ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; DNA; DNA TOPOISOMERASES, TYPE I; DRUG SCREENING ASSAYS, ANTITUMOR; ELECTROPHORESIS, POLYACRYLAMIDE GEL; HUMANS; INDENES; ISOQUINOLINES; MODELS, MOLECULAR;

EID: 7444233119     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm040025z     Document Type: Article

References (41)

1. Cushman, M.; Cheng, L. Stereoselective Oxidation by Thionyl Chloride Leading to the Indeno[1,2-c]isoquinoline System. J. Org. Chem. 1978, 43, 3781-3783.
2. Kohlhagen, G.; Paull, K.; Cushman, M.; Nagafuji, P.; Pommier, Y. Protein-Linked DNA Strand Breaks Induced by NSC 314622, a Novel Noncamptothecin Topoisomerase I Poison. Mol. Pharmacol. 1998, 54, 50-58.
3. Pommier, Y.; Pourquier, P.; Fan, Y.; Strumberg, D. Mechanism of Action of Eukaryotic DNA Topoisomerases and Drugs Targeted to the Enzyme. Biochim. Biophys. Acta 1998, 1400, 83-105.
4. Staker, B. L.; Hjerrild, K.; Feese, M. D.; Behnke, C. A.; Burgin Jr., A. B.; Stewart, L. The Mechanism of Topoisomerase I Poisoning by a Camptothecin Analogue. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 15387-15392.
5. Meng, L. H.; Liao, Z. Y.; Pommier, Y. Non-Camptothecin DNA Topoisomerase I Inhibitors in Cancer Therapy. Curr. Topics Med. Chem. 2003, 3, 305-320.
6. Pommier, Y. Eukaryotic DNA Topoisomerase I: Genome Gate Keeper and Its Intruders, Camptothecins. Semin. Oncol. 1996, 23, 1-10.
7. (a) Jaxel, C.; Kohn, K. W.; Wani, M. C.; Pommier, Y. Structure-Activity Study of the Actions of Camptothecin Derivatives on Mammalian Topoisomerase I: Evidence for a Specific Receptor Site and a Relation to Antitumor Activity. Cancer Res. 1989, 49, 1465-1469.
8. (b) Minami, H.; Beijnen, J. H.; Verweij, J.; Ratain, M. J. Limited Sampling Model for Area under the Concentration Time Curve of Total Topotecan. Clin. Cancer Res. 1996, 2, 43-46.
9. (c) Danks, M. K.; Pawlik, C. A.; Whipple, D. O.; Wolverton, J. S. Intermittent Exposure of Medulloblastoma Cells to Topotecan Produces Growth Inhibition Equivalent to Continuous Exposure. Curr. Topics Med. Chem. 1997, 3, 1731-1738.
10. (d) Haas, N. B.; LaCreta, F. P.; Walczak, J.; Hudes, G. R.; Brennan, J. M.; Ozols, R. F.; O'Dwyer, P. J. Phasel/Pharmacokinetic Study of Topotecan by 24-Hour Continuous Infusion Weekly. Cancer Res. 1994, 54, 1220-1226.
11. Strumberg, D.; Pommier, Y.; Paull, K.; Jayaraman, M.; Nagafuji, P.; Cushman, M. Synthesis of Cytotoxic Indenoisoquinoline Topoisomerase I Poisons. J. Med. Chem. 1999, 42, 446-457.
12. Cushman, M.; Jayaraman, M.; Vroman, J. A.; Fukunaga, A. K.; Fox, B. M.; Kohlhagen, G.; Strumberg, D.; Pommier, Y. Synthesis of New Indeno[1,2-c] isoquinolines: Cytotoxic Non-Camptothecin Topoisomerase I Inhibitors. J. Med. Chem. 2000, 43, 3688-3698.
13. Fox, B. M.; Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Staker, B. L.; Stewart, L.; Cushman, M. Design, Synthesis, and Biological Evaluation of Cytotoxic 11-Alkenylindenoisoquinoline Topoisomerase I Inhibitors and Indenoisoquinoline-Camptothecin Hybrids. J. Med. Chem. 2003, 46, 3275-3282.
14. Nagarajan, M.; Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. Design, Synthesis, and Biological Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Featuring Polyamine Side Chains on the Lactam Nitrogen. J. Med. Chem. 2003, 46, 5712-5724.
15. Pourquier, P.; Ueng, L.-M.; Fertala, J.; Wang, D.; Park, H.-J.; Essigmann, J. M.; Bjornsti, M.-A.; Pommier, Y. Induction of Reversible Complexes between Eukaryotic DNA Topoisomerase I and DNA-containing Oxidative Base Damages. 7,8-Dihydro-8-Oxoguanine and 5-Hydroxycytosine. J. Biol. Chem. 1999, 274, 8516-8523.
16. Antony, S.; Jayaraman, M.; Laco, G.; Kohlhagen, G.; Kohn, K. W.; Cushman, M.; Pommier, Y. 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 Topoisomerase I. Cancer Res. 2003, 63, 7428-7435.
17. Klucar, J.; Al-Rubeai, M. G2 Cell Cycle Arrest and Apoptosis Are Induced in Burkitt's Lymphoma Cells by the Anticancer Agent Oracin. FEBS Lett. 1997, 400, 127-130.
18. Michalský, J. 6-[X-(2-Hydroxyethyl)aminoalkyl]-5, 11-dioxo-5,6-dihydro-11-H-indeno[1,2-c]isoquinolines and Their Use as Antinioplastic Agents.; VUFB a.s., Praha, Czechoslovakia: United States Patent 5,597,831, 1997.
19. Gersl, V.; Mazurová, Y.; Bajgar, J.; Mélka, M.; Hrdina, R.; Palicka, V. Lack of Cardiotoxicity of a New Antineoplastic Agent, a Synthetic Derivative of Indenoisoquinoline: Comparison with Daunorubicin in Rabbits. Arch. Toxicol. 1996, 70, 645-651.
20. Wsól, V.; Kvasnicková, E.; Szotáková, B.; Hais, I. M. High-performance Liquid Chromatography Assay for the Separation and Characterization of Metabolites of the Potential Cytostatic Drug Oracine. J. Chromatogr. B 1996, 681, 169-175.
21. Marhan, J. Mutagenicity of Cytostatic Drugs in Bacterial System. I. Ames Test. Folia Microbiol. 1995, 40, 457-461.
22. Marhan, J. Mutagenicity of Cytostatic Drugs in a Bacterial System. II. DNA-Repair Test. Folia Microbiol. 1995, 40, 462-466.
23. Cushman, M.; Gentry, J.; Dekow, F. W. Condensation of Imines with Homophthalic Anhydrides. A Convergent Synthesis of cis-and trans-13- Methyltetrahydroprotoberberines. J. Org. Chem. 1977, 42, 1111-1116.
24. Cushman, M.; Cheng, L. Total Synthesis of Nitidine Chloride. J. Org. Chem. 1978, 43, 286-288.
25. Johnson, F. Steric Interference in Allylic and Pseudoallylic Systems. I. Two Stereochemical Theorems. J. Am. Chem. Soc. 1965, 68, 5492-5493.
26. Johnson, F. Allylic Strain in Six-Membered Rings. Chem. Rev. 1968, 68, 375-413.
27. Koziara, A.; Osowska-Pacewicka, K.; Zawadzki, S.; Zwierzak, A. One-Pot Transformation of Alkyl Bromides into Primary Amines via the Staudinger Reaction. Synthesis 1985, 202-204.
28. Edwards, M. L.; Snyder, R. D.; Stemerick, D. M. Synthesis and DNA-Binding Properties of Polyamine Analogues. J. Med. Chem. 1991, 34, 2414-2420.
29. Cohen, G. M.; Cullis, P. M.; Hartley, J. A.; Mather, A.; Symons, M. C. R.; Wheelhouse, R. T. Targeting of Cytotoxic Agents by Polyamines: Synthesis of a Chlorambucil-Spermidine Conjugate. J. Chem. Soc., Chem. Commun. 1992, 298-300.
30. Cullis, P. M.; Green, R. E.; Merson-Davies, L.; Travis, N. Probing the Mechanism of Transport and Compartmentalization of Polyamines in Mammalian Cells. Chem. Biol. 1999, 6, 717-729.
31. Delcros, J.-G.; Tomasi, S.; Carrington, S.; Martin, B.; Renault, J. Effect of Spermine Conjugation on the Cytotoxicity and Cellular Transport of Acridine. J. Med. Chem. 2002, 45, 5098-5111.
32. 1-(Anthracen-9-ylmethyl)triamines as Molecular Recognition Elements for the Polyamine Transporter. J. Med. Chem. 2003, 46, 2663-2671.
33. Wang, C.; Delcros, J. G.; Biggerstaff, J.; Phanstiel, O., IV Molecular Requirements for Targeting the Polyamine Transport System. Synthesis and Biological Evaluation of Polyamine-Anthracene Conjugates. J. Med. Chem. 2003, 46, 2672-2682.
34. Wang, C.; Delcros, J. G.; Cannon, L.; Konate, F.; Carias, H.; Biggerstaff, J.; Gardner, R. A.; Phanstiel IV, O. Defining the Molecular Reqirements for the Selective Delivery of Polyamine-Conjugates into Cells Containing Active Polyamine Transporters. J. Med. Chem. 2003, 46, 5129-5138.
35. Wang, L.; Price, H. L.; Juusola, J.; Kline, M.; Phanstiel IV, O. Influence of Polyamine Architecture on the Transport and Topoisomerase II Inhibitory Properties of Polyamine DNA-Intercalator Conjugates. J. Med. Chem. 2001, 44, 3682-3691.
36. Pourquier, P.; Takebayashi, Y.; Urasaki, Y.; Gioffre, C.; Kohlhagen, G.; Pommier, Y. Induction of Topoisomerase I Cleavage Complexes by 1-β-Arabinofuranosylcytosine (ara-C) in vitro and in Ara-C-treated Cells. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 1885-1890.
37. Pommier, Y.; Fesen, M. R.; Goldwasser, F. Topoisomerase II Inhibitors: the Epipodophyllotoxins, m-AMSA, and the Ellipticine Derivatives. Cancer Chemotherapy and Biotherapy: Principles and Practice; Lippincott-Raven: Philadelphia, 1996; pp 435-461.
38. Jayaraman, M.; Fox, B. M.; Hollingshead, M.; Kohlhagen, G.; Pommier, Y.; Cushman, M. Synthesis of New Dihydroindeno-[1,2-clisoquinoline and Indenoisoquinolinium Chloride Topoisomerase I Inhibitors Having High in Vivo Anticancer Activity in the Hollow Fiber Animal Model. J. Med. Chem. 2002, 45, 242-249.
39. Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. New Modification of the Pomeranz-Fritsch Isoquinoline Synthesis. J. Chem. Soc., Perkin Trans. 1 1974, 2185-2190.
40. Jayaraman, M.; Fanwick, P. E.; Cushman, M. Novel Oxidative Transformation of Indenoisoquinolines to Isoquinoline-3-spiro-3-phthalides in the Presence of Osmium Tetroxide and 4-Methylmorpholine N-Oxide. J. Org. Chem. 1998, 63, 5736-5737.
41. Wang, Z.; Yang, D.; Mohanakrishnan, A. K.; Fanwick, P. E.; Nampoothiri, P.; Hamel, E.; Cushman, M. Synthesis of B-Ring Homologated Estradiol Analogues that Modulate Tubulin Polymerization and Microtubule Stability. J. Med. Chem. 2000, 43, 2419-2429.