Synthesis and biological activity of 5-aza-ellipticine derivatives

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 8, 2007, Pages 2380-2384

  Moody, Deborah L ^a   Dyba, Marcin ^a   Kosakowska Cholody, Teresa ^a   Tarasova, Nadya I ^a   Michejda, Christopher J ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

Author keywords

5 Aza ellipticine; Anti tumor agents; Ellipticine; Topoisomerase II

Indexed keywords

ANTINEOPLASTIC AGENT; ELLIPTICINE DERIVATIVE;

ANTINEOPLASTIC ACTIVITY; ARTICLE; DRUG SYNTHESIS; ENZYME INHIBITION; STRUCTURE ACTIVITY RELATION;

ANTINEOPLASTIC AGENTS; AZA COMPOUNDS; CELL LINE; CELL SURVIVAL; DNA TOPOISOMERASES, TYPE II; ELLIPTICINES; HUMANS; INHIBITORY CONCENTRATION 50; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33947589851     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.09.093     Document Type: Article

References (22)

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14. ® Prep RP18 column from Waters (19 mm id × 300 mm, 10 μm pore size). Acetonitrile/water gradient with 0.1% TFA was used as the eluent for all purifications. Mass spectroscopic analysis was preformed using a Agilent Series 1100 MSD HPLC-MS with atmospheric pressure ionization electrospray (API-ES). The colums used were the Agilent Poroshell 300 SB-C18 (2.1 mm id × 75 mm, 5 μm pore size) and the Zorbax 300 SB-C18 (2.1 mm id × 150 mm, 5 μm pore size). NMR's were recorded on Varian 200 or 400 MHz instruments. The de-catenation assay was preformed using a kit from TopoGen, Inc. (Port Orange, FL).
15. Compounds 8-10 were the products of nucleophilic aromatic substitution on 7 under standard conditions. Because the C1 position on 7 was the only site with an activated leaving group for nucleophilic substitution, the structures were verified using HPLC-ESI-MS. The compounds identified were either the starting material 7 or the product 8, 9 or 10. Compounds 11-16 were the products of nucleophilic aromatic substitution on either the 5-methylated or 5-ethylated derivative of 7. Byproducts that were formed were identified with the products by using HPLC-ESI-MS.
16. 1H δ 6.81 (1H, d, J = 2.9 Hz), 6.72 (1H, dd, J = 8.7, 2.9 Hz), 6.63 (1H, D, J = 8.7 Hz), 3.72 (3H, s), 2.11 (3H, s).
17. 1H δ 6.91 (1H, d, J = 8.9 Hz), 6.89 (1H, d, J = 2.9 Hz), 6.75 (1H, dd, J = 8.9, 3.0 Hz), 3.76 (3H, s), 2.12 (3H, s).
18. 13C 161.2, 151.5, 148.6, 151.5, 151.4, 132.6, 132.5, 132.4, 129.6, 129.1, 128.9, 128.6, 117.8, 117.7, 117.6, 117.5.
19. 1H δ 8.19 (1H, d, J = 6.0 Hz), 8.01 (1H, s), 7.85 (2H, dd,) 7.44-7.70 (60H, m), 7.31 (1H, dd, J = 9.1, 2.8 Hz), 7.01 (1H, d, J = 2.7 Hz), 3.92 (3H, s), 2.46 (3H, s).
20. Synthesis of 8. Compound 7 (0.0093 g, 0.03 mmol) was stirred with 3,3′-diamino-N-methyldipropylamine (1 ml, 6.2 mmol) under argon at 150 °C for 46 h. The mixture was concentrated and purified by flash chromatography on basic alumina with methanol in chloroform with a 0-5% gradient in 80 min. The mixture was dissolved in 1:1 acetonitrile/water and purified by preparative HPLC on a C18 column using a water/acetonitrile solvent system. The purity of the compound was established by HPLC-ESI-MS. Compounds 9 and 10 were prepared in an analogous manner.
21. Synthesis of 11 and 13. A solution of 7 (0.0062 g, 0.02 mmol) in anhydrous dichloromethane was treated with methyl trifluoromethane sulfonate (2.8 μl, 0.025 mmol) and stirred at room temperature for 24 h, concentrated, and dissolved directly in an excess of N-(3-aminopropyl)-1,3-propanediamine and stirred for 1 h at room temperature. The product was purified by reverse phase preparative HPLC using a C18 column and water/acetonitrile solvent system. The side product, 13, was isolated from the HPLC separation. The purity of the compounds were established by HPLC-ESI-MS. A similar procedure was used for the preparation of compound 12.
22. Synthesis of 14, 15, and 16. A solution of 7 (0.0055 g, 0.019 mmol) in anhydrous dichloromethane was treated with ethyl trifluoromethanesulfonate (5 μl, 0.039 mmol) and stirred for 160 h at 30 °C. Additional 5 μl portions of ethyl trifluoromethanesulfonate and 1 ml portions anhydrous dichloromethane were added every 48 h. The product was concentrated and used directly in a reaction with N-(3-aminopropyl)-1,3-propanediamine (3.2 μl, 0.022 mmol). The mixture dissolved in 1 ml THF was stirred for 1 h at room temperature. The products were separated and purified by reverse phase preparative HPLC using a C18 column and water/acetonitrile solvent system. Compounds 16 and 15 were side products of the reaction. The purity of the compounds was determined by HPLC-ESI-MS.