2-[3-(Aziridin-1-yl)-2-hydroxypropyl]-5,5-dimethyl-2,5-dihydro-4H-benzo[e]isoindol-4-one (Cytotoxic Oxonaphthalene-Pyrroles, Part III)

Helmut Spreitzer; Christiane Puschmann

doi:10.3390/M772

and

Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna, Althanstraße 14, A- 1090 Vienna, Austria

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Author to whom correspondence should be addressed.

Molbank2012, 2012(3), M772;https://doi.org/10.3390/M772

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Abstract

An hydroxypropyl-aziridine-containing side chain is attached to an oxonaphthalene-annelated pyrrole in expectation of DNA alkylating properties. The cytotoxicity is evaluated against two cell lines, KB-31 and KB-8511, respectively.

Keywords:

pyrrole; DNA-alkylation; anticancer

Introduction

Chlorambucil and melphalan are chemotherapy drugs belonging to the class of nitrogen mustard alkylating agents. Both compounds are believed to exert their antitumor effects by cross-linking DNA via aziridinium cation intermediates arising from the bis(2-chloroethyl)amine moiety [1]. Besides that there are anticancer agents with the aziridine moiety, such as TEPA, thio-TEPA and triethylenemelamine with a 1,3,5-triazine nucleus. In continuation of our department’s previous studies in the field of antitumor agents [2,3,4,5,6,7,8,9,10], we are reporting in this paper the synthesis of the oxonaphthalene-annelated pyrrole 2 with an attached side chain containing an aziridine group. The rationale is that the three-membered aziridine ring is struturally analogous to the immonium-intermediate formed from the nitrogen mustards. The aziridine moietiy is not charged and the reactivity results from the strain on the three-member ring structure [11]. Recent studies with aziridine substituted quinones showed promising results against breast cancer tumor cells [12,13]. The cytotoxic activity of 2 was evaluated.

Results and Discussion

Reaction of 1 [14] with 2-(chloromethyl)oxirane with KOH in DMSO [15] afforded the N-alkylated product. The following reaction with aziridine [16] gave the target compound 2 (Scheme 1). The biological activity of 2 was tested against two cancer cell lines, KB-31 and KB-8511, respectively. KB-31 is a drug sensitive human epidermoid cell line, whereas KB-8511 is a multi-drug resistant subline, typically overexpressing P-glycoprotein. The IC₅₀[μM] values of 2 are 9.362 (KB-31) and 6.452 (KB-8511), respectively (3 days incubation time; staining with 0.05% methylene blue; optical density measured at 665 nm; for further experimental details, see [17,18]).

Scheme 1. Synthesis of target compound 2.

Experimental

2-[3-(Aziridin-1-yl)-2-hydroxypropyl]-5,5-dimethyl-2,5-dihydro-4H-benzo[e]isoindol-4-one (2)

(a) To a solution of 1 [12] (0.5 g, 2.37 mmol) in 4.7 mL of dry DMSO were added at room temperature dropwise under argon 1.5 mL (18.96 mmol) of 2-(chloromethyl)oxirane. Subsequently 0.265 g (4.74 mmol) of KOH were added and stirring was continued for 2 h at room temperature. The reaction mixture was diluted with 9.5 ml of H₂O, extracted with CH₂Cl₂, dried (Na₂SO₄), concentrated in vacuo and isolated after column chromatography (silica gel, ethyl acetate/light petroleum 70/30). Yield 284 mg (45%) of a colorless oil.

(b) The resulting product (284 mg) was dissolved in 4.6 ml EtOH (1% TEA) and after the addition of 0.37 mL (7.2 mmol) of aziridine under argon the reaction mixture was refluxed for 1 h. After concentration in vacuo the resulting crude product was purified by column chromatography (silica gel, ethyl acetate/ethanol 95/5) to afford 104 mg (32%) of colorless crystals of 2. m.p.: 118–119 °C (ethyl acetate/ethanol). IR (KBr): 3397, 1650, 1526, 1208, 1159 cm⁻¹. MS (EI, 70 eV) m/z: 310 (M⁺, 5%), 268 (M⁺-42, 0.5), 101 (20), 59 (100), 58 (42), 57 (33), 56 (28), 55 (26), 45 (26). ¹H-NMR (CDCl₃, 200 MHz) δ = 7.56 (m, 1H, 9-H), 7.43 (m, 1H, 6-H), 7.40 (d, J = 2.2 Hz, 1H, 3-H), 7.22 (m, 2H, 7-H, 8-H), 7.10 (d, J = 2.2 Hz, 1H, 1-H), 4.14–3.99 (m, 3H, 1'-H, 2'-H), 3.8 (s_br, 1H, OH), 2.41 (dd, J = 7.5 and 12 Hz, 1H, 3'-H), 2.12 (dd, J = 3.8 and 12 Hz, 1H, 3'-H), 1.82–1.73 (m, 2H, aziridine-CH₂), 1.50 (s, 6H, (CH₃)₂), 1.29–1.16 (m, 2H, aziridine-CH₂). ¹³C-NMR (CDCl₃, 50 MHz) δ = 198.6 (C-4), 144.1 (C-5a), 127.1(C-6), 126.8 (C-9a), 126.6 (C-7), 126.2 (C-8), 125.0 (C-9b), 124.1(C-3), 122.7 (C-9), 118.3 (C-3a), 116.1 (C-1), 70.3 (C-2'), 64.0 (C-3'), 54.3 (C-1'), 47.6 (C-5), 28.2/28.1((CH₃)₂), 27.6/27.2 (2× aziridine-CH₂). HRMS calc. for C₁₉H₂₂N₂O₂: 310.94 Calc.: 310.1680. Found: 310.1680.

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3

Acknowledgments

We are indebted to Novartis AG (Vienna, Austria) for the evaluation of the cytotoxic activity.

References and Notes

Montgomery, J.A. Agents That React with DNA. In Cancer Chemotherapeutic Agents, ACS Professional Reference Book; Foye, W.O., Ed.; American Chemical Society: Washington, DC, USA, 1995; pp. 111–121. [Google Scholar]
Pongprom, N.; Müller, G.; Schmidt, P.; Holzer, W.; Spreitzer, H. Synthesis of anticancer compounds, III (Bioorg Med Chem Lett 17, 6091, 2007), carbinol derivatives of azanaphthoquinone annelated pyrroles. Monatsh. Chem. 2009, 140, 309–313. [Google Scholar] [CrossRef]
Shanab, K.; Pongprom, N.; Wulz, E.; Holzer, W.; Spreitzer, H.; Schmidt, P.; Aicher, B.; Mueller, G.; Günther, E. Synthesis and biological evaluation of novel cytotoxic azanaphthoquinone annelated pyrrolo oximes. Bioorg. Med. Chem. Lett. 2007, 17, 6091–6095. [Google Scholar] [CrossRef] [PubMed]
Spreitzer, H.; Puschmann, C. Dual function antitumor agents based on bioreduction and DNA-alkylation. Monatsh. Chem. 2007, 138, 517–522. [Google Scholar] [CrossRef]
Haider, N.; Sotelo, E. 1,5-Dimethyl-6H-pyridazino[4,5-b]carbazole, a 3-Aza bioisoster of the antitumor alkaloid olivacine. Chem. Pharm. Bull. 2002, 50, 1479–1483. [Google Scholar] [CrossRef] [PubMed]
Haider, N.; Kabicher, T.; Käferböck, J.; Plenk, A. Synthesis and in-vitro antitumor activity of 1-[3-(indol-1-yl)prop-1-yn-1-yl]phthalazines and related compounds. Molecules 2007, 12, 1900–1909. [Google Scholar] [CrossRef] [PubMed]
Haider, N.; Jbara, R.; Käferböck, J.; Traar, U. Synthesis of tetra- and pentacyclic carbazole-fused imides as potential antitumor agents. ARKIVOC 2009, vi, 38–47. [Google Scholar]
Spreitzer, H.; Puschmann, C. Regioselective alkylation of an oxonaphthalene-annelated pyrrol system. Molbank 2009, 2009, M619. [Google Scholar] [CrossRef]
Spreitzer, H.; Puschmann, C. 2-[4-[Bis(2-chloroethyl)amino]benzyl]-5,5-dimethyl-2,5-dihydro-4H-benzo[e]isoindol-4-one (Cytotoxic Oxonaphthalene-Pyrroles, Part I). Molbank 2010, 2010, M651. [Google Scholar] [CrossRef]
Spreitzer, H.; Holzer, W.; Puschmann, C.; Pichler, A.; Kogard, A.; Tschetschkowitsch, K.; Heinze, T.; Bauer, S.; Shabaz, N. Synthesis and NMR-investigation of annelated pyrrole derivatives. Heterocycles 1997, 45, 1989–1997. [Google Scholar] [CrossRef]
Spreitzer, H.; Holzer, W.; Fülep, G.; Puschmann, C. N-substituted 5,5-dimethyl-2,5-dihydro-4H-isoindol-4-ones: Synthesis and NMR-investigation. Heterocycles 1996, 43, 1911–1922. [Google Scholar] [CrossRef]
Huang, C.H.; Kuo, H.S.; Liu, J.W.; Lin, Y.L. Synthesis and Antitumor Evaluation of Novel Bis-Triaziquone Derivatives. Molecules 2009, 14, 2306–2316. [Google Scholar] [CrossRef] [PubMed]
Lin, Y.L.; Su, Y.T.; Chen, B.H. A study on inhibition mechanism of breast cancer cells by bis-type triziquone. Eur. J. Pharmacol. 2010, 637, 1–10. [Google Scholar] [CrossRef] [PubMed]
Brown, F.J.; Bernstein, P.R.; Cronk, L.A.; Dosset, D.L.; Hebbel, K.C.; Maduskuie, T.P., Jr.; Shapiro, H.S.; Vacek, E.P.; Yee, Y.K.; Willard, A.K.; et al. Hydroxyacetophenone-derived antagonists of the peptidoleukotrienes. J. Med. Chem. 1989, 32, 807–826. [Google Scholar] [CrossRef] [PubMed]
Giancaspro, G.I.; Pizzorno, M.T.; Albonico, S.M.; Bindstein, E.; Garofalo, A.; Zeichen, R. Synthesis of disubstituted tetrahydrocarbazoles with potential antidepressant activity. Farmaco 1989, 44, 483–493. [Google Scholar] [PubMed]
Naylor, M.A.; Threadgill, M.D.; Webb, P.; Startford, I.J.; Stephens, M.A.; Fielder, G.E.; Adams, G.E. 2-Nitroimidazole dual-function bioreductive drugs: Studies on the effects of regioisomerism and side-chain structural modifications on differential cytotoxicity and radiosensitization by aziridinyl and oxiranyl derivatives. J. Med. Chem. 1992, 35, 3573–3578. [Google Scholar] [CrossRef] [PubMed]
Meyer, T.; Regenass, U.; Fabbro, D.; Alteri, E.; Rösel, J.; Müller, M.; Caravatti, G.; Matter, A. A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int. J. Cancer 1989, 43, 851–856. [Google Scholar] [CrossRef] [PubMed]
Nicolaou, K.C.; Scarpelli, R.; Bollbuck, B.; Werschkun, B.; Pereira, M.M.; Wartmann, M.; Altmann, K.H.; Zaharevitz, D.; Guscio, R.; Giannakakou, P. Chemical synthesis and biological properties of pyridine epothilones. Chem. Biol. 2000, 7, 593–599. [Google Scholar] [CrossRef]

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