Abstract
A series of N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones (aminoalkyl=2-aminoethyl, 3-aminoprop-1-yl and 4-aminobut-1-yl) was functionalized with trans-platinum DNA-binding moieties. Cytotoxicity testing in A2780 human ovarian carcinoma cells revealed high anticancer activity of the formed cationic dinuclear platinum complexes. The cationic dinuclear platinum complexes with the shortest aminoalkyl chain were shown to be the most active, which agrees with the structure–activity relationship found for the corresponding free ligands without platinum. The N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones partly circumvent cisplatin resistance, whereas their dinuclear platinum complexes were found susceptible to the resistance mechanisms in A2780cisR. The platinum complexes have resistance factors comparable to the control dinuclear complex BBR3005 [{trans-PtCl(NH3)2}2{μ-(NH2(CH2)6NH2)}](NO3)2. The 1,4-diaminoanthraquinone moiety is fluorescent, and thus the cellular processing of the compounds could be monitored by time-lapse digital fluorescence microscopy. The intercalators without platinum were shown to enter the cells within minutes. The platinum complexes enter the cells more slowly. Most likely, the positive charges of the platinum complexes hamper the diffusion through the membrane. Interestingly, the platinum complexes are processed differently than the platinum-free compounds by the cells. After 24 hours the fluorescent platinum complexes are encapsulated in large vesicles in the cytosol. Co-localization of the anthraquinone fluorescence with Lysotracker Green DND-26 shows that these vesicles are acidic compartments, probably lysosomes.
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Abbreviations
- AQ2:
-
N,N′-bis(2-aminoethyl)-1,4-diaminoanthracene-9,10-dione
- AQ3:
-
N,N′-bis(3-aminoprop-1-yl)-1,4-diaminoanthracene-9,10-dione
- AQ4:
-
N,N′-bis(4-aminobut-1-yl)-1,4-diaminoanthracene-9,10-dione
- MTT:
-
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide
- PAQ2:
-
[{trans-PtCl(NH3)2}2(μ-AQ2)](NO3)2
- PAQ3:
-
[{trans-PtCl(NH3)2}2(μ-AQ3)](NO3)2
- PAQ4:
-
[{trans-PtCl(NH3)2}2(μ-AQ4)](NO3)2
- PBS:
-
phosphate buffered saline
References
Hambley TW (1997) Coord Chem Rev 166:181–223
Wong E, Giandomenico CM (1999) Chem Rev 99:2451–2466
Farrell N, Qu Y, Bierbach U, Valsecchi M, Menta E (1999) Cisplatin, chemistry and biochemistry of a leading anticancer drug. Wiley-VCH, Weinheim, pp 479–496
Farrell N (1999) J Inorg Biochem 74:23–23
Reedijk J (2003) Proc Natl Acad Sci USA 100:3611–3616
Di Blasi P, Bernareggi A, Beggiolin G, Piazzoni L, Menta E, Formento ML (1998) Anticancer Res 18:3113–3117
Pratesi G, Perego P, Polizzi D, Righetti SC, Supino R, Caserini C, Manzotti C, Giuliani FC, Pezzoni G, Tognella S, Spinelli S, Farrell N, Zunino F (1999) Br J Cancer 80:1912–1919
Roberts JD, Peroutka J, Farrell N (1999) J Inorg Biochem 77:51–57
Roberts JD, Beggiolin G, Manzotti C, Piazzoni L, Farrell N (1999) J Inorg Biochem 77:47–50
Manzotti C, Pratesi G, Menta E, Di Domenico R, Cavalletti E, Fiebig HH, Kelland LR, Farrell N, Polizzi D, Supino R, Pezzoni G, Zunino F (2000) Clin Cancer Res 6:2626–2634
Komeda S, Lutz M, Spek AL, Chikuma M, Reedijk J (2000) Inorg Chem 39:4230–4236
Qu Y, Rauter H, Fontes APS, Bandarage R, Kelland LR, Farrell N (2000) J Med Chem 43:3189–3192
Perego P, Gatti L, Caserini C, Supino R, Colangelo D, Leone R, Spinelli S, Farrell N, Zunino F (1999) J Inorg Biochem 77:59–64
Perego P, Caserini C, Gatti L, Carenini N, Romanelli S, Supino R, Colangelo D, Viano I, Leone R, Spinelli S, Pezzoni G, Manzotti C, Farrell N, Zunino F (1999) Mol Pharmacol 55:1108–1108
Jansen BAJ, van der Zwan J, den Dulk H, Brouwer J, Reedijk J (2001) J Med Chem 44:245–249
Rauter H, Di Domenico R, Menta E, Oliva A, Qu Y, Farrell N (1997) Inorg Chem 36:3919–3927
Cox JW, Berners-Price S, Davies MS, Qu Y, Farrell N (2001) J Am Chem Soc 123:1316–1326
Zee-Cheng RK-Y, Podrebarac EG, Menon CS, Cheng CC (1979) J Med Chem 22:501–505
Krapcho AP, Getahun Z, Avery KL, Vargas KJ, Hacker MP, Spinelli S, Pezzoni G, Manzotti C (1991) J Med Chem 34:2373–2380
Gibson D, Binyamin I, Haj M, Ringel I, Ramu A, Katzhendler J (1997) Eur J Med Chem 32:823–831
Gibson D, Mansur N, Gean KF (1995) J Inorg Biochem 58:79–88
Gibson D, Gean KF, Benshoshan R, Ramu A, Ringel I, Katzhendler J (1991) J Med Chem 34:414–420
Kitov S, Benshoshan R, Ringel I, Gibson D, Katzhendler J (1988) Eur J Med Chem 23:381–383
Gean KF, Benshoshan R, Ramu A, Ringel I, Katzhendler J, Gibson D (1991) Eur J Med Chem 26:593–598
Mikata Y, Yokoyama M, Mogami K, Kato M, Okura I, Chikira M, Yano S (1998) Inorg Chim Acta 279:51–57
Mikata Y, Mogami K, Kato M, Okura I, Yano SB (1997) Bioorg Med Chem Lett 7:1083–1086
Ceci E, Cini R, Karaulov A, Hursthouse MB, Maresca L, Natile G (1993) J Chem Soc Dalton Trans 2491–2497
Cullinane C, Wickham G, McFadyen WD, Denny WA, Palmer BD, Phillips DR (1993) Nucleic Acids Res 21:393–400
Goodgame DML, Page CJ, Stratford IJ (1991) Transition Met Chem 16:223–229
Bowler BE, Ahmed KJ, Sundquist WI, Hollis LS, Whang EE, Lippard SJ (1989) J Am Chem Soc 111:1299–1306
Murray V, Motyka H, England PR, Wickham G, Lee HH, Denny WA, McFadyen WD (1992) J Biol Chem 267:18805–18809
Temple MD, McFadyen WD, Holmes RJ, Denny WA, Murray V (2000) Biochemistry 39:5593–5599
Jamieson ER, Lippard SJ (1999) Chem Rev 99:2467–2498
Smith PJ, Desnoyers R, Blunt N, Giles Y, Patterson LH, Watson JV (1997) Cytometry 27:43–53
Molenaar C, Teuben JM, Heetebrij RJ, Tanke HJ, Reedijk J (2000) J Biol Inorg Chem 5:655–665
Qu Y, Farrell N (1992) Inorg Chem 31:930–932
Jansen BAJ, van der Zwan J, Reedijk J, den Dulk H, Brouwer J (1999) Eur J Inorg Chem 1429–1433
Kaufman EB, Cowan DO (1968) Inorg Synth 7:242–245
Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Cancer Res 48:589–601
Krapcho AP, Getahun Z, Avery KJ (1990) Synth Commun 20:2139–2146
Zhen WP, Link CJ, O’Connor PM, Reed E, Parker R, Howell SB, Bohr VA (1992) Mol Cell Biol 12:3689–3698
Kelland LR, Barnard CFJ, Mellish KJ, Jones M, Goddard PM, Valenti M, Bryant A, Murrer BA, Harrap KR (1994) Cancer Res 54:5618–5622
Holford J, Sharp SY, Murrer BA, Abrams M, Kelland LR (1998) Br J Cancer 77:366–373
Kelland LR, Barnard CFJ, Evans IG, Murrer BA, Theobald BRC, Wyer SB, Goddard PM, Jones M, Valenti M, Bryant A, Rogers PM, Harrap KR (1995) J Med Chem 38:3016–3024
Kalayda GV, Jansen BAJ, Wielaard P, Molenaar C, Tanke HJ, Reedijk J (2004) J Biol Inorg Chem 9:(accompanying paper)
Huxham IM, Barlow AL, Lewis AD, Plumb J, Mairs RJ, Gaze MN, Workman P (1994) Int J Cancer 59:94–102
Arancia G, Calcabrini A, Meschini S, Molinari A (1998) Cytotechnology 27:95–111
Bour-Dill C, Gramain MP, Merlin JL, Marchal S, Guillemin F (2000) Cytometry 39:16–25
Beyer U, Rothen-Rutishauser B, Unger C, Wunderli-Allenspach H, Kratz F (2001) Pharm Res 18:29–38
Racoosin EL, Swanson JA (1993) J Cell Biol 121:1011–1020
Kim JH, Lingwood CA, Williams DB, Furuya W, Manolson MF, Grinstein S (1996) J Cell Biol 134:1387–1399
Jansen BAJ, Brouwer J, Reedijk J (2002) J Inorg Biochem 89:197–202
Aggarwal SK (1993) J Histochem Cytochem 41:1053–1073
Litterst CL (1984) Agents Actions 15:520–524
Dietel M (1991) Pathol Res Pract 187:892–905
Edwards PG, Kendall MD, Morris IW (1991) Scanning Microsc 5:797–810
Cece R, Petruccioli MG, Cavaletti G, Barajon I, Tredici G (1995) Histol Histopathol 10:837–845
Muenchen HJ, Aggarwal SK (1998) Anticancer Res 18:2631–2636
Berners-Price SJ, Kuchel PW (1990) J Inorg Biochem 38:305–326
Reedijk J (1999) Chem Rev 99:2499–2510
Oehlsen ME, Qu Y, Farrell N (2003) Inorg Chem 42:5498–5506
Acknowledgements
The authors are indebted to the EU for a grant as a Training Host Institute in the EU programme Human Capital and Mobility. Also support and sponsorship by COST Actions D20/0001/00, D20/0002/00 and D20/003/01 (biocoordination chemistry) is kindly acknowledged. The authors wish to thank Johnson Matthey (Reading, UK) for their generous gift of K2PtCl4. This work has been performed under auspices of the joint BIOMAC Research Graduate School of Leiden University and Delft University of Technology.
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Jansen, B.A.J., Wielaard, P., Kalayda, G.V. et al. Dinuclear platinum complexes with N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones as linking ligands. Part I. Synthesis, cytotoxicity, and cellular studies in A2780 human ovarian carcinoma cells. J Biol Inorg Chem 9, 403–413 (2004). https://doi.org/10.1007/s00775-004-0539-y
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DOI: https://doi.org/10.1007/s00775-004-0539-y