J.Med. Chem. 1990, 33,49-52
49
5-[ (Aminoalkyl)amino]imidazo[4,5,1-de]acridin-6-onesas a Novel Class of Antineoplastic Agents. Synthesis and Biological Activity Wieslaw M. Cholody,*pt Sante Martelli,' Jolanta Paradziej-Lukowicz,t and Jerzy Konopat Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdansk, 80952 Gdansk, Poland, a n d Department of Chemical Sciences, University of Camerino, 62032 Camerino, Italy. Received April 11, 1988
A new class of antineoplastic agents, the 5-substituted imidazo[4,5,1-de]acridin-6-ones with an (aminoalky1)amino group in the side chain, has been made. These compounds were synthesized by reduction of 1-substituted 4nitroacridin-9( lOH)-ones and subsequent reaction of the derived amines with carboxylic acids. Their cytotoxic activity against HeLaSBcells in tissue culture and in vivo antitumor activity against P388 leukemia in mice was demonstrated. A strict relationship between the antineoplastic activity and the number of methylene spacers between proximal and distal nitrogens in the side chain was established.
Several classes of compounds including the anthracenediones, viz. ametantrone' and mitoxantrone,2 anthrapyrazoles (e.g. 1),3 SH-thioxanthen-9-ones,4 acridine-4carboxamide~,~ phenazine-l-carboxamides,6substituted 1-amino-4-nitro acrid in one^^ (e.g. 2), pyrazolo[3,4,5-k1](CH2)2NHCH210H
N -N'
"\N/(CH25N(CH3)2
Q@ HO
0
H/N Y C H ~ ~ N H C H ~ ~ O H
H
acridines,s benzothiopyrano[4,3,2-cd]indazoles~ and 1,8naphthalimides'O can be distinguished among the currently recognized synthetic antineoplastic compounds designated as "DNA complexing agents". These compounds are characterized by two common features which seem to determine their antineoplastic activity: a planar, polycyclic nucleus, capable of binding to DNA by intercalation, and the occurrence of one or two side chains containing polymethylenediamine fragments in a strictly defined orientation to the chromophore. The structure-activity relationship studies for the side chains, particularly for the anthracenediones, point out the importance of the distance between both the amino groups and the type of substituents at the distal nitrogen for antineoplastic a ~ t i v i t y . ' * ~ * ~It J ' -has ~ ~been also suggested that the distal amino group binds electrostatically to the phosphate moieties of DNA1J4 or that the side chain has the function of additionally stabilizing a drug-DNA complex.15 The ethylenediamine moiety could also be important in cross-linking of DNA, according to the postulated mechanisms of action of anthracenediones."j It is generally accepted that the mechanistic role of the chromophore of many antineoplastic DNA binders consists in DNA intercalation. A desirable property of the chromophore should be its ability to act as a charge-transfer One of the most interesting chromophoric modifications of the basic tricyclic system has been the addition of another ring, leading to compounds with high antineoplastic activity. Anthrapyrazoles (1),3 pyrazoloconstitute sigacridines,8 and benzothi~pyranoindazoles~ nificant examples of such compounds. The hypothesized role of the added pyrazole ring is to increase the electron density of the ir system and to make the chromophore more resistant to enzymatic reduction to radical species.3c These findings, as they relate to antitumor activity and cardiotoxicity, suggested to us that further similar modifications could be made. Technical University of Gdansk.
1. nci
/
No2
2
1
* University of Camerino.
3: 1752 4: n d 5: n=5
11-22
En-5
lAc20
9:n-2 10:n:3
Taking into account these considerations, we synthesized and tested for antitumor activity a new class of compounds, (1) Zee-Cheng, R. K.-Y.; Cheng, C. C. J.Med. Chem. 1978,21,291.
(2) (a) Zee-Cheng, R. K.-Y.; Podrebarac, E. G.; Menon, C. S.; Cheng, C. C. J . Med. Chem. 1979,22,501. (b) Murdock, K. C.; Child, R. G.; Fabio, P. F.; Angier, R. B.; Wallace, R. E.; Durr, F. E.; Citarella, R. V. J. Med. Chem. 1979, 22, 1024. (3) (a) Showalter, H. D. H.; Johnson, J. L.; Werbel, L. M.; Leopold, W. R.; Jackson, R. C.; Elslager, E. F. J . Med. Chem. 1984,27, 253. (b) Leopold, W. R.; Nelson, J. H.; Plowman, J.; Jackson, R. C. Cancer Res. 1985,45, 5532. (c) Showalter, H. D. H.; Fry, D. W.; Leopold, W. R.; Lown, J. W.; Plambeck, J. A,; Reszka, K. Anti-Cancer Drug. Des. 1986,1, 73. (d) Showalter, H. D. H.; Johnson, J. L.; Hoftiezer, J. M.; Turner, W. R.; Werbel, L. M.; Leopold, W. R.; Shillis, J. L.; Jackson, R. C.; Elslager, E. F. J . Med. Chem. 1987, 30, 121. (4) Archer, S.; Miller, K. J.; Rej, R.; Periana, C.; Fricker, L. J. Med. Chem. 1982,25, 220. (5) (a) Atwell, G. J.; Cain, B. F.; Baguley, B. C.; Finlay, G. J.; Denny, W. A. J . Med. Chem. 1984,27,1481. (b) Atwell, G. J.; Rewcastle, G. W.; Baguley, B. C.; Denny, W. A. J.Med. Chem. 1987, 30, 664. (c) Wakelin, L. P. G.; Atwell, G. W.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1987,30,855. (6) Rewcastle, G. W.; Denny, W. A.; Baguley, B. C. J. Med. Chem. 1987, 30, 843. (7) Capps, D. B. European Patent Appl. E.P. 145226,1985; Chem. Abstr. 1985, 103, 215182s. (8) (a) Capps, D. B. European Patent Appl. E.P. 138302, 1985; Chem. Abstr. 1985, 103, 196074. (b) Sebolt, J. S.; Scavone, S. V.; Pinter, C. D.; Hamelehle, K. L.; Von Hoff, D. D.; Jackson, R. C. Cancer Res. 1987,47, 4299. (9) (a) Leopold, W. R.; Fry, D. W.; Nelson, J. M.; Plowman, J. Proc. Am. Assoc. Cancer Res. 1985,26, 253. (b) Showalter, H. D. H.; Angelo, M. M.; Berman, E. M.; Kanter, G. D.; Ortwine, D. F.; Ross-Kesten, S. G.; Sercel, A. D.; Turner, W. R.; Werbel, L. M.; Worth, D. F.; Elslager, E. F.; Leopold, W. R.; Shillis, J. L. J . Med. Chem. 1988,31, 1527.
0022-2623/90/1833-0049$02.50/00 1989 American Chemical Society
50 Journal of Medicinal Chemistry, 2990, Vol. 33, No. 1
Cholody et al.
Table I. Physical Properties and Cytotoxic and Antineoplastic Activities of 4-Substituted 1-[[(Dimethylamino)alkyI]aminolacridin-9(10H)-ones and 1-Substituted 5-[[~Dimethylamino)alkyl]amino]imidazo[4,5,l-de]acridin-6-ones Hydrochlorides in vivo P388 leukemiae 7 0 in vitrod compda n R yieldb mp, "C formulaC HeLa Ss ICso, wg/mL opt dose % T/U amentantrone 0.17 f 0.09 12.5 300 (3 cures) 2 250-252h3i 0.15 f 0.01 38 25 160, 166 48 3 250-255hJ 0.04 f 0.02 15 190 0.13 f 0.04 248-250"~~ 5 5 60 144 2.93 f 0.15 6 2 226-23Ohv' 100 toxic" 7 0.25 f 0.07 221-224h 3 25 toxicm 207-21 lh 1.05 f 0.15 8 5 not tested 9 2 166- 170" >5 75 137 179-182" 10 3 >5 not tested 267-26gh.p 11 2 0.06 f 0.05 150 180, 188 12 2 259-2629 0.05 f 0.02 50 190, 230 13 2 223-226' 0.11 f 0.01 100 200 228-231' 0.20 f 0.08 14 2 175 211, 233 15 2 0.20 f 0.09 201-206' 75 toxic'" 16 2 0.37 f 0.01 240-243" 150 166 17 0.43 f 0.02 2 226-228" 50 150 260-264hsW 0.15 f 0.08 18 3 100 133, 120 19 3 0.11 f 0.03 230-236hJ 150 122 20 0.25 f 0.05 228-233h" 90 130 3 21 3 0.28 f 0.08 216-221hf 30 110 22 225-228'" 5 0.50 f 0.20 100 110 'The compounds listed are hydrochlorides of the compounds listed in Scheme I. bYields reported refer to the free base and were not optimized. cAll compounds were analyzed for C, H, W. Values were within f0.4% of the theoretical values. dCytotoxic assay is based on a 72-h exposure time. For a detailed description of the assay, see: Pawlak, K.; Matuszkiewicz, A.; Pawlak, J. W.; Konopa, J. J . Chem. Biol. Inter. 1983,43, 131. A criterion for significant cytotoxic activity is 50% inhibition at a concentration
