QSAR of acridines. II. Features of nitracrine analogs for high anti-tumor activity and selectivity on mice, searched by PCA and MRA methods.

A study of quantitative structure-activity relationships (QSAR) of 32 nitro-9-aminoacridine derivatives has been carried out. The results of the four biological tests in vitro, anti-tumor activity against S-180 and toxicity on healthy as well as on tumor bearing mice were subjected to principal component analysis (PCA). Two significant principal components PC1 and PC2 (containing 81.4% and 8.1% of total data set information, respectively) were extracted. The biological meaning of PCs was identified: PC1 corresponds to a general biological activity, PC2 mainly to selectivity. To obtain predictability of biological activities multiple regression analysis (MRA) for PC1 and PC2 were used. The general biological activity (PC1) is parabolically dependent on the lipophilicity (log P*) of the substituent on 9-amino group (R = 0.97); selectivity (PC2), however, on the shape index 2K and the indicator variable IN2N (R = 0.76). For high antitumor activity and improved therapeutic effectivity (LD50/ED50) 1-nitro-9-amino-acridines should be characterized by: (i) lipophilicity, expressed as log P*, between -1 and -2; (ii) three or more methylene spacers between proximal and distal nitrogen atoms in the side chain, if the distal nitrogen is present; (iii) high 2K value for the side chain, as for a large and preferably unbranched substituent on C9.

Comparison of antitumor properties of nitracrine and amsacrine analogs.

For seven new methoxy and/or nitro derivatives of acridine antitumor drugs, nitracrine and amsacrine, biological activity in a few in vitro tests, as well as activity against experimental murine tumors Sarcoma-180 and Leukemia L1210 were investigated. Acute toxicity on mice (LD50) was also determined. High activity in vitro and specific activity against Sa-180 were found to be characteristic features of nitracrine, whereas amsacrine was characterized by high antileukemic activity. Methoxylation of position 2 of the acridine ring in both drugs suppressed their characteristic activity. Besides, substitution of the aminoalkyl side chain in nitracrine by methanesulfon-m-anisidine group suppressed its high antitumor activity, and the presence of a nitro group in position 1 of amsacrine suppressed its antileukemic activity. Comparison of biological properties of nitracrine, amsacrine and their analogs indicated differences in some steps of their mode of action.

Intercalation model for DNA-cross linking in a 1-nitro-9-aminoacridine derivative, an analog of the antitumor agent "ledakrin" (nitracrine).

Ledakrin (nitracrine), C-283, is a 1-nitro-9-aminoacridine derivative that is used in Poland as an antitumor agent. In order to investigate the basis of the activity of this compound the structure of another analog, [9-(3-dimethyl-1-methylpropylimino)-1-nitro-9,10-dihydroacridin e], C-829, that has similar activity, was determined by X-ray crystallographic techniques and was compared with that of ledakrin, already reported in the literature. In both molecules the proximity of the 1-nitro to the substituted 9-aminoacridine group causes extensive distortions. These compounds are believed to act, after metabolic "activation", by cross-linking DNA. Such cross-linking does not occur in the absence of the 1-nitro group or if the nitro group is moved to the 2-, 3- or 4-position. Computer-assisted model-building has been used to test possible intercalative models. It has shown that functional groups on C-829 or C-283 are, when the acridine portion of the molecule is intercalated as in a proflavine dinucleoside phosphate complex, in positions suitable for DNA cross-linking by activated 1-nitro-9-aminoacridine derivatives.

Antitumor activity of 1-nitro-9-aminoacridine derivatives.

Results of studies on the antitumor activity of 26 newly synthetized 1-nitro-9-aminoacridine derivatives by means of in vitro and in vivo tests are presented. 15 derivatives among those showed repeated activity against the sarcoma growth. There were compounds with alkylaminopropyl chains, with hydroxyalkyl-aminoalkyl chains and also with hydroxyalkyl chains on amino group of 1-nitro-9-aminoacridine molecule. The other compounds with aminoacids in position 9 of 1-nitroacridine were active at higher doses. The remaining 7 compounds did not show any antitumor activity. Some aspects of the cellular antineoplastic response, as well as the morphologic appearance of the tumor invasion zone, were studied in comparison with the results of the screening tests. It seems that apart from the structural similarity each derivative has an individual influence on the host reactivity during the tumor growth.

Search for antitumor compounds. XIII. Biological studies. Antitumor properties of 20 quinolines, carbazoles, acridines nitro derivatives.

Results of the studies on antitumor activity of 20 acridines and related compounds (19 of them were new) in Sa-180-bearing mice are presented. Only several of these compounds i.e. C-258, C-829, C-874, and C-899(21) appeared to inhibit the Sa-180 growth; the activity of the two other compounds (C-783(21) and C-755(21)) requires confirmation in further experiments. The remaining 14 compounds were inactive. Some other general effects exerted by the compounds tested in Sa-180-bearing mice and some aspects of the structure-activity relationship are discussed.

A search for antitumor compounds. XII. Biologic studies. Antitumor properties of 12 new 1-nitro-9alkylaminoalkylaminoacridines.

Results of the studies on antitumor activity of 12 new 1-nitro-9-alkylaminoalkylaminacridines in mice bearing Sa-180 are presented. Only one of these compounds, viz. C-846 was active repeatedly in Sa-180 test; the activity of 5 other compounds tested (C-845, C-848, C-852, C-865 and C-866) requires further elucidation by means of new tests with Sa-180. The remaining 6 compounds were inactive. Some other general effects in mice bearing Sa-180 and some aspects of the structure-activity relationship are discussed.

A search for antitumor compounds. XI. Biologic studies. Antitumor properties of 19 new 9-aminoacridine and 1-or 3-nitro-9-aminoacridine derivatives.

Results of studies on the antitumor activity of six 9-aminoacridine derivatives, four 3-nitro-9-aminoacridine derivatives, four 1-nitro-9-aminoacridine derivatives and five N-oxide of 1-nitro-9-aminoacridine derivatives in mice bearing Sa-180 of compound C-709 requires confirmation by further tests with Sa-180. The remaining 15 compounds were inactive. Some other general effects in the mice and some aspects of the structure-activity relationship are discussed.