Structure−Activity Relationships and Mechanism of Action of Antitumor Benzo[b]pyrano[3,2-h]acridin-7-one Acronycine Analogues

Abstract

The cytotoxic and antitumor activities of cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 3, 6-9 were strongly correlated with their ability to give covalent adducts with purified, as well as genomic, DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug. A transesterification process of the ester group from position 2 to position 1 in aqueous medium accounted for the intense activity of the cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 10-13. Compounds without acyloxy or hydroxy group at position 1, such as 15, 17, 18, and 22, were inert with respect to DNA and almost devoid of significant cytotoxic activity. Condensation of 5-amino-2,2-dimethyl-2H-chromene (26) with 3-bromo-2-naphthoic acid (27), followed by cyclization, gave access to 6-demethoxy analogues. Diacetate 32 and cyclic carbonate 33, both belonging to the latter series, were less reactive toward DNA and less cytotoxic than their 6-methoxy counterparts 3 and 34. DNA alkylation appears thus to play an important role in the antitumor properties of benzo[b]pyrano[3,2-h]acridin-7-one derivatives.

Synthesis and Cytotoxic Activity of Acronycine Analogues in the Benzo[c]pyrano[3,2-h]acridin-7-one and Naphtho[1,2-b][1,7] and [1,10]-Phenanthrolin-7(14H)-one Series

“…9,11,24) In contrast, introduction of an additional aromatic ring angularly fused in position [c] on the acronycine tetracyclic system did not lead to a significant increase in the activity. This result is consistent with the mechanism of action postulated for acronycine and benzo [b]acronycine, which involves bioactivation into the corresponding 1,2-epoxide able to alkylate nucleophilic DNA sites within the tumor cell.…”

“…The strategy used to build up the pentacyclic basic core of benzo[c]acronycine (3) was similar to that previously developed for the syntheses of acronycine, 18) 6-demethoxyacronycine, 19) and 6-demethoxybenzo[b]acronycine, 11) through Ullmann condensation 20) of 7-methoxy-2,2-dimethyl-2H-1-benzopyran-5-ylamine 21) or 2,2-dimethyl-2H-1-benzopyran-5-ylamine 19) with an appropriate ortho-haloaromatic acid.…”

“…Cyclization to the corresponding acridone 15 was achieved in 27% yield by the use of trifluoroacetic anhydride in dichloromethane, which had previously given good results in the course of related syntheses. 11,18,19) Classic reactions previously developed in the acronycine and benzo[b]acronycine series to obtain N-methyl derivatives using methyl iodide or dimethyl sulfate, either in the presence of sodium hydride in dimethylformamide or under phase transfer conditions, gave 6,7-dimethoxy-3,3-dimethyl-3H-benzo[c]pyrano[3,2-h]acridine (4) as the single reaction product. Formation of the desired benzo[c]acronycine (3) could only be ensured when the reaction was performed with methyl iodide and potassium carbonate in acetone.…”

“…The mechanism of its action implies alkylation of the 2-amino group of DNA guanine residues by the carbocation resulting from the elimination of the ester-leaving group at position 1 of the drug. [10][11][12][13] In a continuation of recent studies of the structure-activity relationships in the acronycine series, [14][15][16][17] we describe here the synthesis and biological activities of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2-h]acridin-7-one (ϭbenzo[c]acronycine) (3) and 6,7-dimethoxy-3,3-dimethyl-3H-benzo[c]pyrano[3,2-h]acridine (4). These isomers 3 and 4 of benzo[b]acronycine (5) were prepared together with some corresponding derivatives in the cis-1,2-dihydroxy-1,2-dihydro series to determine the influence of the position of the additional aromatic ring fused onto the basic tetracyclic pyranoacridone core of acronycine on the cytotoxic activity.…”

Synthesis and Cytotoxic and Antitumor Activity of 1,2-Dihydroxy-1,2-dihydrobenzo[b]acronycine Diacid Hemiesters and Carbamates

“…10) Their mechanism of action implies alkylation of the 2-amino group of DNA guanine residues by the carbocation resulting from the elimination of the ester leaving group at position 1 of the drug. 11,12) We describe here the synthesis and biological activities of a new series of cis-1,2-dihydroxy-1,2-dihydrobenzo[b]-acronycine diesters, including bis-diacid hemiesters, mixed diacid hemiesters, and dicarbamates. These compounds were conceived with the goal of obtaining novel drugs as potent as previously described diesters, 9,12) but with improved solubility in aqueous solvents, which is particularly desirable when a parenteral formulation is envisaged.…”