Synthesis and Cytotoxic and Antitumor Activity of Benzo[b]pyrano[3,2-h]acridin-7-one Analogues of Acronycine

Abstract

Benzo¿băcronycine (6-methoxy-3,3,14-trimethyl-3, 14-dihydro-7H-benzo¿bpyrano¿3,2-hăcridin-7-one, 4), an acronycine analogue with an additional aromatic ring linearly fused on the natural alkaloid basic skeleton, was synthesized in three steps, starting from 3-amino-2-naphthalenecarboxylic acid (5). Eight 1, 2-dihydroxy-1,2-dihydrobenzo¿băcronycine esters and diesters (17-24) were obtained by catalytic osmic oxidation, followed by acylation. All these compounds were significantly more cytotoxic than acronycine, when tested against L1210 leukemia cells in vitro. The potency of the cyclic carbonate 24 was in the range of the most active drugs currently used in cancer chemotherapy. Two selected diesters (17 and 24) were evaluated in vivo against P388 leukemia and colon 38 adenocarcinoma implanted in mice. Both compounds were markedly active at doses 16-fold lower than the dose of acronycine itself. Against colon 38 adenocarcinoma, compounds 17 and 24 were highly efficient, inhibiting tumor growth by more than 80%. Diacetate 17 was the most active, inhibiting tumor growth by 96% at 6.25 mg/kg, with two of seven mice being tumor-free on day 43.

Synthesis and Cytotoxic Activity of Benzopyranoxanthone Analogues of Benzo[b]acronycine and Psorospermine.

“…20) These latter compounds were 20 to 1000 fold more potent than acronycine in inhibiting L1210 cell proliferation. In vivo, against P388 leukemia, acronycine was only marginally active, while compounds 4 and 5 were significantly active at doses 16 fold lower.…”

“…16) Based on a hypothesis of bioactivation of acronycine into the corresponding epoxide 17,18) and of intercalation within DNA, 19) we recently prepared the pentacyclic 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo [b]pyrano[3,2-h]-acridin-7-one ("benzo [b]acronycine") (3) and a series of corresponding cis-1,2-dihydrodiol diesters, exemplified by diacetate 4 and carbonate 5. 20) These latter compounds were 20 to 1000 fold more potent than acronycine in inhibiting L1210 cell proliferation. In vivo, against P388 leukemia, acronycine was only marginally active, while compounds 4 and 5 were significantly active at doses 16 fold lower.…”

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

“…Such compounds are exemplified by diesters of cis-1,2-dihydroxy-1,2-dihydroacronycine 8) and diesters of cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine (cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo [b]pyrano [3,2-h]acridin-7-one). 9) Representatives of this latter series, such as diacetate 2, currently being developed under the code S23906-1, are considered valuable candidates for clinical studies. 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.…”

“…, the (Ϯ)-diol 5 9) was treated with 1.5 eq of succinic anhydride, in anhydrous pyridine, at room temperature, in the presence of 4-dimethylaminopyridine. After 17 h, a large excess of acetic anhydride was added to the reaction mixture, which was allowed to stand for a further 1.5 h. Column chromatography over silica gel gave the two desired diesters 3 and 4, in 56% and 20% yield, respectively.…”