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

Abstract

The pyranoacridone alkaloid acronycine (1), which was first isolated from Acronychia baueri SCHOTT (Rutaceae) in 1948, [1][2][3] was later shown to exhibit antitumor properties in a panel of murine solid tumor models, including S-180 and AKR sarcomas, X-5563 myeloma, S-115 carcinoma, and S-91 melanoma. 4,5) Nevertheless, its moderate potency and very low solubility in aqueous solvents severely hampered its clinical trials, which have given only poor results.6) Consequently, the development of structural analogues with increased potency and/or better water solubility was highly desirable.Our efforts to obtain more potent derivatives were guided by a hypothesis of bioactivation of the 1,2-double bond of acronycine into the corresponding epoxide in vivo.7) Significant improvements in terms of potency were obtained with derivatives modified in the pyran ring, which had reactivity toward nucleophilic agents similar to that of acronycine epoxide but improved stability. Such compounds are exemplified by diesters of cis-1,2-dihydroxy-1,2-dihy-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.Chemistry To obtain in a single experiment both (Ϯ)-acronycine (4), 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. The same experimental procedure afforded (Ϯ)-cis-1,2-dihemiglutaryloxy-1,2-dihydrobenzo[b]acronycine (6) and (Ϯ)-cis-1-acetoxy-2-hemiglutaryloxy-1,2-dihydrobenzo[b]acronycine (7) when glutaric anhydride was used as an acylating agent instead of succinic anhydride.bis-Dialkylcarbamates were obtained when the (Ϯ)-cisdiol 5 was treated with a slight excess of an appropriate N,Ndialkylcarbamyl chloride in the presence of potassium hydride in anhydrous tetrahydrofuran (THF). Following this March 2004 Chem. Pharm. Bull. 52(3) 293-297 (2004) 293 * To whom correspondence should be addressed. -1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-

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.…”

Synthesis and Cytotoxic Activity of Benzo[a]pyrano[3,2-h] and [2,3-i]xanthone Analogues of Psorospermine, Acronycine, and Benzo[a]acronycine

“…Construction of the tetracyclic 9,11-dihydroxy-12H-benzo[a]xanthen-12-one (6) basic skeleton was achieved by condensation of 2-hydroxy-1-naphthalenecarboxylic acid (7) with phloroglucinol (8) in the presence of zinc chloride and phosphoryl chloride. 25,26) Chelation of the 11-hydroxy group of 6 by the carbonyl at the 12-position permitted the selective O-alkylation of the 9-hydroxy group with 3-chloro-3-methylbut-1-yne (9), 27) to give the corresponding propargylic ether 10.…”

“…The mode of fusion of the newly formed dimethylpyran ring onto the xanthone basic core, angular for 12 and 14, and linear for 13 and 15, was unambiguously ascribed for each compound from phase-sensitive NOESY experiments. 21,28) In order to obtain dihydrodiols diesters similar to the highly active compounds in the benzo[a] and [b]acronycine series, [5][6][7][8] the (Ϯ)-cis-diols 16 and 17 were prepared by catalytic osmium tetroxide oxidation of 14 and 15, respectively, using N-methylmorpholine N-oxide to regenerate the oxidizing agent.…”

“…4) Based on this latter model, we recently prepared the pentacyclic analogues benzo[a]acronycine (6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[a]-pyrano[3,2-h]acridin-7-one) (2) and and benzo [b]acronycine (6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]-pyrano[3,2-h]acridin-7-one) (3), together with several series of corresponding 1,2-dihydrodiol diesters, which displayed significantly enhanced in vivo antitumor activity when compared to the parent alkaloid. [5][6][7][8] Such compounds are exemplified by cis-diacetate 4, developed under the code S23906-1, which is currently undergoing phase I clinical trials.…”

Synthesis and Cytotoxic Activity of Dimeric Analogs of Acronycine in the Benzo[b]pyrano[3,2-h]acridin-7-one Series

“…Ditercalinium (1), resulting from the dimerization of two pyridocarbazole units related to natural alkaloids ellipticine (2) and olivacine (3) is an excellent example of this approach. [7][8][9] Benzo [b]acronycine derived antitumor derivatives, developed from the model of natural acronycine (4), [10][11][12][13][14] are exemplified by diacetate 5, currently under phase I clinical trials under the code S23906-1. 15,16) These compounds displayed a particularly impressive broad antitumor spectrum, when evaluated against aggressive orthotopic models of human ovarian, lung, and colon cancers.…”