Synthesis and Cytotoxic and Antitumor Activity of Esters in the 1,2-Dihydroxy-1,2-dihydroacronycine Series

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Natural products including a carbazole basic skeleton fused with another heterocyclic system currently receive a strong attention, due to the promising antitumor properties of several of their representatives.1) Of particular interest in this field are the pyrido [4,3-b]carbazole alkaloids and the indolo[2,3-a]carbazole antibiotics. The first series, illustrated by ellipticine (1) and 9-methoxyellipticine (2), both isolated from Ochrosia species (Apocynaceae) include compounds which act by intercalation within the DNA-double strand, followed by inhibition of topoisomerase II.2) A derivative of ellipticine, elliptinium (3), has been commercialized for the treatment of metastatic breast cancer.3) Rebeccamycine (4), isolated from Saccharothrix aerocolonigenes, is a typical representative of the second series currently under clinical trials. It induces topoisomerase I mediated DNA-cleavage. 4)The antitumor activity of several related indolocarbazoles has been recently discussed. 5)The structurally related pyrano[2,3-c]acridone alkaloid acronycine (5) isolated from Achronycia baueri SCHOTT. (Rutaceae) was shown to exhibit antitumor properties against a broad spectrum of solid tumor models.6-8) Nevertheless, its moderate potency and low water solubility rapidly appeared as severe drawbacks for a possible introduction into the clinic. A hypothesis of bioactivation of the 1,2-double bond of the chromene ring system of acronycine into the corresponding epoxide 9) led to the development of several series of more active structural analogues. The most significant improvements were obtained with diesters of 1,2-dihydroxy-1,2-dihydroacronycine 10) and, more recently, of 1,2-dihy-11) Representatives of this latter series, such as diacetate 6, are considered as valuable candidates for clinical studies.12) The mechanism of their action implies alkylation of the 2-amino group of DNA guanine residues by the ester leaving group at position 1 of the drug. 13,14) We describe here the synthesis and cytotoxic properties of various 2,2,5,11-tetramethyl-and 2,2,5,6,11-pentamethyl-2,6-dihydropyrano[3,2-b]carbazole derivatives. Such compounds associate the 1,4-dimethylcarbazole tricyclic system responsible for the intercalating properties of ellipticine related drugs, with the dimethylpyran pharmacophore of acronycine derivatives. ChemistryFor the synthesis of 2,2,5,11-tetramethyl-2,6-dihydropyrano[3,2-b]carbazole (7), the readily available 1,4-dimethyl-9H-carbazole-3-carbaldehyde (8), previously used as key-intermediate in several ellipticine syntheses, 15) was chosen as starting material. It was first oxidized by use hydrogen peroxide in acidic medium, into the corresponding 1,4-dimethyl-9H-carbazol-3-ol (9), according to the Matsumoto's procedure which has been applied by Langendoen et al. to the synthesis of related hydroxycarbazoles.16) Construction of the fused dimethylpyran ring was ensured by condensation of 9 Various 2,2,5,11-tetramethyl-and 2,2,5,6,11-pentamethyl-2,6-dihydropyrano[3,2-b]carbazole derivatives were synthesized by c...

Section: Synthesis and Cytotoxic Activity Of Pyranocarbazole Analoguementioning

confidence: 99%

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confidence: 99%

Synthesis and Cytotoxic Activity of Pyranocarbazole Analogues of Ellipticine and Acronycine

Tran-Thi¹,

Nguyen-Thi²,

Michel³

et al. 2004

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“…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…”

Section: )mentioning

confidence: 99%

“…15,16) Some of those compounds exhibited cytotoxic activities within the same range of magnitude as acronycine, when tested against L1210 murine leukemia cells. 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.…”

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confidence: 99%

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

Sittisombut¹,

Costes²,

Michel³

et al. 2001

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Several simple and fused xanthone derivatives have been reported as promising compounds in the search for new anticancer candidates. Indeed, xanthone-4-acetic acid derivatives induced tumor-growth delays and regressions when evaluated against the sc colon 38 model in mice.1,2) Some natural xanthones have shown an intensive inhibitory effect against topoisomerases I and II in the course of in vitro experiments.3) The furanoxanthone psorospermine (1), isolated from Psorospermum febrifugum, 4-6) exhibited significant cytotoxic and antineoplastic properties due to its interaction with DNA. 7,8) The tetracyclic basic core of psorospermine is closely related to that of the pyranoacridone alkaloid acronycine (2). This latter is an efficient anticancer agent, with a broad spectrum of activity including numerous solid tumors. [9][10][11][12][13][14] The structural relationships between the psorospermine and acronycine series stimulated the synthesis of pyrano[2,3-c]xanthen-7-one and pyrano[3,2-b]xanthen-6-one derivatives.15,16) Some of those compounds exhibited cytotoxic activities within the same range of magnitude as acronycine, when tested against L1210 murine leukemia cells. 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-3,14acronycine") (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. Against the sc colon 38 adenocarcinoma model in mice, compounds 4 and 5 were also highly efficient, inhibiting by more than 80% the tumor growth. These promising results prompted us to prepare pentacyclic xanthone isosters and analogues, in which the acridone nitrogen is replaced by an oxygen atom. We report here the synthesis and biological properties of benzo Chemistry Construction of the tetracyclic 1,3-dihydroxy-12H-benzo[b]xanthen-12-one (6) basic core was obtained by condensation of 3-hydroxy-2-naphthalenecarboxylic acid (7) with phloroglucinol (8) in the presence of zinc chloride and phosphoryl chloride. 21,22) Chelation of the 1-hydroxy group of 6 by the carbonyl at the 12-position permitted the selective O-alkylation of the 3-hydroxy group with 3-chloro-3-methylbut-1-yne (9), 23,24) to give the corresponding propargylic ether 10. Methylation of the 1-hydroxy group of 10, carried out with dimethylsulfate in the presence of sodium hydride gave 11 in almost quantitative yield. When thermal cyclization was performed on the hydroxy ether 10, for 2 h at 130°C in dimethylformamide (DMF), the linear 5-hydroxy-2,2-dimethyl-2H,6H-benzo[b]pyrano[2,3-i]xanthen-6-one (12) was the major reaction product, which could be subsequently methylated to afford the desired 5-methoxy- Biolo...

“…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-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.…”

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confidence: 99%

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

Thi¹,

Gaslonde²,

Michel³

et al. 2004

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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-