Of ellipticine

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

Microbial transformations of ellipticine (15) and 9-methoxyellipticine (16) were reported by Chien and Rosazza (143, 144). Of 211 cultures screened for their abilities to transform 9-methoxyellipticine (16), several, including Botrytis alii (NRRL 2502), Cunninghamella echinulata (NRRL 1386), C. echinulata (NRRL 3655), and Penicillium brevi-compactum (ATCC 10418), achieved O-demethylation of 16 in good yield (Scheme 9). P. brevi-compactum was used to prepare 9-hydroxyellipticine (22) from the methoxylated precursor, and 150 mg of product was obtained from 400 mg of starting material (37% yield). The structure of the metabolite was confirmed by direct comparison with authentic 9-hydroxyellipticine (143). O-Demethylation is a common microbial metabolic transformation with 16 and many other alkaloids (143). Meunier et al. have also demonstrated that peroxidases catalyze the O-demethylation reaction with 9-methoxyellipticine (145). 

Reinhold and Bruni studied the metabolism of 7,9-dideuterioellipticine (17) in rats and found that deuterium originally at position 9 was completely lost during the mammalian hydroxylation process (147). Proton and carbon-13 NMR and mass spectral analyses confirmed the complete elimination of deuterium at position 9, thus ruling out the occurrence of an NIH shift mechanism in the hydroxylation of ellipticine. An oxygen-insertion process was rationalized to account for the mechanism of aromatic hydroxylation in rats since this would not be expected to display the NIH shift but should demonstrate an isotope effect. It was... 

Scheme 9. Metabolism of ellipticine by Aspergillus alliaceus NRRL 315. 

Oxidations of 9-Hydroxyellipticine. 9-Hydroxyellipticine is the major metabolite of ellipticine formed by mammalian cytochrome P-450 hydroxylation (147,153). The reaction is a good example of a bioactivation process because 9-hydroxyellipticine is many times more active as an antineoplastic agent than is ellipticine itself (154). Auclair, Meunier, Paoletti, and co-workers have extensively studied further oxidations of 9-hydroxyellipticine and its derivatives (155-158). 

Since the isolation of ellipticine and its congeners from natural sources, and the initial discovery of their anticancer activity in various experimental and human... 

The UV spectrum (Tmax 240, 268, 278, 288, 295, and 330 nm) of N-oxyellipticine (240) resembled that of ellipticine (228) (see Scheme 2.56), indicating a similar pyrido[4,3-l ]carbazole framework (222). Comparison of the mass spectrum of N-oxyellipticine at m/z 262 (M" ), with that of ellipticine (228) show only the presence of an additional oxygen as an N-oxy function. This conclusion was supported by comparison with the spectral data of synthetic Af-oxyellipticine, obtained by oxidation of ellipticine (228) with H2O2 in dichloromethane, and by reduction of Af-oxyellipticine with zinc to ellipticine. Based on these comparisons. 

The complete in vivo anti-tumor mechanism of action of ellipticine and its derivatives is still not well understood. However, a tremendous amount of work has... 

The strong interest in the synthesis of pyrido[4,3-h]carbazole alkaloids started in the late 1960s with the disclosure of the antitumor activity of ellipticine (228) and 9-methoxyellipticine (229) (see Scheme 2.56) in several animal and human tumor systems. This discovery made these alkaloids to important synthetic targets and induced extensive studies of structure modification. These synthetic efforts have... 

As an extension of this methodology, Gribble et al. reported a formal total synthesis of olivacine (238a). This synthesis starts from the same keto lactam 1181, used for the synthesis of ellipticine (228), and exploits the lower reactivity of the lactam carbonyl as compared to the carbonyl of the keto lactam. Reaction of the keto lactam 1181 sequentially with methyllithium and superhydiide (LiBHEts) led to 11-demethylellipticine (1191) in 57% yield, along with 30% of ellipticine (228). Finally, using Kutney s procedure (220), ll-demethylellipticine (1191) could be transformed to olivacine (238a) (701) (Scheme 5.195). 

Gribble et al. also reported a new annulation strategy for the total synthesis of ellipticine (228) (527). This methodology utilizes a Diels-Alder reaction between... 

Diels-Alder reaction of the furoindole 544 with 3,4-pyridyne (1193), generated in situ via two different ways, led to a mixture of the two possible cycloadducts 1194 and 1195 in approximately equal amounts. Without purification, the crude adducts 1194 and 1195 were treated with basic sodium borohydride (NaBH4) to afford a separable mixture of ellipticine (228) and isoellipticine (1196) in 23% and 29% yield, respectively (527) (Scheme 5.197). 

Six years later, the same authors reported an improved version of their earlier synthesis of ellipticine (228) (527) (Scheme 5.197) by using the l-(p-methoxybenzyl)-5,6-dihydropyridone (1197) as 3,4-pyridyne surrogate (702,703). Thus, the dimethyl-furoindole 544 was treated with the unsaturated lactam 1197 (prepared from 5-valerolactam in three steps) in the presence of trimethylsilyl triflate (TMSOTf) to afford the carbazole 1199 as a single product in 40% yield. The low yield is presumably a consequence of decomposition of the intermediate adduct 1198 during... 

Backvall and Plobeck reported a formal synthesis of ellipticine (228) starting from indole (707). The [4+2] cycloaddition of 1-indolylmagnesium iodide (1208) with 3-(phenylsulfonyl)-2,4-hexadiene (1209) afforded the tetrahydrocarbazole... 

Sha and Yang reported the total synthesis of ellipticine (228) using the... 

Miki et al. reported the total synthesis of ellipticine (228) starting from N-benzylindole-2,3-dicarboxylic anhydride (852) (714,715). Reaction of (3-bromo-4-pyridyDtriisopropoxyltitanium (1232) with 852 gave 2-acylindole-3-carboxylic acid 1233 in 86% yield. Decarboxylation and debenzylation of 1233 led to the ketone 1234. Wittig olefination of the ketone 1234, followed by catalytic hydrogenation. 

Two years later, the same group reported a formal synthesis of ellipticine (228) using 6-benzyl-6H-pyrido[4,3-f>]carbazole-5,ll-quinone (6-benzylellipticine quinone) (1241) as intermediate (716). The optimized conditions, reaction of 1.2 equivalents of 3-bromo-4-lithiopyridine (1238) with M-benzylindole-2,3-dicarboxylic anhydride (852) at —96°C, led regioselectively to the 2-acylindole-3-carboxylic acid 1233 in 42% yield. Compound 1233 was converted to the corresponding amide 1239 by treatment with oxalyl chloride, followed by diethylamine. The ketone 1239 was reduced to the corresponding alcohol 1240 by reaction with sodium borohydride. Reaction of the alcohol 1240 with f-butyllithium led to the desired 6-benzylellipticine quinone (1241), along with a debrominated alcohol 1242, in 40% and 19% yield, respectively. 6-Benzylellipticine quinone (1241) was transformed to 6-benzylellipticine (1243) in 38% yield by treatment with methyllithium, then hydroiodic acid, followed... 

Ishikura et al. reported the total synthesis of ellipticine (228) starting from N-Boc indole (1256) and the vinyl bromide 1258 (719-721). This methodology involves a palladium-catalyzed, tandem cyclization-cross-coupling reaction of the indolyl borate 1257 with the vinyl bromide 1258 as the key step. Using a literature procedure, the vinyl bromide 1258 was prepared as an E/Z mixture starting from CIS- and trans-crotyl alcohol. The indolyl borate 1257 was generated in situ from... 

Guitian et al. reported a total synthesis of ellipticine (228) using a modified Gribble methodology (722,723). This approach applied 2-chloro-3,4-pyridyne (1267) as a synthetic equivalent for 3,4-pyridyne and used the polar effect of the chlorine atom for improved yields and regiocontrol of the cycloaddition with the furoindole 544. Silylation of 2-chloro-3-hydroxypyridine (1263), followed by treatment of 1264 with LDA, afforded the 4-trimethylsilylpyridine 1265. This reaction probably involves... 

Mai et al. reported a formal total synthesis of ellipticine (228) starting from the furoindolone 649 (583,724). In this strategy, the key step is the anionic [4+2] cycloaddition of furoindolone 649 with 3,4-pyridyne (1193). Reaction of compound 1270 with 3,4-pyridyne (1193) in the presence of LDA gave ellipticine quinone (1272)... 

Bowman et al. reported the total synthesis of ellipticine (228) involving an imidoyl radical cascade reaction (730). For this key step, the required imidoyl radical was generated from the imidoyl selanide 1290, which was obtained from ethyl 2-(4-pyridyl)acetate (1286). Reaction of 1286 with LDA, followed by addition of methyl iodide, led to the corresponding methyl derivative 1287. Treatment of 1287 with 2-iodoaniline (743) in the presence of trimethylaluminum (AlMes) afforded the amide 1288. Using Sonogashira conditions, propyne is coupled with the amide 1288 to afford the aryl acetylene 1289. The aryl acetylene 1289 was transformed to the... 

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