Benzophenanthridines

R =OMe, R R =CH2) respectively, followed by y-methylation. (Kessar et al.. Tetrahedron Letters, 1977, 1459 Takao et al.. Heterocycles, 1981, 1, 221). Dihydrochelirubine and cheli-rubine have also been prepared by photochemical cyclisation of the amide (386), which involves the loss of a methoxy group, followed by reduction and dehydrogenation of the resulting di-hydro-compound to chelirubine (Ishii et at., Chem.Pharm.Bul1., 1978, 864). 

The reaction of esters of methylenedioxyphthalic acid (387) with the imine (388) affords the ester-lactam (389) and hydrolysis of this to the lactam-acid followed by Arndt-Eistert homologation and cyclisation yields the ketone (390, R R =0). Reduction of this to the secondary alcohol (390, R =H, R =0H), followed by dehydration and aerial oxidation affords oxosangui-narine (391), from which sanguinarine can be prepared (Shamma and H. Tomlinson, J.org.Chem., 1978, 2852). A similar 

A similar synthesi also been achieved. In th ester (389) is obtained in and the cis form has been the sequence of reactions action sequence is applied product (397, R =H, R =0H) 

Tetrahedron Letters, 1980, 21, s of ( )-corynoline (393, R=MF) has is the c-methylated analogue of the both the cis and the trans forms converted into ( )-corynoline by described above. When the same re-to the trans-ester, however, the is different from isocorynoline 

The amide (398) (prepared by a photocyclisation) has been oxidised with lead (IV) acetate to the phenol acetate (399) which has been converted through the ortho-quinone into the diol (400, R =R =H). The di-ester of this (400, R =MeS02, R =Ac) on treatment with potassium hydroxide in methanol affords (401, R=0Me) which yields ( )-homoche1idonine (401, R=H) on hydrogenolysis (Ninomiya, Yamamoto and Naito, J.chem.Soc., Perkin I, 1983, 2171). 

Chelidonine, dihydrochelerythrine, and dihydrosanguinarine have been isolated from Glaucium vitellinum,109 chelerythrine and sanguinarine from Corydalis ophiocarpa,71 oxysanguinarine and 8-methoxysanguinarine from Fumaria indica,125 a new base corynolamine (149 R = CH2OH) from Corydalis incisa,379 

The absolute stereochemistry of chelidonine has been determined by an X-ray crystallographic study of its p-bromobenzoyl ester.382 Further details of the photolysis of the unsaturated amide (151) to the two dimers reported previously (Vol. 10) have been published. Attempts have been made to trap the initial product with dieneophiles with nitrosobenzene, the adduct (152) was obtained, and this was decomposed by heat to form oxochelerythrine.383 A review of methods of synthesis of ( )-corynoline and of 12-hydroxy-, 11 -epi-, and homo-chelidonine has been published.384 

The cytotoxic effects of sanguinarine,385 chelidonine,385 and chelidonine methiodide386 and the effect of sanguinarine on cardiac ATPase387 have been studied. 

Bessho, M. Kamigauchi, K. Iwasa, K. Tomita, T. Fujiwara, and S. Fujii, Tetrahedron Lett., 1979, 495. 

Ninomiya, O. Yamamoto, T. Kiguchi, and T. Naito, Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 21st, 1978, 42. 

The following species have been shown to contain the alkaloids stated  

Bocconia frutescens110 Corydalis incisa522 Meconopsis cambrica113 Zanthoxylum monophyllum116 Zanthoxylum nitidum146 

Following preliminary work,528 ( )-chelidonine (118) has been synthesized from the acid (115) (obtained from methylenedioxyhomophthalic anhydride and TV-methyldimethoxybenzalimine) by its conversion into the diazo-ketone (116), cyclization of this (using trifluoroacetic acid) to the keto-lactam (117), and reduction with lithium aluminium hydride.529,530 

The fluorescence spectra of chelerythrine, nitidine, and sanguinarine in different solvents have been shown to be dependent on the pH of the solution and to allow the determination of the equilibrium constant for the formation of the pseudobases.531 A salt of chelidonine with 5-carboxymethyl-2-thio-l,3-thiazan-4-one has been prepared.532 The intercalative binding of sanguinarine533 and the anti-tumour activities of chelidonine JV-oxide534 and of nitidine535 have been studied. 

Alkaloids of this group have been isolated from the following species  

In addition, sanguinarine has been isolated from cell cultures of Papaver bracteatum. 

Pancorine, 6-iminosanguinarine, and toddalidimerine are new alkaloids 6-iminosanguinarine has been prepared from oxosanguin-408 

Sanguinarine has been isolated from Corydalis ophiocarpa, and from C. gigan-tea, C. marschalliana, C. remota, C. rosea and C vaginansf sanguinarine, norsanguinarine, chelerythrine, norchelerythrine, bocconoline(162 R = = 

and its methylenedioxy-analogue (162 R R = CHj), which is a new base, from Chelidonium major chelerythrine and nitidine from Zanthoxylum bouetense, chelidonine from Symphoricarpos albus, ° norsanguinarine, oxy-sanguinarine, and a new base luguine (163) from Glaucium flavum Cr. var. vestitum and sanguinarine, chelerythrine, and the carbinolamine ethers (164 R = R = R = Me), (164 R = R = Me,R = Et) and(164 R R = CHj, R = Me) and (164 R R = CH, R = Et) from Hunnemannia fumariae-folia.  

Kamigauchi, and M. Sugiura, Chem. Pharm. Bull., 1978,26,1880. 

Photolysis of the amide (182) has been shown to give tetrahydro-oxochelery-thrine (183) together with two dimers of (182), of structures (184) and (185). In 

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X-ray crystal structure, 6, 516 Benzophenanthridines synthesis from anils, 2, 416 Benzophenanthridines, tetrahydro-synthesis, 2, 469 Benzo[c]phenanthridines synthesis, 2, 414 from aryl isocyanides, 2, 411 from benzynes, 2, 432 Benzo[i]phenanthridines synthesis, 2, 414 Benzophenanthridinones... 

Das S (2000) Biophysical studies on the interaction of benzophenanthridine alkaloids with polymorphic nucleic acid structures. PhD Thesis, Jadavpim University... 

The 6,7-secoberbine alkaloids contain the four following natural products corydalic acid methyl ester (55), corydamine (56), N-formylcorydamine (57), and hypecumine (58). These bases, called 3-arylisoquinolines, were described by Shamma and Moniot (2) as a separate class of isoquinoline alkaloids. Santavy (7) classified them among benzophenanthridines. It seems, however, that they may be considered as biosynthetic intermediates between the protoberberines on the one hand and the benzophenanthridines on the other. 

It was postulated (169) that these amides are 8,8a-secobenzophenanthridine alkaloids produced by oxidative cleavage of ring B of the corresponding benzophenanthridines. The success of Baeyer-Villiger-type oxidations of the immonium bond of benzophenanthridine skeletons (168,171,172,175) indicates that this type of oxidation could be a real biological pathway. 

DITTRICH, H., KUTCHAN, T.M., Molecular cloning, expression, and induction of berberine bridge enzyme, an enzyme essential to the formation of benzophenanthridine alkaloids in the response of plants to pathogenic attack, Proc. Natl. Acad. Sci. USA, 1991,88, 9969-9973. 

KUTCHAN, T.M., DITTRICH, H., Characterization and mechanism of the berberine bridge enzyme, a covalently flavinylated oxidase of benzophenanthridine alkaloid biosynthesis in plants, J. Biol. Chem., 1995,270,24475-24481. 

VavreCkova, C., Gawlik, I. and MUller, K. 1996. Benzophenanthridine alkaloids of Chelidonium majus. I. Inhibition of 5- and 12-lipoxygenase by a non-redox mechanism. Planta Medica, 62 397-401. 

Dupont, C., Couillerot, E., Gillet, R., Caron, C., Zeches-Hanrot, M., Riou, J.-F. and Trentesaux, Ch. 2005. The benzophenanthridine alkaloid fagaronine induces erythroleukemic cell differentiation by gene activation. Planta Medica, 71 489 94. 

Chen, J.-J., Fang, H.-Y., Duh, Ch.-Y. and Chen, I.-S. 2005. New indolopyrido-quinazoline, benzophenanthridines and cytotoxic constiments from Zanthoxylum integrifolium. Planta Medica, 71 470 75. 

Lenfeld, J., Kroutil, M., Marsalek, E., Slavik, J Preininger, V. and Simanek, V. 1981. Anti-inflammatory activity of quaternary benzophenanthridine alkaloids from Chelidonium majus. Planta Medica, 43 161-165. 

Villegas, M., Leon, R. and Brodelius P. E. 1999. Effects of alginate and immobilization by entrapment in alginate on benzophenanthridine alkaloid production in cell suspension cultures of Eschscholtzia californica. Biotechnology Letters, 21(1) 49-55. 

Pyrolysis of anils has long been known to give polycycles, as shown by the synthesis of phenanthridine (120) (1889CB3340) and of the two benzophenanthridines (121) and (122) <1891LA(266)155>. More recently, quinoline has been obtained by flash vacuum pyrolysis of the dianil (123) <80JCS(P1)2200). 

Figure 1. Gas chromatogram of PAH in a work atmosphere a, particulate PAH b, gaseous PAH. The peak identities are 1, naphthalene 2, 2-methylnaphthalene 3, 1 -methylnaphthalene 4, biphenyl 5, acenaphthene 6, dibenzofuran 7, fluorene 8, 2-methylfluorene 9, 1-methylfluorene 10, dibenzothiophene 11, phenanthrene 12, anthracene 13, methylphenanthrene/methylanthracene 14, methylphenan-threne/methylanthracene 15, 2-methylanthracene 16, 4,5-methylenephenanthrene 17, methylphenanthrene/methylanthracene 18,1-methylphenanthrene 19, fluoranthene 20, benzo(def)dibenzothiophene 21, pyrene 22, ethylmethylenephena-threne 23, benzo(a)fluorene 24, benzofb)fluorene 25, 4-methylpyrene 26, meth-ylpyrene 27, 1-methylpyrene 28, benzothionaphthene 29, benzo(c)phenanthrene 30, benzophenanthridine 31, benzo(2i)anthracene 32, chrysene/triphenylene 33, benzo(b)fluoranthene 34, benzof])fluoranthene 35, benzo(k)fluoranthene 36, ben-zo(c)pyrene 37, benzofa)pyrene 38, perylene 39, indenof 1,2,3-cd)pyrene 40, dibenz(a, /a,h)anthracenes 41, benzofghi)perylene 42, anthanthrene 43, coro-...

Sanguinarine 1 is the prototype of benzophenanthridine alkaloids which occur frequently in plants of the family Papaveraceae. It has anticancer activity and has become of commercial interest because of its antibacterial properties. It is known from biosynthetic studies that protopine 2 is a metabolite on the pathway to sanguinarine, and recent work has shown that a microsomal cytochrome P-450 NADPH dependent enzyme will hydroxylate protopine... 

During synthetic studies on the benzophenanthridine alkaloids, the nitrile ester 1 was treated with sodium hydride in THF in the expectation that a Thorpe-Dieckmann type of reaction would... 

The benzo[ a Jphenanthridine ring system resembles the structure of chrysene, another carcinogen. It is intriguing to note that the carcinogenicity of chrysene is drastically increased by the addition of a methyl group at position 5 of that molecule [86-90]. The position of this methyl group (see structure 9) corresponds to that in the aforementioned benzophenanthridine alkaloids. 

The structural elucidation of a new benzophenanthridine alkaloid, luguine (100) was reported (61) in which the 13C spectrum confirmed both the aromatic nature of ring B and the presence of a hydroxyl group at C-11. The spectrum showed four aliphatic carbon resonances and these were assigned by off-resonance decoupling. 

Badger and Sasse have described the preparation of 2-, 3-, and 8-bromophenanthridine by the cyclization of the appropriate bromo-formamidobiphenyl with polyphosphoric acid.25 In the case of 2-bromo-2 -formamidobiphenyl a higher concentration of phosphorus pentoxide in the acid was necessary to effect ring closure, and a simple steric effect was invoked.26 Nevertheless, the Morgan-Walls reaction has been used to obtain several overcrowded compounds in which unfavorable steric factors operate. Following the original report of the preparation of the 1,10-dimethylphenanthridine (5a) by this procedure,27 several other examples have been described, notably the synthesis of the related phenanthridine (5b),28 the l,2-(6)29 and 9,10-benzophenanthridines (7),30 and the 1,2 9,10-dibenzophenanthridine (8).29... 

The Morgan-Walls cyclization has also been employed in eases where the acylamino group is attached to a reduced ring. For example, the amides (13a-c,41 and d42) are readily cyclized by phosphoryl chloride and the tetrahydro-l,2-benzophenanthridine (14) has been prepared... 

The ferrous oxalate procedure has been employed successfully to prepare 8,10-dimethyl-3,4-benzophenanthridine from 2-mesityl-l-nitronaphthalene.85 However, an attempted preparation of 4,9-diazachrysene from 2,2 -dimethyl-6,6/-dinitrobiphenyl failed, while treatment with an excess of triethyl phosphite gave 1,10-dimethyl -benzo[c]cinnoline (11%) as the only recognizable product. Failure... 

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