The Benzophenanthridines

Some new benzophenanthridine alkaloids and their sources are shown below  

Arnottianamide, isoarnottianamide, and iwamide are three unusual amidic alkaloids present in Zanthoxylum spp. (Rutaceae). They are clearly related to the benzophenanthridines, but possess an open ring C. 

Bocconine has been found to be identical with chelirubine, so that the older name chelirubine will be used in the following discussion of the structural elucidation of this alkaloid. 

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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. 

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. 

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... 

Enhanced production of some of the benzophenanthridine alkaloids was found in an in situ extraction system that was composed of silicone fluid and a suspension culture of Eschscholtzia californica [10]. The time course changes of alkaloid production and distribution are shown in Fig. 1. 

S)-Reticuline is a branch-point intermediate in the biosynthesis of most BAs. Most work has focused on branch pathways leading to the benzophenanthridine (e.g., sanguinarine), protoberberine (e.g., berberine), and morphinan (e.g., morphine and codeine) alkaloids.19 Most enzymes involved have been isolated, many have been purified, and four corresponding cDNAs have been cloned.19 The first committed step in benzophenanthridine and protoberberine alkaloid biosynthesis involves the conversion of (S)-reticuline to (5)-scoulerine by the berberine bridge enzyme (BBE) (Fig.7.2). BBE was purified from Berberis beaniana,20 corresponding cDNAs were cloned from E. californica and B. stolonifera,21 22 and BBE genes have been isolated from P. somniferum and E. californica.23,24... 

Figure 2.7 Biosynthesis of protopine and the benzophenanthridine alkaloids. STS, stylopine synthase SNMT, stylopine N-methyltransferase DBOX, dihydrosanguinarine oxidase SanR, sanguinarine reductase.

The benzophenanthridine alkaloid chelerythrine (37) isolated from Zanthoxylum simulans (Rutaceae) is a potent, selective antagonist of PKC from rat brain (IC50 = 0.66 pM). Inhibition was competitive with respect to the phosphate acceptor (histone Ills) and non-competitive with respect... 

In the benzophenanthridine group didehydrochelidonine has been shown to lave the internal carbinolamine ether structure (170). The minor alkaloids of... 

The investigations carried out during the past 15 years have shown that the benzophenanthridine bases of the sanguinarine type are the most widely distributed 195) alkaloids (Tables I, II, and XXV) of the plant family Papaveraceae. More recently, the group of the known alkaloids was augmented by the alkaloids norchelidonine, chelirubine, chelilutine. 

Besides the benzophenanthridine bases having oxygen constituents at the C-3 and C-4 atoms, some bases having oxygen substituents in the positions C-2 and C-3 (alkaloids nitidine, oxynitidine, and avicine) could be isolated from the plant genera Toddalia and Zanthoxylum (Rutaceae). Sanguinarine and similar bases have recently been synthesized by Dyke et al. (134a-c). 

Whereas most alkaloids appear to be specifically directed towards animals, others show a broader activity spectrum. For example, alkaloids with marked antibacterial activities include ajmaline, berberine, boldine, cinchonidine, cinchonine, harmaline, harmine, lobeline, narcotine, norharman, quinidine, quinine, sanguinarine, strychnine and yohimbine (see reviews [5, 73, 96]. Only the benzophenanthridine alkaloid... 

Eschscholtzia oregana, and E. califomica and the /3-form in Glaucium comiculatum, Papaver rhoeas, and P. syriacum. The alkaloid content of Argemone mexicana, and particularly the presence of four quaternary bases, namely (—)-/3-scoulerine methohydroxide, (-)-cheilanthifoline, and both the a- and /8-methohydroxides of (-)-stylopine, suggests a close relationship between this plant and A. ochroleuca and A. albiflora (cf Vol. 5). ° Similarly, the presence of (-)-scoulerine and the benzophenanthridine norchelerythrine in A. polyanthemos confirms its close biochemical relationship with A. albiflora. ... 

A number of reviews on various aspects of QBA have been published. The principal information can be found in the two books on isoquinoline alkaloids by Shamma [1,2] and the reviews by Santavy [3,4] and Simanek [5] in The Alkaloids series. A highly valuable review of the physical and spectral data and the occurence of the 88 benzophenanthridine alkaloids has been compiled by the Shamma group [6], Preininger has summarized the distribution of QBA in plant species of the Papaveraceae and Fumariace-ae families [7]. A review by Dostal and Potacek specifically devoted to the in vitro nucleophilic conversions of QBA appeared in 1990 [8], Surveys on the biological activities [9-11] and biosynthetic formation [12,13] of these alkaloids have been published. Well-designed reviews of the syntheses of the QBA are also available [14-16]. Hanaoka and Mukai presented a treatise on the biomimetic syntheses of the benzophenanthridines from the protoberberines in volume 14 of the Studies in Natural Products Chemistry series [17]. Quite recently, a book by Bentley treating isoquinoline alkaloids also involved benzophenathridines [18]. 

Allocryptopine, chelerythrine, ( )-chelidonine (= diphylline), cheiirubine, coptisine, corydine, dihydrochelerythrine, glaucine, 184, 185 glauvine, isoboldine, isocorydine, O-methylatheroline, protopine, sanguinarine, and quaternary bases of the benzophenanthridine alkaloids... 

The benzophenanthridine alkaloids were also isolated from plants which do not belong to the Papaveraceae family, e.g., Xanthoxylon tsihanimposa... 

Sanguinaria canadensis L. is indigenous to North America. In the roots, the major alkaloids are the benzophenanthridines, which form —75% of the total... 

C.S-N.4 may be found in processes which relate the berberine (CCXXXIl) and the benzophenanthridine (CCXXXIII) groups. 

This methodology has since been applied to constructing [6]-an-nelated carbazoles, and benz[/]indole, and the tetracyclic skeleton of the benzophenanthridine alkaloids. Arynes used in this type of reaction include 3,4-didehydropyridine in the synthesis of ellipticine 8 and isoellipticine 9," 3,4-(methylenedioxy)benzyne, and 2,3-naphthalyne. ... 

De Stefano 1, Raspaglio G, Zannoni GF, Travaglia D, Prisco MG, Mosca M, et al. Antiproliferative and antiangiogenic effects of the benzophenanthridine alkaloid sanguinarine in melanoma. Biochem Pharmacol 2009 78(11) 1374-81. 

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