Benzophenanthridine alkaloids, formation

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. 

Zenk MH. The formation of benzophenanthridine alkaloids. Pure Appl. Chem. 1994 66 2023-2028. 

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]. 

Benzophenanthridines (cf. Fig. 4) are mainly biosynthesized and stored in idioblasts of the root cortex parenchyma that are not connected to the lacticifer system (with the exception of Chelidonium, cf. below). Five ofthe seven enzymes between (S)-reticulin and sanguinarine, the first benzophenanthridine alkaloid, have been localized to a membrane fraction with a specific density of D 1.14 g/mL, that appears similar to the alkaloid producing vesicles isolated from Berberis and Papaver (cf above). Except BBE, these enzymes are P450-dependent monooxygenases, i.e. integral proteins of ER membranes (Zenk, 1994 Facchini, 2001). The final step of benzophenanthridine formation is catalyzed by dihydrobenzophenanthridiae oxi-... 

Amann M, Nagakura N, Zenk MH (1984) (S>Tetrahydroprotoberberineoxidase, the final enzyme in protoberberine biosynthesis. Tetrahedron Lett 25 953-954 Berlin J, Forche E, Wray V, Hammer J, Hosel W (1983) Formation of benzophenanthridine alkaloids by suspension cultures of Eschscholtzia califomica, Z Naturforsch 38C 346-r352 Bohm H, Franke J (1982) Accumulation and excretion of alkaloids by Macleaya microcarpa cell cultures, I. Experiments on solid medium. Biochem Physiol Pflanz 177 345--356 Bohm H, Franke J, Lammel L (1980) Chelidonium mafus alkaloids. GDR Pat 143, 270 (Cl C12P17/00)... 

Another important route stems from the formation of the N-methylated moieties of the (S)-tetrahydroprotoberberines, which serve as precursors for the protopine, benzophenanthridine, tetrahydrobenzazepines (rhoeadines) and spirobenzylisoquinoline alkaloids (Kutchan and Zenk, 1993 Liscombe and Facchini, 2008 Ziegler and Facchini, 2008) (Fig. 2.7). 

The benzophenanthridine skeleton is encountered in approximately 30 alkaloids, principally of the family Papaveraceae (Cordell, 1978a). In contrast to the biosynthesis of protopine alkaloids, phenanthridine alkaloids are synthesized in the cytoplasm (Hartmann, 1991). This type of system arises from a protoberberine precursor by fission of the C-6-N bond and recyclization. The biogenetic sequence leading to chelidonine (80) biosynthesis in Chelidonium majus has been supported by feeding experiments with multiply-labeled (-t-)-reticuline [(5)-reticuline] (20) and with labeled stylopine (79) (Fig. 32.25) (Hutchinson, 1986 Sim ek, 1985 Tanahashi and Zenk, 1988). (5)-Z-V-Methylstylopine and protopine (60) have been shown to be metabolites in this pathway. Reticuline is oxidatively cyclized to ( —)-scoulerine (72). Formation of two methylenedioxy groups results in the formation of stylopine (79) (Hartmann, 1991). 

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