Cularine alkaloids structure

Since the isolation of the first cularine alkaloid, more than 40 years ago, two reviews in Vols. 4 and 10 of this treatise (7, 2) and chapters in the books of Shamma 3a, 3b) and Kametani 4a, 4b) have dealt with four representative alkaloids of the cularine group. In the last decade, more than 25 other alkaloids have been isolated and characterized, including several with modified structures and different oxidation states. This group of alkaloids is regularly reviewed in the Specialist Reports of the Chemical Society (Alkaloid Series) (5). A complete listing of cularine alkaloids was published in 1984 6). It is now accepted that the dibenzoxepine skeleton is the characteristic structure of cularine alkaloids, although these may have evolved from several well-differentiated biogenic routes. The cularine-morphine dimer cancentrine and its derivatives have been excluded from this chapter as there have been no reports since the last review in Vol. 14 of this treatise (7). 

Although structurally classified as cularine alkaloids tetradehydrocularines not only have anomalous substitution patterns and functional groups but they also originate from different plant sources. This suggests that they are products of biosynthetic pathways different from those of all other cularine alkaloids. They show characteristic bathochromic shifts under acidic conditions due to the presence of totally or partially dehydrogenated B rings in their skeletons. 

Phenolic oxidative coupling of the diphenolic bis(phenethyl)amine 101 to the 11-membered ring structure (102) controls the formation of the isoquinoline system at the stage of iminium salt 103 and explains the 7,8-substitution pattern in the isoquinoline part of cularine alkaloids (40, 63). However, to date, no such precursors have been isolated from natural sources. Moreover, phenolic oxidative coupling of synthetic precursors such as 101, using a variety of one electron oxidation reagents, gives rise to polymerized compounds or products with the skeleton of erythrine alkaloids (104) (68). 

A close relationship exists between the alkaloids of the two families Papaveraceae and Fumariaceae. Their relationship, as well as their independence, is particularly well demonstrated by the external structure of the flowers and various anatomical characteristics of different organs (Novak and Preininger 1983). Characteristically, the Fumariaceae contain spirobenzylisoquinoline (7), indenobenzazepine (8), se-cophthalideisoquinoline (10) and phthalideisoquinoline (9) alkaloids, whereas rhoeadine (11), pavine (12) and isopavine (13) type alkaloids, which are characteristic of Papaveraceae, are absent. The secoberbines have been found in C. incisa (Thunb.) Pers. and in C. ochotensis Turcz. (37—39). The cularine alkaloids (40) which are characteristic of the genus Corydalis are also found in species of Dicentra which is a member of the Papaveraceae. 

The cularines are a group of isoquinoline alkaloids with the general structure (1), which incorporates an oxepine system in its molecular skeleton. If the nitrogen is secondary the alkaloid can be called a norcularine. The occurrence of cularine alkaloids in nature seems to be associated mainly with the Fumariaceae family (Sham-ma 1972, Shamma and Moniot 1978). 

The therapeutic value of cularine alkaloids is virtually unknown due chiefly to the small number of cularine alkaloids that were known until quite recently. A few pharmacological properties of cularine were reported in 1940 when it was compared with hydrastine and papaverine (Reynolds 1940). Recently, in a study to establish the structural features responsible for the important biological activities of the alkaloids (—)-emetine, (—)-cryptopleurine and (—)-tylocrebrine, which belong to different families, a large number of related compounds have been examined. Cularine was found to exhibit no cross-resistance to emetine-resistant mutants of Chinese hamster ovary cells (Gupta et al. 1980). 

Campello MJ, Castedo L, Sad JM, Suau R, Vidal MC (1982) Cancentrine-type cularine alkaloids sarcocapnine and oxosarcocapnine. Tetrahedron Lett 23 239—240 Castedo L, Suau R, Mourino A (1976) A revised structure for pontevedrine. Tetrahedron Lett 501-502... 

Cancentrine (43) is a complex alkaloid that embodies within its structure a modified codeine skeleton and a cularine skeleton. Its 13C spectrum along with that of some derivatives was studied (36) in order to obtain chemical... 

Alkaloids of the cularine group have always been assumed to be derived by internal oxidative coupling of a diphenolic base or triphenolic base of general structure (89, R=Me or H) though no such base was known until the isolation of crassifoline (89, R=Me) from Corydalis olavioulata (G. Blaschke and G. Scriba, Z.Naturforsch., 1983, 38C, 370) and from Saraooapnos crassifolia (J.M. Boente et al., Tetrahedron Letters, 1983, 2303),... 

In Ottawa he began a systematic investigation of Fumariaceous plants for their alkaloid content. By developing new methods of separation of the alkaloids he found many new bases of the aporphine, benzophenanthridine, phthalideisoquinoline, protopine, and protoberberine ring systems. Three new classes of isoquinoline alkaloids also owe their discovery to this work. In his examination of Dicentra cucullaria he found the alkaloid cularine, determined its structure, and thereby demonstrated that it belonged to a new ring system. In the same period he isolated many of the alkaloids that are now known as the spirobenzylisoquinolines. Some 25 years later he was... 

Structural elucidation work on the cancentrine alkaloids has been concisely reviewed. A biogenetic proposal for these unusual morphine-cularine dimers was also advanced. 

In studies carried out with emetine-resistant mutants of Chinese hamster ovary cells to establish the structural basis for cross-resistance and the common site of action of benzoisoquinoline, phenanthroindolizidine, and phenanthroqui-nolizidine alkaloids (77), no cross-resistance was observed with cularine or other isoquinoline alkaloids. 

Since 1982 substantial advances in the field of cularines have occurred with the isolation of a large number of new alkaloids with novel structures making research in this area of considerable current interest. 

Kametani T, Honda T, Shimanouchi H, Sasada Y (1972) Absolute configuration of the alkaloid cularine an X-ray structure determination. Chem Commun 1072-1073... 

Leboeuf M, Cortes D, Hoquemiller R, Cav A, Chiaroni A, Riche C (1982) Structure de la gour-egine, alcaloide original apparente aux cularines. Tetrahedron 38 2889-2896 Manske RHF (1950) The alkaloids of fumariaceous plants. XLIII. The structures of cularine and of cularimine. J Am Chem Soc 72 55-59... 

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