Benzodiazepine alkaloids

Anthramycin is a benzodiazepine alkaloid with potent antitumor and antibiotic activity produced by the thermophilic actinomycete Streptomyces refuineus sbsp. thermotolerans. Using a genome-scanning approach, the biosynthesis was found to involve condensation of 4 methyl-3-hydroxy anthranilic acid 136 and a... 

VII. Biological Activity of Naturally Occurring Benzodiazepine Alkaloids. 93... 

The first correct structures of benzodiazepine alkaloids, namely, those of cyclopenin (3) and cyclopenol (4), were published in 1963 by Mohammed and Luckner (47). In 1965 the structure of the antibiotic anthramycin (8) was established (28), followed by tomaymycin (12) and oxotomaymycin (13) in 1971 (26). The biosynthetic pathway to both the cyclopenin group and the anthramycin-tomaymycin group of alkaloids was elucidated in the following years and has been included in previous reviews (32,33). Later additions to the small list of naturally occurring benzodiazepines comprise aszonalenin (6) (16), asperlicin (7) (31), and auranthine (5) (85). The biosynthesis of the latter alkaloids has not yet been investigated in detail. 

Fig. 1. Overview of the structures of naturally occurring benzodiazepine alkaloids (see Table I for references).

Table II compiles melting points, optical rotations, and methods used for the structural elucidation of the known benzodiazepine alkaloids. Intensive studies of the degradation of the molecules as well as attempts at total synthesis have been undertaken only with members of the cyclopenin and the anthramycin-tomaymycin groups. In the following a short summary is given of the reactions and intermediates that provided essential information about the structures of the basic skeletons of the alkaloids.

In this review, all microbial species are named as published by the authors who first described the occurrence and chemical structures of benzodiazepine alkaloids. However, according to the modem taxonomic typification by Pitt (J. I. Pitt, The Genus Penicillium and Its Teleomorphic States EupenicUlium and Talaromyces." Academic Press, London, 1974), the names of some taxa have to be changed, as noted. 

Physicochemical Properties and References for the Structural Elucidation of Benzodiazepine Alkaloids... 

Thus, it appears that the activating effect exerted by the benzodiazepine alkaloids rests on a specific property of the primary metabolic enzymes involved in the biosynthesis of benzodiazepine precursors and present during the phase of alkaloid formation. If this effect would also occur in vivo (as suggested by the above characteristics), it would serve the coordination of precursor (and alkaloid) biosynthesis within a far-reaching feedback mechanism. Such a regulatory circuit... 

The benzodiazepine alkaloids are thoroughly excreted into the medium, thus keeping the cellular content of the hyphal cells very low. The alkaloid content cannot be substantially increased, even after artificial breakdown of membrane barriers. Permeabilization of hyphal cell membranes by lowering the ATP content (see above) is reversible by adding ATP or by allowing ATP net synthesis after removal of the metabolic inhibitors. Even if cyclopenin is present during such a permeabilization—reimpermeabilization cycle, the resealed cells do not... 

Benzodiazepine Alkaloids.—Cyclopenin (49) and cyclopenol (50) are isolated from Penicillium cyclopium. Their biosynthesis would appear to involve one molecule of phenylalanine and one of anthranilic acid and indeed the biosynthetic pathway to viridicatin and viridicatinol in Penicillium viridicatum from these two amino-acids has (49) and (50) as intermediates. ... 

Pinidine and Coniine Nicotiana Alkaloids yV-Methylpelletierine Lycopodium Alkaloids Lyduraceae Alkaloids Pyrrolizidine Group Tropane and Pyrrolidine Alkaloids Quinoline and Acridme Alkaloids Benzodiazepine Alkaloids Tylophora Alkaloids Cactus Alkaloids Ephedrine... 

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