Tropane alkaloids calystegines

A clever total synthesis of both enantiomers of animated 6a-carbahexoseptanoses 336 and ent-336, the immediate precursors of the tropane alkaloids calystegines A3 (337 and ent-337), was accomplished by Johnson and Bis [77], which centered upon the enzymatic desymmetrization of meso aminotropanediol 333. 

N-raethyl group and occur occasionally as minor constituents in plants producing tropane alkaloids [76,77]. A recent survey of the occurrence of calystegines in Solanaceae and Convolvulaceae plants discovered that they are widely distributed in these families [1,2,78-80],... 

Drager, B., Funck, C., Hohler, A., Mrachatz, G., Portsteffen, A., Schaal, A. and Schmidt, R. (1994) Calystegines as a new group of tropane alkaloids in Solanaceae. Plant Cell Tiss. Org. Cult., 38, 235 0. 

Both alkaloids have (+) and (-) forms but only the (-) hyoscyamine and (-) scopolamine are active. The biosynthetic pathway of tropane alkaloids, Fig. (1) is not totally understood, especially at the enzymatic level. Edward Leete has pioneered the biosynthetic studies of tropane alkaloid since 1950"s using whole plants and isotope labels [85-86]. The tropane alkaloid hyoscyamine is bioconverted by the enzyme H6H (hyoscyamine 6p-hydroxylase, EC 1.14.11.11) to scopolamine via 6p-hydroxyhyoscyamine. Hyoscyamine is the ester of tropine and (S)-tropic acid. The (S)-tropic acid moiety derives from the amino acid L-phenylalanine, while the bicyclic tropane ring derives from L-omithine primarily or L-arginine via tropinone. Tropinone is stereospecifically reduced to form either, tropine which is incorporated into hyoscyamine, or on the other hand into pseudotropine which proceeds to calystegines, a group of nortropane derivates that were first found in the Convolvulaceae family [87]. 

Tropinone is stereospecifically reduced to yield both tropine (3a-hydroxytropine), which led to the formation of tropane alkaloids, and pseudotropine (3p-hydroxytropine), the precursor of calystegines. These stereospecific reductions are catalyzed by two different tropinone reductases, tropinone reductase I and II (TRI and TRII). Both enzymes have been isolated from many Solanaceous species. Thus, TR I and TR II were isolated from D. innoxia roots and the crude extract favoured the production of pseudotropine over tropine [151]. Also, from transformed root cultures of D. stramonium two different tropinone reductases were obtained. In this species, TRI showed about 5-fold larger activity than TRII, and TRI displayed a pronounced pH-dependency, while TRII was more tolerant to different pH values [152]. Moreover, two tropinone reductases were also isolated from H. niger root cultures. TRI-reduction was reversible, whereas TRII-reduction was essentially irreversible [153]. In subsequent studies it was found that the accumulation of both TRs was the highest in the lateral roots of H. niger throughout development, with different cell-specific patterns [154]. 

This Chapter is designed to review the chemistry and biological activity of the calystegines, which at the present time are rarely found to occur in association with the correspondingly substituted tropane alkaloids. However, new sources of calystegines are rapidly bong discovered and die occurrence of additional polyhydroxy tropane alkaloids cannot be excluded. 

Calystegines. General name for a group of poly-hydroxylated tropane alkaloids. ... 

Tropane alkaloids Tropane alkaloids Quinine Indole alkaloids Calystegins Glycoalkaloids... 

Hyoscyamine and its racemic form atropine (extracted from Hyoscyamus niger, Atropa belladonna, and Mandragora officinarum), scopolamine (a co-product of hyoscyamine in Datura plants), cocaine (isolated from Erytroxylon coca), and calystegine (isolated from Solanum tuberosum) are tropane alkaloids that have widespread pharmacological use [38, 39], Atropine, hyoscyamine, and scopolamine... 

Unusual pyronotropane tropane alkaloids have been fotmd in the family Proteaceae. Tropine and pseudotropine esters of benzoic acid have been isolated from the family Euphorbiaceae. Novel dithiolane esters, along with tropine esters of acetic, propionic, n-butyric, isobutyric, isovaleric, and benzoic acids have been fotmd in the Rhizophoraceae. Calystegines, as well as a 3-hydroxybenzoate ester, have been fotmd in Brassicaceae. The calystegines have been used as chemotaxonomic markers in the Convolvulaceae family [20]. Tropine esters with methoxy-substituted benzoic acids are also characteristic for the later family. 

In contrast to GC-MS, a wide range of tropane alkaloids, including A -oxides and calystegines, can be analyzed by HPLC without prior derivatization. Enantiomeric separation of atropine 5 and scopolamine 6 racemic mixtures has been also achieved [22]. A number of HPLC methods have been published for routine quantification of the major tropane alkaloids hyoscyamine 1 and scopolamine 6 in plant samples. The use of UV detectors however is limited to compounds with UV adsorbing (aromatic or other) functionality. This disadvantage, however, is easily overcome by using HPLC coupled with MS detectors [22]. A typical HPLC separation of hyoscyamine 1 and scopolamine 6 is presented on Fig. 7.2. 

The next step from the biosynthetic pathway is a branch point of the tropane alkaloid pathway [1,2]. Tropinone 24 is the first intermediate with a tropane ring, and it is converted into intermediates that lead to hyoscyamine 1 or calystegines production depending on the stereochemistry of the reduction [37], Two stereospecific tropinone reductases (TR EC 1.1.1.236) - tropinone reductase I (TR-I) reduces the 3-carbonyl group of tropinone 24 to the 3a-hydroxy group of tropine 27 and tropinone reductase II (TR-II) to the 3p-hydroxy group of pseudotropine 25. TR-I leads to hyoscyamine 1 and scopolamine 6 formation via tropine 27, whereas pseudotropine 25 produced by TR-II is converted into calystegines and other nortropane alkaloids [1, 7, 36]. 

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