Bisindole alkaloids, structure

The growing interest in secondary metabolites of plants leads to the requirement of the development on analytical method for the secondary product analysis. Chromatographic procedures for the determination of alkaloids have been well established. Based on the literatures published in past years, further improvement of the current methods for the analysis of Catharanthus alkaloids are needed [4]. Besides, the chemical complexity and unique bisindole alkaloid structure of the aforementioned molecules hindered their laboratorial synthesis. The isolation of VLB and VCR is laborious and costly, mainly due to their low contents in the plant and coexistence in a large number of other alkaloids [5]. Therefore, it is important for separation, identihcation, and quantiflcation of these Catharanthus alkaloids. The methods of extraction and purification were focused on liquid-liquid extraction, solid-phase extraction, supercritical fluid extraction (SFE), and molecularly imprinted polymers (MlPs)-based extraction. For separation, GC is not suitable for the bisindole alkaloids due to their high boiling point. The major methods for analysis of Catharanthus alkaloids are liquid chromatography (LC) and capillary electrophoresis (CE). 

In addition to monomeric compounds, Tabemaemontana plants contain many bisindole alkaloids that are classified on the basis of constituent monomeric units, as in the extensive review by Cordell and Saxton in Volume XX of this series (14). This classification is more rational and comprehensive than others (I, 13, 15) and will be used as a guide for the representation of structural formulas and for the discussion of the chemistry of single alkaloids. 

The great number of different alkaloids found in Tabemaemontana precludes a discussion of the structure elucidation and chemistry of all of them. To keep the treatment concise, a major compromise was necessary. The alkaloids that have been reported in previous volumes of this treatise (as indicated in Table I) and their trivial modification will not be mentioned here. This compromise eliminates from the discussion well-established and long-known alkaloids that were isolated not only from Tabemaemontana but also from other genera. Moreover, the plumeran alkaloids isolated up to 1976 and ebuman-type and bisindole alkaloids isolated up to 1979 are covered in Volumes XVII and XX. The main efforts of this chapter will be focused on more recently isolated compounds, some of which are structurally and biogenetically relevant and have been found only in plants of the genus Tabemaemontana. 

Ervafoline did not fragment under the acidic conditons used for the cleavage of other bisindole alkaloids. The complete structure and relative stereochemistry of ervafoline, as shown in formula 246, were determined by a single-crystal X-ray study. 

ISOLATION, STRUCTURE ELUCIDATION, AND BIOSYNTHESIS OF THE BISINDOLE ALKALOIDS OF CATHARANTHUS... 

The occurrence of structurally established bisindole alkaloids in Cath-aranthus roseus (L.) G. Don and in the minor species of Catharanthus, namely, C. lanceus (Boj. ex DC.) Pich., C. longifolius Pich., C. ovalis Mgf., C. pusillus (Murr.) G. Don, and C. trichophyllus (Bak.) Pich, is... 

Bisindole Alkaloids with Established Structures Isolated from Catharanthus Species... 

Since the last major review of the biosynthesis of the monoterpenoid indole alkaloids (97), there have been several full and partial 98-104) reviews of various aspects of the work that has been conducted since 1974. Two major developments have dominated the field in this period, namely, the demonstrations that (i) strictosidine (33) is the universal precursor of the monoterpenoid indole alkaloids and (ii) selected cell-free systems of C. roseus have the ability to produce the full range of alkaloid structure types, including the bisindoles. This section traces some aspects of these developments, paying particular attention to work been carried out with C. roseus, and omitting work, important though it may be, on other monoterpenoid indole alkaloid-producing plants, e.g., Rauwolfia, Campto-theca, and Cinchona. 

From the perspective of organic chemistry, the medicinal chemistry of the bisindole alkaloids derived from Catharanihus roseus (L.) G. Don circumscribes a large and exceedingly diverse collection of structurally complex molecules. There can be no doubt that the breadth and diversity of these compounds is due, in large part, to the remarkable biological... 

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

Partial structures (lacking ring D ) of the bisindole alkaloids have been prepared by reaction of a substituted chloroimine with vindoline (21) under conditions that promote ionization to yield the coupled products as a mixture of diastereomers (59). Reaction of 27 with silver fluoroborate followed by addition of 21 gives 29 as a mixture of diastereomers in 49% yield. Treatment of this mixture with potassium borohydride under acid... 

The vinca alkaloids vinblastine and vincristine are capable of producing the MDR phenotype in a wide variety of cell types. Furthermore, cells that are made resistant to antitumor drugs such as doxorubicin, actinomy-cin D, or the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26) are often resistant to the effects of the bisindole alkaloids. The structural and mechanistic diversity of these compounds is even more striking against the backdrop of collateral resistance. 

The bisindole alkaloids are clearly closely associated with MDR from both historical and structural perspectives. The clinical relevance of this mechanism of drug resistance has not been unambiguously established however, the tissue-specific expression of P-gp has been noted for several normal as well as malignant tissues (105). Therefore, the natural resis-... 

Dihydroarcyriarubin C (104), a new bisindole alkaloid, has been isolated from fruit bodies of a myxomycete Arcyria ferruginea, which was collected at Hao, Yasu-cho, Kochi Prefecture, together with two known bisindoles, arcyriarubin C (2) and arcyriaflavin C (4), and the structure of 104 was elucidated by spectral data. Arcyriaflavin C (4) was also obtained, together with arcyriaflavin B (3), from fruit bodies of Tub if era casparyi, which ( 16839) was collected at Mt. Miune, Monobe-mura, Kochi Prefecture, in November 1997. Arcyriaflavin C (4) was revealed to exhibit cell cycle inhibition activity on HeLa cells on the basis of flow cytometry studies. Fruit bodies of Fuligo Candida, which ( 23446) was collected at Motoyama-cho, Kochi Prefecture, in August 2002, were revealed to contain a relatively high quantity of cycloanthranilylproline (105). 

The structure of ervafoline (314), one of the eight bisindole alkaloids from the leaves of Stenosolen heterophyllus, was elucidated earlier by the 3f-ray method. A detailed 400 MHz H n.m.r study of three of the other seven bisindole alkaloids has allowed the structures of 19 -hydroxyervafoline (315), ervafolene (316), and 19 -hydroxyervafolene (317) to be elucidated,u7d from which it appears that ervafoline and 19 -hydroxyervafoline are the 14, 15 -/ -epoxides of ervafolene and 19 -hydroxyervafolene.11 ld... 

Gardmultine (C45H54N4O10) a bisindole alkaloid isolated from Gardneria multiflora Makino, comprises gardneramine and chitosenine linked by a spiro five-membered ring. The structure proposed from chemical and spectroscopic properties (50) was confirmed by the crystal-structure analysis (51). The structural formula and the stereodrawing, shown in Fig. 25, illustrate the spiro junction at atom C-16 between the two component alkaloids of gardmultine. 

Conoduramine occurs in the root bark of Tabemaemontana elegans, together with seven new bisindole alkaloids, tabernaelegantines A—D, tabernaelegantinines A and B, and tabernaelegantinidine. tabernaelegantines A—D are formulated as the two pairs of C-20 epimers (248)—(251), but the detailed evidence on which these structures are based is not yet available, ... 

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