Clausena carbazole alkaloids

The dimeric carbazole alkaloids often occur along with the corresponding monomeric carbazoles in terrestrial plants [7,62] (Scheme 7). Clausenamine-A was obtained by Wu from the stem bark of Clausena excavata [63]. Clausen-amine-A and its synthetic analogs, like bis(O-demethylmurrayafoline-A), show cytotoxic activities against diverse human cancer cell lines [64] and exhibit moderate antimalarial activity [65,66]. Furukawa isolated l,r-bis(2-hy-droxy-3-methylcarbazole) and bismurrayaquinone-A, the first dimeric car-bazolequinone alkaloid found in nature, from Murraya koenigii [67]. 

The bis-carbazole alkaloids typically contain previously known monomeric carbazoles as structural subunits. To date, bis-carbazole alkaloids have been isolated from plants of two genera of the family Rutaceae, Murraya and Clausena, and are linked either by a methylene unit, a bisbenzylic ether bridge, a bond joining one aromatic portion directly to an annotated dihydropyran unit, or by a biaryl bond. Many reviews have appeared on the monomeric carbazole alkaloids. However, in these articles only a few bis-carbazole alkaloids were listed (3,5-7). For the first time, in 1992, Furukawa et al. compiled all of the bis-carbazole alkaloids that were known to the end of 1992 (158). Taster and Bringmann summarized to the end of 2001, the occurrence, stereochemistry, synthesis, and biological activity of the bis-carbazoles linked through a biaryl bond (159). We compiled to the mid of 2002, the occurrence, stereochemistry, synthesis, and the biological activity of all classes of bis-carbazoles (8). In this section, we cover the total syntheses of the natural bis-carbazole alkaloids reported since 1990. 

Potterat, O., Puder, C., Bolek, W., Wagner, K., Ke, C., Ye, Y. and Gillardon, F. 2005. Clauzine Z, a new carbazole alkaloids from Clausena excavata with inhibitory activity on CDK5. Die Pharmazie, 60 637-639. 

The known alkaloid heptaphylline has been isolated from the roots of Clausena harmandiana Pierre (Rutaceae) along with two new carbazole alkaloids identified as 2-hydroxy-3-formyl-7-methoxycarbazole (58) and 7-methoxyheptaphylline (59). The H- and l3C-NMR spectra have been analyzed and used to position the various functional groups (54,55). Other carbazole alkaloids isolated from the roots of Murraya siamensis Craib are identified as murrayanine, girinimbine, and mukonal, which occur together with heptaphylline and compounds 58 and 59 (56-55). Three new alkaloids have also been isolated from M. siamensis and named 3-formyl-2,7-dimethoxycarbazole (60), 3-formyl-2-methoxylcarbazole (O-methylmukonal) (61), and 7-methoxymurrayacine (62) (59). From the roots of Rauwolfia serpentina, the new alkaloid indobine (63) (60), the benzyl ester, and indobinine (64) (61), the cyclohexyl ester of indolepropionic acid, have been isolated and identified. 

A number of dimeric carbazole alkaloids have been isolated from various natural sources in recent years, which have been found to exhibit various biological activities including antitumor, anti-inflammatory, and cytotoxic activities. In 1996, clausenamine A was isolated from the stem and root bark of Clausena excavata, which is used in Chinese herbal medicine for detoxification treatment following poisonous snakebites. The first total synthesis of clau-... 

Clauszoline-K and dausine C (clauszoline-L) have been isolated from the stem bark of the Chinese medidnal plant Clausena excavata [72], Clausine M and dausine N have been found in the root bark of the same plant [73]. The bioassay-guided fractionation of the organic extract of Murraya siamensis, collected in Thailand, led to the isolation of siamenol, which shows HIV-inhibitory activity [74], A simple route to these 7-oxygenated carbazole alkaloids has been developed, based on a highly efficient palladium-catalyzed approach (Scheme 15.21) [75] (Table 15.4). 

Maneerat W, Phakhodee W, Chenpracha S, Ritthiwigrom T, Deachathai S, Laphookhieo S. Clausenawallines G-K, carbazole alkaloids from Clausena wallichii twigs. Phytochemistry 2013 88 74-8. 

Maneerat W, Phakhodee W, Ritthiwigrom T, Cheenpracha S, Promgool T, Yossathera K, et al. Antibacterial carbazole alkaloids from Clausena harmandiana twigs. Fitoterapia 2012 83(6) 1110-4. 

Maneerat W, Ritthiwigrom T, Cheenpracha S, Laphookhieo S. Carbazole alkaloids and coumarines from Clausena lansium roots. PkytochemLett 2012 5(l) 26-8. Manners GD, Panter KE, Ralphs MH, Pfister JA, Olsen JD, James LF. Toxicity and chemical phenology of norditerpenoid alkaloids in the tail Larkspurs Delphinium Species). J Agric Food Chem 1993 41 96-100. 

Peng WW, Zeng GZ, Song WW, Tan NH. A new cytotoxic carbazole alkaloid and two new other alkaloids from Clausena excavate. Chem Biodivers 2013 10(7) 1317-21. 

Taxonomically the Rutaceae carbazole alkaloids are of interest as they have been isolated exclusively from four closely related genera GlycosmiSf Murraya, Clausena and Micromelum)... 

Carbazole alkaloids are found in the genera Clausena, Gly-cosmis, Micromelum, and Murray a of the Rutaceae. There is a single report from the genus Ekebergia of the Meliaceae (Bhattacharyya and Chakraborty, 1987 Chakraborty and Roy, 1991). 

Ngadjui, B.T., J.F. Ayafor, B.L. Sondengam, and J.D. Connolly Quinolone and Carbazole Alkaloids from Clausena anisata. Phytochem. 28, 1517 (1989). 

O-Demethylmurrayanine (217) C13H9NO2 (M 211), m.p. 237-39° was isolated from stem and root bark of Clausena anisata (55). The uv spectrum 226, 244, 255, 278, 291, 336, 346 nm with log e 4.40,4.51, 4.39,4.59,4.45,4.22,4.22) showed it to be a 3-formyl carbazole derivative. This and colour reactions showed it to be a phenolic carbazole. The H-NMR spectrum indicated the presence of deshielded metacoupled H-4 and H-2 protons, the four protons of the ring A and the proton of the CHO group (89.89). Hence the alkaloid was formulated as l-hydroxy-3-formyl-carbazole. The C-NMR spectrum also support the structure. 

---