Nitidine

Nitidine was isolated from the root bark and root of Zanthoxylum nitidum, which is a woody climber of the Rutaceae (4). The same compound has been isolated from Zanthoxylum tsihanimposa (root) and Z. ailanthoides (root). It is also present in the stem bark of Zanthoxylum americanum together with coumarins (44). 

The aerial part of Zanthoxylum inerme was divided into bark and wood. From the bark, more than 0.07% of nitidine was isolated together with other related alkaloids. By contrast, none of these alkaloids were found in the wood, and 4-methoxy-l-methyl-2-quinoline was the only nitrogeneous compound occurring together with several coumarins and lignans. These results are shown in Table 5.2.2 (75). Nitidine has been shown to have cytotoxic and antitumor activities. 

Nitidine and its derivatives are generally called benzo-[c]-phenanthridine alkaloids. This group of alkaloids is biosynthesized from the tetrahydroprotober-berine alkaloids through ring cleavage at the C-N bond and cyclization between Q and Cj3 (Fig. 5.2.11). 

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The above biomimetic method was successfully applied to synthesis of 2,3,8,9-tetraoxygenated fully aromatized benzo[c]phenanthridine alkaloids such as nitidine (243) (134,135), fagaronine (244) (134,135), and oxyterihanine (242) (136) (Scheme 42). The former two alkaloids attract many synthetic... 

Scheme 42. Biomimetic synthesis of nitidine (243), fagaronine (244), and oxyterihanine (242) via enamide aldehydes.

Synthesis of all four 8,8a-secobenzophenanthridine alkaloids was carried out chiefly by Baeyer-Villiger oxidation of appropriate benzophen-anthridines (Scheme 32). Thus, arnottianamide (206) was obtained from chelerythrine (210) (172,175), iwamide (207) from N-methyldecarine (211) (168,172), integriamide (208) from avicine (212) (171,172), and isoarnottiamide (209) from nitidine (213) (172,175). The proposed mechanism of this reaction (168,172,175) consists of initial attack of the peroxide ion on the C=N+ double bond followed by rearrangement and hydrolysis. 

Fagaronine and nitidine from Zanthoxylum species represent two of the more potent antitumor benzo[c]phenanthridines of Rutaceae. Both of these alkaloids have been shown to inhibit the enzymatic activity of topoisomerase in a way similar to camptothecin (28,29). It would be interesting to learn whether further study on Z. ailanthoid.es Sieb. Zucc. discloses any benzo[c]phenanthridine alkaloid of anti-neoplastic value. 

Wang LK, Johnson RK, Hecht SM. Inhibition of topoisomerase I function by nitidine and fagaronine. Chem Res Toxicol 1993 6 813-818. 

So far only a few examples of the uses of organosilicon compounds in cross-couplings have been published. Noteworthy is the smooth reaction with a sterically hindered substrate (87).295 The synthesis of the alkaloid nitidine included a cross-coupling step using an alkenylsilane (88),296 while the syntheses of some antitumor agents involved the alkenylation of unprotected iodouracyls using alkenyl-silicon species.297... 

Zanthoxylum nitidum (Roxb.) DC Shuang Mian Ci (Shiny bramble) (root) Nitidine, oxynitidine, vitexin, 6-ethoxy-chelerythrin, diosmin, oxynitidine, oxychelerythrine, N-desmethylchelerythrine, skimmianine.33 50 53 Analgesic, anodyne, antitumor against leukemia, carminative, detoxicant, increase blood flow. 

The wood of this plant yielded, among other and neutral products, 4-methoxy-l-methyl-2-quinolone (mp 99-103°). The bark yielded nitidine, aricine, chelerythrine, isolated as derivatives, and oxynitidine (mp 283-285°). In addition l-( + )-armepavine metho salt was also found (171). 

A variety of alkaloids bind to or intercalate with DNA or DNA/RNA processing enzymes and affect either transcription or replication (quinine, harmane alkaloids, melinone, berberine), act at the level of DNA and RNA polymerases (vinblastine, coralyne, avicine), inhibit protein synthesis (sparteine, tubulosine, vincrastine, lupanine), attack electron chains (pseudane, capsaicin, solenopsine), disrupt biomembranes and transport processes (berbamine, ellipticine, tetrandrine), and inhibit ion channels and pumps (nitidine, caffeine, saxitoxin). In addition, these natural products attack a variety of other systems that can result in serious biochemical destabilization... 

The fluorescence spectra of chelerythrine, nitidine, and sanguinarine in different solvents have been shown to be dependent on the pH of the solution and to allow the determination of the equilibrium constant for the formation of the pseudobases.531 A salt of chelidonine with 5-carboxymethyl-2-thio-l,3-thiazan-4-one has been prepared.532 The intercalative binding of sanguinarine533 and the anti-tumour activities of chelidonine JV-oxide534 and of nitidine535 have been studied. 

Avicine and Nitidine. Among many 2,3,8,9-tetrasubstituted alkaloids, nitidine (77) and fagaronine (79) have been shown to possess very potent antileukemic activity, therefore becoming targets for their synthesis 82,83). 

Photocyclization of the enamide 80 and the o-methoxy-substituted enamide 85 under nonoxidative conditions afforded the trans lactams 81 (52%) and 86 (53%) and the dehydrolactams 82 (41%) and 87 (50%), respectively. Since dehydrogenation of the trans lactams 81 and 86 with 30% Pd/C gave lactams 83 and 88, although in low yields, the dehydrolactams (82) and (87) were used for ready dehydrogenation with the same reagent, followed by reduction to the desired alkaloids dihydroavicine (84) and dihydronitidine (89), natural alkaloids that had been converted already to nitidine and avicine, respectively (1,2) (Schemes 44 and 45). 

A more direct approach to nitidine and avicine was reported by Kessar et al. (88) who showed that o-bromonaphthalide (90) was directly converted to the lactam 91 in 70% yield. Subsequently, they also demonstrated that when the enamide was reduced to the amine, photocyclization and dehydrogenation occurred to give the fully aromatized compound 92 (88) (Scheme 46). 

Begley and Grimshaw (94) reported a modified synthesis of nitidine (77) by shortening the steps in Kessar s route (88) by using the A -methylbenza-mide (93) under photochemical conditions. However, they failed to obtain benzo[c]phenanthridone by electrochemical means (94) (Scheme 47). 

Nitidine Antileukemic to mouse, L1210, P388 cells Antitrypanosomal — 300... 

Cells carefully control the homeostasis of their ion concentrations by the action of ion channels (Na, K , Ca " channels) and throu Na, K -ATPase and Ca -ATPase. These channels and pumps are involved in signal transduction, active transport processes, and neuronal and neuromuscular signaling. Inhibition of transport processes (ion channels, carriers) is achieved by (Table IV) acronycine, ervatamine, harmaline, quinine, reserpine, colchicine, nitidine, salsolinol, sanguinarine, stepholidine, caffeine, sparteine, monocrotaline, steroidal alkaloids, aconitine, capsaicine, cassaine, maitoxin, ochratoxin, palytoxin, pumiliotoxin, saxitoxin, sole-nopsine, and tetrodotoxin. 

Another application of the cro,ss-coupling reaction is demonstrated in Scheme 10-3 with an efficient synthesis [13] of the precursor of an alkaloid, nitidine, which inhibits DNA topoisomerase I. 

Nitidine (5) was isolated for the first time from Z nitidum [49,50]. Alkalization of the quaternary salts leads to a mixture of 5,6-dihydroniti-dine and 6-oxonitidme [49,50]. The salts are relatively stable as is the pseudocyanide [49]. Avicine (6), first isolated from Z avicennae DC., is also an unstable species [51]. Fagaronine (7), a phenolic QBA of the nitidine type, has been isolated from Fagara xanthoxyloides Lam [52] and exhibits a high antileukemic activity. 

The alkaloids sanguinaiine and cbelerythrine are in most cases accompanied by the minor alkaloids chelirubine, chelilutine, sangudutine, sangui-rubine, and, in several plants, macarpine. These minor alkaloids have never been found in the Rutaceae frmily. In contrast, alkaloids of the nitidine type occur exclusively in the Rutaceae and are one of the chemotaxonomic features of some genera. 

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