Rutaecarpine

There are several alkaloids in the structure of which are both quinazoline and indole nuclei. Evodiamine (1001 R = H) and rutaecarpine (1002) were both isolated from the seeds of Evodia rutaecarpa about 1916 and synthesized in 1927. They were found subsequently to occur also in Xanthoxylum rhetsa, which in addition yielded rhetsinine (1001 R = OH) (59T(7)257). The plant Hortia arborea afforded two more related alkaloids, hor-tiacine and hortiamine, each characterized by a methoxy group in the benzene ring of the indole portion (60JA5187). 

Rutaecarpine, C gHuON, crystallises om boiling alcohol in colourless... 

These formulae explain the scission products of the two alkaloids and the conversion of evodiamine into rutaecarpine, and were accepted by Asahina. A partial synthesis of rutaecarpine was effected by Asahina, Irie and Ohta, who prepared the o-nitrobenzoyl derivative of 3-)3-amino-ethylindole-2-carboxylic acid, and reduced this to the corresponding amine (partial formula I), which on warming with phosphorus oxychloride in carbon tetrachloride solution furnished rutaecarpine. This synthesis was completed in 1928 by the same authors by the preparation of 3-)S-amino-ethylindole-2-carboxylic acid by the action of alcoholic potassium hydroxide on 2-keto-2 3 4 5-tetrahydro-3-carboline. An equally simple synthesis was effected almost simultaneously by Asahina, Manske and Robinson, who condensed methyl anthranilate with 2-keto-2 3 4 5-tetrahydro-3-carboline (for notation, see p. 492) by the use of phosphorus trichloride (see partial formulae II). Ohta has also synthesised rutaecarpine by heating a mixture of 2-keto-2 3 4 5-tetrahydrocarboline with isatoic anhydride at 195° for 20 minutes. 

In a recent paper, Schopf and Steuer ° describe the synthesis under physiological conditions of rutaecarpine from 4 5-dihydro-3-carboline perchlorate and a-aminobenzaldehyde. 

According to Ra rmond-Hamet, evodiamine and rutaecarpine on injection induce increased arterial pressure. 

The synthesis of alkaloids from dihydronorharmane, condensation of which with o-aminobenzaldehyde gives rutaecarpine (204) 321-323), is of a particular interest. 

Alkaloids containing a quinazoline nucleus form a small but important group of natural products and have been isolated from a number of different families in the plant kingdom. The quinazoline alkaloids are of the four types (48), (49), (50), and (51). The structures of arborine, peganine, febrifugine, rutaecarpine, and evodi-amine have been elucidated by degradation and synthesis and are described in recent reviews on quinazoline alkaloids. ... 

Like peganine a laboratory synthesis of rutaecarpine (51a) under physiological conditions has been realized by condensation of o-aminobenzaldehyde with a -carboline (Scheme 16). 

An early attempt to synthesize rutaecarpine (111) from the urea derivative 110 by a method analogous to that of Clemo and Swan was unsuccessful. ... 

The alkaloid rutaecarpine (111) was synthesized from l-oxo-1,2,3,4-tetrahydro-)3-carboline (183 R = H) by condensation with methyl anthranilate in the presence of phosphorous chloride or by heating... 

Substituted and aza analogues of febrifugine have been prepared in the search, with a certain amount of success, for a better anti-malarial activity/ toxicity balance <06BMCL1854>. A number of analogues of rutaecarpine, including substituents in and fusion onto ring D were prepared by condensation reactions on iminothio ethers 55... 

Rutaecarpine (46) is the major alkaloid found in Evodia rutaecarpa (Juss.) Benth., and activities relevant to AD have been identified with the extract and with rutaecarpine. Dehydroevodiamine (47), another alkaloid from the same species, inhibited AChE in vitro, and reversed scopolamine-induced memory impairment in rats and increased cerebral blood flow in vivo in cats, a property which would supplement its usefulness in AD. The structures of (46) and (47) and tacrine (28) have been used as templates for the development of a series of synthetic compounds which have been evaluated for their antiChE activity. These were found to be inhibitory against both AChE and BuChE with A -(2-phenylethyl)-A -[(12Z)-7,8,9,10-tetrahydroazepino [2,l- ]quinazolin-12(6//)-ylidene] amine (48) showing higher affinity for BuChE. 

Decker M, Novel inhibitors of acetyl- and butyrylcholinesterase derived from the alkaloids dehydroevodiamine and rutaecarpine, Eur J Med Chem 40 305-313,... 

There is evidence in literature that alkaloid biology is connected with regulation, stimulation and induction functions. Tsai et al. proved that caffeine levels in the blood, brain and bile of rats decreased when given a treatment of rutaecarpine, an alkaloid from Evodia rutaecarpa (Figure 78). It is known that caffeine has been found to enter the brain by both simple diffusion and saturable carrier-mediated transport . The hepatobiliary excretion of caffeine has also been reported in humans rabbits and rats. ... 

A treatment of rutaecarpine causes an increase in renal microsomal enzymes related to CYPIA and enhances the activity and protein levels of CYPIA. It is known that caffeine is a mild stimulant. It is metabolized in the hver by... 

Figure 78. Rutaecarpine, an alkaloid from Evodia rutaecarpa.

CYP1A2, and it also has been shown to be an inducer of CYP1A2 in rodents on account of the increase in hepatic microsomal CYP1A2. Rutaecarpine is an inducer of cytochrome P450(CYP)1A in mouse liver and kidney ". ... 

Ueng, Y. E., Wang, J. J., Lin, L. C., Park, S. S. and Chen, C. F. 2001. Induction of cytochrome P450-dependent monooxygenase in mouse liver and kidney by rutaecarpine, an alkaloid of the herbal drug Evodia rutaecarpa. Life Sciences, 70 207-217. 

Evodia rutaecarpa (Juss.) Berth Wu Zhu Yu (Evodia) (fruit) Alkyl methyl quinolone alkaloids, evodiamine, limonin, evocarpine, rutaecarpine, N-methyl anthranilic acid, evodol, hydroxyevodiamine, N-methylanthranflamide, N,N-dimethyl-5 -methoxytryptamine, dehydroevodiamine.32,33,237 Antiemetic, analgesic, lower blood pressure, antibacterial. 

Tetrahydro- and l,2,3,4,6,7,8,9-octahydro-ll//-pyrido[2,l-fe]quina-zolin-ll-ones and their 6-arylhydrazino derivatives (134) are key intermediates in the total synthesis of rutaecarpine alkaloid (409) and its derivatives (183) (85JHC1373 87JHC1045). 

Iwata H, Tezuka Y, Kadota S, et al. Mechanism-based inactivation of human liver microsomal CYP3A4 hy rutaecarpine and limonin from Evodia fruit extract. Drug Metah Pharmacokinet 2005 20(1) 34-45. 

Details of Kametani s synthesis of evodiamine and rutaecarpine by the retro mass-spectral approach22" have also been published.23" An extension of this method afforded a new synthesis23 of rutaecarpine (26) thus, condensation of the... 

An extension of Kametani s earlier synthesis has afforded a neat synthesis of rutaecarpine (24) and hortiacine (10-methoxyrutaecarpine).22" In this modification, the presence of a trifluoromethyl group in (23) (instead of hydrogen, as in Kametani s synthesis) increases the electrophilicity of the protonated form, and also provides a useful leaving group for the final stage of the synthesis a dehydrogenation step is therefore unnecessary (Scheme 3). Rutaecarpine has also been synthesized.226 11-Methoxyrutaecarpine has been simply synthesized by condensation of 7-methoxy- 1-oxo-l,2-dihydro-/ -carboline with methyl anthranilate and phosphorus oxychloride.22c... 

The quinazolinocarboline alkaloids, as the name indicates, contain both carboline and quinazoline nuclei. The first known representatives were rutaecarpine and evodiamine, and two more representatives have been encountered more recently. Rhetsinine, which was at one time regarded as belonging here, is included in this chapter because of its affinity with rhetsine, though it does not contain the quinazoline ring system. This chapter is a summary and an extension of that dealing with these alkaloids in Volume II, p. 402. 

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