Structure Of Villalstonine

Alstonia is a widespread genus of evergreen trees and shrubs from Apocynaceae (dogbane family). Alstonia (devil tree) consisting of about 40-60 species, native to tropical and subtropical Africa, Central America, Southeast Asia and Australia (Sidiyasa, 1998). About 200 alkaloids have been reported from the genus, many of which are pharmacologically active.

Alstonia macrophylla Wall. ex A. DC. is native of Malaysia and frequently planted as an ornamental. The decoctions of A. macrophylla leaves and stem bark are widely used by the Onge and Nicobarese of Little Andaman Islands, India, to treat stomachache, skin diseases and urinary infections. Leaves are reported to have anticholeretic and vulnerary effect, and are greased with hot coconut oil for sprains, bruises and dislocated joints as poultice and used as a febrifuge.

Phytochemistry: A. macrophylla is a rich source of monomeric and dimeric indole alkaloids. The total alkaloid content is the highest in the stem bark and lowest in leaves. Alstophylline, macralstonine, macralstonidine, macrocasalhine, macrosalhine, macrocapamine (Fig. 17.1) and villalstonine (Fig. 17.2) have been reported from the stem bark.

Stem bark of the Indian plant yields villalstonine (0.8-1.0%) and macralstonine (0.06%). 11-methoxy-geissaschizine (Fig. 17.3),10-11-dimethoxy-geissaschizine (Fig. 17.4) and 16-hydroxy-Nb—demethylalstophylline (Fig. 17.5) have been reported from plants growing in Sri Lanka.

Fig. 17.1 Structure of macrocapamine. Fig. 17.2 Structure of villalstonine.

och3

Fig. 17.1 Structure of macrocapamine. Fig. 17.2 Structure of villalstonine.

ch3o ch3o

ch3ooc oh

Fig. 17.3 Structure of 11-methoxy-geissaschizine. CH3O

ch3ooc oh

Fig. 17.3 Structure of 11-methoxy-geissaschizine. CH3O

CH3O'

CH3OOC

Fig. 17.4 Structure of 10, 11-dimethoxy-geissaschizine.

Fig. 17.5 Structure of 16-hydroxy-Nb-demethylalstophylline.

Alstozine N-oxide (Fig. 17.6) has been isolated from the leaves of A.macrophylla.

Fig. 17.5 Structure of 16-hydroxy-Nb-demethylalstophylline.

Alstozine N-oxide (Fig. 17.6) has been isolated from the leaves of A.macrophylla.

Fig. 17.6 Structure of Alstozine N-oxide.

Oxindole alkaloids, Nb-demethylalstophyllal oxindole and alstonal have been isolated. Activity-directed fractionation led to the isolation of a novel indole alkaloid, O-methylmacralstonine, from the most active fraction of A. macrophylla along with four known alkaloids, talcarpine, villalstonine, pleiocarpamine (Fig. 17.7), and macralstonine.

Fig. 17.6 Structure of Alstozine N-oxide.

Oxindole alkaloids, Nb-demethylalstophyllal oxindole and alstonal have been isolated. Activity-directed fractionation led to the isolation of a novel indole alkaloid, O-methylmacralstonine, from the most active fraction of A. macrophylla along with four known alkaloids, talcarpine, villalstonine, pleiocarpamine (Fig. 17.7), and macralstonine.

Fig. 17.7 Structure of Pleiocarpamine.

Three new indole alkaloids, viz. 10-methoxyaffinisine, 10-methoxycathafoline and alstonerinal, in addition to alstonerine, alstonisine (Fig. 17.8), alstonal, alstophylline, vincamajine (Fig. 17.9), lochnerine and cathafoline have been isolated from the stem-bark extract.

Fig. 17.7 Structure of Pleiocarpamine.

Three new indole alkaloids, viz. 10-methoxyaffinisine, 10-methoxycathafoline and alstonerinal, in addition to alstonerine, alstonisine (Fig. 17.8), alstonal, alstophylline, vincamajine (Fig. 17.9), lochnerine and cathafoline have been isolated from the stem-bark extract.

Fig. 17.8 Structure of Alstonisine. Fig. 17.9 Structure of vincamajine.

Alstoctazine (Fig. 17.10), a novel bisindole alkaloid has been isolated from plants growing in Malaysia.

Fig. 17.8 Structure of Alstonisine. Fig. 17.9 Structure of vincamajine.

Alstoctazine (Fig. 17.10), a novel bisindole alkaloid has been isolated from plants growing in Malaysia.

Fig. 17.10 Structure of alstoctazine.

Ten new indole alkaloids, alstomaline, 10,11-dimethoxynareline, alstohentine, alstomicine, 16-hydroxyalstonisine, 16-hydroxyalstona, 16-hydroxy-N(4)-demethylalstophyllal oxindole, alstophyllal, 6-oxoalstophylline, and 6-oxoalstophyllal, in addition 21 other known ones, were obtained from the leaf extract of the Malayan A. macrophylla. Recently alstiphyllanines A-D (Fig. 17.11-17.14) have been reported.

Fig. 17.10 Structure of alstoctazine.

Ten new indole alkaloids, alstomaline, 10,11-dimethoxynareline, alstohentine, alstomicine, 16-hydroxyalstonisine, 16-hydroxyalstona, 16-hydroxy-N(4)-demethylalstophyllal oxindole, alstophyllal, 6-oxoalstophylline, and 6-oxoalstophyllal, in addition 21 other known ones, were obtained from the leaf extract of the Malayan A. macrophylla. Recently alstiphyllanines A-D (Fig. 17.11-17.14) have been reported.

Fig. 17.11 Structure of Alstiphyllanine A. Fig. 17.12 Structure of Alstiphyllanine B.

Fig. 17.13 Structure of Alstiphyllanine C. Fig. 17.14 Structure of Alstiphyllanine D.

Other alkaloids reported in literature include alstonidine (Fig. 17.15), alstomacrocine (Fig. 17.16), alstomacroline (Fig. 17.17), alstopicralamine (Fig. 17.18), alstoumerine (Fig. 17.19), macroxine (Fig. 17.20), quebrachidine (Fig. 17.21), 10-Hydroxystrictamine (Fig. 17.22), and Nb-demethylalstophyllinoxindole (Fig. 17.23).

Fig. 17.15 Structure of Alstonidine. Fig. 17.16 Structure of Alstomacrocine.

h3co o ch3

Fig. 17.17 Structure of Alstomacroline. Fig. 17.18 Structure of Alstopicralamine.

Fig. 17.20 Structure of Macroxine.

Fig. 17.19 Structure of Alstoumerine.

o h c och3

Fig. 17.20 Structure of Macroxine.

h

Fig. 17.21 Structure of quebrachidine. Fig. 17.22 Structure of 10-Hydroxystrictamine.

Fig. 17.21 Structure of quebrachidine. Fig. 17.22 Structure of 10-Hydroxystrictamine.

Fig. 17.23 Structure of Nb-demethylalstophyllinoxindole.

Pharmacology

A. macrophylla extracts

Antimicrobial activity: The methanolic crude and methanol-aqueous extract of A. macrophylla leaves and n-butanol part of the crude extract showed antimicrobial activity against various strains of Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus faecalis, Escherichia coli, Proteus mirabilis, Trichophyton rubrum, Trichophyton mentagrophytes var. mentagrophytes and Microsporum gypseum. The minimum inhibitory concentration (MIC) values ranges from 64 to 1000 microg/ml for bacteria and 32-128 mg/ml for dermatophytes. The stem- bark extract prepared similarly was found to be less active when compared to the leaves.

Anti-inflammatory activity: Methanolic extract of dried leaves of A. macrophylla and its fractions were investigated for its anti-inflammatory activity. The extract at a concentration of 200 mg [kg.sup.-1] and 400 mg [kg.sup.-1], p.o. and its fractions at 25 mg [kg.sup.-1] and 50 mg [kg.sup.-1], p.o. showed the significant dose dependent anti-inflammatory activity in carrageenan and dextran-induced rats hind paw edema (acute models) as well as in cotton pellet-induced granuloma (chronic model) in rats. Antipyretic activity: The methanol extract of A. macrophylla and its fractions were tested on normal body temperature and yeast-induced pyrexia in Wistar Albino rats. The leaf extract at oral doses of 200 and 300 mg/kg, and the n-butanol fractions of the extract at 50 mg/kg showed significant reduction in normal body temperature and yeast-provoked elevated temperature in a dose-dependent manner comparable to that of standard antipyretic drug paracetamol. The antipyretic effect was started at 1h and extended for at least 5h after the drug administration.

CNS activity: Methanol extract at 100-200 mg/kg p.o. and major nonpolar fraction B at 50 mg/kg of A. macrophylla leaves caused a significant reduction in spontaneous activity, remarkable decrease in exploratory behavioral pattern, a reduction in muscle relaxant activity and also significantly potentiated phenobarbitone sodium-induced sleeping time.

Alkaloids of A. macrophylla

Antihypertensive effect: Root alkaloidal mixture is reported to be antihypertensive in animals and humans with no side-effects. Total alkaloid mixture is reported to decrease 10-60% blood pressure in dogs.

Intravenous administration of macroxine is reported to decrease in arterial blood pressure and slight bradycardia in pentothal sodium anaesthetized rats. Four doses viz. 50^g/kg, 100^g/kg, 250^g/kg and 1000^g/kg of macroxine were injected. The effects of macroxine on % fall on mean arterial blood pressure were studied. The dose of 100 ^g/ kg showed 24.03% fall in the mean arterial blood pressure and resulted in 6.6% bradycardia (Table 1.1).

Table 17.1 Effect of macroxine on mean arterial blood pressure.

Dose (^g/kg i.v.)

Mean arterial blood pressure (% fall)

50

17.31

100

24.03

250

16.96

1000

10.0

Alstopicralamine demonstrated 55.36% fall in blood pressure with a dose of 30^g/kg given intravenous in an anaesthetized rat (Table 1.2).

Table 17.2 Effect of alstopicralamine on mean arterial blood pressure.

Dose (^g/kg i.v.)

Mean arterial blood pressure (% fall)

20

42.50

30

55.36

Macralstonine has marked antihypertensive effect. Villastonine, in a dose of 2mg/kg body wt of an anaesthetized cat caused fall in blood pressure which was unaffected by atropine. Villastonine is reported to be neuroleptic; 20 mg/kg i.p. dose caused depletion of 5-OH-tryptamine on rat brain after 15 min.

Cytotoxic activity: Significant cytotoxic activity was exhibited by the extract of A. macrophylla on two human lung cancer cell lines, MOR-P (adenocarcinoma) and COR-L23 (large cell carcinoma). Activity-directed fractionation led to the isolation of O-methylmacralstonine, talcarpine, villalstonine, pleiocarpamine, and macraistonine. Villalstonine was found to possess pronounced activity on both cell lines with an IC50 value less than 5 ^M.

Thirteen indole alkaloids isolated from the root bark of A. macrophylla and a semisynthetic bisindole O-acetylmacralstonine were assessed for cytotoxic activity against two human lung cancer cell lines, MOR-P (adenocarcinoma) and COR-L23 (large cell carcinoma), using the SRB assay. Pronounced cytotoxic activity was exhibited by the bisindoles on both cell lines.

The potent alkaloids were further tested against a human normal cell line (breast fibroblasts) and other human cancer cell lines including StMll la (melanoma), Caki-2 (renal cell carcinoma), MCF7 (breast adenocarcinoma), and LS174T (colon adenocarcinoma). O-acetylmacralstonine, villalstonine and macrocarpamine were found to possess pronounced activity against cancer cell lines with IC50 values in the range of 2-10 ^M, with no discernible cell-type selectivity. However, O-acetylmacralstonine displayed discernibly less toxicity against the normal breast fibroblasts. Mutagenic activity: The Ames Salmonella typhimurium microsomal screening system was standardized and pleiocarpamine was screened for mutagenic potential. The results indicated that pleiocarpamine exhibited mutagenic activity in TA98 tester strain.

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