Melanie J. O'Neill

In vittro studies on the mode of action of quassinoids with activity against chloroquine-resistant Plasmodium falciparum

Using the incorporation of [3H]isoleucine or [3H]hypoxanthine into acid-insoluble products as indices of protein- and nucleic acid-synthetic activity, respectively, it was shown that seven plant-derived quassinoids with differing chemical substitutions all inhibited protein synthesis more rapidly than nucleic acid synthesis in human erythrocytes infected with Plasmodium falciparum, in vitro. Five quassinoids (ailanthinone, bruceantin, bruceine B, glaucarubinone and holacanthone) were effective within 30 min at doses 10 times their 48 hr in vitro IC50 values. Chaparrin and glaucarubol differed in that they did not inhibit protein synthesis during the time course of these experiments when applied at 10 times their in vitro IC50 values. When these compounds were used at 209 and 114 times their respective IC50 values, their observed effects were identical to those of the other quassinoids studied. The time (t50) at which nucleic acid synthesis was reduced to 50% of control was directly proportional to the t50 for protein synthesis, suggesting that failure of nucleic acid synthesis is a consequence of inhibition of protein synthesis. It is concluded that in the malaria parasite, as in eukaryote models, quassinoids are rapid and potent inhibitors of protein synthesis, and that this is most likely due to effects upon the ribosome, rather than upon nucleic acid metabolism.

Inducible isoflavonoids from the lima bean, Phaseolus lunatus

Abstract Phaseolus lunatus seedlings treated with aqueous cuprous chloride produced 25 isoflavonoids which were isolated and characterized by UV, mass and 1H NMR spectroscopy as kievitone, isoferreirin, 5-deoxykievitone, kievitone hydrate, cyclokievitone, cyclokievitone hydrate, daidzein, 2′-hydroxydaidzein, genistein, 2′-hydroxygenistein, 2,3-dehydrokievitone, luteone, phaseollidin, 2-(γ,γ-dimethylallyl)-phaseollidin, coumestrol, psoralidin, 7,8,2′,4′-tetrahydroxyisoflavone, 5,7,8,2′,4′-penta hydroxyisoflavone, 2,3-dehydrokievitol, lunatone, 5-deoxykievitol, kievitol, 3′-(γ,γ-dimethylallyl)-kievitone, 4-(γ,γ-dimethylallyl)-phaseollidin and 2-(γ,γ)-dimethylallyl)-6a-hydroxy-phaseollidin. The last nine compounds have novel structures. Possible biogenetic routes for these isoflavonoids and the taxonomic implications of their occurrence are discussed.

Plants as sources of antimalarial drugs, Part 6: Activities of Simarouba amara fruits.

Extracts prepared from Simarouba amara fruits collected in Panama have been found to be active against Plasmodium falciparum in vitro and against Plasmodium berghei in mice. Four active quassinoids have been identified as ailanthinone, 2-acetylglaucarubinone, glaucarubinone and holacanthone.

Flavonoids and chromenes from Artemisia annua

Abstract The ethyl acetate fraction obtained from the extraction of Artemisia annua yielded 11 flavones, four flavone glycosides and two chromene derivatives. Three new compounds were isolated: quercetagetin 4′-methyl ether, 2,2-dihydroxy-6-methoxychromene and 2,2,6-trihydroxychromene.

Isoflavonoids from Phaseolus coccineus

Abstract After treatment with CuCl 2 , the following isoflavonoids have been isolated from the runner bean, Phaseolus coccineus : daidzein, genistein, isoprunetin, 2′-hydroxygenistein, phaseoluteone, 2′-hydroxydihydrodaidzein, isoferreirin, kievitone, cyclokievitone, glycinol, phaseollidin, phaseollin, demethylvestitol, phaseollinisoflavan, 2′-hydroxyisoprunetin and 7,4′-dihydroxy-5,2′-dimethoxyisoflavanone. The latter two compounds are novel natural products.

Isosojagol, a coumestan from Phaseolus coccineus

Abstract A novel coumestan isolated from Phaseolus coccineus has been characterized as 3,9-dihydroxy-10-(γ,γ-dimethylallyl)-coumestan and named isosojagol.

Antiamoebic activity of indole analogues of emetine with in vitro potency greater than that of emetine

Nitroimidazole drugs such as metronidazole are highly effective in the treatment of acute amoebiasis. However, there is a need for new antiamoebic drugs because tolerance to nitroimidazoles may be poor due to adverse effects and there is the possibility that amoebae may develop resistance. Many attempts have been made to synthesise analogues of emetine (1: C-1HB) with greater activity against Entamoeba histolytica but potency tends to be reduced with increasing divergence of structure (Openshaw et al, 1969).

VARIATION IN OESTROGENIC ISOFLAVONE AND TOTAL ALKALOID CONTENT DURING EARLY GROWTH OF A COMMERCIAL VARIETY OF LUPINUS ALBUS

I.R. Pant ry , M . J . O N e i l l a n d M.F. Roberts , Department of Pharmacognosy, The S c h o o l o f Pharmacy , U n i v e r s i t y o f London , 29 -39 B r u n s w i c k S q u a r e , London W C l N 1 A X I n s e v e r a l c o u n t r i e s , l u p i n s e e d s a r e u s e d a s a s o u r c e o f p r o t e i n i n b o t h human and a n i m a l f o o d . S e l e t i v e b r e e d i n g h a s r e d u c e d t h e a l k a l o i d c o n t e n t t o a non t o x i c l e v e l (< lo mg.g- , (Hudson S 2 1 9 7 6 ) . L u p i n s a l s o p r o d u c e i s o f l a v o n e s ( I n g h a m & a 1 9 8 3 ) , some o f w h i c h e x e r t o e s t r o g e n i c e f f e c t s i n mammals ( P r i c e and F e n w i c k 1 9 8 5 ) and we h a v e shown t h a t s i g n i f i c a n t l e v e l s o f i s o f l a v o n e s a r e p r e s e n t i n s e e d l i n g s o f a s w e e t v a r i e t y o f L . a l b u s ( P a n t r y S 2 1 9 8 5 ) . F u r t h e r work h a s b e e n c a r r i e d o u t on a n o t h e r s w e e t v a r i e t y o f L . a l b u s and we w i s h t o rep o r t on t h e i s o f l a v o n e and a l k a l o i d c o n t e n t a t v a r i o u s s t a g e s d u r i n g t h e p l a n t s g r o w t h p e r i o d . L . a l b u s c v T i f w h i t e 7 8 s e e d s w e r e s u r f a c e s t e r i l i z e d and a l l o w ed t o g e r m i n a t e and grow i n m o i s t v e r m i c u l i t e a t a p p r o x i m a t e l y 2 0 * C i n n a t u r a l l i g h t . E t h a n o l i c e x t r a c t s o f 50 s e e d l i n g s w e r e made a t 8 t i m e s b e t w e e n d a y s 0 and 4 2 o f g e r m i n a t i o n . I s o f l a v o n e c o n s t i t u e n t s were m o n i t o r e d u s i n g a n i s o c r a t i c r e v e r s e p h a s e HPLC s y s t e m , p r e v i o u s l y c a l i b r a t e d f o r g e n i s t e i n , 2 h y d r o x y g e n i s t e i n and l u t e o n e . A l k a l o i d s were a l s o e x t r a c t e d a t t h e same 8 s t a g e s o f d e v e l opment u s i n g a s t a n d a r d t e c h n i q u e i n v o l v i n g Merck E x t r e l u t c o l u m n s . The t o t a l c o n c e n t r a t i o n o f t h e t h r e e i s o f l a v o n e s r e a c h e d i t s maximum 1 3 d a y s a f t e r g e r m i n a t i o n ( T a b l e 1) a n d g e n i s t e i n v a s p r e s e n t i n t h e h i g h e s t c o n c e n t r a t i o n a t t h i s s t a g e (1 .44 mg.g-). I 1 s known t h a t o t h e r p l a n t s c o n t a i n i n g g e n i s t e i n a t a l e v e l as l o w a s 20pg.g e x e r t o e s t r o g e n i c e f f e c t s i n sheep ( B r a d b u r y and W h i t e 1 9 5 1 ) . I n o u r s t u d y , p o t e n t i a l l y t o x i c l e v e l s o f i s o f l a v o n e s were p r e s e n t i n t h i s s w e e t v a r i e t y o f L . a l b u s f r o m t h e 4 t h day a f t e r g e r m i n a t i o n . A l t h o u g h t h e s e e d s w e r e a p p a r e n t l y f r e e f r o m g e n i s t e i n , 2 h y d r o x y g e n i s t e i n and l u t e o n e , t h e y c o n t a i n e d a c o n s i d e r a b l e q u a n t i t y o f h i g h l y p o l a r p h e n o l i c s u b s t a n c e s w h i c h c o u l d b e o e s t r o g e n i c i s o f l a v o n e g l y c o s i d e s ( P r i c e and F e n w i c k 1 9 8 5 ) . T h e r e i s no o b v i o u s c o r r e l a t i o n b e t w e e n i s o f l a v o n e a n d a l k a l o i d c o n c e n t r a t i o n s i n t h s p l a n t ( T a b l e 1). The t o t a l a l k a l o i d c o n t e n t was a t a maximum o f 2.16 mg .9 * in t h e d r y s e e d s and n e v e r e x c e e d e d a t o x i c l e v e l d u r i n g g e r m i n a t i o n . D e v e l o p m e n t o f l o w i s o f l a v o n e c o n t a i n i n g v a r i e t i e s s h o u l d be c o n s i d e r e d if l u p i n s a r e t o be g r o w n a s a c o m m e r c i a l f o d d e r c r o p . -i .

NOVEL PRENYLATED PTEROCARPANS FROM PHASEOLUS LUNATUS (LEGUMINOSAE)

Phaseolus species produce fungitoxic isoflavonoids in response to stress (ONeill et a1 1983). Certain pterocarpanoid isoflavonoids are highly fungitoxic and may be potentially useful antifungal agents in horticulture or medicine. In the present study we have isolated 4 prenylated pterocarpans from an extract of P. lunatus. CuClz-treated seedlings were extracted with EtOH and fungitoxic substances in the extract were detected using a TLC-bioassay against Cladosporium cucumerinum. Chromatography over polyamide and silica gel yielded phaseollidin (l), 2-(yy-dimethylallyl)-phaseollidin (2) and two novel natural products (3) and ( 4 ) , which were identified by their UV, MS and H-NMR characteristics. Mass spectroscopy revealed (3) to be an isomer of (2) and H-NMR spectroscopy confirmed the pterocarpan nature (Pachler and Underwood, 1967) and the presence of 2 isopentenyl chains. and (2) were identical but the A-ring for (3) had two ortho coupled protons. The use of W shift reagents (Ingham, 1982) indicated that a phenolic hydroxyl moiety was located at C-3. This compound was therefore characterised as 4(YYdimethylally1)-phaseollidin (3). The remaining pterocarpan (4 ) was identified as a 6a-hydroxy derivative by its dehydration in acid to form a pterocarpene (Ingham, 1982) pterocarpan possessed two phenolic hydroxyls and two isopentenyl chains and enabled (4 ) to be characterised as 2-(yy dimethylallyl)-6a-hydroxy-phaseollidin. The occurrence of the pterocarpans in p. lunatus is of taxonomic interest. Phaseollidin (1) has been isolated from all Phaseolus species examined to date whereas diprenylated isoflavonoids have not previously ceen isolated fros the genus. Compound (2) has been reported to occur only in the genus Erythrina (Kamat et a1 1981). Phaseollidin inhibits spore germination in C. cucumerinum at 25 uFm

Plants as Sources of Antimalarial Drugs Part. 1. In vitro Test Method for the Evaluation of Crude Extracts from Plants

. from p. lunatus deserve investigation. --1