Journul of Ethnopharmacology, 31(1991) 59-65 Elsevier Scientific Publishers Ireland Ltd.
ANTITUMOR
ACTIVITY
59
OF QUASSINOIDS
FROM HANNOA
KLAINEANA
LUYENGI LUMONADIO’, GHANEM ATASSP, RENEE VANHAELEN-FASTRE’
MAURICE VANHAELEN’
and
“Institut de Recherche Sciences de la Santa K&has&Gombe (Zaire), bLaboratoire de Pharmacologic celluluire, CP 14.4 and ‘Laboratoire de Pharmacognosie, Inatitut de Pharmacie, CP 205-4, Univeraitk Libre de Bruxelles. Boulevard de Triomphe, B-1050 Bruxelles (Belgium) (Accepted July 24, 1990)
Summary
Of the five quassinoids isolated from the root bark of Hannoa kldneana, only 15desacetylundulatone was found active against P388 mouse lymphocytic leukemia cells and colon 38 adenocarcinoma. Undulatone and especially 15-0-13_~glucopyranosyl-2l-hydroxy-glaucarubolone were found to be more toxic while Ga-tigloyloxy-glaucarubol and 21-hydroxyglaucarubolone were found inactive. Structure-activity relationships are discussed.
Introduction
Root barks of Hannoa klaineanu Pierre et Engl. (Simaroubaceae) are widely used in traditional medicine in most parts of Central Africa against intestinal diseases, fever and malaria (Basilevskaia, 1969; Bouquet, 1969). Phytochemical studies have led to the isolation of several quassinoids, indole alkaloids, coumarins and coumarinolignoids (Luyengi and Vanhaelen, 1984a,b, and 1985; Vanhaelen-Fast& et al., 1987). Since several quassinoids have been shown to possess antitumor activity and since structure-activity relationships have been elucidated in several series of cytotoxic quassinoids (Liao et al., 1976), the present study was undertaken to evaluate the potential antitumoral activity of the quassinoids previously isolated from the plant.
Correspondence to: Professor Maurice Vanhaelen. 0378-8741nO3.50 0 1991 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland
Material and Methods Chemicals
15-Desacetylundulatone (NSC # 3675431, undulatone (NCS # 2677091, 6atigloyloxyglaucarubol (NSC # 3747631, 15-0-/3-D-glucopranosyl-21-hydroxyglaucarubolone (NSC # 380531) and 21-hydroxyglaucarubolone (NSC # 380531) were isolated from root material following the extraction procedures reported earlier (Luyengi and Vanhaelen, 1984a,b, 1985; Vanhaelen-Fast& et al., 1987). Activity
against P388 leukaemia
/‘primary screening)
CDFl mice (17-20 g) were inoculated i.p. on day 0 with lo6 P388 cells. Animals were treated i.p. for the next 5 consecutive days and surviving mice were recorded daily up to day 30. Six animals per test group and 30 per control group were used. A minimal T/C value of 127% was required to demonstrate positive biological activity. Activity
against B16 melanoma
tumor
The B16 melanoma tumor was removed from donor animals and minced in a sterile saline suspension at a l/10 concentration (1 g of tumor + 9 ml of saline). B6C3Fl mice (17- 20 g) received 0.5 ml i.p. of the tumor suspension on day 0 and were then treated for the next 9 consecutive days. Ten animals per test group and 30 control animals were used. Activity
against colon 38 adenocarcinoma
Chemically induced tumors were obtained by repeated injections of 1,2dimethylhydrazine to mice. Tumor fragments (3 x 3 mm) were implanted S.C.on day 0 to B6D2F2 mice (17-20 g). Animals were treated on day 2 and 9 after transplantation. Tumor weights were evaluated on day 20. Ten animals per test group and 30 controls were used (first and second experiment); alternatively, animals were treated twice a day (within a 6-h interval) on days 2, 8 and 14 (chronic schedule of treatment). Results and Discussion The structures of the five quassinoids are given in Fig. 1 and their activities against the P388 leukaemia are presented in Table 1. Only 15-desacetylundulatone, which presents in the A ring a A3’4’-2-oxomoiety, free hydroxyl functions at C-l, C-11 and C-12 and an ester chain at C-6, exhibited a significant activity. Undulatone has been studied following the same model using a dose range between 0.5 and 5.0 mg/kg (Cassady and Suffness, 1980). The optimal T/C value (163%) was obtained with a 5-mg/kg dose; however, the lowest toxic dose was not reported. Therefore, undulatone was tested at doses higher than 5 mg/kg. At a dose of 7.5 mg/kg, toxic effects were observed. The higher toxicity of undulatone appeared related to esterification at C-15;
61 OH
OH
HO
c( R = OCCH3
’
W
6 a -Tigloyloxyglaucarubol
1SDesacetylundulatone
R=H
R = Glucosyl R=H Fig. 1. Structure studied
cd
‘CH,
Undulatone
15-0-O-D-glucopyranosyl-21
-hydroxyglaucarubolone
21 -Hydroxyglaucarubolone
of the five quassinoids for their antitumoral activity.
isolated
from the root bark of Hannoa
klaineana
and
a similar difference has been observed with sergeolide and its 15-desacetyl derivative (Polonsky and Bhatnagar, 1984). The inactivity of Ga-tigloyloxy glaucarubol must be assigned to the reduction of the carbonyl at C-2; the loss of the a-/?-unsaturated keton moiety is, as earlier published, essential to a deficiency of electrons at C-4 where the DNA nucleophile functions of tumor cells will be fixed and the duplication of malignant cells prevented (Kupchan and Lacadie, 1975; Liao et al., 1976). The inactivity of 21-hydroxyglaucarubolone must be attributed to the substitution of the methyl at C-13 by a primary alcohol function of the potent antitumor glaucarubolone (Cassady and Suffness, 1980). An unfavorable alteration in the hydrophilic-hydrophobic balance of 15-0-/3-D-glucopyranosyl-21-glaucarubolone is probably at the origin of the higher toxicity of this glycosidic quassinoid.
62 TABLE 1 ACTIVITY OF FIVE QUASSINOIDS FROM HANNOA KEMIA IN MICE (FIRST SCREENING) Quassinoid
Dose (mgkg)
15Desacetylundulatone
2.5 5.0 10.0 Control
Undulatone
KLAINEANA
Mean body weight change, day 5-day 1 (g)
AGAINST P388 LEU-
Median survival time (days)
TIC (x 100)
- 0.1 0 -1.0 + 1.3
12.5 14.5 16.5 9.9
126 146 166 100
7.5 15.0 Control
> -3.0 > -3.0 + 3.5
3.0 2.0 10.7
28 18 100
Ga-Tigloyloxyglaucarubol
2.5 5.0 10.0 20.0 Control
+ 0.1 0 + 0.5 + 0.6 + 0.1
11.0 10.4 10.2 10.7 10.1
108 102 100 105 100
lbO-/3-n-Glupyranosyl-21hydroxyglaucarubolone
1.9 3.8 7.5 15.0 Control
- 0.6 - 2.0 - 3.0 - 2.1 + 0.5
10.8 4.0 6.0 3.5 11.8
96 35 53 31 100
21-Hydroxyglaucarubolone
4.0 8.0 12.0 16.0 Control
+ 0.7 + 1.3 + 1.3 + 1.3 + 0.2
10.3 10.4 9.8 9.8 10.3
100 101 95 95 100
TABLE 2 ACTIVITY OF 15DESACETYLUNDULATONE (CONFIRMATION TESTING)
AGAINST P388 LEUKAEMIA IN MICE
Dose (mg/kg)
Mean body weight change, day 5-day 1 ig)
Median survival time (days)
TIC (x 100)
7.5 15.0 30.0 60.0 120.0
- 0.1 - 1.9 - 2.5 > -3.0 > -3.0
18.8 19.3 20.3 2.9 2.1
175 180 189 27 19
+ 3.5
10.7
100
Control
63 TABLE 3 ACTIVITY
OF lS_DESACETYLUNDULATONE
Dose
(mg/kg)
Mean body weight change, day 5-day
AGAINST
B16 MELANOMA
IN MICE
Median survival time (days)
TIC (x 100)
1
W 7.6 15.0 30.0
+ 0.1 + 1.1 + 0.8
26.4 28.3 23.0
132 141 145
Control
+ 1.6
28.0
180
As shown in Table 1, l~desacetylundulatone displayed activity (T/C x 100 > 127) at all doses and none of these doses was toxic since no loss of body weight was recorded. Therefore, the activity of this quassinoid was investigated at doses higher than 15 mglkg. As shown in Table 2, the compound showed toxic effects at doses superior or equal to 60 mglkg but its antitumor activity was confirmed at doses equal to or lower than 30 mg/kg (TIC x 100 = 189). Since the quassinoid was active against leukaemia P388, it was further tested against two solid tumors, namely B16 melanoma and colon adenocarcinoma. As shown in Table 3, it produced only marginal activity against the B16 melanoma (in this tumor model, a T/C value of 130% is necessary to demonstrate activity). The quassinoid did not produce any activity at doses of 15-60 mg/kg against colon 38 (Table 41, a tumor growth inhibition model, where the tumor is transplanted subcutaneously. The treatment is usually administered on days 2 and 9 and tumor weights evaluated on day 20. At the 60 mg/kg dose, tumor growth inhibition reached only
TABLE 4 ACTIVITY OF EXPERIMENT) Dose
(m&kg)
l&DESACETYLUNDULATONE Mean body weight change, day 20-day
2
AGAINST
COLON
Median survival time (day 20) (mgi
38 IN
MICE
T/C ix 1001
(g) 15 38
+ 1.8 + 1.7
1544 1298
60
+ 1.5
938
50 78 93
Control
+ 1.9
1648
100
(FIRST
64 TABLE
5
ACTIVITY OF 1~DESAC~TYLUNDULATONE EXPERIMENT) Dose
Mean body weight change,
(mg/kg)
day 20-day (a)
2
AGAINST
Median tumor weight (day 20) (mg)
COLON
38 IN MICE
T/C (x 100)
(SECOND
Quanta1 free of tumor W
60 80
+ 3.1 + 2.9
325 196
37 22
0110 2/10
100
+ 2.0
149
17
3/10
Control
+ 3.2
864
100
0110
44% while a tumor growth inhibition of 58% (T/C of 42%) is necessary to demonstrate activity. Therefore, the doses were increased up to 100 mglkg in a second experiment as summarized in Table 5. At 80 and 100 mgikg, 2 and 3 animals, respectively, were free of tumors on the day of evaluation. Since activity was observed with two injections of the previous doses, it was decided to split the dose up and to administer treatment i.p. twice a day within a 6-h interval on days 2, 9 and 16. in these experimental conditions, small tumor weights (4-392 mg) were measured at 60 mg/kg but only one animal without tumor was recorded on day 20 (Table 6). Among the five quassinoids isolated from H. kluineana root-bark, only 15 desa~etylundula~ne showed significant antitumor activity against P388 leukaemia and colon 38 adenocarcinoma. The apparent structure-activity relationships were in agreement with earlier observations published for other quassinoids. We plan to prepare new semi-synthetic derivatives to increase activity and to investigate further structure-activity relationships within this group of secondary metabolites. TABLE
6
ACTIVITY OF 1~DESACETYLUNDULATONE TREATMENT) Dose (mgkg)
Mean body weight change, day 20 -day
2
AGAINST
Median tumor weight (day 20) (mg)
COLON
T/C (x
38 IN MICE (CHRONIC
100)
Quanta1 free of tumor !iW
(g) 30 40 50 60
+ + + +
4.3 4.1 3.6 4.5
528 206 189 30
40 15 14 2
0110 0110 0110 1110
Control
+ 5.6
1296
100
0110
65
References Bouquet, A. (1969) Fe’ticheurs et Mkdecines Traditionnelles du Congo IBrazaviElel. ORSTOM, Paris, p. 229. Basilevskaia, V. (1969) Pluntes Mbdicinales de Guine’e. Conakry, Republique de Guinee, p. 126. Cassady, J.M. and Suffness, M. (1980) Anticancer Agents Based on Natural Products Models (Medicinal Chemistry, Volume 16). Academic Press, New York, p. 254. Kupchan, S.M. and Lacadie, J.A. (1975) Dehydroailanthinone, a new antileukemic quassinoid from Pierreodendron
kerstingii.
Journal
of Organic
Chemistry
40, 654-656.
Liao. L.L., Kupchan. S.M. and Horwitz, S.B. (1976) Mode of action of the antitumor compound bruceantin, an inhibitor of protein synthesis. Moleculur Pharmacology 12, 167 - 176. Luyengi, L. and Vanhaelen, M. (1984a) CanthineB-one, undulatone and two quassinoids from Hannoa
klaineanu.
Phytochemistry
27.2121-22123.
Luyengi, L. and Vanhaelen, M. (1984b) lndole alkaloids from Hannoa klaineana roots. Phytochemistry 23,453 - 455. Luyengi, L and Vanhaelen, M. (1985) Two quassinoid glycosides and a fi-carboline-l-propiopic acid from Hannoa klaineana. Phytochemistry 24, 2387-2389. Polonsky, J. and Bhatnagar, S. (1984) 15Desacetylsergeolide, a potent antileukemic quassinoid from Picrolemma pseudocoffea. Journul of Natural Products 47,994-996. Vanhaelen-Fast& R., Luyengi, L., Vanhaelen, M., Declercq, J.P. and Van Meerssche, M. (1987) Two quassinoids and two coumarinolignoids from Hannoa kluineana roots. Phytochemistry 26,317319.
ANTITUMOR
ACTIVITY
59
OF QUASSINOIDS
FROM HANNOA
KLAINEANA
LUYENGI LUMONADIO’, GHANEM ATASSP, RENEE VANHAELEN-FASTRE’
MAURICE VANHAELEN’
and
“Institut de Recherche Sciences de la Santa K&has&Gombe (Zaire), bLaboratoire de Pharmacologic celluluire, CP 14.4 and ‘Laboratoire de Pharmacognosie, Inatitut de Pharmacie, CP 205-4, Univeraitk Libre de Bruxelles. Boulevard de Triomphe, B-1050 Bruxelles (Belgium) (Accepted July 24, 1990)
Summary
Of the five quassinoids isolated from the root bark of Hannoa kldneana, only 15desacetylundulatone was found active against P388 mouse lymphocytic leukemia cells and colon 38 adenocarcinoma. Undulatone and especially 15-0-13_~glucopyranosyl-2l-hydroxy-glaucarubolone were found to be more toxic while Ga-tigloyloxy-glaucarubol and 21-hydroxyglaucarubolone were found inactive. Structure-activity relationships are discussed.
Introduction
Root barks of Hannoa klaineanu Pierre et Engl. (Simaroubaceae) are widely used in traditional medicine in most parts of Central Africa against intestinal diseases, fever and malaria (Basilevskaia, 1969; Bouquet, 1969). Phytochemical studies have led to the isolation of several quassinoids, indole alkaloids, coumarins and coumarinolignoids (Luyengi and Vanhaelen, 1984a,b, and 1985; Vanhaelen-Fast& et al., 1987). Since several quassinoids have been shown to possess antitumor activity and since structure-activity relationships have been elucidated in several series of cytotoxic quassinoids (Liao et al., 1976), the present study was undertaken to evaluate the potential antitumoral activity of the quassinoids previously isolated from the plant.
Correspondence to: Professor Maurice Vanhaelen. 0378-8741nO3.50 0 1991 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland
Material and Methods Chemicals
15-Desacetylundulatone (NSC # 3675431, undulatone (NCS # 2677091, 6atigloyloxyglaucarubol (NSC # 3747631, 15-0-/3-D-glucopranosyl-21-hydroxyglaucarubolone (NSC # 380531) and 21-hydroxyglaucarubolone (NSC # 380531) were isolated from root material following the extraction procedures reported earlier (Luyengi and Vanhaelen, 1984a,b, 1985; Vanhaelen-Fast& et al., 1987). Activity
against P388 leukaemia
/‘primary screening)
CDFl mice (17-20 g) were inoculated i.p. on day 0 with lo6 P388 cells. Animals were treated i.p. for the next 5 consecutive days and surviving mice were recorded daily up to day 30. Six animals per test group and 30 per control group were used. A minimal T/C value of 127% was required to demonstrate positive biological activity. Activity
against B16 melanoma
tumor
The B16 melanoma tumor was removed from donor animals and minced in a sterile saline suspension at a l/10 concentration (1 g of tumor + 9 ml of saline). B6C3Fl mice (17- 20 g) received 0.5 ml i.p. of the tumor suspension on day 0 and were then treated for the next 9 consecutive days. Ten animals per test group and 30 control animals were used. Activity
against colon 38 adenocarcinoma
Chemically induced tumors were obtained by repeated injections of 1,2dimethylhydrazine to mice. Tumor fragments (3 x 3 mm) were implanted S.C.on day 0 to B6D2F2 mice (17-20 g). Animals were treated on day 2 and 9 after transplantation. Tumor weights were evaluated on day 20. Ten animals per test group and 30 controls were used (first and second experiment); alternatively, animals were treated twice a day (within a 6-h interval) on days 2, 8 and 14 (chronic schedule of treatment). Results and Discussion The structures of the five quassinoids are given in Fig. 1 and their activities against the P388 leukaemia are presented in Table 1. Only 15-desacetylundulatone, which presents in the A ring a A3’4’-2-oxomoiety, free hydroxyl functions at C-l, C-11 and C-12 and an ester chain at C-6, exhibited a significant activity. Undulatone has been studied following the same model using a dose range between 0.5 and 5.0 mg/kg (Cassady and Suffness, 1980). The optimal T/C value (163%) was obtained with a 5-mg/kg dose; however, the lowest toxic dose was not reported. Therefore, undulatone was tested at doses higher than 5 mg/kg. At a dose of 7.5 mg/kg, toxic effects were observed. The higher toxicity of undulatone appeared related to esterification at C-15;
61 OH
OH
HO
c( R = OCCH3
’
W
6 a -Tigloyloxyglaucarubol
1SDesacetylundulatone
R=H
R = Glucosyl R=H Fig. 1. Structure studied
cd
‘CH,
Undulatone
15-0-O-D-glucopyranosyl-21
-hydroxyglaucarubolone
21 -Hydroxyglaucarubolone
of the five quassinoids for their antitumoral activity.
isolated
from the root bark of Hannoa
klaineana
and
a similar difference has been observed with sergeolide and its 15-desacetyl derivative (Polonsky and Bhatnagar, 1984). The inactivity of Ga-tigloyloxy glaucarubol must be assigned to the reduction of the carbonyl at C-2; the loss of the a-/?-unsaturated keton moiety is, as earlier published, essential to a deficiency of electrons at C-4 where the DNA nucleophile functions of tumor cells will be fixed and the duplication of malignant cells prevented (Kupchan and Lacadie, 1975; Liao et al., 1976). The inactivity of 21-hydroxyglaucarubolone must be attributed to the substitution of the methyl at C-13 by a primary alcohol function of the potent antitumor glaucarubolone (Cassady and Suffness, 1980). An unfavorable alteration in the hydrophilic-hydrophobic balance of 15-0-/3-D-glucopyranosyl-21-glaucarubolone is probably at the origin of the higher toxicity of this glycosidic quassinoid.
62 TABLE 1 ACTIVITY OF FIVE QUASSINOIDS FROM HANNOA KEMIA IN MICE (FIRST SCREENING) Quassinoid
Dose (mgkg)
15Desacetylundulatone
2.5 5.0 10.0 Control
Undulatone
KLAINEANA
Mean body weight change, day 5-day 1 (g)
AGAINST P388 LEU-
Median survival time (days)
TIC (x 100)
- 0.1 0 -1.0 + 1.3
12.5 14.5 16.5 9.9
126 146 166 100
7.5 15.0 Control
> -3.0 > -3.0 + 3.5
3.0 2.0 10.7
28 18 100
Ga-Tigloyloxyglaucarubol
2.5 5.0 10.0 20.0 Control
+ 0.1 0 + 0.5 + 0.6 + 0.1
11.0 10.4 10.2 10.7 10.1
108 102 100 105 100
lbO-/3-n-Glupyranosyl-21hydroxyglaucarubolone
1.9 3.8 7.5 15.0 Control
- 0.6 - 2.0 - 3.0 - 2.1 + 0.5
10.8 4.0 6.0 3.5 11.8
96 35 53 31 100
21-Hydroxyglaucarubolone
4.0 8.0 12.0 16.0 Control
+ 0.7 + 1.3 + 1.3 + 1.3 + 0.2
10.3 10.4 9.8 9.8 10.3
100 101 95 95 100
TABLE 2 ACTIVITY OF 15DESACETYLUNDULATONE (CONFIRMATION TESTING)
AGAINST P388 LEUKAEMIA IN MICE
Dose (mg/kg)
Mean body weight change, day 5-day 1 ig)
Median survival time (days)
TIC (x 100)
7.5 15.0 30.0 60.0 120.0
- 0.1 - 1.9 - 2.5 > -3.0 > -3.0
18.8 19.3 20.3 2.9 2.1
175 180 189 27 19
+ 3.5
10.7
100
Control
63 TABLE 3 ACTIVITY
OF lS_DESACETYLUNDULATONE
Dose
(mg/kg)
Mean body weight change, day 5-day
AGAINST
B16 MELANOMA
IN MICE
Median survival time (days)
TIC (x 100)
1
W 7.6 15.0 30.0
+ 0.1 + 1.1 + 0.8
26.4 28.3 23.0
132 141 145
Control
+ 1.6
28.0
180
As shown in Table 1, l~desacetylundulatone displayed activity (T/C x 100 > 127) at all doses and none of these doses was toxic since no loss of body weight was recorded. Therefore, the activity of this quassinoid was investigated at doses higher than 15 mglkg. As shown in Table 2, the compound showed toxic effects at doses superior or equal to 60 mglkg but its antitumor activity was confirmed at doses equal to or lower than 30 mg/kg (TIC x 100 = 189). Since the quassinoid was active against leukaemia P388, it was further tested against two solid tumors, namely B16 melanoma and colon adenocarcinoma. As shown in Table 3, it produced only marginal activity against the B16 melanoma (in this tumor model, a T/C value of 130% is necessary to demonstrate activity). The quassinoid did not produce any activity at doses of 15-60 mg/kg against colon 38 (Table 41, a tumor growth inhibition model, where the tumor is transplanted subcutaneously. The treatment is usually administered on days 2 and 9 and tumor weights evaluated on day 20. At the 60 mg/kg dose, tumor growth inhibition reached only
TABLE 4 ACTIVITY OF EXPERIMENT) Dose
(m&kg)
l&DESACETYLUNDULATONE Mean body weight change, day 20-day
2
AGAINST
COLON
Median survival time (day 20) (mgi
38 IN
MICE
T/C ix 1001
(g) 15 38
+ 1.8 + 1.7
1544 1298
60
+ 1.5
938
50 78 93
Control
+ 1.9
1648
100
(FIRST
64 TABLE
5
ACTIVITY OF 1~DESAC~TYLUNDULATONE EXPERIMENT) Dose
Mean body weight change,
(mg/kg)
day 20-day (a)
2
AGAINST
Median tumor weight (day 20) (mg)
COLON
38 IN MICE
T/C (x 100)
(SECOND
Quanta1 free of tumor W
60 80
+ 3.1 + 2.9
325 196
37 22
0110 2/10
100
+ 2.0
149
17
3/10
Control
+ 3.2
864
100
0110
44% while a tumor growth inhibition of 58% (T/C of 42%) is necessary to demonstrate activity. Therefore, the doses were increased up to 100 mglkg in a second experiment as summarized in Table 5. At 80 and 100 mgikg, 2 and 3 animals, respectively, were free of tumors on the day of evaluation. Since activity was observed with two injections of the previous doses, it was decided to split the dose up and to administer treatment i.p. twice a day within a 6-h interval on days 2, 9 and 16. in these experimental conditions, small tumor weights (4-392 mg) were measured at 60 mg/kg but only one animal without tumor was recorded on day 20 (Table 6). Among the five quassinoids isolated from H. kluineana root-bark, only 15 desa~etylundula~ne showed significant antitumor activity against P388 leukaemia and colon 38 adenocarcinoma. The apparent structure-activity relationships were in agreement with earlier observations published for other quassinoids. We plan to prepare new semi-synthetic derivatives to increase activity and to investigate further structure-activity relationships within this group of secondary metabolites. TABLE
6
ACTIVITY OF 1~DESACETYLUNDULATONE TREATMENT) Dose (mgkg)
Mean body weight change, day 20 -day
2
AGAINST
Median tumor weight (day 20) (mg)
COLON
T/C (x
38 IN MICE (CHRONIC
100)
Quanta1 free of tumor !iW
(g) 30 40 50 60
+ + + +
4.3 4.1 3.6 4.5
528 206 189 30
40 15 14 2
0110 0110 0110 1110
Control
+ 5.6
1296
100
0110
65
References Bouquet, A. (1969) Fe’ticheurs et Mkdecines Traditionnelles du Congo IBrazaviElel. ORSTOM, Paris, p. 229. Basilevskaia, V. (1969) Pluntes Mbdicinales de Guine’e. Conakry, Republique de Guinee, p. 126. Cassady, J.M. and Suffness, M. (1980) Anticancer Agents Based on Natural Products Models (Medicinal Chemistry, Volume 16). Academic Press, New York, p. 254. Kupchan, S.M. and Lacadie, J.A. (1975) Dehydroailanthinone, a new antileukemic quassinoid from Pierreodendron
kerstingii.
Journal
of Organic
Chemistry
40, 654-656.
Liao. L.L., Kupchan. S.M. and Horwitz, S.B. (1976) Mode of action of the antitumor compound bruceantin, an inhibitor of protein synthesis. Moleculur Pharmacology 12, 167 - 176. Luyengi, L. and Vanhaelen, M. (1984a) CanthineB-one, undulatone and two quassinoids from Hannoa
klaineanu.
Phytochemistry
27.2121-22123.
Luyengi, L. and Vanhaelen, M. (1984b) lndole alkaloids from Hannoa klaineana roots. Phytochemistry 23,453 - 455. Luyengi, L and Vanhaelen, M. (1985) Two quassinoid glycosides and a fi-carboline-l-propiopic acid from Hannoa klaineana. Phytochemistry 24, 2387-2389. Polonsky, J. and Bhatnagar, S. (1984) 15Desacetylsergeolide, a potent antileukemic quassinoid from Picrolemma pseudocoffea. Journul of Natural Products 47,994-996. Vanhaelen-Fast& R., Luyengi, L., Vanhaelen, M., Declercq, J.P. and Van Meerssche, M. (1987) Two quassinoids and two coumarinolignoids from Hannoa kluineana roots. Phytochemistry 26,317319.
