Sesquiterpene lactones with potential use as natural herbicide models (I): trans, trans-germacranolides

Article abstract of DOI:10.1021/jf9903612

A structure-activity study to evaluate the effect of the trans,trans- germacranolide sesquiterpene lactones costunolide, parthenolide, and their 1,10-epoxy and 11,13-dihydro derivatives (in a range of 100-0.001 μM) on the growth and germination of several mono and dicotyledon target species is accomplished. Results are compared with those obtained in the same bioassay with an internal standard, the commercial herbicide Logran, to validate the results with a known active formulation and to compare the results with a commercial product to test their potential use as natural herbicide models. These compounds appear to have a more selective effects on the radicle growth of monocotyledons. Certain factors such as the presence of nucleophile- acceptor groups and their accessibility enhance the inhibitory activity. The levels of radicle inhibition obtained with some compounds on wheat are totally comparable to those of Logran and allow to propose them as lead compounds.

Full text of DOI:10.1021/jf9903612

J. Agric. Food Chem. 1999, 47, 4407−4414
4407
Sesqu iter p en e La cton es w ith P oten tia l Use a s Na tu r a l Her bicid e
†
Mod els (I): tr a n s,tr a n s-Ger m a cr a n olid es
Francisco A. Mac ´ı as,* J uan C. G. Galindo, Diego Castellano, and Ra u´ l F. Velasco
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias, Universidad de C a´ diz, c/Rep u´ blica Saharaui s/n,
Apdo. 40, 11510-Puerto Real, C a´ diz, Spain
A structure-activity study to evaluate the effect of the trans,trans-germacranolide sesquiterpene
lactones costunolide, parthenolide, and their 1,10-epoxy and 11,13-dihydro derivatives (in a range
of 100-0.001 µM) on the growth and germination of several mono and dicotyledon target species is
accomplished. Results are compared with those obtained in the same bioassay with an internal
standard, the commercial herbicide Logran, to validate the results with a known active formulation
and to compare the results with a commercial product to test their potential use as natural herbicide
models. These compounds appear to have a more selective effects on the radicle growth of
monocotyledons. Certain factors such as the presence of nucleophile-acceptor groups and their
accessibility enhance the inhibitory activity. The levels of radicle inhibition obtained with some
compounds on wheat are totally comparable to those of Logran and allow to propose them as lead
compounds.
Keyw or d s: trans,trans-Germacranolide; costunolide; parthenolide; Logran; phytoxicity; allelopathy;
herbicide; Lactuca sativa L.; Lycopersicum esculentum L.; Lepidium sativum L.; Allium cepa L.;
Triticum aestivum L.
INTRODUCTION
Modern agricultural techniques heavily rely on the
use of pesticides and herbicides with the subsequent
environmental risks. Otherwise, the development of
resistant species and cross-resistance phenomena are
challenging the use of herbicides for certain weeds
(
Maxwell and Mortimer, 1994). Allelopathy offers a new
approach for the discovery of new lead compounds and
their use as herbicides and pesticides from plants, fungi,
and microorganisms (Duke et al., 1996). Several classes
of compounds have been named as common allelopathic
agents: phenolic compounds, monoterpenes, sesquiter-
penes, and alkaloids among them (Waller, 1987).
Sesquiterpene lactones have been reported as allelo-
pathic agents (Spring et al., 1981; Mac ´ı as et al., 1993)
in many plants belonging to the family Compositae.
Despite the high number of sesquiterpene lactones
described (more than 7500 (Fraga, 1998)) and their
biological activities (Marles et al., 1995; Francois et al.,
1
996; Beekman et al., 1997), little has been done to
F igu r e 1. trans,trans-Germacranolides tested.
determine which of them are really phytotoxic, the
necessary structural requirements to show this kind of
bioactivity (Ando et al., 1992; Baruah et al., 1994), or
their possible modes of action in plants (Lotina-Hennsen
et al., 1992; Galindo et al., 1999). Going on with our
systematic study of sesquiterpene lactones as natural
herbicide models (Mac ´ı as et al., 1992; Mac ´ı as et al.,
epoxycostunolide (3), 1,10-epoxyparthenolide (4), and
their 11,13-dihydro derivatives (5-7) (Figure 1) have
been tested for germination and growth activity on
dicotyledoneous and monocotyledoneous standard target
species. Dicots assayed are lettuce (Lactuca sativa L.
cv. Roman), tomato (Lycopersicon esculentum L. cv. Tres
Cantos), and cress (Lepidium sativum L. cv. Com u´ n).
Monocots assayed are onion (Allium cepa L. cv. Valen-
ciana) and wheat (Triticum aestivum L. cv. Cortex). The
study has been centered on the three main macroscopic
parameters: germination and root and shoot elongation.
These parameters are accepted as indirect measures of
other different physiological processes affected by the
assayed chemicals. A commercial herbicide is introduced
within the same bioassay to serve as internal standard.
1
999a), the results of bioassays with seven different
trans,trans germacrane-type sesquiterpene lactones are
presented. Costunolide (1), parthenolide (2), 1,10-
*
To whom correspondence should be addressed. E-mail:
famacias@uca.es. Phone: +34-956-016370. Fax: +34-956-
34924.
8
†
Natural Products as Allelochemicals. 11. For part 10, see:
Mac ´ı as et al., 1999a.
1
0.1021/jf9903612 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/24/1999

4408 J. Agric. Food Chem., Vol. 47, No. 10, 1999
Mac ´ı as et al.
All of the aqueous phases were extracted with DCM, and the
combined organic phases were dried on anhydrous sodium
sulfate. After separation by CC, compound 3 was obtained in
a crystalline form (77%). Epoxidation of 2 as described for 1
yield the crystalline product 4 (60%).
Red u ction of 1-3. A 2 mL methanolic solution with 15
F igu r e 2. Michael nucleophilic attack of a nucleophile to the
R-methylene moiety.
mg of each compound was kept in a Dewar glass at 0 °C. While
4
the solution was stirring, NaBH (1:1.4 molar relationship) was
added during the first 5 min of reaction. After 1 h, the reaction
was stopped by addition of 2 mL of distilled water. Extraction
with AcOEt and HPLC purification (hexane/ethyl acetate mixt)
yielded the dihydro derivatives 5-7 (average 90%).
Molecu la r Mod elin g. Minimum energy conformations and
molecular properties were obtained by using MMX calculations
Thus, the comparison of the commercial herbicide effects
in the same conditions as the sesquiterpene lactones
tested allow to validate the results with a well-known
active formulation and to establish the relative levels
of activity of these natural products respect to the
herbicides actually in the market.
(PCModel ver. 6.0, Serena Software, Bloomington, IN).
Ger m in a tion a n d Seed lin g Gr ow th Bioa ssa ys. Seeds
of L. sativa L. cv. Roman, L. esculentum L. cv. Tres Cantos, L.
sativum L. cv. Com u´ n, A. cepa L. cv. Valenciana, and T.
aestivum L. cv. Cortex were obtained from FIT OÄ , S. L.
EXPERIMENTAL PROCEDURES
Costunolide (1) was obtained from costus resin oil (Saus-
surea lappa) by previous column chromatography (CC) separa-
tion and then purified by crystallization from hexane/ethyl
acetate mixtures. Parthenolide (2) was easily available from
magnolia leaf extract (Magnolia grandiflora L.) by CC and
purification by crystallization from hexane/ethyl acetate. Ep-
oxide derivatives 3 and 4 were prepared by treatment with
m-chloroperbenzoic acid from 1 and 2, respectively, as previ-
ously described (Rodr ´ı guez et al., 1978). Dihydro derivatives
(Barcelona, Spain). All undersized or damaged seeds were
discarded, and the assay seeds were selected for uniformity.
Bioassays were carried out in 9 cm L plastic Petri dishes, using
Whatman No. 1 filter paper as support.
Bioa ssa y Meth od ology. The general procedure was as
follows: L. sativum, 25 seeds per dish, 5 mL of test soln, 4
days in the dark, 25 °C, and four replicates of each conc; L.
sativa and L. esculentum, 25 seeds per dish, 5 mL of test soln,
5 days in the dark, 25 °C, and four replicates of each conc; A.
cepa, 25 seeds per dish, 5 mL of test soln, 7 days in the dark,
25 °C, and four replicates of each conc; T. aestivum, 10 seeds
per dish, 5 mL of test soln, 5 days in the dark, 25 °C, and 10
replicates of each conc (Mac ´ı as et al., 1999b).
5
-7 were prepared respectively from 1-3 by reduction with
NaBH in a 0 °C methanolic solution during 1 h. All the
structures were confirmed by comparison of their spectroscopi-
4
1
13
cal data (IR, EIMS, and H and C NMR) with those in the
literature. Logran (terbutryn 59.4% + triasulfuron 0.6%) was
supplied by Novartis.
-
4
-5
Test solutions (10 or 10 M) were prepared using MES
(2-[N-morpholino]ethanesulfonic acid) 10 mM, and the rest
were obtained by dilution. Parallel controls were performed.
All pH values were adjusted to 6.0 before bioassay with MES.
All products were purified prior to the bioassay using HPLC
equipped with a refractive index detector. Minimum degree
of purity was of 99% as extracted from the chromatograms.
Data are presented as percentage differences from control
in graphics (Figures 4-6). Thus, zero represents the control;
positive values represent stimulation of the studied parameter
and negative values represent inhibition.
Ep oxid a tion of Costu n olid e (1) a n d P a r th en olid e (2).
Fifty milligrams of 1 was dissolved in 10 mL of dried meth-
ylene chloride (DCM), and then 50 mg of sodium acetate was
added. Afterward, 50 mg of m-chloroperbenzoic acid (m-CPBA)
dissolved in dried DCM was added dropwise with stirring.
After 1 h, the reaction was stopped and the workup was carried
out as follows: the reaction mixture was extracted with NaOH
(
aq) 5% (2×) to separate the rest of the m-CPBA and m-
chlorobenzoic acid; then, the pH of the organic phase was
adjusted to nearly 7.0 by washing with distilled water (2×).
F igu r e 3. Selected comparison of minimum energy conformers obtained by using MMX calculations. Each figure represents the
superimposed structures obtained by fixing those atoms of the γ-lactone ring taking as the reference structure the corresponding
of costunolide (1).

trans,trans-Germacranolides as Potential Natural Herbicide Models
J. Agric. Food Chem., Vol. 47, No. 10, 1999 4409
F igu r e 4. Germination and root length effects of compounds 1-7 on lettuce. Values are expressed as percentage differences
from the control: (a) P e 0.01; (b) 0.01 < P e 0.05; rest of the values, P > 0.05.
Sta tistica l Tr ea tm en t. Germination and root and shoot
length values were tested by Welch’s test (Zar, 1984), the
differences between test solutions and controls being signifi-
cant with P e0.01.
Root length is the other sensitive parameter. The
activity of costunolide (1) at 10 µM over root growth of
Phaseolus vulgaris (Kalsi et al., 1983) has been reported.
Nevertheless, it has no important root-promoting effects
on lettuce. Otherwise, the presence of an epoxide moiety
in C4-C5 (2), C1-C10 (3), or both of them (4) seems to
have an enhancing effect on the root growth. On the
other hand, the reduction of the R-methylene group of
parthenolide (2) to yield 6 results in a decrease of the
activity. Reduction of 1 and 3 to yield 5 and 7, respec-
tively, turns the activity on inhibitory.
There is no activity on shoot length (data not shown)
except that showed by compound 5, which inhibits shoot
growth. All of these data are in good accordance with
previous results obtained for the root-promoting activity
of some guaianolides and some other sesquiterpenes
(Kalsi et al., 1981, 1983).
RESULTS
Bioassay results are presented in Figures 4-6. Table
presents a resume of the main trends showed by every
1
test compound on each target species.
L. sa tiva L. (F igu r e 4). Test compounds tend to
stimulate the germination, with costunolide (1) being
the most active. This effect reaches the maximum at
0
.1-0.001 µM, and then it is lowered with the concen-
tration. The introduction of an epoxide moiety (com-
pounds 2-4, 6, 7) or an 11,13-dihydro functionalitation
(
5-7) appears to have a decreasing effect on the activity.
No big differences of activity appear between partheno-
lide (2) and its 11,13-dihydroderivative. The internal
standard (Logran) presents a clear inhibitory activity
at 1 and 0.1 µM.
L. sa tivu m L. (F igu r e 5). Costunolide (1) strongly
inhibits cress germination at 100 µM, decreasing the
activity with the dilution in a typical dose-response

4410 J. Agric. Food Chem., Vol. 47, No. 10, 1999
Mac ´ı as et al.
F igu r e 5. Germination and root length effects of compounds 1-7 on cress. Values are expressed as percentage differences from
the control: (a) P e 0.01; (b) 0.01 < P e 0.05; rest of the values, P > 0.05.
format. Compounds 2-4, bearing an epoxide ring,
generally tend to stimulate the germination, although
the values are low. Reduction of costunolide (1) results
in an enhancing of the inhibition at the lower concen-
trations, while reduction of compounds 2 and 3 results
on a loss of the activity. Logran presents no phytotoxic
effects in cress germination.
Root length and shoot length parameters present a
similar behavior: both are stimulated by all the R-meth-
ylene-containing compounds, root length being more
stimulated in cress than in lettuce. Otherwise, 100 µM
costunolide (1) shows a higher activity (inhibitory at
high concentrations and stimulatory at low concentra-
tions) in cress than in lettuce. This effect is more
pronounced when an epoxide function is introduced
A. cepa L. Tested compounds have no effects in
germination and little effects on root or shoot growth
(data not shown). Though the effects measured are low,
all of them show a general trend to inhibit either root
or shoot, the roots being a little more affected. This
represents behavior opposite of that shown over dicot-
yledonous species. There are no big differences between
compounds with or without epoxide and/or R-methylene
moiety. Only compound 4, with two epoxide function-
alizations, seems to maintain the activity at the lower
concentrations.
T. a estivu m L. (F igu r e 6). There is a general trend
to enhance germination, but only the 11,13-dihydro
derivative of costunolide (5) presents important values.
Except for this case, little difference can be found on
the activity related with the presence or absence of
epoxides and/or R-methylene groups. Logran inhibitory
effect is low and only significant for the highest con-
centration.
(compounds 2-4). Comparison of the activities of com-
pounds 1-4 with their dihydroderivatives 5-7 results
again in a decrease of the stimulatory activity, changing
some of them to inhibitors of the root growth (5, 7).
Logran presents a pronounced root length inhibitory
activity only at 1000 and 100 µM and a weaker activity
in shoot length.
Root and shoot length are both generally inhibited by
almost all compounds, except for the 11,13-dihydro
derivative 7. The higher levels of root inhibition are

trans,trans-Germacranolides as Potential Natural Herbicide Models
J. Agric. Food Chem., Vol. 47, No. 10, 1999 4411
F igu r e 6. Germination and growth effects of compounds 1-7 on wheat. Values are expressed as percentage differences from the
control: (a) P e 0.01; (b) 0.01 < P e 0.05; rest of the values, P > 0.05.
those from compounds 5 and 6, both without the
R-methylene group. At any rate, no distinctions can be
made on the basis of the presence of an epoxide moiety
or an 11,13-exomethylene group. This behavior is also
illustrated in the shoot length parameter, where com-
pound 5 is again the most active one.
Second, no activity is observed in the three param-
eters studied in tomato, which appears to be the less
sensitive species. This result has been previously ob-
served for other sesquiterpene lactones (Mac ´ı as et al.,
1999b).
Third, comparison of the values and profiles of activity
shown by these lactones and those of the herbicide
reveals that they are less effective than the commercial
product on dicotyledons but show similar values of
activity on monocotyledons.
The response of many test compounds with the
concentrations may depend on their ability to act as
inhibitors or as stimulants (phytohormone-like activity).
In the case when they act as inhibitors, and if the range
of test concentrations is correctly chosen, compounds
DISCUSSION
From the results shown in Table 1 and Figures 4-6,
three main observations can be made. First, the differ-
ent mode of action shown by these compounds depends
on if the target species belongs to a monocotyledons or
dicotyledons, or even among the same family. While
monocots are generally inhibited, dicots are stimulated.

4412 J. Agric. Food Chem., Vol. 47, No. 10, 1999
Mac ´ı as et al.
Ta ble 1. Resu m e of th e Bioa ctivity Da ta of Com p ou n d s
it has been reported to enhance rooting in stem cuttings
of Phaseolus aureus (Kalsi et al., 1983). Its activity has
been related to the presence of an R-methylene moiety
in the γ-lactone ring and is enhanced up to four times
when replaced by a cyclopropyl ring, very tensioned and
susceptible to undergo ring-opening reactions by differ-
ent reagents attacking in the same way as R-methylenes
do with nucleophiles (Figure 2).
Recent reports show also costunolide (1) and the 1,10-
epoxy (3) and 11,13-dihydro derivatives (5, 7) to elicitate
the germination of the parasitic weed witchweed (Striga
asiatica L., Kuntze) (Fischer et al., 1990). No significant
differences were found among them, no matter the
functionalization they possess. These compounds, and
some other eudesmanolides with the same “double
crown” conformation in the Decalin part of the molecule,
are very active elicitors, while other guaiananolides
present low or even no activity. Thus, it was hypoth-
esized that activity is given by a conjunction between
the lactone moiety, also present in the natural witch-
weed germination promoter strigol, and the conforma-
tion of the medium ring, also close to that of strigol. No
other reports about the effects of these kind of com-
pounds on growth or germination have been published
so far.
In a previous study (Mac ´ı as et al., 1992), it has been
proposed that the conformation of the molecule deter-
mines the accessibility of the lactone ring and thus, the
activity of the molecule. Dramatic changes in the
medium backbone ring cause important changes in the
orientation of the lactone moiety and similar changes
in the bioactivity should be expected. Some important
theoretical molecular properties of the tested com-
pounds, such as selected dihedral angles in the lactonic
ring and van der Waals and water solvation surfaces,
are shown in Table 2. These parameters have been
selected since they are related to the orientation of the
lactonic ring, the total volume of the molecule, and their
solvation ability, which could be related with the activ-
ity.
Main changes in the orientation of the lactonic ring
are observed when an epoxy group is introduced at
positions C4-C5 and (C1-C10, C4-C5) (see Table 2,
Figure 3, selected dihedral angles entry; comparison of
compound 1 with compounds 2, 4, 6, and 8). Neverthe-
less, the most important differences can be observed in
the distances between the two methyl groups at C-14
and C-15 where the closest position is obtained when
the two epoxy groups at C1-C10, C4-C5 are presents
in the molecule. These structural changes can be related
with the different activity behavior of the tested com-
pounds but not exclusively.
a
1
-7
lettuce tomato cress onion wheat
logran germination
root length
0
-
0
)
-
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
-
0
)
-
(-)
(-)
+
shoot length
)
-
)
1
2
3
4
5
6
7
germination
root length
shoot length
germination
root length
shoot length
germination
root length
shoot length
germination
root length
shoot length
germination
root length
shoot length
germination
root length
shoot length
germination
root length
shoot length
++
0
0
-
0
(-)(+)
(-)+
(+)
++
+
(-)
(-)
0
(-)
(-)
0
0
(-)
0
-
(-)
(+)
(-)
(-)
(+)
(-)
-
+
+
0
(+)
++
0
(+)
+
+
(+)
(+)
+
(+)
(-)
-
+
-
0
+
(-)
0
-
-
(+)
(+)
0
0
0
-
0
0
+
-
-
(-)
(-)
0
-
0
0
0
0
0
(+)
0
(+)
-
+
(-)
(-)
(+)
(-)
(-)
+
(-)
0
0
(-)
(-)
0
0
0
a
0
: not active; (+), (-): stimulatory or inhibitory values below
0%; +′, ′-′ Stimulatory or inhibitory values between 20% and 40%;
+, ): stimulatory or inhibitory values higher than 40%.
2
+
usually exhibit a dose-response format activity pro-
file: at the highest concentrations they tend to act as
inhibitors and the activity decreases as the concentra-
tion lowers. In many cases, the activity can turn
stimulatory as the test solution is diluted. This behavior
can be found in the following cases: lettuce, compound
7
, germination; cress, compound 1, germination and root
growth, and compound 7, root growth; wheat, compound
6
, root growth.
When the test compound is not a powerful inhibitor
or the range of concentrations chosen falls out of the
inhibitory” zone, a different scenario can be drawn:
there is low or no activity at the higher concentrations
no inhibition) and as the test solutions are more diluted
“
(
the activity turns on stimulatory. Once the maximum
of stimulatory activity has been reached, the activity
decreases again toward to zero. This behavior can be
observed in the following cases: cress, compounds 2-4,
germination and root length; wheat, compound 1,
germination and root length and compounds 3-6,
germination; and lettuce, compounds 1-4, germination
and root length.
Since these compounds seem to have enhancing and
inhibiting activities depending on the concentration and
they seem to be related with defensive roles in nature
(
mainly antifeeding and allelopathic), it does not look
From the functional point of view, it should be
expected that the introduction of a new electrophilic
moiety will cause an enhancement of the inhibition, if
a nucleophilic attack of the biomolecule to the inhibitor
is postulated. The introduction of an oxirane ring at 4,5
causes a depletion in the inhibitory activity of 1.
However, the introduction of an oxirane ring at 1,10
presents just the opposite effect (see effects on wheat
root growth, Figure 6), which can be observed also in
the 1,10-4,5 derivative 4. This behavior can be ex-
plained by the different accessibility of the oxirane ring
in each side. The lactonic â-face is very hindered, and
the effect of the introduction of this moiety is the change
in the orientation of the lactonic ring (Table 2, Figure
3). The presence of an epoxide at 1,10 does not change
like they have a phytohormone-like activity, and it does
not matter if they have a stimulatory activity at low
concentrations.
Previously, the inhibitory effect of the trans,trans-
germacranolides argophyllins A and B (Helianthus
tuberosus) on the IAA-induced elongation of Azukia
angulariz hypocotyl sections (Watanabe et al., 1982), the
inhibitory effect on the root growth of chinese cabbage
by tatridin B and (11R)-11,13-dihydrotatridin B (Sash-
ida et al., 1983), or the stimulation of witchweed
germination by several germacranolide-type lactones
(
Fischer et al., 1990) have been reported.
Costunolide (1) is one of the two major constituents
of the roots of Saussurea lappa (Kalsi et al., 1977), and

trans,trans-Germacranolides as Potential Natural Herbicide Models
J. Agric. Food Chem., Vol. 47, No. 10, 1999 4413
Ta ble 2. Th eor etica l Molecu la r P r op er ties Obta in ed Usin g MMX Ca lcu la tion sa
1
2
3
4
5
6
7
8
Selected Dihedral Angles (deg)
H3R,C14
H5,H6
H6,H7
H7,C13
H6,C)O
H6,C12
-151.05
161.99
-167.77
95.44
-89.21
-91.65
-162.72
147.96
-159.68
87.01
-93.76
-96.03
-149.01
-161.16
143.64
-160.54
87.17
-92.17
-94.89
-151.21
-163.56
150.81
-161.62
34.14
-92.05
-93.92
-148.84
160.49
-168.15
38.60
-87.95
-90.42
-161.68
148.06
-163.73
35.59
-89.92
-92.10
157.81
-168.21
95.00
163.18
-166.64
37.79
-87.72
-90.63
-89.62
-91.84
van der Waals Area (A2)
NPSSA
NPSUA
PSA
184.2
24.3
31.9
240.
184.4
18.6
49.0
252.
176.2
21.9
49.8
247.
181.9
11.7
62.3
255.
210.3
13.1
35.9
259.
210.2
4.7
51.1
265.
202.7
6.6
49.8
259.
203.8
0.0
61.1
265.
TSA
Water Solvation Shell (A2)
NPSSA
NPSUA
PSA
314.5
30.5
71.0
416.
309.2
18.9
89.1
417
310.0
21.1
90.3
304.0
14.6
106.8
425.
349.2
10.6
67.4
427.
342.9
2.6
85.6
430.
341.7
6.0
86.9
434.
336.9
0.0
103.9
440.
TSA
421.
Accessible Water Solvation Shell (A2)
NPSSA
NPSUA
PSA
296.4
21.8
56.7
374.
291.4
13.5
71.1
376.
292.6
15.0
72.1
379.
286.9
10.4
85.4
382.
328.6
7.5
53.9
390.
323.1
1.8
68.5
393.
322.1
4.3
69.6
396
317.6
0.0
83.3
400.
TSA
a
Key: NPSSA, nonpolar saturated surface area; NPUSA, nonpolar unsaturated surface area; PSA, polar surface area; TSA, total
surface area.
so much the orientation of the lactone moiety (Figure
), but introduces a more accessible and nucleophilic
group, as can be observed in compound 4. Thus, the
observed increment of the inhibition could be explained
through the introduction of the new electrophilic and
accessible epoxy group.
(e) The levels of activity of some of these compounds
are similar to those of Logran on monocotyledons.
(f) Compounds such as costunolide (1) and its 11,13-
dihydro derivative 5 can be proposed as lead compounds
for the development of new models of herbicides.
3
Another point to compare is the effect on the activity
of the reduction of the double bond conjugated with the
lactonic carbonyl group. An enhancement of the growth
inhibitory activity or a depletion of the stimulatory
activity is observed on lettuce, cress, and wheat for the
pairs (1, 5), (2, 6), and (3, 7) (Figures 4-6). Thus, the
reactivity cannot be related with the presence of an R,â-
unsatured carbonyl system. On the other hand, the
polar surface area (PSA) in both the van der Waals and
the solvation shells are smaller in the dihydroderiva-
tives 5-7 than in the unsatured compounds 1-4. Thus,
it should be possible that the hydrophobic interactions
could be more important in this case for the activity.
Another possibility is to consider the total van der Waals
surface, which can be related with the total volume of
the molecule. This is higher in the reduced compounds
and could induce a greater change once they are
bounded to the target site due to their higher steric
requirements.
ABBREVIATIONS USED
DCM, methylene chloride; mixt, mixture; conc, con-
centration; soln, solution.
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