Synthesis of novel brassinosteroid biosynthesis inhibitors based on the ketoconazole scaffold

Article abstract of DOI:10.1016/j.bmcl.2011.12.120

Brassinosteroids (BRs) are steroidal plant hormones that control several important agronomic traits such as plant architecture, seed yield, and stress tolerance. Inhibitors that target BR biosynthesis are candidate plant growth regulators. We synthesized

Full text of DOI:10.1016/j.bmcl.2011.12.120

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1625–1628
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel brassinosteroid biosynthesis inhibitors based
on the ketoconazole scaffold
⇑
,
Keimei Oh a, , Kazuhiro Yamada a, , Tadao Asami b, Yuko Yoshizawa a
a Department of Biotechnology, Faculty of Bioresource Sciences, Akita Prefectural University, 241-438, Shimoshinjo Nakano, Akita 010-0195, Japan
b Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Brassinosteroids (BRs) are steroidal plant hormones that control several important agronomic traits such
as plant architecture, seed yield, and stress tolerance. Inhibitors that target BR biosynthesis are candidate
plant growth regulators. We synthesized novel triazole derivatives, based on the ketoconazole scaffold,
that function as inhibitors of BR biosynthesis. The biological activity of the test compounds was evaluated
by determining their ability to induce dwarfism in Arabidopsis seedlings grown in the dark. The chemically
induced dwarfism of Arabidopsis seedlings was further evaluated by a rescue experiment using the co-
application of brassinolide and/or gibberellins (GA). The structure–activity relationship studies revealed
Received 20 October 2011
Revised 12 December 2011
Accepted 27 December 2011
Available online 4 January 2012
Keywords:
Brassinosteroid biosynthesis inhibitor
Plant hormone
a
potent BR biosynthesis inhibitor, 2RS, 4RS-1-{2-(4-chlorophenyl)-4-[2-(2-ethoxyphenyl)-ethyl]-1,
3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole (7m), with an IC50 value of 0.10 0.03 M for retardation of
Arabidopsis seedling stem elongation. The compound-induced hypocotyl dwarfism was counteracted by
the co-application of 10 nM brassinolide, but not 1 M GA3, which produced seedlings that resembled
l
Triazole derivatives
l
BR-deficient mutants. This result suggests that 7m is a potent and specific inhibitor of BR biosynthesis.
Ó 2011 Elsevier Ltd. All rights reserved.
Brassinosteroids (BRs) are steroidal plant hormones that play
critical roles in regulating broad aspects of plant growth and devel-
opment.1 When applied exogenously at nanomolar to micromolar
levels, BRs exhibit a wide spectrum of physiological effects, includ-
ing the promotion and/or enhancement of stem elongation, pollen
tube growth, leaf bending, ethylene biosynthesis, and stress resis-
tance.2,3 The functions of endogenous BRs have been elucidated
by the characterization of BR synthesis mutants of Arabidopsis, to-
mato, rice, and pea.4–7 Mutants with impaired BR synthesis display
dramatic growth defects such as decreased cell elongation, result-
ing in pleiotropic dwarf phenotypes.4–7 Because BRs control several
important agronomic traits such as flowering, plant architecture,
seed yield, and stress tolerance,1–3 efforts have recently been made
to genetically control BR levels in plant tissues. The use of trans-
genic techniques to control the BR levels in plant tissues increased
grain yields in rice, and available evidence indicates that mutations
in BR biosynthesis may be a means to improve biomass produc-
tion.8,9 Thus, the biosynthetic pathway of BRs is a potential target
site for enhancing the crop yield and/or stress tolerance of plants.
The importance of BRs in plant growth and development has
sparked great interest in the regulation of BR biosynthesis. An alter-
native method to control the BR levels in plant tissues is the use of
specific inhibitors that target the enzymes responsible for BR bio-
synthesis; BR biosynthesis inhibitors have consequently become
highly viable candidates for plant growth regulators.
With the establishment of the biosynthetic pathways of BRs10 and
functional analysis of BR biosynthesis enzymes, an educated search
for specific inhibitors of BR biosynthesis can be conducted. Several
steps in BR biosynthesis are carried out by P450 enzymes. CYP90s
are involved in C22 and C23 side-chain hydroxylation of BRs,11
CYP92A6 catalyzes the biochemical conversion of castasterone from
typhasterol,12 and CYP85A2 catalyzes the lactonization of castaster-
one to brassinolide.13 Accordingly, strategies for designing P450
inhibitors can be applied to the identification of BR synthesis inhibi-
tors. Cytochrome P450 inhibition mechanisms have been studied in
considerable detail.14 Triazole derivatives demonstrate widespread
inhibition of P450s, due to the intrinsic affinity of the nitrogen elec-
tron pair in heterocyclic molecules for the prosthetic heme iron.
The triazoles thus bind not only to lipophilic regions of the protein
but also simultaneously to the prosthetic heme iron.15 Our research
interests are in developing novel plant hormone biosynthesis inhib-
itors and using these compounds to explore the functions of plant
hormones in plant growth and development.16–19 Toward this end,
we carried out a systemic search for novel BR biosynthesis inhibitors
by the optimization of known BR biosynthesis inhibitors.
Abbreviations: BRs, brassinosteroids; Brz, brassinazole; GA, gibberellin.
Corresponding author. Tel.: +81 18 872 1590; fax: +81 18 872 1670.
E-mail address: jmwang@akita-pu.ac.jp (K. Oh).
⇑
Asami and Yoshida reported the discovery of brassinazole
(Brz91, Chemical structure was shown in Fig. 1), the first synthetic
Both authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.120

1626
K. Oh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1625–1628
BR biosynthesis inhibitor.20 Subsequent screening of azole deriva-
tives revealed a series of potent inhibitors of BR synthesis (Fig
1).21–23 The Brz series have been characterized as potent inhibitors
of BR biosynthesis with respect to their high binding affinity to
CYP90s.24,25 The inhibition of other P450 enzymes, such as
CYP92A6 and CYP85A2, that are also involved in BR biosynthesis
remain unexplored. CYP90s catalyze the hydroxylation of BRs at
their side chains, whereas CYP92A6 and CYP85A2 alter the steroid
skeleton. The steroid skeleton is a multi-cyclic structure, implying
that the introduction of ring structures to an analogue inhibitor
may enhance the potency and/or selectivity of those inhibitors.
To explore this possibility, we carried out a systemic search for no-
vel BR inhibitors based on the chemical structure of ketoconazole
(Fig. 1). Ketoconazole was selected as a molecular scaffold for the
following reasons: (1) ketoconazole shares a 1,3-dioxolane moiety
with Brz220 (Fig. 1), the most potent inhibitor of BR biosynthesis
reported to date;21 (2) ketoconazole is a well-known P450 inhibi-
tor that is widely used experimentally and clinically,27 suggesting
that analogues of ketoconazole may inhibit P450 enzymes involved
in BR synthesis; and (3) the target compounds (Fig. 1) would be
analogues with a substituted phenoxy moiety, a ring structure, in-
stead of the propyl moiety found in BRz220 (Fig. 1). Based on this
rationale, we synthesized a series of novel triazole derivatives and
evaluated their inhibitory activity on BR biosynthesis.
by reacting a-bromoketone 1 with triazole in DMF using a method
that we described previously.26 The tosylation of isopropylidene
glycerol 3 was achieved using a standard protocol (tosyl chloride
in pyridine at 0 °C), and hydrolysis with 1 M HCl in MeOH yielded
glyceryl tosylate 5. Ketal formation to generate 6 was carried out
using 3 equiv of trifluoromethanesulfonic acid (TfOH) in toluene
at room temperature for 60 h, according to a method previously
described.28 The target compound 7 was prepared by reacting 6
with corresponding phenols in a basic condition, as described pre-
viously.29 All of the compounds synthesized in this work consist of
four stereoisomers, and they were subjected to biological studies
without further purification.
The bioassay for evaluating the activity of BR biosynthesis
inhibitors was carried out using Arabidopsis seedlings grown in
the dark, as previously described.21 In the postembryonic develop-
ment of higher plants, light signals activating the phytochrome or
photoreceptors induce photomorphogenesis and de-etiolation,
resulting in the inhibition of hypocotyl elongation, the opening of
the apical hook of cotyledons, the induction of greening, and the
elongation of leaf primordia. In the absence of light, the elongation
of the hypocotyl and root is not inhibited, and the apical hook of
cotyledons is maintained. Arabidopsis BR synthesis-deficient mu-
tants such as dwarf 1 show remarkable dwarfism and the opening
of the apical hook of cotyledons in the dark.4 This unique de-etio-
lation in the dark phenotype has been used for screening for BR
biosynthesis inhibitors.21 In the present study, we adapted this as-
say method to determine the effects of test compounds on hypo-
cotyl elongation of Arabisopsis seedlings grown in the dark, and
we co-applied BL and GA with the test compounds to determine
the reversibility of their effects. With this assay system, we evalu-
ated the biological activities of synthesized compounds.
The development of a synthetic route for the preparation of tar-
get compound 7 is outlined in Scheme 1. The key transformation of
2 with 5 consisted of four steps: (1) formation of 1-(4-chloro-
phenyl)-2-(1H-1,2,4-triazol-1yl) ethanone 2; (2) tosylation of iso-
propylideneglycerol 3; (3) deprotection of isopropylidene ketal 4;
and (4) ketal formation to generate 6. Compound 2 was prepared
The chemical structures of compounds tested in the biological
studies are shown in Table 1. To identify the chemical substituent
on the phenoxy moiety that was responsible for the retardation of
Arabidopsis stem elongation, various substituents were introduced
onto the aromatic ring (compounds 7a–j). Compound 7a, which
has no substituent on the phenyl ring, was used as a baseline ref-
erence, and brassinazole (Brz) was used as a positive control for
structure–activity relationship discussions. The concentrations of
all of the test compounds were assigned to be 0, 0.1, 0.5, and
1 lM, and the IC50 values were calculated accordingly. As shown
in Table 1, compound 7a exhibits inhibitory activity, retarding
hypocotyl elongation of Arabidopsis seedling grown in the dark,
with an IC50 value of 0.41 0.13
lM, whereas the IC50 of Brz was
0.58 0.38 M in our assay system. Analogues 7b and 7c contain
l
a chlorine atom at position 2 and 3 of phenyl ring and enhanced
the inhibitory activity, with IC50 values of 0.13 0.02 and
0.11 0.04
atom to position 4 (7d) reduced the inhibitory activity, with an
IC50 value of 0.32 0.10 M. The IC50 values of analogues 7e–7j,
which contain two chlorines atoms with different variations on
the phenyl ring, are between 0.14 and 0.87 M. These results sug-
lM, respectively. Interestingly, moving the chlorine
l
l
gest that the introduction of two chlorines atoms on the phenyl
moiety (7e–7j) did not produce a significant effect on the com-
pound’s ability to retard hypocotyl elongation of Arabidopsis seed-
lings, compared with that of mono-chloride substitute analogues
(7b–7d). It is worthwhile to note that chlorine substitution at posi-
tion 4 seemed to have a negative effect on the inhibitory potency.
As shown in Table 1, analogue 7b is more potent than 7f, and ana-
logue 7c is more potent than 7i. Among the compounds with chlo-
rine atom(s) substituents in Table 1 (7a–7j), compound 7b, 7c, 7g,
and 7h exhibit potent inhibitory activity.
GA biosynthesis inhibitors such as paclobutrazol retard the
stem elongation of many plant species by blocking ent-kaurene
oxidation and also mildly affect other cytochrome P450 monooxy-
genases.22 This retardation can be rescued by the application of GA.
Figure 1. Chemical structure of brassinosteroid biosynthesis inhibitors.

K. Oh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1625–1628
1627
Scheme 1. Reagents and conditions: (a) 1,2,4-triazole, triethylamine, DMF, À10 °C, 1 h, rt, 3 h; (b) TsCl, pyridine, 0 °C, acetone; (c) HCl, Reflux, 6 h; (d) 3 equiv TfOH, toluene,
rt, 60 h; and (e) phenol, KOH, DMF, 50 °C, 12 h.
Table 1
Table 2
Inhibitory activity of triazole derivatives on Arabidopsis seedling growth
Retardation of Arabidopsis seedling growth by triazole derivatives and rescue of
growth by BL and GA
No.
R
Inhibition of Arabidopsis stem elongation (IC50) (l
M)*
No.
R
Hypocotyl length, % relative to untreated Arabidopsis
seedlings (%)
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
Brz
H
2-Cl
3-Cl
4-Cl
0.41 0.13
0.13 0.02
0.11 0.04
0.32 0.10
0.51 0.08
0.36 0.10
0.14 0.05
0.17 0.09
0.39 0.05
0.87 0.04
0.14 0.06
0.17 0.03
0.10 0.03
0.14 0.05
0.17 0.04
0.58 0.38
Chem.
Chem. + BL (10 nM)
Chem. + GA (1 lM)
Control
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
—
H
100
117
111
104
72
90
72
87 11
102 12
100
81 13
96
96
83
93
92
95
63
6
7
9
8
9
9
112
53
33
46
58
57
62
38
56
63
85
34
26
22
34
32
n.d.*
8
2,3-Cl2
2,4-Cl2
2,5-Cl2
2,6-Cl2
3,4-Cl2
3,5-Cl2
2-F
2-OCF3
2-OEt
2-OMe
2-Me
—
50
30
36
53
3
4
7
3
5
6
5
5
6
5
4
3
4
5
4
4
5
3
5
4
4
5
2-Cl
3-Cl
4-Cl
2,3-Cl2 44
2,4-Cl2 58
2,5-Cl2 32
2,6-Cl2 43
3,4-Cl2 58
3,5-Cl2 78
2-F
2-OCF3 20
2-OEt 22
2-OMe 25
2-Me
—
4
8
4
6
4
5
4
3
5
4
6
6
5
29
*
7m
7n
7o
Brz
4
The IC50 values of the test compounds for the inhibition of Arabidopsis stem
4
5
6
elongation were calculated by determining the hypocotyl length of untreated
Arabidopsis seedlings as 0% inhibition and using hypocotyl length of 0 mm as 100%
inhibition. Data were collected from 15 to 20 seedlings. All of the experiments were
performed at least in duplicate to establish their replicability.
28
34
*
n.d.: not determined.
To rule out the possibility of GA biosynthesis inhibition by our ana-
logues, we tested the effects of brassinolide, the most biologically
active BR, and GA on the recovery of chemically induced dwarfism
of Arabidopsis seedlings grown in the dark. Compounds 7a to 7j
pounds 7a–7j listed in Table 2, compound 7b, 7g, and 7h showed
good recovery with BL application; the hypocotyl lengths were
104 9, 102 12, and 100 8% of the untreated control, respec-
tively. Although compound 7c exhibited potent inhibitory activity
on Arabidopsis seedling growth, the recovery with BL was relatively
low (72 8%) and was partially recovered by the application of GA
(from 36 7% to 46 5%). This result suggests that 7c may partially
inhibit GA biosynthesis.
The data obtained here clearly indicate that compound 7b is the
most potent compound among the chlorine substituent analogues,
showing strong inhibition of hypocotyl elongation in Arabidopsis
seedlings. This activity can be reversed to control levels (30 4%
to 104 9%) by the co-application of BL (10 nM), whereas the co-
were subjected to the bioassay at a concentration of 0.5
Arabidopsis seedlings were grown in the presence of BL (10 nM)
or GA (1 M) for 5 days in the dark. Data shown in Table 2 are ex-
pressed in percentage relative to the untreated control. As shown
in Table 2, in the presence of BL (10 nM) or GA (1 M), the average
lM, and
l
l
hypocotyl length of Arabidopsis seedlings was approximately
117 6 and 112 8%, respectively. This result indicates that BL
and GA stimulate hypocotyl elongation of Arabidopsis seedlings.
We found that compound 7b, 7c, 7g, and 7h exhibited high inhib-
itory activity on Arabidopsis seedling elongation. The hypocotyl
length of chemically treated Arabidopsis seedlings was approxi-
mately 30 4, 36 7, 32 5, and 43 5% of the untreated seed-
lings, respectively, whereas the positive control Brz (1 lM) was
approximately 34 4%. Co-application of BL (10 nM) showed dif-
ferent recoveries for different test compounds. Among the com-
application of GA (1 lM) did not show significant recovery (from
30 4% to 33 3%). Thus, we conclude that compound 7b is the
best compound among the chlorine substituted analogues.
To further study the structure–activity relationship of this syn-
thetic series, we carried out the chemical modification of 7b by
introducing different substituents at position 2 of the phenyl

1628
K. Oh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1625–1628
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exhibited potent inhibitory activity on the elongation of Arabidop-
sis seedlings. We next investigated the primary site of action of
these compounds by the co-application BL and GA, as described
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series.
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inhibitors of BR biosynthesis. The compounds used in the biological
assays consisted of four stereoisomers, but the asymmetric synthe-
sis of these stereoisomers has been well established.28 We expect
that further studies on the stereochemical structure–activity rela-
tionship of this synthetic series may provide insights regarding
the binding site of this synthetic series. Work on BR biosynthesis
inhibitors such as brassinazole (Brz) has demonstrated the useful-
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allowed the identification of novel components such as bzr1 that
affect brassinosteroid signal transduction.30 The development of
chemicals that induce phenotypes of interest would provide a use-
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complement to classical biochemical and genetic methods.
In conclusion, we have discovered and evaluated the activity of
a novel series of BR biosynthesis inhibitors. Structure–activity rela-
tionship studies revealed that 2RS, 4RS-1-{2-(4-chlorophenyl)-4-
[2-(2-ethoxyphenyl)-ethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.12.120.
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