Design, synthesis and structure-activity relationships studies on the d ring of the natural product triptolide

Article abstract of DOI:10.1002/cmdc.201300409

Triptolide is a diterpene triepoxide natural product isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal herb. Triptolide has previously been shown to possess antitumor, anti-inflammatory, immunosuppressive, and antifertility activities. Earlier reports suggested that the five-membered unsaturated lactone ring (D ring) is essential for potent cytotoxicity, however, to the best of our knowledge, systematic structure- activity relationship studies have not yet been reported. Here, four types of D ring-modified triptolide analogues were designed, synthesized and evaluated against human ovarian (SKOV-3) and prostate (PC-3) carcinoma cell lines. The results suggest that the D ring is essential to potency, however it can be modified, for example to C18 hydrogen bond acceptor and/or donor furan ring analogues, without complete loss of cytotoxic activity. Interestingly, evaluation of the key series of C19 analogues showed that this site is exquisitely sensitive to polarity. Together, these results will guide further optimization of this natural product lead compound for the development of potent and potentially clinically useful triptolide analogues.

Full text of DOI:10.1002/cmdc.201300409

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DOI: 10.1002/cmdc.201300409
Design, Synthesis and Structure–Activity Relationships
Studies on the D Ring of the Natural Product Triptolide
Hongtao Xu, Huanyu Tang, Huijin Feng, and Yuanchao Li*[a]
Triptolide is a diterpene triepoxide natural product isolated
from Tripterygium wilfordii Hook F, a traditional Chinese medici-
nal herb. Triptolide has previously been shown to possess anti-
tumor, anti-inflammatory, immunosuppressive, and antifertility
activities. Earlier reports suggested that the five-membered un-
saturated lactone ring (D ring) is essential for potent cytotoxici-
ty, however, to the best of our knowledge, systematic struc-
ture–activity relationship studies have not yet been reported.
Here, four types of D ring-modified triptolide analogues were
designed, synthesized and evaluated against human ovarian
(SKOV-3) and prostate (PC-3) carcinoma cell lines. The results
suggest that the D ring is essential to potency, however it can
be modified, for example to C18 hydrogen bond acceptor
and/or donor furan ring analogues, without complete loss of
cytotoxic activity. Interestingly, evaluation of the key series of
C19 analogues showed that this site is exquisitely sensitive to
polarity. Together, these results will guide further optimization
of this natural product lead compound for the development of
potent and potentially clinically useful triptolide analogues.
All of the studies mentioned above greatly support the po-
tential development of triptolide (1) as an antineoplastic
agent. Structural modifications at C14 or on the C ring previ-
ously emerged as promising approaches for improving the bio-
availability of this compound class, and these studies led to
the discovery of clinically important anticancer or anti-inflam-
matory compounds.[24] Findings described in our previous
paper and a report by Takeya et al.[25,26] suggest that the five-
membered unsaturated lactone ring (D ring) of triptolide is es-
sential to its potent anticancer activity. However, systematic
SAR studies are needed to investigate the role of the C3,C4
double bond, the substituent properties of C19, and the po-
tential replacement of the five-membered unsaturated lactone
ring with other ring systems. Herein, as part of our ongoing in-
vestigation into the SAR of triptolide and in an attempt to
identify triptolide analogues with desirable physicochemical,
pharmacokinetic, and pharmacodynamic properties, we de-
scribe the design and synthesis of four types of novel triptolide
analogues (3–17).
First, to investigate the role of the C3,C4 double bond, com-
pounds with saturated lactone rings (3 and 4) were synthe-
sized. Second, to further explore the role of the C3 carbonyl
group, compounds in which the C3 carbonyl group conforma-
tion is flexible (5 and 6) and in which the conformation is fixed
by a 3-pyrone D ring (7) were synthesized. Then, furan-ring-
containing compounds with hydrogen-bond acceptors and/or
donor groups at C18 (8–11) were synthesized to study whether
hydrogen bonding interactions between the target and the
C18 hydrogen accepter are crucial to the cytotoxic activity of
the parent compound, triptolide. Finally, a series of C19-substi-
tuted compounds (12–17) were synthesized to probe and
define the importance of the C19 substituent. These tripolide
analogues were then evaluated in human ovarian (SKOV-3) and
prostate (PC-3) carcinoma cell lines.
Triptolide (1),[1] a diterpene triepoxide isolated from the Chi-
nese medicinal herb Tripterygium wilfordii Hook F (TWHF),[2–4]
commonly known as Lei Gong Teng or Thunder God Vine,
whose extracts have been used to treat autoimmune and in-
flammatory diseases such as rheumatoid arthritis for centuries.
Right after its isolation, it was shown to possess potent antitu-
mor, anti-inflammatory, immunosuppressive, and antifertility
activities.[1,5–23] At the cellular level, triptolide (1) shows potent
antiproliferative activity and inhibits the proliferation of all 60
cancer cell lines of the US National Cancer Institute, with IC50
values in a low nanomolar range (average IC50 =12 nm). Tripto-
lide (1) also inhibits the growth of xenograft models of differ-
ent solid tumor cell types.[11] Meanwhile, it interferes with
a number of transcription factors including NF-kB, Hsp70, p53,
NF-AT and HSF-1 at the molecular level.[11,20,23] Compared with
some conventional chemotherapeutic drugs, triptolide has sim-
ilar or even superior anticancer activity, especially over p53-
mutated or multidrug-resistant cells.[14]
The synthetic strategy followed for the preparation of satu-
rated D ring triptonide analogues 3 and 4 is depicted in
Scheme 1. Abietic acid (18), which was converted to triptophe-
nolidemethyl ether 19 via a known procedure,[27] was used as
the starting material. After several different conditions were
tried, 19 was reduced by Raney nickel/hydrogen gas in ethanol
to give a 2:3 mixture of saturated lactone intermediates 20a
and 20b. Benzylic oxidation of 20a/20b with ammonium ceric
[a] H. Xu, H. Tang, H. Feng, Prof. Y. Li
Department of Medicinal Chemistry
Shanghai Institute of Materia Medica
Chinese Academy of Sciences
555 Zu Chong Zhi Road , Zhang Jiang Hi-Tech Park
Pudong, Shanghai 201203 (China)
E-mail: ycli@mail.shcnc.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201300409.
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tion of phenols 22a/22b with
sodium borohydride in methanol
gave C7-b-alcohols 23a/23b as
the sole isomer. Periodate oxida-
tion of 23a/23b afforded epoxy
dienones 24a/24b.[28] Epoxida-
tion of 24a/24b by in situ gen-
erated methyl(trifluoromethyl)-
dioxirane yielded C9,C11-b-epox-
ides 25a/25b.[29] Further epoxi-
dation with basic hydrogen
peroxide gave the desired com-
pounds 3/4 in high yield. X-ray
crystallographic analysis of com-
pounds 20a and 3 confirmed
their structure to be as shown in
Figure 1.
With both 3 and 4 in hand,
focus was then switched to the
synthesis of compounds 5 and
6. The route employed started
with the transformation of abiet-
ic acid (18) to 26 via an
eight-step procedure previous-
ly reported by our group
(Scheme 2).[27] Treatment of 26
with mercuric chloride afforded
Scheme 1. Synthesis of compounds 3 and 4. Reagents and conditions: a) Raney Ni, H2 (1 atm), EtOH, RT, 64 h, 20a
(58.8%), 20b (39.2%); b) (NH4)2Ce(NO3)6, CH3CN/H2O (1:1), RT, 1.5 h, then DMP, CH2Cl2, RT, o/n, 21a (83%), 21b
(80%); c) BBr3, CH2Cl2, ꢀ788C!RT, 1 h, 22a (92%), 22b (90%); d) NaBH4, CH3OH, 08C, 1 h, 23a (97%), 23b (96%);
e) NaIO4, CH3OH/H2O (3:1), 08C, 1 h, 24a (88%), 24b (91%); f) CF3COCH3, oxone, NaHCO3, CH3CN/aq Na2(EDTA)
(1:1), RT, 3.5 h, 25a (84%), 25b (83%); g) H2O2, NaOH, MeOH, RT, 2 h, 3 (80%), 4 (83%).
a
mixture of the C3-a and
nitrate in water/acetonitrile gave the benzyl alcohol as the in-
termediate, which was used in the next step without purifica-
tion. Oxidation of the hydroxy group with 1,1,1-triacetoxy-1,1-
dihydro-1,2-benziodoxol-3(1H)-one (DMP) delivered C7 ketones
21a/21b in high yield. Subsequent treatment of ketones 21a/
21b with boron trifluoride diethyl etherate removed the
methyl protecting group to afford phenols 22a/22b. Reduc-
b methyl ester, which, without purification, was further reacted
with sodium borohydride and subsequently dehydrated to
provide methyl ester 27. Oxidation of 27 with ammonium ceric
nitrate and Jones reagent, delivered ketone 28. Deprotection
of the methyl ether with boron trifluoride diethyl etherate, fol-
lowed by reduction of the C7 ketone with sodium borohydride
gave C7-b-alcohol 30. Finally, a three-step sequence similar to
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that developed previously for construction of the C-ring func-
tionality using sodium periodate, in situ generated methyl(tri-
fluoromethyl)dioxirane, and basic hydrogen peroxide yielded
a 1:1 mixture of analogues 5 (33% over three steps) and 6
(32% over three steps).[29] X-ray crystallographic analysis of
compound 5 confirmed its structure to be as shown in
Figure 2.
The synthesis of analogues 7–10 and 12–16 used triptonide
(2), which was obtained through extraction from TWHF of our
region, as the starting material (Scheme 3). Treatment of tripto-
nide (2) with (isopropoxy-dimethylsilyl)methylmagnesium chlo-
ride in tetrahydrofuran at 08C and subsequent Tamao oxida-
tion provided a 2:1 mixture of 31 and 32.[30,31] The C-14 diol of
compound 32 was then converted into C14 ketone 8 using
sodium periodate. Oxidative Achmatowicz rearrangement of 8,
followed by reduction of the resulting hemiacetal afforded
Figure 2. X-ray single-crystal structure of analogue 5.
Figure 1. X-ray single-crystal structures of analogues a) 20a and b) 3.
pyrone analogue 7. Oxidation of
8 with DMP provide aldehyde 9.
Pinnick oxidation of 9 followed
by methylation provided methyl
ester 10.[32] Treatment of tripto-
nide 2 with lithium diisopropyl-
amide (LDA) at ꢀ788C, followed
by quenching of the resulting
enolate with methyl iodide, thus
generated C19-a-methyl substi-
tute analogue 12 as the sole
isomer. Similarly, quenching the
enolate by addition of paraform-
aldehyde yielded a 1.5:1 mixture
of C19 dimethoxy-substituted
triptonide 16 and C19 dime-
thoxy-substituted epi-triptolide
15. Treatment of triptonide 2
with lithium bis(trimethylsilyl)-
amide (LiHMDS) followed by ad-
dition of Eschenmoser’s salt gen-
Scheme 2. Synthesis of compounds 5 and 6. Reagents and conditions: a) 1. HgCl2, BF3·Et2O, MeOH, RT, 3 h;
2. NaBH4, MeOH, 08C, 1.5 h; 3. MsCl, DMAP, pyridine, 08C!RT, 2 h, then 608C, 4 h, 50% (three steps); b) (NH4)2Ce-
(NO3)6, CH3CN/H2O (1:1), RT, 1.2 h, then Jones’ reagent, acetone, 08C, 15 min, 72% (two steps); c) BBr3, CH2Cl2,
ꢀ788C!RT, 1 h, 91%; d) NaBH4, CH3OH, 08C, 1 h, 93%; e) 1. NaIO4, CH3OH/H2O (3:1), 1 h; 2. CF3COCH3, oxone,
NaHCO3, CH3CN/aq Na2(EDTA) (1:1), RT, 4 h; 3. H2O2, NaOH, MeOH, RT, 2.5 h, 5 (33%; three steps), 6 (32%; three
steps).
erated compound 14. Finally, ox-
idative elimination of dimethyl
amine 14 provide dien analogue
13. X-ray crystallographic analy-
sis of compounds 15 and 16
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Scheme 3. Synthesis of analogues 7–10 and 12–16. Reagents and conditions: a) 1. (isopropoxydimethylsilyl)methyl chloride, Mg, THF; 2. KF, KHCO3, 30% H2O2,
08C, 2 h, 31 (59%; two steps), 32 (28%; two steps); b) NaIO4, THF/H2O (1:1), RT, 3 h, 95%; c) m-CPBA, CH2Cl2, 08C, 3 h; d) Et3SiH, TFA, 08C, 2 h, 52%, two steps;
e) DMP, NaHCO3, RT, 5 h, 91%; f) NaClO2, NaH2PO4·H2O, 2-methyl-2-butene, THF/tBuOH/H2O (3:3:1), then 50% KOH, a-nitroso-a-methylurea, Et2O, 08C, 15 min,
83%; g) LDA, CH3I, ꢀ788C!RT, 1.5 h, 55%; h) LDA, paraformaldehyde, ꢀ788C!RT, 2 h, 16 (45%), 15 (30%); (i) LiHMDS, Eschenmoser’s salt, ꢀ788C!RT, 1 h,
62%; (j) m-CPBA, NaHCO3, ꢀ788C!RT, 1.5 h, 90%. Abbreviations: 3-chloroperoxybenzoic acid (m-CPBA); trifluoroacetic acid (TFA).
confirmed their structure to be
as shown in Figure 3.
The synthesis of analogues 11
and 17 used triptolide (1) as the
starting material (Scheme 4). Di-
rectly treatment of triptolide
with vinylmagnesium bromide
generated the vinyl-substituted
furan ring analogue (11). Next,
protection of the hydroxy group
with dimethyl sulfoxide (DMSO)
and acetic anhydride (Ac2O) in
acetic acid (AcOH) gave methyl-
thiomethyl ether 34 in 39%
yield, along with a substantial
amounts (58%) of oxidation
product triptonide (2).[25] Reduc-
tion of 34 using diisobutylalumi-
nium hydride (DIBAL-H) followed
Scheme 4. Synthesis of analogues 11 and 17. Reagents and conditions: a) CH2CHMgBr, ꢀ208C!RT, 2 h, 25%;
by quenching of the reaction
b) DMSO, Ac2O, AcOH, RT, o/n, 34 (39%), 2 (58%); c) DIBAL-H, CH2Cl2, ꢀ788C, 1 h, then 0.5n HCl, 15 min, 75%;
with dilute hydrochloride acid d) O2, hn, rose bengal, iPr2EtN, CH2Cl2, ꢀ788C, 2 h, 75%; e) HgCl2, CH3CN, H2O, RT, o/n, 80%.
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analogues 3/4, C3 carbonyl
group conformation-flexible ana-
logues 5/6, and carbonyl group
conformation-locked analogue 7
were shown to be only weakly
cytotoxic or inactive relative to
the parent compound against
both PC-3 and SKOV-3 cell lines.
However, with the exception of
10, furan ring analogues 8, 9,
and 11 exhibited potent cytotox-
icity against both cell lines. C19
hydroxy- and dihydroxymethyl-
substituted analogues 15, 16
and 17 were shown to be only
weakly cytotoxic or inactive
against both the PC-3 and SKOV-
3 cell lines, while analogues 12,
13 and 14 with methyl, methyl-
ene, and dimethylaminomethyl
substituents, respectively, were
found to be equipotent against
the two cell lines as the natural
product (Table 1). Based on the
above results, we surmise that
the five-membered unsaturated
Figure 3. X-ray single-crystal structures of analogues a) 15 and b) 16.
lactone ring (D ring) of triptolide
is essential for potent cytotoxici-
ty, and it might play a crucial
produced furan ring analogue 35. Photochemical oxidation of
35 use molecular oxygen and rose bengal afford hemiacetal
36.[33] Subsequent deprotection of compound 36 with mercu-
ry(II) chloride generated compound 17. X-ray crystallographic
analysis of compound 17 confirmed its structure to be as
shown in Figure 4.
role in defining the three dimensional shape and the electron
properties of the whole molecule. Meanwhile, the furan ring
analogues with different hydrogen bond acceptor and/or
donor groups at the C18 position still exhibit moderate to
potent cytotoxicity (8>9>11), and this apparently challenges
the classical structure–activity relationship of triptolide that
considers the five-membered unsaturated lactone ring as un-
modifiable. The evaluation of the key series of C19 analogues
revealed that this site is exquisitely sensitive to polarity (1, 12,
13>17>16).
With target analogues 3–17 in hand, the in vitro cytotoxic
activity was evaluated against two human tumor cell lines de-
rived from human ovarian (SKOV-3) and prostate (PC-3) carci-
noma cells using sulforhodamine B (SRB) assays (Table 1).[34]
The results revealed that saturated five-membered lactone ring
In summary, a systematic structure–activity relationship
study on the D ring of triptolide was carried out. Four types of
novel D ring-modified triptolide analogues were synthesized
and tested for their cytotoxicity against two human tumor cell
lines. The results of the current investigation suggest that the
five-membered unsaturated lactone ring (D ring) of triptolide is
essential to its potent cytotoxic activity; this moiety could play
a crucial role in defining the three dimensional shape and elec-
tron properties of the whole molecule. That said, some modifi-
cations are tolerated, since the C18 hydrogen bond acceptor
and/or donor furan ring analogues retain cytotoxic activity. In
addition, evaluation of the key series of C19-substituted ana-
logues showed that this site is exquisitely sensitive to polarity.
These findings, while preliminary, further guide the develop-
ment of potent and potentially clinically useful triptolide ana-
logues, and confirm the importance of the D ring for cytotoxic
activity. Further studies targeting some potent analogues are
still in progress and will be disclosed in due course.
Figure 4. X-ray single-crystal structures of analogue 17.
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Compd
IC50 [mm][a]
Compd
IC50 [mm][a]
SKOV-3
PC-3
SKOV-3
PC-3
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1
2
3
4
5
6
7
8
9
0.006ꢁ0.001
0.017ꢁ0.002
0.020ꢁ0.003
0.075ꢁ0.09
10
11
12
13
14
15
16
17
1.100ꢁ0.064 >10
0.414ꢁ0.051
0.171ꢁ0.025
0.096ꢁ0.016
0.270ꢁ0.022
0.633ꢁ0.039
1.803ꢁ0.135
0.506ꢁ0.074
2.546ꢁ0.929
>10
>10
1.756ꢁ0.135
>10
9.320ꢁ0.444
>10
1.264ꢁ0.101 >10
>10
>10
1.246ꢁ0.178 >10
>10
0.953ꢁ0.057
0.097ꢁ0.009
0.154ꢁ0.013
6.820ꢁ0.925
>10
0.397ꢁ0.047
0.492ꢁ0.055
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Keywords: antitumor agents · cytotoxicity · natural products ·
structure–activity relationships · triptolide
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Published online on December 11, 2013
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