Bioorganic & Medicinal Chemistry Letters
Semisynthesis of triptolide analogues: Effect of B-ring substituents
on cytotoxic activities
Hongtao Xu a, Yi Chen b, Huanyu Tang a, Huijin Feng a, Yuanchao Li a,
⇑
a Department of Medical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China
b Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of B-ring modified analogues of triptolide were synthesized and tested for their cytotoxicity
against two human tumor cell lines (U251 and PC-3). From the current investigation, the structure–cyto-
toxic activity relationships of these analogues suggested that the introduction of hydroxyl, epoxide,
halogen or olefinic groups on C5 and/or C6 could still retain the cytotoxicity, albeit a little less potency,
and the C7,C8-b-epoxide group of triptolide was essential to its potent cytotoxic activity.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 30 July 2014
Revised 9 October 2014
Accepted 22 October 2014
Available online 29 October 2014
Keywords:
Diterpenoid
Triptolide
Structure–cytotoxic activity relationships
Cytotoxic
Synthesis
Triptolide (1, Fig. 1) is a naturally occurring diterpenoid isolated
from extracts of Tripterygium wilfordii Hook F. (TWHF),1 commonly
known as Lei Gong Teng or Thunder God Vine, a well-known Chi-
nese traditional medicine herbal, whose extracts have been used
to treat autoimmune and inflammatory diseases, such as rheuma-
toid arthritis and systemic lupus erythematosus for centuries.2 As
one of the primary biologically active ingredients of TWHF, tripto-
lide display a wide array of biological activities like antitumor,
anti-inflammatory and immunosuppressive.3 It shows strong anti-
proliferative activity at the cellular level and inhibits the prolifera-
tion of all 60 cancer cell lines of US National Cancer Institute with
nanomolar IC50 values (average IC50 = 12 nM). However, before
triptolide can reach its clinical potential, great challenges remain
to overcome, such as multi-organ toxicity, narrow therapeutic win-
dow and poor water solubility. In order to find ways to enhance its
efficacy and reduce toxicity, extensive synthesis and structural
modifications of triptolide and its derivatives have been carried
out in many research groups worldwide in the past few decades,
and already yielded lots of important structure activity relation-
ships information.4 Triptolide derivatives (e.g., 5R-5-hydroxytri-
ptolide, PG490-88 and Minnelide) have already entered human
clinical trials for cancer and rheumatoid arthritis.5
D-ring, the C-ring epoxide groups and the C14-hydroxy group,
and have emerged as the most promising approach for improving
bioavailability that led to the discovery and development of clini-
cally important anticancer or antiinflammatory compounds.4 How-
ever, due to the lack of preactivated group, the structure activity
relationship of B-ring is still obscure, no systematic SARs studies
have been reported.
As an ongoing work of our research on the SARs of triptolide, we
think that it is important to execute a systemic SARs studies of
B-ring. In addition to further evaluation of the structure–cytotoxic
activity relationship of B-ring, for which only limited data are cur-
rently available, the ability to access this complex SARs to find new
modification site and new triptolide analogues with good pharma-
cokinetic–pharmacodynamic properties are also what we want.
In the present study, we designed and synthesized a series of
B-ring modified analogues of triptolide (Fig. 2), that is, analogues
(4–20) with hydroxyl, epoxide or halogen groups on C5,C6 and
16
O
O
O
O
O
12
15
11
9
20
13
14
OH
17
O
O
O
O
1
C
Previous studies on the structure–cytotoxic activity relation-
ships (SARs) of triptolide were mainly focused on the lactone
2
3
O
10
5
8
A
B
O
4
7
O
O
O
D
6
H
H
H
18
O
O
19
O
Triptolide(1)
(14S)-14,21-epoxytriptolide(3)
Triptonide(2)
⇑
Corresponding author. Tel.: +86 21 50806600x3502; fax: +86 21 50807288.
Figure 1. Structure of triptolide, triptonide and (14S)-14,21-epoxytriptolide.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.