Identification of dialkyl diacetylene diols with potent cancer chemopreventive activity

Article abstract of DOI:10.1016/j.bmcl.2015.05.098

Abstract An increasing importance of chemoprevention for controlling cancer risks prompted the discovery of new active cancer chemopreventive agents. In this study, we designed and synthesized substituted hexa-2,4-diyne-1,6-diols, more structurally simplified, tunable, and easily preparable than natural gymnasterkoreaynes, and evaluated their cancer chemopreventive activities by measuring concentration of doubling quinone reductase activity (CD), cell viability, and chemopreventive index (CI). Most of the diols exhibited good CD activity and low cytotoxicity. In particular, tetradeca-5,7-diyne-4,9-diol and 2-methyltetradeca-5,7-diyne-4,9-diol showed the best cancer chemopreventive activity, approximately equipotent to that of sulforaphane. And, by synthesizing optically active stereoisomers of selected active compounds, the effect of stereochemistry was also studied. Eventually, we produced a chemopreventive compound for in vivo study.

Full text of DOI:10.1016/j.bmcl.2015.05.098

Bioorganic & Medicinal Chemistry Letters 25 (2015) 4020–4023
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of dialkyl diacetylene diols with potent cancer
chemopreventive activity
Chang-Yong Lee a, Ji Ho Yun b, Kyungsu Kang b, Chu-Won Nho b, Dongyun Shin a,
⇑
a College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 406-799, Republic of Korea
b Functional Food Center, Korea Institute of Science and Technology, 290 Daejeon-dong, Gangneung 210-340, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An increasing importance of chemoprevention for controlling cancer risks prompted the discovery of new
active cancer chemopreventive agents. In this study, we designed and synthesized substituted
hexa-2,4-diyne-1,6-diols, more structurally simplified, tunable, and easily preparable than natural
gymnasterkoreaynes, and evaluated their cancer chemopreventive activities by measuring concentration
of doubling quinone reductase activity (CD), cell viability, and chemopreventive index (CI). Most of the
diols exhibited good CD activity and low cytotoxicity. In particular, tetradeca-5,7-diyne-4,9-diol and
2-methyltetradeca-5,7-diyne-4,9-diol showed the best cancer chemopreventive activity, approximately
equipotent to that of sulforaphane. And, by synthesizing optically active stereoisomers of selected active
compounds, the effect of stereochemistry was also studied. Eventually, we produced a chemopreventive
compound for in vivo study.
Received 15 February 2015
Revised 17 April 2015
Accepted 28 May 2015
Available online 6 June 2015
Keywords:
Cancer
Chemoprevention
Diyne
Quinone reductase
Stereoisomeric
Ó 2015 Published by Elsevier Ltd.
Cancer chemoprevention is defined as the inhibition, retarda-
tion, and/or reversal of the carcinogenesis steps that include initi-
ation, promotion, and progression by chemicals with otherwise
low cytotoxicity.1–3 Chemoprevention was categorized in three
main areas by Russo group: (1) prevention of carcinogenesis in
healthy individuals; (2) inhibition or retardation of cancer in indi-
viduals with pre-malignant lesions or; (3) secondary prevention or
inhibition of cancer recurrence in patients already having treat-
ment for a primary cancer.4 Many studies have been reported on
mechanisms for chemoprevention, especially prevention of car-
cinogenesis.5,6 Among them, detoxification of toxic quinones by
quinone reductase (QR, also called NQO1) is one of recognized
mechanisms for chemoprevention. Quinone reductase, a represen-
tative phase II detoxification enzyme, is revealed to have a close
relationship with prevention of cancer by blocking cancer initia-
tion. Thus, QR induction is used as a biomarker of chemopreventive
activities and their potency.7,8
phase II clinical trial, though it failed due to the low efficacy and
side effects.11
In previous publications, we reported the isolation of gym-
nasterkoreaynes B, E, and
G from Gymnaster koraiensis by
activity-guided fractionations and their potent cancer chemopre-
ventive effects.12 These compounds induced phase II detoxification
enzymes known to have cytoprotective functions, such as
glutathione-S-transferase, UDP-glucuronosyltransferase, NAD(P)H:
quinone oxidoreductase (NQO1), and glutathione reductase (GSR),
in normal and HepG2 human hepatocarcinoma cells. The gym-
nasterkoreaynes are naturally occurring polyacetylenic com-
pounds. Our group recently completed the total synthesis of
gymnasterkoreaynes E and G, which contain octa-4,6-diyne-2,3,
8-triol as a major functional backbone (Fig. 1).13 We also described
the structure–activity relationship (SAR) of these polyacetylenes on
cancer chemopreventive activity.14 In that study, important
structural information regarding the use of diyne triols in cancer
chemoprevention was revealed: the reduction of the diyne moiety
to a saturated alkyl group fully eliminated both chemopreventive
activity and cytotoxicity, and the variations of the terminal alkyl
groups had significant effects on the induction potency of quinone
reductase and cellular toxicity.
Up to date, various natural compounds with chemopreventive
effects were isolated mostly from dietary plants, and most of them
were reported to show their activities by preventing carcinogene-
sis. Some representative agents include sulforaphane from crucif-
erous vegetables, lycopene from tomato products, and resveratrol
from grapes.9,10 In particular, oltipraz,
a
dithiolethione class
Structurally, gymnasterkoreaynes G, E and B have cis-olefin and
three stereocenters. Such molecular complexities limited the syn-
thesis of optically pure form of active stereoisomers and also the
production of a large amount of active compounds for in vivo
study. Hence, on the basis of the established SAR, we hypothesized
chemopreventive agent, has evaluated its anti-cancer activity in
⇑
Corresponding author. Tel.: +82 32 899 6111; fax: +82 32 820 4829.
E-mail address: dyshin@gachon.ac.kr (D. Shin).
http://dx.doi.org/10.1016/j.bmcl.2015.05.098
0960-894X/Ó 2015 Published by Elsevier Ltd.

C.-Y. Lee et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4020–4023
4021
S
that a structurally simplified diyne-based scaffold which retains
diacetylenic diol moiety might have similar biological activities
and is much easier to synthesize as stereoisomeric mixtures or sin-
gle stereoisomers than diacetylenic triols. Herein, we report the
synthesis and cancer chemopreventive activities of new diyne diols
and eventually, creation of compounds for in vivo study (Fig. 2).
Syntheses of the diacetylene diol analogues were conducted
using the previously established synthetic procedure by our group,
as illustrated in Scheme 1. Starting from the commercially avail-
able 1,4-bis(trimethylsilyl)buta-1,3-diyne, various alkyl aldehydes
were installed on both ends of 1,3-butadiyne. Generation of acety-
lenic anions from 1,4-bis(trimethylsilyl)buta-1,3-diyne through a
metal-silicon exchange reaction by treating methyl lithium–
lithium bromide in THF, followed by the addition of alkyl aldehyde
produced acetylenic alcohols 4a–4d in excellent yields.15
Sequential protection of the secondary alcohol with THP and desi-
lylation of terminal trimethylsilyl by TBAF gave compounds 5a–5d.
In the THP protection step, two diastereomeric mixtures were
detected in thin-layer chromatography and were barely separable,
and so both diastereomers were used for the next step without
separation. Terminal alkynes were deprotonated by ethylmagne-
sium bromide and treated with alkyl aldehydes to give
THP-protected dialkyl hexa-2,4-diyne-1,6-diols 6a–6n. Finally,
deprotection of THP under the condition of a 9:1 mixture of 70%
AcOH in H2O and THF gave the desired diols 7a–7n. After synthesis
of the derivatives, we recognized that 7b, 7e, 7f, 7j, and 7m had
been previously reported.16–20 Overall, 14 diyne diols were synthe-
sized by modification of both terminals with different alkyl groups.
By fixing the left terminal with n-propyl, n-pentyl, n-nonyl, or
cyclohexyl groups, the right terminal was derivatized with other
alkyl groups.
N
N
S
O
S
S
C
Me
Oltipraz
Me
N
Sulforaphane
OH
2
3
OH
O
8
OH
Gymnasterkoreayne G ; 2,3-trans
Gymnasterkoreayne E ; 2,3-cis
OH
Gymnasterkoreayne B
Figure 1. Structures of gymnasterkoreayne E, G, and B.
Key scaffold in Gymnasterkoreayne
HO
Me
OH
R
Derivatization
OH
Octa-4,6-diyne-2,3,8-triol
In this research: simplified, tunable, easily synthesizable
HO
R2
R1
We exploited the potency of cancer chemopreventive activity
induced by dialkyl diacetylene diols by measuring the quinone
reductase (QR) assay in Hepa1c1c7 murine hepatoma cells. The
QR assay, a useful tool for the evaluation of cancer chemopreven-
tive activity, was performed according to the Prochaska modified
method.8,21 The potency of the cancer chemopreventive activity
Derivatization
OH
Derivatization
hexa-2,4-diyne-1,6-diol scaf f old
Figure 2. Design of diyne diols based on diyne triols.
TMS
TMS
a
b, c
d
R1
R1
TMS
OTHP
, R1 = CH2CH2CH3
5b
OH
, R1 = CH2CH2CH3
4a
4b
5a
, R1 = CH2(CH2)3CH3
, R1 = CH2(CH2)3CH3
4c, R1 = CH2(CH2)7CH3
5c, R1 = CH2(CH2)7CH3
, R1 = cyclohexyl
, R1 = cyclohexyl
5d
4d
OH
R2
OH
R2
e
R1
R1
OTHP
OH
Aldehydes
6a, R1 = CH2CH2CH3, R2 = H
7a, R1 = CH2CH2CH3, R2 = H
H
, R1 = CH2CH2CH3, R2 = CH2(CH2)3CH3
, R1 = CH2CH2CH3, R2 = CH2(CH2)3CH3
7b
6b
6c, R1 = CH2CH2CH3, R2 = CH2(CH2)7CH3
7c, R1 = CH2CH2CH3, R2 = CH2(CH2)7CH3
O
H
O
, R1 = CH2CH2CH3, R2 = cyclohexyl
, R1 = CH2(CH2)3CH3, R2 = H
, R1 = CH2CH2CH3, R2 = cyclohexyl
, R1 = CH2(CH2)3CH3, R2 = H
6d
6e
7d
7e
O
6f, R1 = CH2(CH2)3CH3, R2 = CH2(CH2)3CH3
7f, R1 = CH2(CH2)3CH3, R2 = CH2(CH2)3CH3
O
, R1 = CH2(CH2)3CH3, R2 = CH2(CH2)7CH3
6g
, R1 = CH2(CH2)3CH3, R2 = CH2(CH2)7CH3
7g
O
6h, R1 = CH2(CH2)3CH3, R2 = cyclohexyl
7h, R1 = CH2(CH2)3CH3, R2 = cyclohexyl
, R1 = CH2(CH2)3CH3, R2 = CH2CH(CH3)2
, R1 = CH2(CH2)7CH3, R2 = CH2(CH2)7CH3
, R1 = CH2(CH2)3CH3, R2 = CH2CH(CH3)2
, R1 = CH2(CH2)7CH3, R2 = CH2(CH2)7CH3
6i
6j
7i
7j
O
6k, R1 = CH2(CH2)7CH3, R2 = cyclohexyl
7k, R1 = CH2(CH2)7CH3, R2 = cyclohexyl
, R1 = CH2(CH2)7CH3, R2 = CH2CH(CH3)2
6m, R1 = cyclohexyl, R2 = cyclohexyl
6n
, R1 = CH2(CH2)7CH3, R2 = CH2CH(CH3)2
7m, R1 = cyclohexyl, R2 = cyclohexyl
7n
6l
7l
, R1 = cyclohexyl, R2 = CH2CH(CH3)2
, R1 = cyclohexyl, R2 = CH2CH(CH3)2
Scheme 1. Synthesis of diyne diols. Reagents and conditions: (a) MeLi–LiBr, THF, 0 °C to rt; then aldehyde, 78–83%; (b) DHP, p-TsOH, CH2Cl2, rt, 77–88%; (c) TBAF, THF, rt, 82–
87%; (d) EtMgBr, 0 °C to rt; then aldehyde, 67–78%; (e) 70% AcOH in H2O/THF (9:1), 40 °C, 71–83%.

4022
C.-Y. Lee et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4020–4023
Table 1
Cancer chemopreventive activity of diols
Compound
R1
R2
CD (
l
M)*
IC50
>50
19 ( 13.3)
30 ( 6.4)
>50
(
l
M)*
CI
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
n-Propyl
n-Propyl
n-Propyl
n-Propyl
n-Pentyl
n-Pentyl
n-Pentyl
n-Pentyl
n-Pentyl
n-Nonyl
n-Nonyl
n-Nonyl
Cyclohexyl
Cyclohexyl
H
6.0 ( 0.7)
0.8 ( 0.5)
4.2 ( 2.1)
6.2 ( 0.6)
4.7 ( 2.1)
3.1 ( 4.5)
2.6 ( 0.7)
3.2 ( 1.5)
1.3 ( 0.2)
26 ( 4.5)
11 ( 0.5)
10 ( 1.3)
8.4 ( 3.1)
5.6 ( 2.3)
8.2 ( 3.3)
0.5
>8.3
24
7.2
>8.1
>11
>16
4.6
>16
32
n-Pentyl
n-Nonyl
Cyclohexyl
H
n-Pentyl
>50
>50
n-Nonyl
12 ( 4.2)
>50
41 ( 9.0)
26 ( 3.7)
44 ( 2.0)
>50
>50
>50
>50
15 ( 0.5)
Cyclohexyl
2-Methylpropyl
n-Nonyl
Cyclohexyl
2-Methylpropyl
Cyclohexyl
2-Methylpropyl
1.0
4.0
>5.0
>6.0
>8.9
>6.1
27
Gymnasterkoreayne G
SFN
*
CD and IC50 values represent the mean SD, n = 6.
was expressed as a chemoprevention index (CI), calculated by
dividing the concentration that inhibited 50% of the cell prolifera-
tion (IC50) by the concentration required to double the QR activity
(CD value). Sulforaphane (SFN) and gymnasterkoreayne G were
used as positive controls.
As shown in Table 1, chemopreventive activities of the synthe-
sized compounds which most of the compounds presented by
chemopreventive index (CI) values. Among the tested dialkyl dia-
cetylene diols, 11 derivatives displayed good activities with CD of
OH
a
*
n-Pentyl
*
OH
OH
7e ;
(R)-
7e ; α
(S)-
(R)-oct-1-yn-3-ol
(S)-oct-1-yn-3-ol
[α]D -10.16 (c = 0.13 in CH2Cl2)
D +10.74 (c = 0.37 in CH2Cl2)
[
]
OH
n-Pentyl
b
c
0.8–8.4 lM and just three compounds exhibited two digit micro-
n-Pentyl
molar activity. In particular, 7b displayed the best cancer CD activ-
ity (CD = 0.8) which is much better than gymnasterkoreayne G
(CD = 8.2) and almost equipotent with sulforaphane (SFN;
CD = 0.5). Another advantage of dialkyl diacetylene diols is their
low cytotoxicity. All compounds except 7g showed lower toxicity
than sulforaphane and 7a, 7d–7f, 7h, and 7l–7n exhibited no cyto-
Br
7f
meso-
OH
OH
OH
n-Pentyl
OH
8
(R)-
n-Pentyl
toxicity under 50 lM. One tendency is that every nonyl derivative
7f;
(R,R)- [α]D -13.82 (c = 0.094 in CH2Cl2)
except 7l showed mild cytotoxicity and long alkyl chain dimin-
ished the CD value. Considering both biological activity and safety,
7e, 7f, and 7h were thought to be optimal for in vivo study
OH
n-Pentyl
Br
b
n-Pentyl
(CD = 4.7, 3.1, 3.2
respectively), although 7b and 7e were slightly better in terms of
CD activity (CD = 0.8 and 1.3 M, respectively).
lM; IC50 = >50, >50, >50 lM; CI = >11, >16, >16,
OH
(S)-8
OH
7f
l
(S,S)- ; [α]D +11.59 (c = 0.10 in CH2Cl2)
In the early stage of drug discovery, compounds with one or
more chiral carbon are often used for assays as stereoisomeric mix-
tures, and then biologically active compounds are requested to
prove which optical stereoisomers exert influence on its activity
or toxicity. In this study, selected 7e, 7f, and 7h are stereoisomeric
mixtures; 7e is racemates and 7f and 7h are diastereomeric mix-
tures. Considering synthetic feasibility as well as biological activity,
we carried out synthesis of all stereoisomers of 7e and 7f as opti-
cally pure form in order to address the effect of stereochemistry
on their chemopreventive activity and toxicity, and eventually to
make a final selection of compounds for in vivo animal study.
Synthesis of the compounds (R)-7e and (S)-7e was accomplished
by copper-mediated cross coupling of commercially available (R)
and (S)-oct-1-yn-3-ol with 3-bromoprop-2-yn-1-ol.22 In case of
7f, there exist three stereoisomers, (R,R)-7f, (R,S)-7f, and meso-7f
due to the existence of a symmetry plane of (R,S)-7f. As shown in
Scheme 2, bromoalkyne (R)-8 prepared from (R)-oct-1-yn-3-ol
was coupled with (S)-oct-1-yn-3-ol and (R)-oct-1-yn-3-ol to afford
meso-7f and (R,R)-7f, respectively. In th same way, (S,S)-7f was also
synthesized by coupling of (S)-8 and (S)-oct-1-yn-3-ol.
Scheme 2. Synthesis of optically pure stereoisomers of 7e and 7f. Reagents and
conditions: (a) 3-bromoprop-2-yn-1-ol, CuCl2, NH2OH–HCl, EtNH2, MeOH, rt, 37%;
(b) (S)-oct-1-yn-3-ol, CuCl2, NH2OH–HCl, EtNH2, MeOH, rt, 42–52%; (c) (R)-oct-1-
yn-3-ol, CuCl2, NH2OH–HCl, EtNH2, MeOH, rt, 46%.
Table 2
Cancer chemopreventive activities of chiral diols
CD (lM)
IC50
(lM)
CI
(R)-7e
(S)-7e
meso-7f
(R,R)-7f
(S,S)-7f
SFN
2.3 ( 1.7)
3.2 ( 0.8)
4.7 ( 2.1)
0.6 ( 2.8)
2.6 ( 1.9)
0.4
>100
>100
68 ( 3.2)
12 ( 2.3)
47 ( 4.6)
11
>43
>31
14
20
18
28
profiles with ( )-7e in terms of CD activity and cellular toxicity.
The stereochemistry of chiral carbon in 7e did not affect their bio-
logical activities. The better is both stereoisomers did not display
cytotoxicity under 100 lM. In case of 7f, chemopreventive activi-
ties were slightly different depending on the stereochemistry.
Quinone reductase induction activity, cell viability, and CI val-
ues of the synthesized optically pure compounds are presented
in Table 2. Both of the (R)-7e and (S)-7e showed similar biological
(R,R)-7f exhibited most potent quinone reductase induction effect

C.-Y. Lee et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4020–4023
4023
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M), which was almost
lM), while meso-7f
and (S,S)-7f displayed comparable activities. In this case, all
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designed based on gymnasterkoreaynes E and G, naturally occur-
ring diyne triols with cancer chemopreventive activity. The diols
were readily obtained using a five-step procedure that was much
easier than that of the corresponding triols. Most diols exhibited
good biological activity in terms of quinone reductase induction,
cell viability, and CI. In particular, as diastereomeric mixtures, 7b
and 7i showed the best cancer chemopreventive activity, which
was nearly equipotent to that of SFN, and 7e, 7f, and 7h were con-
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synthesized full series of stereoisomers of 7e and 7f as optically
pure forms from chiral building blocks and evaluated their chemo-
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Acknowledgements
Further reading
This work was supported by Basic Science Research Program
through the National Research Foundation of South Korea (NRF)
funded by the Ministry of Education, Science and Technology of
South Korea (NRF-2012R1A1A1007057) and partly by KIST intra-
mural grant (2Z03850).
23. Spectral data of selected compounds; 7e: Colorless oil; Rf = 0.23
(EtOAc/hexanes, 1:3); 1H NMR (600 MHz, CDCl3): d 4.44 (dd, J = 6.0, 6.6 Hz,
1H), 4.35 (m, 2H), 1.79 (d, J = 6.0 Hz, 1H), 1.76–1.69 (m, 2H), 1.6 (t, J = 6.6 Hz,
1H), 1.47–1.42 (m, 2H), 1.34–1.30 (m, 4H), 0.90 (t, J = 6.6 Hz, 3H); 13C NMR
(150 MHz, CDCl3): d 80.6, 77.5, 69.9, 68.8, 62.9, 51.5, 37.5, 31.4, 24.7, 22.5,
14.0; FT-IR mmax 3315.3, 2923.4, 2854.8, 1459.1, 1335.2, 1020.0; MS (ESI)
[M+H]+ 181; 7f: Colorless oil; Rf = 0.3 (EtOAc/hexanes, 1:3); 1H NMR
(600 MHz, CDCl3): d 4.43 (t, J = 5.7 Hz, 2H), 1.81 (s, 1H), 1.72 (m, 4H), 1.45
(m, 4H), 1.32 (m, 8H), 1.90 (t, J = 6.9 Hz, 6H); 13C NMR (150 MHz, CDCl3): d
80.5, 68.9, 62.9, 37.5, 31.4, 24.7, 22.5, 14.0;FT-IR mmax 331.4, 2927.5, 2859.1,
2360.6, 2341.2, 1458.5, 1020.4; MS (ESI) [M+H]+ 251.
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