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%.