Tetrahedron Letters
Synthesis and antiproliferative activity of RITA and its analogs
a,
Jianhua Jiang a,b, Chao Ding a,b, Lulu Li c, Chunmei Gao b, Yuyang Jiang b,d, Chunyan Tan b, , Ruimao Hua
⇑
⇑
a Department of Chemistry, Tsinghua University, Beijing 100084, China
b The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University,
Shenzhen 518055, China
c Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China
d Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2014
Revised 9 September 2014
Accepted 10 October 2014
Available online 16 October 2014
The synthesis of RITA and a variety of five-membered heterocyclic triads by the cyclocondensation of 1,4-
bis(5-substituted-2-thienyl or 2-furyl)-1,3-butadiynes with water or Na2Sꢀ9H2O in the presence of KOH
in DMSO is described. The study on the antiproliferative activities against K562, MCF-7, A549, and
HCT116 tumor cells has revealed that some of the heterocyclic triads show higher antiproliferative activ-
ities than RITA, depending on the structures of substituents, the property of heteroatoms as well as their
numbers.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Antiproliferative activity
1,3-Butadiynes
Cyclocondensation
Heterocyclic triads
RITA
The tumor suppressor gene P53 plays a central transcription role
in the regulation of DNA repair, cell cycle, apoptosis, and senes-
cence.1 MDM2 (murine double minute 2, also known as HDM2 in
human) is a key negative regulator of P53 to inhibit the transcrip-
tional activity.2 RITA (Scheme 1), a five-membered heterocyclic
triad: 2,5-bis(5-hydroxymethyl-2-thienyl)furan has been demon-
strated to show high antitumor activity via its binding to p53 to
block the interaction between p53 and HDM-2 (human double min-
ute 2), so as to activate p53 function in antitumors.3 Therefore, the
investigation of antitumor activity of RITA and its analogs as well as
their synthetic methods have become one of the interesting and
important research topics in the filed of chemistry and biology.4
In continuation of our interest on the development of the syn-
thetic routes with high-atom efficiency to construct five-membered
heterocyclic compounds using 1,3-butadiyne derivatives as starting
materials,5 and evaluating and screening the antitumor activity of
RITA and its analogs,4d in this Letter we would like to report not
only an efficient and practical procedure for the synthesis of RITA
and its analogs via the cyclocondensation reaction of 1,4-bis(5-
substituted-2-thienyl or 2-furyl)-1,3-butadiynes with water or
Na2Sꢀ9H2O in the presence of KOH in DMSO,6 but also their antitumor
activities against K562, MCF-7, A549, and HCT116 tumor cells.
Very recently, a general approach to arylated furans, pyrroles,
and thiophenes via the cyclocondensation of 1,4-diaryl-1,3-but-
adiynes with water, primary amines, and Na2Sꢀ9H2O in the pres-
ence of superbase (KOH in DMSO) was reported by our group.7 In
order to develop an efficient procedure for the formation of RITA
and its analogs via the cyclocondensation of 1,3-butadiynes bearing
heteroaryl substituents, we re-optimized the reaction conditions,
and found that in DMSO solvent, KOH could efficiently promote
the formation of RITA and its analogs as concluded in Table 1.8
Since the synthesis of 2da and 2ea direct from the cycloconden-
sation of the corresponding 1,3-butadiynes was not successful
under the present base conditions, they were then obtained by
I2-catalyzed deprotection of 2d and 2e in acetone (Scheme 2).
For comparison of antitumor activities of RITA’s analogs, several
other five-membered triheterocyclic compounds having the thienyl
group as the central ring were also prepared via the cyclocondensa-
tion reactions of the corresponding 1,4-bis(5-substituted-2-
thienyl or 2-furyl)-1,3-butadiynes with Na2Sꢀ9H2O. As shown in
Table 2, under the re-optimizing reaction conditions, the desired
S
X
R'
OH
O
Y
S
X
HO
R
RITA's analogs
X, Y: S or O
RITA
Scheme 1. RITA and its analogs.
⇑
Corresponding authors.
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.