Bioorganic & Medicinal Chemistry Letters
Discovery of 1-arylpyrrolidone derivatives as potent p53–MDM2
inhibitors based on molecule fusing strategy
Jin Li a, , Yuelin Wu a,b, , Zizhao Guo a, Chunlin Zhuang a, Jianzhong Yao a, Guoqiang Dong a,
Zhiliang Yu a, Xiao Min a, Shengzheng Wang a, Yang Liu a, Shanchao Wu a, Shiping Zhu a,
a,
a,
Chunquan Sheng a, , Zhenyuan Miao , Wannian Zhang
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a School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People’s Republic of China
b School of Chemical Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei, Nanjing 210094, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 December 2013
Revised 2 April 2014
Accepted 17 April 2014
Available online 26 April 2014
Introducing an aryl moiety to our previous pyrrolidone scaffold by molecule fusing strategy afforded two
sets of isopropylether–pyrrolidone and
a-phenylethylamine–pyrrolidone derivatives. Two novel com-
pounds 8b and 8g of the latter serial showed potent p53–MDM2 inhibitory activities with Ki values of
90 nM which were three-time higher than that of the parent compound. We also confirmed compound
8b can activate p53 proteins in lung cancer A549 cells. The results offered us valuable information for
further lead optimization.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Arylpyrrolidone
p53–MDM2 inhibitor
Molecule fusing
Synthesis
The human tumor suppressor p53, as one of the most potent
transcriptional activator proteins, plays a protective role in normal
tissues. The p53 is also short-lived in normal cells under physiolog-
ical conditions and is mainly regulated by the murine double min-
ute 2 protein (MDM2).1–3 However, in approximately 50% of all
human cancers p53 has been found to be inactivated. Overexpres-
sion of MDM2 was discovered as the main reason for p53 function
impairment.4 Recently, restoration of p53 activity by inhibiting the
p53–MDM2 interaction has been demonstrated as a successful
strategy for anticancer drug development.5,6 To date, an increasing
number of small molecule inhibitors have been generated and
six excellent compounds RG7112, RO5503781, MK-8242,
SAR405838, CGN097 and DS-3032b have entered clinical trials.7–14
In 2012, Zhuang et al. discovered a novel lead structure with
pyrrolidone scaffolds by virtual screening method based on co-
crystal structures of p53–MDM2 interaction.15,16 Further hit opti-
mization and SAR led to the discovery of two compounds Z41
(Ki = 260.0 nM) and Z60a (Ki = 150.0 nM) which showed potent
antitumor efficacy both in vitro and vivo (Fig. 1). These optimized
compounds Z41 and Z60a showed the similar interaction manner
of MDM2 protein with benzoyl group and 4-bromophenyl group
located in the Trp23 pocket and Leu26 pockets. However, imidaz-
ole group could not work well in concert with Phe19 pocket.
According to binding mode of RG7112 which was the first genera-
tion small molecule inhibitor in clinical trial, two 4-chlorophenyl
groups respectively entered Trp23 pocket and Leu26 pocket, while
the 2-ethoxy-4-butylphenyl group projected into the Phe19 pocket
(PDB code 4IPF).7 In this paper, we present two novel classes of
small-molecule inhibitors of p53–MDM2 protein–protein interac-
tion based on pyrrolidone scaffold by a molecule fusing strategy
(Fig. 2). Fourteen compounds with substituted phenyl groups on
N1 position had synthesized and insight into the SAR of pyrroli-
dones was also revealed for further research.
The general synthetic route of target compounds is outlined in
Scheme 1. Benzylamines 3a–3d were prepared by the etherifica-
tion of 2-fluoro-4-(trifluoro-methyl)benzonitrile 1 and four ali-
phatic alcohols, and subsequently reduction by LiAlH4 in dried
ether in good yield. With these benzylamines in hand, compounds
6a–6g were readily obtained by an efficient three-component
coupling reaction.15 Followed Mitsunobu reaction and Leuckart–
Wallach reaction afforded isopropylether–pyrrolidone derivatives
7a–7g and
a-phenylethylamine–pyrrolidone derivatives 8a–8g,
respectively.
The binding constants Ki of all target compounds were mea-
sured by fluorescence polarization (FP) binding assay method. Nut-
lin-3 was used as the reference drug who was one of the most
active small-molecule p53–MDM2 inhibitors. The results were
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Corresponding authors. Tel./fax: +86 21 81871241.
Both authors contributed equally to this work.
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