Design, synthesis and biological evaluation of quinoline-indole derivatives as anti-tubulin agents targeting the colchicine binding site

Article abstract of DOI:10.1016/j.ejmech.2018.11.070

A series of novel isocombretastatin A-4 (isoCA-4) analogs were designed and synthesized by replacing 3,4,5-trimethoylphenyl and isovanillin of isoCA-4 with quinoline and indole moieties, respectively. The structure activity relationships (SARs) of these synthesized quinoline-indole derivatives have been intensively investigated. Two compounds 27c and 34b exhibited the most potent activities against five cancer cell lines with IC₅₀ values ranging from 2 to 11 nM, which were comparable to those of Combretastatin A-4 (CA-4, 1). Further mechanism investigations revealed that 34b effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further cellular mechanism studies elucidated that 34b disrupted cell microtubule networks, arrested the cell cycle at G2/M phase, induced apoptosis and depolarized mitochondria of K562 cells. Moreover, 34b displayed potent anti-vascular activity in both wound healing and tube formation assays. Importantly, 27c and 34b significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, suggesting that 27c and 34b deserve further research as potent antitumor agents for cancer therapy.

Full text of DOI:10.1016/j.ejmech.2018.11.070

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Accepted Manuscript
Design, synthesis and biological evaluation of quinoline-indole derivatives as anti-
tubulin agents targeting the colchicine binding site
Wenlong Li, Wen Shuai, Honghao Sun, Feijie Xu, Yi Bi, Jinyi Xu, Cong Ma, Hequan
Yao, Zheying Zhu, Shengtao Xu
PII:
S0223-5234(18)31029-8
DOI:
https://doi.org/10.1016/j.ejmech.2018.11.070
EJMECH 10928
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 11 October 2018
Revised Date: 20 November 2018
Accepted Date: 28 November 2018
Please cite this article as: W. Li, W. Shuai, H. Sun, F. Xu, Y. Bi, J. Xu, C. Ma, H. Yao, Z. Zhu, S. Xu,
Design, synthesis and biological evaluation of quinoline-indole derivatives as anti-tubulin agents
targeting the colchicine binding site, European Journal of Medicinal Chemistry (2018), doi: https://
doi.org/10.1016/j.ejmech.2018.11.070.
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Graphic Abstract

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Design, Synthesis and Biological Evaluation of Quinoline-Indole
Derivatives as Anti-tubulin Agents Targeting the Colchicine
Binding Site
Wenlong Lia, Wen Shuaia, Honghao Suna, Feijie Xua, Yi Bib, Jinyi Xua,*, Cong Mac,
Hequan Yaoa, Zheying Zhud, Shengtao Xua,*
aState Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China
Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China
bSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai
University, Yantai, 264005. P. R. China
cState Key Laboratory of Chemical Biology and Drug Discovery, and Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kon
g
dDivision of Molecular Therapeutics & Formulation, School of Pharmacy, The University of
Nottingham, University Park Campus, Nottingham NG7 2RD, U. K.
*Corresponding Author:
E-mail addresses: jinyixu@china.com (J. Xu); cpuxst@163.com (S. Xu).
Abstract
A series of novel isocombretastatin A-4 (isoCA-4) analogs were designed and
synthesized by replacing 3,4,5-trimethoylphenyl and isovanillin of isoCA-4 with
quinoline and indole moieties, respectively. The structure activity relationships (SARs)
of these synthesized quinoline-indole derivatives have been intensively investigated.
Two compounds 27c and 34b exhibited the most potent activities against five cancer
cell lines with IC50 values ranging from 2 to 11 nM, which were comparable to those
of Combretastatin A-4 (CA-4, 1). Further mechanism investigations revealed that 34b
effectively inhibited the microtubule polymerization by binding to the colchicine site
of tubulin. Further cellular mechanism studies elucidated that 34b disrupted cell
microtubule networks, arrested the cell cycle at G2/M phase, induced apoptosis and
depolarized mitochondria of K562 cells. Moreover, 34b displayed potent anti-vascular
activity in both wound healing and tube formation assays. Importantly, 27c and 34b
significantly inhibited tumor growth in H22 xenograft models without apparent
toxicity, suggesting that 27c and 34b deserve further research as potent antitumor

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agents for cancer therapy.
Key words: quinoline; indole; microtubule; tubulin inhibitor; colchicine binding
site; antitumor
1. Introduction
CA-4 (1) (Figure 1) was a natural cis-stilbene derivative which was isolated from
the bark of the African willow tree Combretum caffrum [1]. It has been identified as a
typical tubulin polymerization inhibitor that target the colchicine binding site [2].
CA-4 displayed potent cytotoxicity against a wide range of cancer cell lines including
multidrug resistant (MDR) cells at nanomolar levels [3]. Moreover, CA-4P, the
phosphate prodrug of CA-4, induced vascular shutdown within tumors at doses less
than one-tenth of the maximum tolerated dose, demonstrating the clinical potential of
CA-4P as vascular disrupting agent [4]. CA-4P had been evaluated in clinical trials,
however, it had been discontinued due to the lack of a meaningful improvement in
progression-free survival (PFS) and unfavorable partial response data [5]. The
Z-isomer of CA-4 is prone to isomerization to produce the E-isomer during storage,
administration and metabolization, that is significantly less potent at inhibiting tubulin
polymerization and cancer cell growth [6,7]. The isomerization could be avoided by
the discoveries of Phenstatin (3) and isoCA-4 (4) [8,9]. IsoCA-4 held the similar
properties as CA-4 but was more metabolically stable than CA-4 [10]. Other similar
1,1-diarylethylene derivatives such as compounds 5-9, which have more restricted
conformations than isoCA-4, were also discovered [11-14]. Another interesting
isoCA-4 analog 10 was synthesized by replacing two hydrogens of the olefinic linker
of isoCA-4 with two fluorine atoms, which was about 3-fold more potent than
isoCA-4 against HCT-116 cells [15].
Fig. 1. CA-4, isoCA-4 and isoCA-4 analogs.