Synthesis and anticancer activity of novel quinoline-docetaxel analogues

Article abstract of DOI:10.1016/j.bmcl.2014.04.091

A series of novel quinoline-docetaxel analogues (6a-6g, 13a-13g) were designed and synthesized by introducing bioactive quinoline scaffold to C2′-OH of docetaxel. The anticancer activities of these novel analogues were investigated against different human cancer cell lines including Hela, A549, A2780, MCF-7 and two resistant strains A2780-MDR and MCF-7-MDR. The data showed these analogues possessed similar to better cytotoxicity than docetaxel. Compound 6c was found to be the most potent one, and its IC₅₀ value against MCF-7-MDR was 8.8 nM (IC₅₀ of docetaxel was 180 nM). The work indicated that the introduction of quinolyl group in docetaxel could enhance cytotoxicity and reduce drug-resistance.

Full text of DOI:10.1016/j.bmcl.2014.04.091

Accepted Manuscript
Synthesis and anticancer activity of novel quinoline-docetaxel analogues
Ming Chen, Hui Chen, Jiangwei Ma, Xueying Liu, Shengyong Zhang
PII:
S0960-894X(14)00448-X
http://dx.doi.org/10.1016/j.bmcl.2014.04.091
BMCL 21584
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 February 2014
20 April 2014
24 April 2014
Please cite this article as: Chen, M., Chen, H., Ma, J., Liu, X., Zhang, S., Synthesis and anticancer activity of novel
quinoline-docetaxel analogues, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/
j.bmcl.2014.04.091
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Synthesis and anticancer activity of novel quinoline-docetaxel
analogues
Ming Chen a, Hui Chen a, Jiangwei Ma a, Xueying Liu a,*, Shengyong Zhang a,*
aDepartment of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University, 169 Changle Road, Xian 710032,
People’s Republic of China
*Corresponding author.Tel.: +86 29 84776945
E-mail address: syzhang@fmmu.edu.cn (SY Zhang), wqwlxy@fmmu.edu.cn (XY Liu)
ABSTRACT
A series of novel quinoline-docetaxel analogues (6a-6g, 13a-13g) were designed and synthesized by introducing
bioactive quinoline scaffold to C2’-OH of docetaxel. The anticancer activities of these novel analogues were investigated
against different human cancer cell lines including Hela, A549, A2780, MCF-7 and two resistant strains A2780-MDR
and MCF-7-MDR. The data showed these analogues possessed similar to better cytotoxicity than docetaxel. Compound
6c was found to be the most potent one, and its IC50 value against MCF-7-MDR was 8.8 nM ( IC50 of docetaxel was 180
nM). The work indicated that the introduction of quinolyl group in docetaxel could enhance cytotoxicity and reduce
drug-resistance.
Keywords: Docetaxel, Quinoline, Anticancer, Cytotoxicity, Drug-resistance
As two of the most important chemotherapeutic drugs, taxol and its semisynthetic derivative docetaxel
(Fig. 1) are widely used for the treatment of various cancers, including advanced ovarian cancer, metastatic
breast cancer, melanoma, non-small cell lung cancer and Karposi's sarcoma. Recently, these drugs also have
been used for the treatment of neck, prostate and cervical cancers.1,2 Although taxol and docetaxel exhibit
excellent bioactivity, chemotherapy with these drugs encounters intractable obstacle such as multi-drug
resistance (MDR). Therefore, it is essential to seek novel taxoid analogues possessing more potent anticancer
activity and less drug-resistance. Up to now, there have been a number of new taxoid analogues launched by
different groups, some of which exhibited potential anticancer activity.3-8 According to the general
structure-activity relationship (SAR) of taxol, C2’-OH at C-13 side chain is important for cytotoxicity, which
could decrease obviously even disappear absolutely when C2’-OH was removed or replaced with F atom.9
However, esterification at C2’-OH couldn’t result in loss of cytotoxicity because endogenous esterases could
hydrolyze 2’-OH esters to release taxol readily in vivo.10,11 Ojima et al12 conjugated natural fatty acids (such
as docosahexaenoic acid, linolenic acid, and linoleic acid) to the C2’-OH of taxol to give the novel
analogues, which exhibited strong activity against drug-resistant colon cancer and drug-sensitive ovarian
cancer in vivo. Recently, Damian Plazuk et al13 prepared a series of ferrocenylated taxanes by introducing
ferrocenic acids into the C2’-OH. The prepared compounds showed high activities against multi-drug
resistant colon adenocarcinoma cell lines.
Quinoline scaffold has received considerable attention because of their pivotal role in various biological
processes, numerous quinoline derivatives14-24 have been reported to have wide biological activities
including the anticancer activity depending on various mechanisms like tubulin inhibition,25 free radical
regulation and so on.26-30 Meanwhile, some natural, semisynthetic and synthetic bioactive molecules based
on a quinoline scaffold have been reported to possess MDR reversal activity when combined with anticancer
1

drug.31-39 For example, the molecules containing quinoline scaffold such as chloroquine, quinine, quinidine
and primaquine improved the cytotoxicity of doxorubicin in multi-drug resistant cancer cell lines at nontoxic
concentration.33
Fig. 1 The structure of taxol, docetaxel and compound 7
We envisioned that a combination of docetaxel with a quinoline moiety into a single molecule might
improve the anticancer activity of docetaxel. Therefore, we designed and synthesized a series of novel
quinoline-docetaxel analogues by esterification of C2’-OH of docetaxel with quinoline acids , and evaluated
their cytotoxicities against human cancer cell lines including multi-drug resistant cancer cell lines to
docetaxel.
The synthesis of 6a-6g were conducted in five steps using 1 (10-DAB) as starting material (Scheme 1).
The selective protection of 1 employing 2,2,2-trichloroethyl chloroformate (TrocCl) as protective group in
pyridine gave 7,10-diTroc-10-DAB 2 in a good yield. The coupling reaction of 2 with commercially
available 7 (Fig. 1) in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine
(DMAP) gave compound 3 in an excellent yield. Next, the protective group of 3 was removed with TsOH in
methanol to give nearly quantitative compound 4. Then, the coupling reaction of compound 4 with different
quinoline acids in the presence of DCC and DMAP gave corresponding intermediates 5a-5g, which were
then removed protective groups with Zn/AcOH in AcOEt to give target products 6a-6g in a satisfied yield.
Scheme. 1 The synthetic route of 6a-6g. reagents and conditions: a: TrocCl, pyridine, 80℃. b: 7, DCC, DMAP, CH2Cl2, rt. c:
TsOH, CH3OH, rt. d: quinoline acids, DCC, DMAP, CH2Cl2, rt. e: Zn, AcOH, AcOEt, rt.
2

Scheme. 2 The synthetic route of 13a-13g. reagents and conditions: a: (Ac)2O, ZnCl2, THF, rt. b: TrocCl, pyridine, 80℃. c: 7,
DCC, DMAP, CH2Cl2, rt. d: TsOH, CH3OH, rt. e: quinoline acids, DCC, DMAP, CH2Cl2, rt. f: Zn, AcOH, AcOEt, rt.
Meanwhile, to investigate the influence of C10-OH site on the cytotoxicities of novel
quinoline-docetaxel analogues, the corresponding C10-acetyl compounds 13a-13g were synthesized with
similar synthetic route outlined in Scheme 2. Compound 9 was obtained by acetylation at C10-OH with
(Ac)2O in the presence of ZnCl2,40 followed by selective protection of C7-OH with TrocCl.
The cytotoxicities of these novel analogues (6a-6g, 13a-13g) against four normal human cancer cell
lines, Hela, A549, A2780, MCF-7, and two drug-resistant cancer cell lines, A2780-MDR and MCF-7-MDR
were evaluated by MTT assays with docetaxel as positive control after exposure of cells to the tested
compounds for 72 h. As shown in Table 1, these novel analogues exhibited similar to better cytotoxicities
than docetaxel. For example, 6b and 6e were approximately 2-3 times potent than docetaxel against MCF-7.
6f was approximately 2 times potent against A549. Meanwhile, 13c and 13d also possessed 2 times stronger
inhibition against A2780. Interestingly, compound 13f showed significant inhibitiory preference to Hela, 5
times more potent than docetaxel.
Importantly, all of these novel analogues exhibited obvious inhibition against two drug-resistant cancer
cell lines. Compounds 6d, 13d and 6a, 6c were found to possess the most potent inhibitory effects among
these analogues against A2780-MDR and MCF-7-MDR, respectively. The inhibition of compound 6c
against MCF-7-MDR was 20 times more potent than docetaxel. It seemed that different substitution
positions of carboxyl group at quinoline scaffold played an important role in the activity.
3

Table. 1 The anticancer activities of analogues against human cancer cell lines
IC50a (nM)
analogues
Hela
30.7
41
A549
38.2
41.2
38.8
28.1
33.4
16
A2780
35
A2780-MDRb
33.2
MCF-7
26.4
17.8
30.7
16.8
12.8
39.8
42
MCF-7-MDRc
9.3
6a
6b
44.8
23.1
49.3
32.9
41.6
45.3
45.7
34.2
16.3
16.9
30.1
28.2
39.8
33
34.9
36.3
8.8
34.6
33.2
39
30.2
6c
12.2
17.8
25.6
28.4
21.2
24.1
37.8
35.7
45.9
18.2
18.3
38.9
180
6d
43.9
6e
19.3
32.6
19.9
36.3
18.5
41.2
34.9
11.8
25.3
50.1
32.5
6f
38.5
27.1
41
29.7
6g
29.8
37.3
43.3
29.8
26.6
47.6
31.4
30.2
38.53
13a
13b
13c
13d
13e
13f
29
28.4
35.3
32.3
42.5
28.8
35.2
35.1
18.6
21.3
49.8
34.5
13g
docetaxel
126
aIC50:concentration which produces 50% inhibition of proliferation after 72 h of incubation. HeLa: cervical cancer, A549:
non-small cell lung cancer, A2780: ovarian cancer, MCF-7: breast cancer. bA2780-MDR: multidrug-resistant ovarian cancer.
cMCF-7-MDR: multidrug-resistant breast cancer.
In summary, a series of novel quinoline-docetaxel analogues were successfully synthesized by
esterification of C2’-OH of docetaxel with quinoline acids, and their structures were characterized by
1HNMR, 13CNMR and HRMS. The cytotoxicities of these novel analogues were evaluated against different
human cancer cell lines containing resistant ones. The data indicated most analogues exhibited more potent
inhibitory activities than docetaxel, especially against resistant cancer cell lines. The results showed that
synergism indeed existed in quinoline-docetaxel molecule.
Acknowledgments
We gratefully acknowledge financial support of this work by the National Natural Science Foundation
of China (21172262) and the Chinese National Science
2010ZXJ0900X-007).
& Technology Major Project (Grants
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