Accepted Manuscript Synthesis and anticancer activity of novel quinoline-docetaxel analogues Ming Chen, Hui Chen, Jiangwei Ma, Xueying Liu, Shengyong Zhang PII: DOI: Reference:
S0960-894X(14)00448-X http://dx.doi.org/10.1016/j.bmcl.2014.04.091 BMCL 21584
To appear in:
Bioorganic & Medicinal Chemistry Letters
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
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Synthesis and anticancer activity of novel quinoline-docetaxel analogues Ming Chen a, Hui Chen a, Jiangwei Ma a, Xueying Liu a,*, Shengyong Zhang a,* a
Department 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: [email protected] (SY Zhang), [email protected] (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, CH3 OH, rt. d: quinoline acids, DCC, DMAP, CH2 Cl 2, 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, CH2Cl 2, rt. d: TsOH, CH3 OH, 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) Hela
A549
A2780
A2780-MDRb
MCF-7
MCF-7-MDRc
30.7
38.2
35
33.2
26.4
9.3
6b
41
41.2
44.8
34.9
17.8
36.3
6c
34.6
38.8
23.1
30.2
30.7
8.8
6d
33.2
28.1
49.3
12.2
16.8
17.8
6e
39
33.4
32.9
43.9
12.8
25.6
6f
19.3
16
41.6
32.5
39.8
28.4
6g
32.6
38.5
45.3
29.7
42
21.2
analogues 6a
a
13a
19.9
27.1
45.7
29.8
37.3
24.1
13b
36.3
41
34.2
29
43.3
37.8
13c
18.5
28.4
16.3
35.1
29.8
35.7
13d
41.2
35.3
16.9
18.6
26.6
45.9
13e
34.9
32.3
30.1
21.3
47.6
18.2
13f
11.8
42.5
28.2
49.8
31.4
18.3
13g
25.3
28.8
39.8
34.5
30.2
38.9
docetaxel
50.1
35.2
33
126
38.53
180
IC50 :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. c
MCF-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 1
HNMR, 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 & Technology Major Project (Grants 2010ZXJ0900X-007). References and notes 1.
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6
S0960-894X(14)00448-X http://dx.doi.org/10.1016/j.bmcl.2014.04.091 BMCL 21584
To appear in:
Bioorganic & Medicinal Chemistry Letters
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
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Synthesis and anticancer activity of novel quinoline-docetaxel analogues Ming Chen a, Hui Chen a, Jiangwei Ma a, Xueying Liu a,*, Shengyong Zhang a,* a
Department 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: [email protected] (SY Zhang), [email protected] (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, CH3 OH, rt. d: quinoline acids, DCC, DMAP, CH2 Cl 2, 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, CH2Cl 2, rt. d: TsOH, CH3 OH, 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) Hela
A549
A2780
A2780-MDRb
MCF-7
MCF-7-MDRc
30.7
38.2
35
33.2
26.4
9.3
6b
41
41.2
44.8
34.9
17.8
36.3
6c
34.6
38.8
23.1
30.2
30.7
8.8
6d
33.2
28.1
49.3
12.2
16.8
17.8
6e
39
33.4
32.9
43.9
12.8
25.6
6f
19.3
16
41.6
32.5
39.8
28.4
6g
32.6
38.5
45.3
29.7
42
21.2
analogues 6a
a
13a
19.9
27.1
45.7
29.8
37.3
24.1
13b
36.3
41
34.2
29
43.3
37.8
13c
18.5
28.4
16.3
35.1
29.8
35.7
13d
41.2
35.3
16.9
18.6
26.6
45.9
13e
34.9
32.3
30.1
21.3
47.6
18.2
13f
11.8
42.5
28.2
49.8
31.4
18.3
13g
25.3
28.8
39.8
34.5
30.2
38.9
docetaxel
50.1
35.2
33
126
38.53
180
IC50 :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. c
MCF-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 1
HNMR, 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 & Technology Major Project (Grants 2010ZXJ0900X-007). References and notes 1.
Rowinsky, E. K. Ann Rev Med. 1997, 48, 353.
2.
FDA. 2004. http://www.fda.gov/cder/approval/t.htm
3.
Lee, J. W.; Lu, J. Y.; Low, P. S.; Fuchs, P. L. Bioorg. Med. Chem. 2002, 10, 2397.
4.
Ohtsu, H.; Nakanishi, Y.; Bastow, K. F.; Lee, F. Y.; Lee, K. H. Bioorg. Med. Chem. 2003, 11, 1851.
5.
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