Bioorganic & Medicinal Chemistry Letters 24 (2014) 973–975
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel C6-amino substituted 4-azasteroidal purine nucleoside analogues Li-Hua Huang a,b,c, Hong-De Xu b,c, Zhen-Yu Yao a, Yan-Guang Wang b,c, Hong-Min Liu b,c,⇑ a
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China c New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, China b
a r t i c l e
i n f o
Article history: Received 24 July 2013 Revised 2 December 2013 Accepted 13 December 2013 Available online 19 December 2013 Keywords: 4-Azasteroid Purine Nucleoside analogues Amines Anticancer activity
a b s t r a c t Novel C6-amino substituted purine nucleoside analogues (2–12) bearing a modified pyranose-like D ring of the 4-azasteroid moiety were efficiently synthesized through nucleophilic substitution at C6 position of the steroidal nucleoside precursors (1a, b) with versatile amines. All the synthesized new compounds were evaluated for their anticancer activity in vitro against Hela, PC-3 and MCF-7 cell lines. Among them, compounds 4b, 7b and 9b exhibited significant cytotoxicity with the IC50 values of 2.99 lM (PC-3), 2.84 lM, (PC-3) and 2.69 lM (Hela), respectively. Ó 2014 Published by Elsevier Ltd.
Nucleoside analogues including a variety of purine and pyrimidine nucleoside derivatives have played an important role in the development of antiviral and antitumor drugs.1–3 These groups of compounds behave as antimetabolites, compete with physiological nucleosides during DNA or RNA synthesis, and interact with key cell enzymes of the nucleotide metabolism to induce cytotoxicity.4,5 Currently, cytotoxic nucleoside analogues such as cladribine, fludarabine and gemcitabine are used as the first line of chemotherapeutic agents for the treatment of hematological malignancies and certain solid tumors.4–6 Due to the pharmacological significance, nucleoside analogues have attracted extensive investigation for small molecule drug discovery through decades, and modifications have been made to both the heterocyclic base and the sugar moiety.1,7 In 1977, van Lier et al. reported a novel class of compounds prepared through coupling steroids with naturally occurring purines and pyrimidines by way of a C–N linkage.8 These newly-synthesized steroid–nucleosides exhibited great antitumor activity and were less likely to have adverse side effects. Subsequently, several other classes of steroidal nucleosides analogues were synthesized which included nucleobases and nucleoside analogues linked through a spacer group9 or linked directly to the steroid skeleton.10 Recently, we have described a novel series of steroid– nucleoside analogues, in which the modified sugar-like D ring of
the 4-azasteroid moiety was directly attached to the bases.11 Preliminary biological evaluation results suggested that compounds 1a, b (Fig. 1) showed great anticancer activity. On the other hand, C6-aminopurines derivatives possess wide range of biological properties and have been shown to have antitumor activity as inhibitors of various protein kinases.12,13 Therefore, it is of great interest to explore new purine analogues with modifications by introduction of an amino group at C6 position. Herein, we present the synthesis of C6-amino substituted steroid–nucleosides analogues by displacement of the C6 chloro on the purine ring of compounds 1a, b with versatile amines and their anticancer activity in vitro. The protocol for the synthesis of C6-amino substituted 4-azasteroidal purine nucleoside analogues was outlined in Scheme 1, which involved the nucleophilic substitution of 6-chloro-purine with appropriate amines. The reaction was carried out in the presence of Et3N as an auxiliary base in refluxing MeOH for 5-20 min to give the desired purine nucleoside analogues 2–12 in excellent yields. The 2-chloro group on purine ring was less reactive and N O
N
E-mail address: [email protected] (H.-M. Liu). 0960-894X/$ - see front matter Ó 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.bmcl.2013.12.056
Cl N R1
O
⇑ Corresponding author. Tel./fax: +86 371 67781739.
N
N H
1a: R1 = H; 1b: R1 = Cl
Figure 1. Novel class of steroidal purine nucleosides analogues.
974
L.-H. Huang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 973–975
N O
N O
N
Cl
N
O
N R1
N H
Amines
N N
Et3N, MeOH, ref lux, 5-20 min
R2 N R1
O
N H
1
2-12
Scheme 1. Synthesis of steroidal C6-aminopurine nucleoside analogues 2-12.
its substitution usually required higher temperature and extended reaction time.14 As a result, products with the 2-chloro group substituted with amines were not observed. All the newly-synthesized compounds were characterized by 1H, 13C NMR and HRMS spectra. The newly-synthesized C6-aminopurin derivatives 2–12 were evaluated for their anticancer activity in vitro against Hela, PC-3 and MCF-7 cell lines using the MTT assay and the results were presented in Table 1. As shown in Table 1, it was evident from the data that change of substituents on the purine ring had a significant influence on the cytotoxicity. Replacement of the 6-chloro group of the purine ring with amines did not enhance the inhibitory activity. On the contrary, for most C6-aminopurines derivatives, introduction of an amino group resulted in a marked decrease in potency compared to compounds 1a, b. For example, replacement of the 6-chloro atom with di(hydroxyethyl)amino group (compounds 8a, b) led to loss of potency against all tested cell lines. Among the screened C6-aminopurines derivatives, three of them (compounds 4b, 7b and 9b) showed promising anticancer activity on certain cancer cell lines in vitro. Compound 4b, which contained the 2-chloro group and 6-hydrazino group on the purine ring, displayed remarkable inhibition of PC-3 cells, with the IC50 values of 2.99 lM. However, this compound exhibited no Table 1 The in vitro anticancer activity of 4-azasteroidal purine nucleoside analogues 1–12 Compound
R1
R2
IC50 (lM)
Cl
Hela
PC-3
MCF-7
17.67 7.57
3.25 11.19
20.92 34.21
inhibitory activity against Hela and MCF-7 cell lines, indicating the selective inhibition of PC-3 cells. Similar activity was found for compound 7b, which also showed potent inhibitory activity against PC-3 cells (IC50 = 2.84 lM) and no inhibitory activity against Hela and MCF-7 cell lines. For C6-benzylamino substituted purine nucleoside analogues 9–12, substituent on the phenyl ring did not show significant influence on the cytotoxic activity. Compound 9b with the 2-chloro-6-benzylaminopurine ring demonstrated the best anticancer activity against Hela cell lines with the IC50 values of 2.69 lM, which also showed good inhibitory activity against PC-3 and MCF-7 cell lines (IC50 = 17.86 lM, 12.75 lM, respectively). However, compound 9a bearing the same substituent at C6-position exhibited no inhibitory activity on Hela and MCF-7 cell lines, suggesting that substituent at the C2-position of purine ring also affect the activity. It was noteworthy that the three compounds 4b, 7b and 9b displaying potent anticancer activity contained the same 2-chloro substituent. Generally, the 2-chloro substituted purine analogues showed higher activity compared to C2-unsubstituted compounds (R1 = H). In summary, novel C6-amino substituted 4-azasteroidal purine nucleoside analogues 2–12 were efficiently prepared by nucleophilic substitution of the C6-chloro of 1a, b with amines in excellent yields. For most newly-synthesized compounds, introduction of an amino substituent at C6 position resulted in a loss of potency compared to compounds 1a, b. Among the screened compounds 2–12, compounds 4b, 7b and 9b exhibited significant anticancer activity against certain cancer cell lines. The research on their possible mechanism of inhibiting proliferation of cancer cell lines is underway, which will be reported in due course.
1a 1b
H Cl
2a 2b
H Cl
70.50 61.31
>100 >100
57.71 >100
Acknowledgment
N
3a 3b
H Cl
N
33.81 31.10
>100 58.06
>100 16.42
We are grateful to the National Natural Sciences Foundation of China (No.81172937) for financial support.
4a 4b
H Cl
>100 >100
87.16 2.99
34.59 >100
5a 5b
H Cl
NH2
66.15 22.65
>100 63.40
>100 70.28
6a 6b
H Cl
OH
>100 >100
49.22 >100
>100 >100
7a 7b
H Cl
>100 >100
15.78 2.84
>100 >100
8a 8b
H Cl
>100 >100
>100 >100
>100 >100
9a 9b
H Cl
>100 2.69
20.60 17.86
>100 12.75
10a 10b
H Cl
28.16 67.18
44.25 26.55
32.71 12.93
11a 11b
H Cl
OCH 3
38.74 10.14
>100 >100
60.32 >100
12a 12b
H Cl
F
>100 59.14
91.55 >100
34.77 13.50
NHNH 2 N H N H
OH N H N(C2H 4OH) 2
NH
NH NH NH
Hela: human cervical carcinoma; PC-3: human prostatic carcinoma, MCF-7: human breast carcinoma.
Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.2013. 12.056. References and notes 1. (a) Haines, D. R.; Tseng, C. K.; Marquez, V. E. J. Med. Chem. 1987, 30, 943; (b) Lin, T. S.; Luo, M. Z.; Liu, M. C.; Clarke-Katzenburg, R. H.; Cheng, Y. C.; Prusoff, W. H.; Mancini, W. R.; Birnbaum, G. I.; Gabe, E. J.; Giziewicz, J. J. Med. Chem. 1991, 34, 2607. 2. (a) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745; (b) Sagi, G.; Otvos, L.; Ikeda, S.; Andrei, G.; Snoeck, R.; Clercq, E. D. J. Med. Chem. 1994, 37, 1307. 3. (a) Bello, A. M.; Konforte, D.; Poduch, E.; Furlonger, C.; Wei, L.; Liu, Y.; Lewis, M.; Pai, E. F.; Paige, C. J.; Kotra, L. P. J. Med. Chem. 2009, 52, 1648; (b) Tuncbilek, M.; Guven, E. B.; Onder, T.; Atalay, R. C. J. Med. Chem. 2012, 55, 3058. 4. (a) Sampath, D.; Rao, V. A.; Plunkett, W. Oncogene 2003, 22, 9063; (b) Robak, T.; Lech-Maranda, E.; Korycka, A.; Robak, E. Curr. Med. Chem. 2006, 13, 3165; (c) Parker, W. B. Chem. Rev. 2009, 109, 2880. 5. (a) Galmarini, C. M.; Mackey, J. R.; Dumontet, C. Lancet Oncol. 2002, 3, 415; (b) Robak, T.; Korycka, A.; Kasznicki, M.; Wrzesien´-Kus, A.; Smolewski, P. Curr. Cancer Drug Targets 2005, 5, 421; (c) Robak, T.; Korycka, A.; Lech-Maranda, E.; Robak, P. Molecules 2009, 14, 1183.
L.-H. Huang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 973–975 6. Storniolo, A. M.; Enas, N. H.; Brown, C. A.; Voi, M.; Rothenberg, M. L.; Schilsky, R. Cancer 1999, 85, 1261. 7. (a) Choi, W. J.; Lee, H. W.; Kim, H. O.; Chinn, M.; Gao, Z. G.; Patel, A.; Jacobson, K. A.; Moon, H. M.; Jung, Y. H.; Jeong, L. S. Bioorg. Med. Chem. 2009, 17, 8003; (b) Gupta, P. K.; Daunert, S.; Nassiri, M. R.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1989, 32, 402. 8. van Lier, J. E.; Kan, G.; Autenrieth, D.; Nigam, V. N. Nature 1977, 267, 522. 9. (a) van Lier, J. E.; Kan, G.; Autenrieth, D.; Hulsinga, E. Cancer Treat. Rep. 1978, 62, 1251; (b) Ali, H.; Ahmed, N.; Tessier, G.; van Lier, J. E. Bioorg. Med. Chem. Lett. 2006, 16, 317; (c) Zeinyeh, W.; Mahiout, Z.; Radix, S.; Lomberget, T.; Dumoulin, A.; Barret, R.; Grenot, C.; Rocheblave, L.; Matera, E. L.; Dumontet, C.; Walchshofer, N. Steroids 2012, 77, 1177. 10. (a) Cadenas, R. A.; Mosettig, J.; Gelpi, M. E. Steroids 1996, 61, 703; (b) Akanni, A.; Tabakovic, K.; Abul-Hajj, Y. J. Chem. Res. Toxicol. 1997, 10, 477; (c) Gelpi, M. E.;
11. 12. 13.
14.
975
Cadenas, R. A.; Mosettig, J.; Zuazo, B. N. Steroids 2002, 67, 263; (d) Cadenas, R. A.; Gelpi, M. E.; Mosettig, J. J. Heterocycl. Chem. 2005, 42, 1. Huang, L. H.; Wang, Y. G.; Xu, G.; Zhang, X. H.; Zheng, Y. F.; He, H. L.; Fu, W. Z.; Liu, H. M. Bioorg. Med. Chem. Lett. 2011, 21, 6203. Norman, T. C.; Gray, N. S.; Koh, J. T.; Schultz, P. G. J. Am. Chem. Soc. 1996, 118, 7430. (a) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987; (b) Bressi, J. C.; Choe, J.; Hough, M. T.; Buckner, F. S.; Van Voorhis, W. C.; Verlinde, C. L.; Hol, W. G.; Gelb, M. H. J. Med. Chem. 2000, 43, 4135. (a) Fiorini, M. T.; Abell, C. Tetrahedron Lett. 1827, 1998, 39; (b) Wan, Z.; Boehm, J. C.; Bower, M. J.; Kassis, S.; Lee, J. C.; Zhao, B.; Adams, J. L. Bioorg. Med. Chem. Lett. 2003, 13, 1191; (c) Chang, J.; Dong, C.; Guo, X.; Hu, W.; Cheng, S.; Wang, Q.; Chen, Y. Bioorg. Med. Chem. 2005, 13, 4760.
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel C6-amino substituted 4-azasteroidal purine nucleoside analogues Li-Hua Huang a,b,c, Hong-De Xu b,c, Zhen-Yu Yao a, Yan-Guang Wang b,c, Hong-Min Liu b,c,⇑ a
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China c New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, China b
a r t i c l e
i n f o
Article history: Received 24 July 2013 Revised 2 December 2013 Accepted 13 December 2013 Available online 19 December 2013 Keywords: 4-Azasteroid Purine Nucleoside analogues Amines Anticancer activity
a b s t r a c t Novel C6-amino substituted purine nucleoside analogues (2–12) bearing a modified pyranose-like D ring of the 4-azasteroid moiety were efficiently synthesized through nucleophilic substitution at C6 position of the steroidal nucleoside precursors (1a, b) with versatile amines. All the synthesized new compounds were evaluated for their anticancer activity in vitro against Hela, PC-3 and MCF-7 cell lines. Among them, compounds 4b, 7b and 9b exhibited significant cytotoxicity with the IC50 values of 2.99 lM (PC-3), 2.84 lM, (PC-3) and 2.69 lM (Hela), respectively. Ó 2014 Published by Elsevier Ltd.
Nucleoside analogues including a variety of purine and pyrimidine nucleoside derivatives have played an important role in the development of antiviral and antitumor drugs.1–3 These groups of compounds behave as antimetabolites, compete with physiological nucleosides during DNA or RNA synthesis, and interact with key cell enzymes of the nucleotide metabolism to induce cytotoxicity.4,5 Currently, cytotoxic nucleoside analogues such as cladribine, fludarabine and gemcitabine are used as the first line of chemotherapeutic agents for the treatment of hematological malignancies and certain solid tumors.4–6 Due to the pharmacological significance, nucleoside analogues have attracted extensive investigation for small molecule drug discovery through decades, and modifications have been made to both the heterocyclic base and the sugar moiety.1,7 In 1977, van Lier et al. reported a novel class of compounds prepared through coupling steroids with naturally occurring purines and pyrimidines by way of a C–N linkage.8 These newly-synthesized steroid–nucleosides exhibited great antitumor activity and were less likely to have adverse side effects. Subsequently, several other classes of steroidal nucleosides analogues were synthesized which included nucleobases and nucleoside analogues linked through a spacer group9 or linked directly to the steroid skeleton.10 Recently, we have described a novel series of steroid– nucleoside analogues, in which the modified sugar-like D ring of
the 4-azasteroid moiety was directly attached to the bases.11 Preliminary biological evaluation results suggested that compounds 1a, b (Fig. 1) showed great anticancer activity. On the other hand, C6-aminopurines derivatives possess wide range of biological properties and have been shown to have antitumor activity as inhibitors of various protein kinases.12,13 Therefore, it is of great interest to explore new purine analogues with modifications by introduction of an amino group at C6 position. Herein, we present the synthesis of C6-amino substituted steroid–nucleosides analogues by displacement of the C6 chloro on the purine ring of compounds 1a, b with versatile amines and their anticancer activity in vitro. The protocol for the synthesis of C6-amino substituted 4-azasteroidal purine nucleoside analogues was outlined in Scheme 1, which involved the nucleophilic substitution of 6-chloro-purine with appropriate amines. The reaction was carried out in the presence of Et3N as an auxiliary base in refluxing MeOH for 5-20 min to give the desired purine nucleoside analogues 2–12 in excellent yields. The 2-chloro group on purine ring was less reactive and N O
N
E-mail address: [email protected] (H.-M. Liu). 0960-894X/$ - see front matter Ó 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.bmcl.2013.12.056
Cl N R1
O
⇑ Corresponding author. Tel./fax: +86 371 67781739.
N
N H
1a: R1 = H; 1b: R1 = Cl
Figure 1. Novel class of steroidal purine nucleosides analogues.
974
L.-H. Huang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 973–975
N O
N O
N
Cl
N
O
N R1
N H
Amines
N N
Et3N, MeOH, ref lux, 5-20 min
R2 N R1
O
N H
1
2-12
Scheme 1. Synthesis of steroidal C6-aminopurine nucleoside analogues 2-12.
its substitution usually required higher temperature and extended reaction time.14 As a result, products with the 2-chloro group substituted with amines were not observed. All the newly-synthesized compounds were characterized by 1H, 13C NMR and HRMS spectra. The newly-synthesized C6-aminopurin derivatives 2–12 were evaluated for their anticancer activity in vitro against Hela, PC-3 and MCF-7 cell lines using the MTT assay and the results were presented in Table 1. As shown in Table 1, it was evident from the data that change of substituents on the purine ring had a significant influence on the cytotoxicity. Replacement of the 6-chloro group of the purine ring with amines did not enhance the inhibitory activity. On the contrary, for most C6-aminopurines derivatives, introduction of an amino group resulted in a marked decrease in potency compared to compounds 1a, b. For example, replacement of the 6-chloro atom with di(hydroxyethyl)amino group (compounds 8a, b) led to loss of potency against all tested cell lines. Among the screened C6-aminopurines derivatives, three of them (compounds 4b, 7b and 9b) showed promising anticancer activity on certain cancer cell lines in vitro. Compound 4b, which contained the 2-chloro group and 6-hydrazino group on the purine ring, displayed remarkable inhibition of PC-3 cells, with the IC50 values of 2.99 lM. However, this compound exhibited no Table 1 The in vitro anticancer activity of 4-azasteroidal purine nucleoside analogues 1–12 Compound
R1
R2
IC50 (lM)
Cl
Hela
PC-3
MCF-7
17.67 7.57
3.25 11.19
20.92 34.21
inhibitory activity against Hela and MCF-7 cell lines, indicating the selective inhibition of PC-3 cells. Similar activity was found for compound 7b, which also showed potent inhibitory activity against PC-3 cells (IC50 = 2.84 lM) and no inhibitory activity against Hela and MCF-7 cell lines. For C6-benzylamino substituted purine nucleoside analogues 9–12, substituent on the phenyl ring did not show significant influence on the cytotoxic activity. Compound 9b with the 2-chloro-6-benzylaminopurine ring demonstrated the best anticancer activity against Hela cell lines with the IC50 values of 2.69 lM, which also showed good inhibitory activity against PC-3 and MCF-7 cell lines (IC50 = 17.86 lM, 12.75 lM, respectively). However, compound 9a bearing the same substituent at C6-position exhibited no inhibitory activity on Hela and MCF-7 cell lines, suggesting that substituent at the C2-position of purine ring also affect the activity. It was noteworthy that the three compounds 4b, 7b and 9b displaying potent anticancer activity contained the same 2-chloro substituent. Generally, the 2-chloro substituted purine analogues showed higher activity compared to C2-unsubstituted compounds (R1 = H). In summary, novel C6-amino substituted 4-azasteroidal purine nucleoside analogues 2–12 were efficiently prepared by nucleophilic substitution of the C6-chloro of 1a, b with amines in excellent yields. For most newly-synthesized compounds, introduction of an amino substituent at C6 position resulted in a loss of potency compared to compounds 1a, b. Among the screened compounds 2–12, compounds 4b, 7b and 9b exhibited significant anticancer activity against certain cancer cell lines. The research on their possible mechanism of inhibiting proliferation of cancer cell lines is underway, which will be reported in due course.
1a 1b
H Cl
2a 2b
H Cl
70.50 61.31
>100 >100
57.71 >100
Acknowledgment
N
3a 3b
H Cl
N
33.81 31.10
>100 58.06
>100 16.42
We are grateful to the National Natural Sciences Foundation of China (No.81172937) for financial support.
4a 4b
H Cl
>100 >100
87.16 2.99
34.59 >100
5a 5b
H Cl
NH2
66.15 22.65
>100 63.40
>100 70.28
6a 6b
H Cl
OH
>100 >100
49.22 >100
>100 >100
7a 7b
H Cl
>100 >100
15.78 2.84
>100 >100
8a 8b
H Cl
>100 >100
>100 >100
>100 >100
9a 9b
H Cl
>100 2.69
20.60 17.86
>100 12.75
10a 10b
H Cl
28.16 67.18
44.25 26.55
32.71 12.93
11a 11b
H Cl
OCH 3
38.74 10.14
>100 >100
60.32 >100
12a 12b
H Cl
F
>100 59.14
91.55 >100
34.77 13.50
NHNH 2 N H N H
OH N H N(C2H 4OH) 2
NH
NH NH NH
Hela: human cervical carcinoma; PC-3: human prostatic carcinoma, MCF-7: human breast carcinoma.
Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.2013. 12.056. References and notes 1. (a) Haines, D. R.; Tseng, C. K.; Marquez, V. E. J. Med. Chem. 1987, 30, 943; (b) Lin, T. S.; Luo, M. Z.; Liu, M. C.; Clarke-Katzenburg, R. H.; Cheng, Y. C.; Prusoff, W. H.; Mancini, W. R.; Birnbaum, G. I.; Gabe, E. J.; Giziewicz, J. J. Med. Chem. 1991, 34, 2607. 2. (a) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745; (b) Sagi, G.; Otvos, L.; Ikeda, S.; Andrei, G.; Snoeck, R.; Clercq, E. D. J. Med. Chem. 1994, 37, 1307. 3. (a) Bello, A. M.; Konforte, D.; Poduch, E.; Furlonger, C.; Wei, L.; Liu, Y.; Lewis, M.; Pai, E. F.; Paige, C. J.; Kotra, L. P. J. Med. Chem. 2009, 52, 1648; (b) Tuncbilek, M.; Guven, E. B.; Onder, T.; Atalay, R. C. J. Med. Chem. 2012, 55, 3058. 4. (a) Sampath, D.; Rao, V. A.; Plunkett, W. Oncogene 2003, 22, 9063; (b) Robak, T.; Lech-Maranda, E.; Korycka, A.; Robak, E. Curr. Med. Chem. 2006, 13, 3165; (c) Parker, W. B. Chem. Rev. 2009, 109, 2880. 5. (a) Galmarini, C. M.; Mackey, J. R.; Dumontet, C. Lancet Oncol. 2002, 3, 415; (b) Robak, T.; Korycka, A.; Kasznicki, M.; Wrzesien´-Kus, A.; Smolewski, P. Curr. Cancer Drug Targets 2005, 5, 421; (c) Robak, T.; Korycka, A.; Lech-Maranda, E.; Robak, P. Molecules 2009, 14, 1183.
L.-H. Huang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 973–975 6. Storniolo, A. M.; Enas, N. H.; Brown, C. A.; Voi, M.; Rothenberg, M. L.; Schilsky, R. Cancer 1999, 85, 1261. 7. (a) Choi, W. J.; Lee, H. W.; Kim, H. O.; Chinn, M.; Gao, Z. G.; Patel, A.; Jacobson, K. A.; Moon, H. M.; Jung, Y. H.; Jeong, L. S. Bioorg. Med. Chem. 2009, 17, 8003; (b) Gupta, P. K.; Daunert, S.; Nassiri, M. R.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1989, 32, 402. 8. van Lier, J. E.; Kan, G.; Autenrieth, D.; Nigam, V. N. Nature 1977, 267, 522. 9. (a) van Lier, J. E.; Kan, G.; Autenrieth, D.; Hulsinga, E. Cancer Treat. Rep. 1978, 62, 1251; (b) Ali, H.; Ahmed, N.; Tessier, G.; van Lier, J. E. Bioorg. Med. Chem. Lett. 2006, 16, 317; (c) Zeinyeh, W.; Mahiout, Z.; Radix, S.; Lomberget, T.; Dumoulin, A.; Barret, R.; Grenot, C.; Rocheblave, L.; Matera, E. L.; Dumontet, C.; Walchshofer, N. Steroids 2012, 77, 1177. 10. (a) Cadenas, R. A.; Mosettig, J.; Gelpi, M. E. Steroids 1996, 61, 703; (b) Akanni, A.; Tabakovic, K.; Abul-Hajj, Y. J. Chem. Res. Toxicol. 1997, 10, 477; (c) Gelpi, M. E.;
11. 12. 13.
14.
975
Cadenas, R. A.; Mosettig, J.; Zuazo, B. N. Steroids 2002, 67, 263; (d) Cadenas, R. A.; Gelpi, M. E.; Mosettig, J. J. Heterocycl. Chem. 2005, 42, 1. Huang, L. H.; Wang, Y. G.; Xu, G.; Zhang, X. H.; Zheng, Y. F.; He, H. L.; Fu, W. Z.; Liu, H. M. Bioorg. Med. Chem. Lett. 2011, 21, 6203. Norman, T. C.; Gray, N. S.; Koh, J. T.; Schultz, P. G. J. Am. Chem. Soc. 1996, 118, 7430. (a) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987; (b) Bressi, J. C.; Choe, J.; Hough, M. T.; Buckner, F. S.; Van Voorhis, W. C.; Verlinde, C. L.; Hol, W. G.; Gelb, M. H. J. Med. Chem. 2000, 43, 4135. (a) Fiorini, M. T.; Abell, C. Tetrahedron Lett. 1827, 1998, 39; (b) Wan, Z.; Boehm, J. C.; Bower, M. J.; Kassis, S.; Lee, J. C.; Zhao, B.; Adams, J. L. Bioorg. Med. Chem. Lett. 2003, 13, 1191; (c) Chang, J.; Dong, C.; Guo, X.; Hu, W.; Cheng, S.; Wang, Q.; Chen, Y. Bioorg. Med. Chem. 2005, 13, 4760.
