Chinese Journal of Organic Chemistry >
Synthesis and Preliminary Antitumor Activity Evaluation of 17-(5-(Substituted cinnamamido)pentylamino)-17-demethoxygeldan-amycin Derivatives as Potent Hsp90 Inhibitors
Received date: 2015-02-13
Revised date: 2015-05-06
Online published: 2015-06-12
Supported by
Project supported by the National Basic Research Program (973 Program, No. 2010CB833802), the National Natural Science Foundation of China (Nos. 81373304, 91313303), the Program for Changjiang Scholars and Innovative Research Team in University (No. IRT13028) and the National Science Found for Distinguished Young Scholars of China (No. 30325044).
Geldanamcyin (GA) is the first potent inhibitor of heat shock protein 90 (Hsp90) from natural products. However, its clinical application was limited by the unwanted hepatotoxicity. Our previous studies on the structure-activity relationships of GA derivatives indicated that the introduction of hepatoprotective cinnamyol group via an alkyldiamino linker decreased the hepatotoxicity evidently. In this study, using pentyldiamine as the linker, twenty-six 17-(5-(substituted cinnamamido)pentylamino)-17-demethoxygeldanamycins were designed and synthesized as the inhibitors of Hsp90. All the compounds showed potent antitumor activities against human breast cancer cell line MDA-MB-231 with IC50 ranging from 0.12 to 1 μmol·L-1. Particularly, 17-(5-(cinnamamido)pentylamino)-17-demethoxygeldanamycin (3a) and 17-(5-(2,5-methoxycinn-amamido)pentylamino)-17-demethoxygeldanamycin (3u) were proved to be the most potent compounds (IC50＝0.12 μmol·L-1), more active than the positive control 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (IC50＝0.27 μmol· L-1) and showed lower hepatotoxicity. Additionally, the preliminary structure-activity relationships among these newly synthesized congeners are briefly discussed, which should provide valuable basis for the structure optimization of GA-type Hsp90 inhibitors and antitumor lead compounds.
Xu Hongjiao , Li Zhenyu , Wang Zhen , Hao Huilin , Lu Chunhua , Zhu Jing , Shen Yuemao . Synthesis and Preliminary Antitumor Activity Evaluation of 17-(5-(Substituted cinnamamido)pentylamino)-17-demethoxygeldan-amycin Derivatives as Potent Hsp90 Inhibitors[J]. Chinese Journal of Organic Chemistry, 2015 , 35(10) : 2125 -2134 . DOI: 10.6023/cjoc201502023
[1] DeBoer, C.; Meulman, P. A.; Wnuk, R. J.; Peterson, D. H. J. Antibiot. (Tokyo) 1970, 23, 442.
[2] Stebbins, C. E.; Russo, A. A.; Schneider, C.; Rosen, N.; Hartl, F. U.; Pavletich, N. P. Cell 1997, 89, 239.
[3] Roe, S. M.; Prodromou, C.; O'Brien, R.; Ladbury, J. E.; Piper, P. W.; Pearl, L. H. J. Med. Chem. 1999, 42, 260.
[4] Stebbins, C. E.; Russo, A. A.; Schneider, C.; Rosen, N.; Hartl, F. U.; Pavletich, N. P. Cell 1997, 89, 239.
[5] Russell, R. Chem. Commun. 2013, 49, 8441.
[6] Kitson, R. R.; Chang, C. H.; Xiong, R.; Williams, H. E.; Davis, A. L.; Lewis, W.; Dehn, D. L.; Siegel, D.; Roe, S. M.; Prodromou, C.; Ross, D.; Moody, C. J. Nat. Chem. 2013, 5, 307.
[7] Kitson, R.; Moody, C. J. Chem. Commun. 2013, 49, 8441.
[8] Tian, Z. Q.; Wang, Z.; MacMillan, K. S.; Zhou, Y.; Carreras, C. W.; Mueller, T.; Myles, D. C.; Liu, Y. J. Med. Chem. 2009, 52, 3265.
[9] Rastelli, G.; Tian, Z. Q.; Wang, Z.; Myles, D.; Liu, Y. Bioorg. Med. Chem. Lett. 2005, 15, 5016.
[10] Tian, Z. Q.; Liu, Y.; Zhang, D.; Wang, Z.; Dong, S. D.; Carreras, C. W.; Zhou, Y.; Rastelli, G.; Santi, D. V.; Myles, D. C. Bioorg. Med. Chem. 2004, 12, 5317.
[11] Kasuya, Y.; Lu, Z.; Kopeckova, P.; Kopecek, J. Bioorg. Med. Chem. Lett. 2001, 11, 2089.
[12] Ronnen, E. A.; Kondagunta, G. V.; Ishill, N.; Sweeney, S. M.; DeLuca, J. K.; Schwartz, L.; Bacik, J.; Motzer, R. J. Invest. New Drugs 2006, 24, 543.
[13] Glaze, E. R.; Lambert, A. L.; Smith, A. C.; Page, J. G.; Johnson, W. D.; McCormick, D. L.; Brown, A. P.; Levine, B. S.; Covey, J. M.; Egorin, M. J. Cancer Chemother. Pharmacol. 2005, 56, 637.
[14] Modi, S.; Stopeck, A.; Linden, H.; Solit, D.; Chandarlapaty, S.; Rosen, N.; D'Andrea, G.; Dickler, M.; Moynahan, M. E.; Sugarman, S. Clin. Cancer Res. 2011, 17, 5132.
[15] Li, Z.; Jia, L.; Wang, J.; Wu, X.; Hao, H.; Xu, H.; Wu, Y.; Shi, G.; Lu, C.; Shen, Y. Eur. J. Med. Chem. 2014, 85, 359.
[16] Li, Z.; Jia, L.; Wang, J.; Wu, X.; Shi, G.; Lu, C.; Shen, Y. Chem. Biol. Drug Des. 2015, 85, 181.
[17] Li, Z.; Jia, L.; Wang, J.; Wu, X.; Hao, H.; Wu, Y.; Xu, H.; Wang, Z.; Shi, G.; Lu, C. Eur. J. Med. Chem. 2014, 87, 346.
[18] Wu, Y.; Li, Z.; Wang, Z.; Xu, H.; Wu, X.; Lu, C.; Shen, Y. Chin. J. Org. Chem. 2014, 34, 1870 (in Chinese).(吴云飞, 李震宇, 王贞, 徐洪蛟, 武兴康, 鲁春华, 沈月毛, 有机化学, 2014, 34, 1870.)
/
| 〈 |
|
〉 |
