Bioorganic & Medicinal Chemistry Letters 24 (2014) 1597–1599
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Suzuki coupling based synthesis and in vitro cytotoxic evaluation of 7-heteroaryl-substituted camptothecin analogs Lei Wang a, Ying Huang a, Jie Zhang b, Linjiang Tong b, Yi Chen b,⇑, Wei Lu a, Qingqing Huang a,⇑ a Institute of Drug Discovery and Development, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, Shanghai 201203, PR China
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Article history: Received 6 December 2013 Revised 15 January 2014 Accepted 20 January 2014 Available online 29 January 2014 Keywords: Camptothecin C-7-heteroaryl-substituted camptothecin Suzuki coupling Antitumor
a b s t r a c t In an effort to discover potent antitumor agents, a series of novel C-7-heteroaryl-substituted camptothecin derivatives were designed and synthesized via microwave-promoted Suzuki coupling reaction. These analogs were then assessed for cytotoxicity against three human tumor cell lines, A549, HCT116, HT-29, and inhibitory effects on topoisomerase I. All of the new compounds showed potent inhibition of human tumor cell growth, among which compound 10a showed higher cytotoxic activity than that of SN-38. Furthermore, this series of compounds retained or enhanced Topo I inhibition. Ó 2014 Elsevier Ltd. All rights reserved.
20(S)-Camptothecin (CPT, 1, Fig. 1), an antitumor alkaloid first isolated by Wall and Wani in 1966 from Camptotheca acuminate, showed potent inhibitory activity against a broad spectrum of tumors.1 The antitumor activity of CPT is attributed to its selective poisoning of DNA topoisomerase I (Topo I), a nuclear enzyme required for topological manipulation of DNA during cell division.2 Because of its remarkable antitumoral and antileukemic activity, CPT became one of the prominent lead compounds in anticancer drug development. However, the therapeutic application of unmodified CPT is hindered due to its poor aqueous solubility and severe hepatotoxicity. Subsequently, the structural modification of natural CPT has generated many new CPT derivatives with improved pharmacological or pharmacokinetic profiles. Among those, topotecan (hycamtin, 2)3 and irinotecan (camptosar, 3)4 are successfully commercialized and used successfully in the clinic for treatment of ovarian and colon cancers respectively, and several other analogs such as gimatecan (4, Fig. 1), namitecan, karenitecin, 9-aminocamptothecin, 9-nitrocamptothecin, lurtotecan are now in various stages of clinical trials.5 From the structure–activity relationship (SAR) of CPT, it appears that substituents at C-7 position is very important for the cytotoxicity of CPT analogs.6 The previous studies have also demonstrated that there is a wide space for accommodating substitutions at C-7 ⇑ Corresponding authors. Tel./fax: +86 21 50801552 (Y.C.); +86 21 62602475 (Q.H.). E-mail addresses: [email protected] (Y. Chen), [email protected] (Q. Huang). http://dx.doi.org/10.1016/j.bmcl.2014.01.049 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
position of CPT without steric clash.7 A number of derivatives with substituents at C-7 position (such as gimatecan, namitecan, karenitecin) showed enhanced biological profiles.8 Currently, most substituents at C-7 position of CPT were alkyl groups, and few aromatic substituted derivatives were studied. To evaluate the influence of substituted heteroaromatic ring at C7 position, a series of novel 7-triazole-substituted CPT derivatives were studied, wherein 7-(1-butyl-1H-1,2,3-triazol-4-yl) CPT (6, Fig. 1) exhibited impressive cytotoxicity activity against human tumor cell lines A549 (human lung adenocarcinoma epithelial cell line, IC50
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Suzuki coupling based synthesis and in vitro cytotoxic evaluation of 7-heteroaryl-substituted camptothecin analogs Lei Wang a, Ying Huang a, Jie Zhang b, Linjiang Tong b, Yi Chen b,⇑, Wei Lu a, Qingqing Huang a,⇑ a Institute of Drug Discovery and Development, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, Shanghai 201203, PR China
a r t i c l e
i n f o
Article history: Received 6 December 2013 Revised 15 January 2014 Accepted 20 January 2014 Available online 29 January 2014 Keywords: Camptothecin C-7-heteroaryl-substituted camptothecin Suzuki coupling Antitumor
a b s t r a c t In an effort to discover potent antitumor agents, a series of novel C-7-heteroaryl-substituted camptothecin derivatives were designed and synthesized via microwave-promoted Suzuki coupling reaction. These analogs were then assessed for cytotoxicity against three human tumor cell lines, A549, HCT116, HT-29, and inhibitory effects on topoisomerase I. All of the new compounds showed potent inhibition of human tumor cell growth, among which compound 10a showed higher cytotoxic activity than that of SN-38. Furthermore, this series of compounds retained or enhanced Topo I inhibition. Ó 2014 Elsevier Ltd. All rights reserved.
20(S)-Camptothecin (CPT, 1, Fig. 1), an antitumor alkaloid first isolated by Wall and Wani in 1966 from Camptotheca acuminate, showed potent inhibitory activity against a broad spectrum of tumors.1 The antitumor activity of CPT is attributed to its selective poisoning of DNA topoisomerase I (Topo I), a nuclear enzyme required for topological manipulation of DNA during cell division.2 Because of its remarkable antitumoral and antileukemic activity, CPT became one of the prominent lead compounds in anticancer drug development. However, the therapeutic application of unmodified CPT is hindered due to its poor aqueous solubility and severe hepatotoxicity. Subsequently, the structural modification of natural CPT has generated many new CPT derivatives with improved pharmacological or pharmacokinetic profiles. Among those, topotecan (hycamtin, 2)3 and irinotecan (camptosar, 3)4 are successfully commercialized and used successfully in the clinic for treatment of ovarian and colon cancers respectively, and several other analogs such as gimatecan (4, Fig. 1), namitecan, karenitecin, 9-aminocamptothecin, 9-nitrocamptothecin, lurtotecan are now in various stages of clinical trials.5 From the structure–activity relationship (SAR) of CPT, it appears that substituents at C-7 position is very important for the cytotoxicity of CPT analogs.6 The previous studies have also demonstrated that there is a wide space for accommodating substitutions at C-7 ⇑ Corresponding authors. Tel./fax: +86 21 50801552 (Y.C.); +86 21 62602475 (Q.H.). E-mail addresses: [email protected] (Y. Chen), [email protected] (Q. Huang). http://dx.doi.org/10.1016/j.bmcl.2014.01.049 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
position of CPT without steric clash.7 A number of derivatives with substituents at C-7 position (such as gimatecan, namitecan, karenitecin) showed enhanced biological profiles.8 Currently, most substituents at C-7 position of CPT were alkyl groups, and few aromatic substituted derivatives were studied. To evaluate the influence of substituted heteroaromatic ring at C7 position, a series of novel 7-triazole-substituted CPT derivatives were studied, wherein 7-(1-butyl-1H-1,2,3-triazol-4-yl) CPT (6, Fig. 1) exhibited impressive cytotoxicity activity against human tumor cell lines A549 (human lung adenocarcinoma epithelial cell line, IC50
