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. 2014 Nov;23(11):4926-4931.
doi: 10.1007/s00044-014-1042-9.

Synthesis of novel spin-labeled podophyllotoxin derivatives as potential antineoplastic agents: Part XXV

Liu Yang  1 , Xiang Nan  2 , Wen-Qun Li  2 , Mei-Juan Wang  2 , Xiao-Bo Zhao  2 , Ying-Qian Liu  2 , Zhi-Jun Zhang  2 , Kuo-Hsiung Lee  3
Affiliations

Synthesis of novel spin-labeled podophyllotoxin derivatives as potential antineoplastic agents: Part XXV

Liu Yang et al. Med Chem Res. 2014 Nov.

Abstract

A series of novel spin-labeled 4β-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin derivatives (17a-h) were firstly designed and synthesized with significant regioselectivity by employing Cu(I) catalyzed click approach, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU145, KB, and KBvin). Among them, compound 17h displayed the highest cytotoxic activity against the tumor cell lines tested. Significantly, compound 17h showed superior cytotoxic activity compared with etoposide (IC50 6.30 to>10 μM), a clinically available anticancer drug. Significant activity toward the drug resistant KBvin cell line revealed promising future for compound 17h as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidate.

Keywords: Click chemistry; Cytotoxic activity; Podophyllotoxin; Spin-labeled.

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Conflict of interest statement

Conflict of interest The authors report no conflict of interest. The authors alone are responsible for the content and writing of the article.

Figures

Fig. 1
Fig. 1
Structures of podophyllotoxin derivatives
Scheme 1
Scheme 1
Synthesis of N-(1-oxyl-2,2,6,6-tetramethyl-4-piperidinyloxycarbonyl) amino acids 14a–h Reagents and conditions: (i) Na2WO4/H2O2/EDTA; (ii) N,N′-carbonyldimidazole/THF; (iii) p-toluenesulfonic acid monohydrate; (iv) NaN3/water, stir; (v) amino acids/MgO, stir, 24 h.
Scheme 2
Scheme 2
Synthesis of target compounds 3a–f Reagents and conditions: (i) HN3/BF3·Et2O, CH2Cl2; (ii) Propargyl alcohol, CuSO4,Sodium ascorbate, H2O: t-BuOH=2:1; (iii) DIPC/DMAP, dry CH2Cl2
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