Synthesis and Cytotoxicity of Heterocyclic Amine Derivatives of Podophyllotoxin
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SYNTHESIS AND CYTOTOXICITY OF HETEROCYCLIC AMINE DERIVATIVES OF PODOPHYLLOTOXIN
Dan-li Tian,1 Hong Chen,2 Gang Luo,2 and Chun-po Liang3*
A series of amine podophyllotoxin derivatives was designed and synthesized by aldehydes reacting with 4β-amino-desoxypodophyllotoxin or 4′-demethyldesoxypodophyllotoxin. The MTT assay was used to test the cytotoxic activity of 11 target compounds on HeLa cells and MCF-7 cells. All the compounds had varying degrees of antitumour activity in vitro. Several compounds showed improved activities against HeLa cells compared to that of the positive control etoposide (VP-16). Keywords: multidrug resistance, podophyllotoxin, synthesis, cytotoxicity. Aryltetralin lignan podophyllotoxin, a well known cytotoxic natural product isolated from various plant species within the podophyllum family, has been used for decades as antitumor drugs. After King and Sullivan reported that podophyllotoxin can exert antitumor activity by inhibiting tubulin through binding with its colchicine domain in 1946, a series of medical researches has carried out on podophyllotoxin to make it possible for clinical use as an anticancer medicine [1]. Two less toxic semi-synthetic podophyllotoxin analogues, etoposide (VP-16) and teniposide (VM-26), have been widely used in frontline cancer chemotherapy against various cancer types [2]. However, their low aqueous solubility, acquired drug resistance, bone-marrow depression, and severe gastrointestinal disturbances have limited their application [3]. Therefore, a search for many novel, efficient, and low-toxic derivatives of podophyllotoxin is imperative. Over the years, modifications at the C-4 position of ring C were frequently adopted, and bulky substitution at this position was found to enhance the cytotoxicity and DNA topoisomerase-II inhibition activity [4, 5]. Through C-4 modication, nitrogen-substituted derivatives at the C-4 position were found to exhibit superior anti-tumor activity [6, 7]. In recent years, many novel podophyllotoxin analogs have been prepared, and relevant structure–activity studies have been performed [8]. Due to the prevalence of heterocycles in drug molecules, we sought to introduce the heterocyclic moiety at the C-4 position to identify more hints for drug design. In this study, a series of amine podophyllotoxin derivatives (5a–5k) was synthesized (Scheme 1) with the aim of developing broad-spectrum and highly efficient anticancer agents. The structures of all the obtained compounds were characterized by 1 H NMR, 13C NMR, and HR-MS. The podophyllotoxin C ring has four chiral carbon atoms and 2α,3β-configuration. Numerous studies of the structure–activity relationship have shown that the trans-lactone D ring with the 2α,3β-configuration of substituents was essential for potency [9]. We can easily determine its configuration from the J3,4 coupling constants or by X-ray crystal diffraction. Assignment of the conguration of the C-4 position of compounds 5a–5k was based on J3,4 coupling constants. The C-4 β-substituted compounds have J3,4 = 3–5
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