Design and Synthesis of 4-O-Podophyllotoxin Sulfamate Derivatives as Potential Cytotoxic Agents.

Ammar Bader,Dima A Sabbah,Hamed I Ali,Qasem M A Abdallah,Ghadeer Albadawi,Ghassan M Abushaikha,Ashraf N Abdalla,Majdi M Bkhaitan,Akhilesh K Tamrakar

doi:10.1155/2021/6672807

Abstract

4-O-Podophyllotoxin sulfamate derivatives were prepared using the natural lignan podophyllotoxin. The prepared compounds were afforded by reacting O-sulfonyl chloride podophyllotoxin with ammonia or aminoaryl/heteroaryl motif. Biological evaluation was performed in human breast cancer (MCF7), ovarian cancer (A2780), colon adenocarcinoma (HT29), and normal lung fibroblast (MRC5) cell lines. Compound 3 exhibited potent inhibitory activity and good selectivity margin. Compounds 2, 3, and 7 exerted apoptotic effect in MCF7 cells in a dose-dependent manner. The cytotoxicity of the verified compounds was inferior to that of podophyllotoxin.

Highlights

Podophyllotoxin 1 (PPT) is a natural lignan of the aryl tetralin class and the main component of Podophyllum peltatum L., and it was used in folk medicine since remote times [1, 2]
Chemistry. e synthesis of podophyllotoxin sulfamates, compounds 2–7, was achieved by reaction of podophyllotoxin (1) with chlorosulfonic acid in dry dichloromethane (DCM) (Scheme 1). en, the podophyllotoxin sulfonyl chloride intermediate derivatives were immediately treated with ammonia or with the corresponding aryl and heteroaryl amines in the presence of triethylamine (TEA). e structures of the target compounds 2–7 were identified by IR, 1H-Nuclear Magnetic Resonance (NMR), and 13CNMR spectral analysis
Compound 3 shows the highest activity against the three cell lines (0.150–0.220 μM), and it was 9.1–13.5-fold more selective against MCF7, A2780, and HT29 compared to MRC5 cells

Summary

Introduction

Podophyllotoxin 1 (PPT) is a natural lignan of the aryl tetralin class and the main component of Podophyllum peltatum L., and it was used in folk medicine since remote times [1, 2]. It is generally considered as an effective anticancer agent with the ability to inhibit microtubules assembly by interacting with the tubulin proteins at the same binding site of colchicine, preventing the formation of the mitotic spindle [3, 4].

Methods

Results

Conclusion