Synthesis and in Vitro Antiproliferative Evaluation of Some B-norcholesteryl Benzimidazole and Benzothiazole Derivatives

Jianguo Cui,Zhipin Liu,Qifu Lin,Dandan Zhao,Binbin Qi,Hu Huang,Yanmin Huang,Chunfang Gan

doi:10.3390/md13042488

Abstract

Taking orostanal (a compound from a Japanese marine sponge, Stelletta hiwasaensis) as a lead compound, some novel B-norcholesteryl benzimidazole and benzothiazole derivatives were synthesized. The antiproliferative activity of the compounds against human cervical carcinoma (HeLa), human lung carcinoma (A549), human liver carcinoma cells (HEPG2) and normal kidney epithelial cells (HEK293T) was assayed. The results revealed that the benzimidazole group was a better substituent than benzothiazole group for increasing the antiproliferative activity of compounds. 2-(3β′-Acetoxy-5β′-hydroxy-6′-B-norcholesteryl)benzimidazole (9b) with the structure of 6-benzimidazole displays the best antiproliferative activity to the cancer cells in all compounds, but is almost inactive to normal kidney epithelial cells (HEK293T). The assay of compound 9b to cancer cell apoptosis by flow cytometry showed that the compound was able to effectively induce cancer cell apoptosis. The research provided a theoretical reference for the exploration of new anti-cancer agents and may be useful for the design of novel chemotherapeutic drugs.

Highlights

Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries [1]
The results showed that the presence of a cholesterol-type side chain was very important in determining the cytotoxicity of these compounds, and the presence of a thiosemicarbazone group at the C-6 position of steroid nucleus could enhance the antiproliferative activity of the compounds
Scheme 1 outlines the synthetic procedure of B-norcholesteryl benzimidazole compounds (7–11)

Summary

Introduction

Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries [1]. 50%, and the global annual increase of the number of cancer patients will reach 15,000,000 in 2020. The past decade has witnessed an increase in the number of compounds from the screening of diverse marine invertebrates, such as soft corals, sponges and tunicates. Orostanal induced apoptosis in HL-60 cells at 10 μg/mL, and inhibited 50% cell growth at 1.7 μM [3]. After that, another novel 5(6-7)abeo-sterol named parguesterol B (2) was obtained from the Caribbean Sea sponge Svenzea zeai, and it was a moderately strong anti-tuberculosis molecule with a MIC value of 7.8 μg/mL [4]

Methods

Results

Conclusion