Structural characterization, antiproliferative and anti-inflammatory activities of alkaloids from the roots of Zanthoxylum austrosinense

Highlights

• Three new carbazole alkaloids were isolated and characterized from Zanthoxylum austrosinense.

• The antiproliferative and anti-inflammatory activities of all isolated alkaloids were tested in vitro.

• Alkaloids 1–12 showed remarkable antiproliferative activities equivalent to that of cisplatin.

• Alkaloids 1–12 exhibited significant anti-inflammatory effects comparable with that of hydrocortisone.

Abstract

Three new carbazole alkaloids, zanthoaustrones A–C (1–3), as well as nine known compounds 4–12, were isolated and characterized from the roots of Zanthoxylum austrosinense Huang (Rutaceae). Their chemical structures were elucidated on the basis of extensive and comprehensive spectroscopic methods, while the known alkaloids were identified by the comparison of their observed spectroscopic data including NMR data, MS data and optical rotation values with the data described in the literature. Furthermore, the antiproliferative activities as well as the anti-inflammatory effects of all isolated alkaloids in vitro were evaluated. All obtained alkaloids 1–12 displayed notable antiproliferative activities against diverse human cancer cell lines exhibiting IC₅₀ values in range of 0.85 ± 0.06 to 29.56 ± 0.17 µM, which is equivalent to the positive control (cisplatin) showing IC₅₀ values ranging from 1.58 ± 0.09 to 28.69 ± 0.21 µM. Moreover, compounds 1–12 exhibited pronounced inhibitory activities on nitric oxide (NO) production with IC₅₀ values displaying IC₅₀ values in range of 0.89 ± 0.05 to 9.62 ± 0.15 µM, which is comparable to the positive control (hydrocortisone) holding an IC₅₀ value of 4.06 ± 0.11 µM. These findings indicate that the separation and characterization of these alkaloids displaying significant antiproliferative activities together with anti-inflammatory effects from the roots of Z. austrosinense could be meaningful to the research and development of new anti-cancer drugs as well as anti-inflammatory agents.

Introduction

The genus Zanthoxylum (Rutaceae) consisting of approximately 250 species, are widely scattered in subtropical and tropical regions of Asia, North America, Africa and Oceania. In China, there are about 39 species along with 14 varieties distributed abroad from the Liaodong Peninsula to Hainan Island [1]. So far, a variety of structurally interesting natural products including alkaloids, lignans, coumarins, phenylpropenoids, chromenes and orbitides have been separated and characterized from the genus Zanthoxylum, which exhibited various biological activities including antibacterial, antimalarial, anti-tumor, neuroprotective, anti-platelet, anti-tubercular, analgesic, anti-inflammatory, antispasmodic and monoamine oxidase inhibitory activities [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. As a folk medicinal plant named “Sou Shan Hu” in Guangxi Zhuang Autonomous Region of China, Zanthoxylum austrosinense shows the medical functions of expelling wind, detoxifying, relieving exterior syndrome, removing blood stasis and reducing swelling, and is used for the treatment of rheumatic bone pain and bruises [1]. Up to now, there is only a very preliminary study on the chemical constituents of Z. austrosinense. Our preliminary research results revealed that the methanol extract of the roots of Z. austrosinense collected from Guangxi Zhuang Autonomous Region displayed notable antiproliferative effects with IC₅₀ values ranging from 5.12 ± 0.08 to 30.87 ± 0.16 μg/mL together with significant inhibitory activity against NO production possessing an IC₅₀ value of 6.78 ± 0.12 μg/mL. In continuation of our ongoing study into natural products with novel chemical structures and various biological activities from tropical medicinal plants as well as tropical fruits in China [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], a chemical investigation on the roots of Z. austrosinense was thence carried out and had led to the isolation and characterization of 12 alkaloids, including three previously undescribed carbazole alkaloids, zanthoaustrones A–C (1–3), along with nine known alkaloids 4–12. Their chemical structures were elucidated in view of comprehensive spectroscopic methods, while the known compounds 4–12 were determined by means of comparing their experimental spectroscopic data including NMR data, MS data and optical rotation values with the data reported in the literature. In addition, the antiproliferative and anti-inflammatory activities of all isolated compounds in vitro were assessed. As a result, compounds 1–12 exhibited obviously antiproliferative activities against various human cancer cell lines with IC₅₀ values ranging from 0.85 ± 0.06 to 29.56 ± 0.17 µM. Meanwhile, alkaloids 1–12 displayed notable inhibitory activities on nitric oxide (NO) production showing the IC₅₀ values which were comparable to hydrocortisone. Herein, we describe the isolation and structural characterization of the new carbazole alkaloids, zanthoaustrones A–C (1–3), as well as the antiproliferative and anti-inflammatory activities of these isolated alkaloids from the roots of Z. austrosinense.