Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies.

Katarzyna Piechowska,Wojciech Płaziński,Magdalena Mizerska-Kowalska,Kamil Łuczykowski,Stefan Kruszewski,Barbara Bojko,Barbara Zdzisińska,Krzysztof Z Łączkowski,Konrad Misiura,Joanna Cytarska,Angelika Baranowska-Łączkowska,Karol Jaroch

doi:10.3390/ijms21239050

Abstract

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a–3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC50 values of 1.51–3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8–70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC50 distinct correlation with experiment.

Highlights

Cancer is a complex genetic and environmental disease and is currently the second largest cause of death after heart disease [1]
It is observed that the value of the cancer mortality rate is dangerously close to the incidence rate, which makes cancer a serious problem in a rapidly developing world
Melanin belongs to a group of dyes that strongly absorb harmful UV radiation, which can protect melanoma cells during radiotherapy, and as the antioxidant may reduce the effectiveness of the chemotherapy used [3]

Summary

Introduction

Cancer is a complex genetic and environmental disease and is currently the second largest cause of death after heart disease [1]. The most common types of cancer are lung, breast, colorectal, and prostate cancers. Lung and colorectal cancers are the two most common cancers in terms of incidence and mortality, both for males and females. As for males, the most common cause of death is prostate cancer, and for females it is breast cancer [1]. Another serious problem are the highly aggressive melanoma and multiple myeloma. The process of melanin production catalyzed by tyrosinase is highly deregulated leading to its accumulation in cells. The TYR gene (encoding tyrosinase) is expressed only in specified cells that produce melanin. A possible solution to this problem is the use of tyrosinase inhibitors, inhibiting the sequential oxidation of L-tyrosine to L-DOPA-quinone—a substrate for melanin synthesis

Methods

Results

Conclusion