Synthesis of Jacaranone-Derived Nitrogenous Cyclohexadienones and Their Antiproliferative and Antiprotozoal Activities

Armin Presser,Nadine Kretschmer,Robert Saf,Marc-Manuel Kalt,Marcel Kaiser,Wolfgang Schuehly,Gunda Lainer

doi:10.3390/molecules23112902

Abstract

The cytotoxic and antiprotozoal activities of the phytoquinoide, jacaranone, and related compounds have been an ongoing topic in recent drug discovery. Starting from the natural product-derived cyclohexadienone scaffold, a series of nitrogen-containing derivatives were synthesized and subsequently evaluated for their antiproliferative and antiprotozoal activity. Anticancer potency was analyzed using different types of cancer cell lines: MDA-MB-231 breast cancer, CCRF-CEM leukemia, HCT-116 colon cancer, U251 glioblastoma, and, in addition, non-tumorigenic MRC-5 lung fibroblasts. Antiproliferative activities at micromolar concentrations could be shown. Antiprotozoal activity was assessed against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. For all compounds, selectivity indices (SI) were calculated based on assessed cytotoxicity towards L6 cells. In addition, the structure-activity-relationships and physicochemical parameters of these compounds are discussed.

Highlights

Natural products (NPs) play vital roles in drug discovery
On jacaranone imides, we searched for an efficient method that we could use to construct the NDuring our initial attempts, we followed a Mitsunobu route [22] as summarized in Scheme 1 dienone scaffold
We have synthesized a series of jacaranone imides and amines with promising antiproliferative activities from commercially available methyl hydroxyphenyl acetate (4) and tyramine

Summary

Introduction

Natural products (NPs) play vital roles in drug discovery. More than half of the drugs that have been approved over the past 30 years are natural compounds or compounds based on these [1].Approximately 68% of anti-infectives are classified as nature-derived or inspired, and 80% of all anticancer compounds fall into this category [2]. Natural products (NPs) play vital roles in drug discovery. More than half of the drugs that have been approved over the past 30 years are natural compounds or compounds based on these [1]. 68% of anti-infectives are classified as nature-derived or inspired, and 80% of all anticancer compounds fall into this category [2]. Examples of well-known drugs derived from natural products are paclitaxel or doxorubicin (anticancer), artemisinin (antimalarial), daptomycin (antibacterial), and morphine (analgesic). The most striking feature of many natural products is their structural diversity, which is still largely untapped. The importance of NPs in drug development has been described in a number of reviews and reports [2,4,5,6,7,8,9,10]

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