In Vitro Antiproliferative Evaluation of Synthetic Meroterpenes Inspired by Marine Natural Products

Abstract

Several marine natural linear prenylquinones/hydroquinones have been identified as anticancer and antimutagenic agents. Structure-activity relationship studies on natural compounds and their synthetic analogs demonstrated that these effects depend on the length of the prenyl side chain and on the type and position of the substituent groups in the quinone moiety. Aiming to broaden the knowledge of the underlying mechanism of the antiproliferative effect of these prenylated compounds, herein we report the synthesis of two quinones 4 and 5 and of their corresponding dioxothiazine fused quinones 6 and 7 inspired to the marine natural product aplidinone A (1), a geranylquinone featuring the 1,1-dioxo-1,4-thiazine ring isolated from the ascidian Aplidium conicum. The potential effects on viability and proliferation in three different human cancer cell lines, breast adenocarcinoma (MCF-7), pancreas adenocarcinoma (Bx-PC3) and bone osteosarcoma (MG-63), were investigated. The methoxylated geranylquinone 5 exerted the highest antiproliferative effect exhibiting a comparable toxicity in all three cell lines analyzed. Interestingly, a deeper investigation has highlighted a cytostatic effect of quinone 5 referable to a G0/G1 cell-cycle arrest in BxPC-3 cells after 24 h treatment.

The Ascidian-Derived Metabolites with Antimicrobial Properties

“…This latter generates an oxidative burst accompanied by a huge and transient amount of reactive oxygen species (ROS), responsible for cellular damage. For this reason, both natural and synthetic prenylated quinones and hydroquinones found extensive application in the field of chemotherapy and cancer-preventive treatment [41][42][43]. A number of antimicrobial prenylated quinones from ascidians have been discovered too.…”

Investigating the Antiparasitic Potential of the Marine Sesquiterpene Avarone, Its Reduced Form Avarol, and the Novel Semisynthetic Thiazinoquinone Analogue Thiazoavarone

“…In the course of a systematic chemical study of the macroflora and macrofauna of the coastal area of Turkey in theİzmir Bay (Aegean Sea), as a part of our ongoing search for bioactive marine-derived metabolites as leads for drug discovery [15][16][17][18][19][20], we isolated from the sponge Dysidea avara (Schmidt, 1862) the known sesquiterpene quinone avarone (1), along with its reduced form avarol (3, Figure 2) [21][22][23]. A wide range of pharmacological properties have been reported for the redox couple avarone (1) and avarol (3) including anti-tumor [24][25][26], anti-inflammatory [27][28][29], anti-mutagenic [30], anti-bacterial [31,32], anti-viral [33,34], anti-oxidant [23,35], anti-platelet [28], anti-psoriatic [36] and anti-biofouling [37,38] activities.…”

Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones

“…After 24 h exposure to IC 50 concentrations of 5a , 5e , 5g , and 5h , MCF-7 cells were collected and stained with annexin-V-fluorescein isothiocyanate (FITC) and propidium iodide, using the FITC Annexin V Apoptosis Detection kit I (Becton Dickinson, BD, Franklin, NJ, USA) for detection of apoptotic and necrotic cells by flow cytometry, as previously reported [ 68 ]. Samples were prepared according to manufacturer’s protocol.…”