## 3 Chemistry and Biological Activities of Selected Meroterpenoids
focusing on its effects on a panel of ovarian cancer cell lines. The antiproliferative effect (EC\({}_{50}\)) of euperinfeldin on three ovarian cancer cell lines (OVCAR-3, OVCAR-5, OVCAR-8) and nontumorigenic fallopian tube cells (FTT3-Tag) were determined to be 10, 11, 12, and 170 nM respectively [77]. The results indicate the selectivity of the compound for cancer cell models over normal tissue with a greater than 10-fold difference. Additional mechanistic studies included cell migration assays, which provided favorable outcomes [77]. To validate their in vitro findings, hollow fiber studies were conducted in murine models. OVCAR-3 and OVCAR-8 hollow fibers were implanted in mice, which were treated with euperinfeldin or vehicle daily for 4 days. A significant reduction of OVCAR-3 cell model was observed while no significant inhibition of OVCAR-8 cell model was recorded suggesting the compound is working via a specific pathway. To further investigate the mechanism of action specific protein evaluation was conducted for apoptosis pathway (caspase 3/7 activation, PARP cleavage, autophagy assays) and global protein analysis using tandem mass tag (TMT), a chemical label technique that facilitates sample multiplexing in mass spectrometry (MS)-based quantification and identification of the proteome. Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, was used as a co-treatment with euperinfeldin on their selected ovarian cancers cell lines (OVCAR-3, OVCAR-5, and OVCAR-8) to determine if this compound is mediating cell death through autophagy as a primary cell death modality. The resultant data indicated that indeed bafilomycin was able to significantly rescue the cells from death. Their combined findings indicate that this natural product displays selectivity. It is likely mediating cell death through autophagy [77]. Pycnidione (**140**, Figure 5) is another example of bioactive sesquiterpene-bistropolone meroterpenoid natural products. First isolated from fungal species, _Phoma_ sp., this compound has been studied extensively for its biological activities. [PERSON] studied the effects of pycnidione on leukemia cell models [78]. This compound alone or in combination with bleomycin against a panel of human cancer cell lines had a significant anti-proliferative effect. Ongoing studies indicate that pycnidione inhibits of topoisomerase II at an IC\({}_{50}\) value of 19 \(\upmu\)M and modulates the cell cycle at the G2 phase [78]. These biological studies highlight the importance of having access to large quantities of these natural products for further derivatization to improve efficacy. The recent total synthesis of the structurally revised flagship members of the pycnidione family, namely (+)-pycnidione (**140**), dehydroxypycmidione (**137**) and (-)-epolone B (**130**) was elegantly designed on a modular [4+2] inverse electron-demand hetero-Diels-Alder (HDA) reaction between the in situ generated _ortho_-quinone methode (\(o\)-QM) **82** and the corresponding dienophile, hydroxyhumulene **83** or humulene **84** (Scheme 11). While the majority of [4+2] cycloaddition reactions require heat, microwave assistance can also promote the rection, and minimize decomposition of starting materials or intermediates. A unified synthetic endeavor was recently used to generate various members of these complex meroterpenes through the in situ generation of compound **82** (Scheme 11). The resultant transition state of either dienophile **83** or **84** can proceed either as a single monocyclic formation step, TS1 or a bis-cyclization formation, TS2. They indicated that the reaction can be modified to favor one or various products. However, the diastereomers of euperinfeldin series have yet to be synthesized and remain a highly active area of research [79]. The synthesis capitalizes on the advantages to access building blocks **83**, \(o\)-quinone methide precursors **85a** and **85b** in sufficient quantities (Scheme 12) [79].