On Nietzsche’s Concept of ‘European Nihilism’

<div><p>Aplog-1 is a simplified analog of the tumor-promoting aplysiatoxin with anti-proliferative and cytotoxic activities against several cancer cell lines. Our recent findings have suggested that protein kinase Cδ (PKCδ) could be one of the target proteins of aplog-1. In this study, we synthesized amide-aplog-1 (<b>3</b>), in which the C-1 ester group was replaced with an amide group, to improve chemical stability <i>in vivo</i>. Unfortunately, <b>3</b> exhibited seventy-fold weaker binding affinity to the C1B domain of PKCδ than that of aplog-1, and negligible anti-proliferative and cytotoxic activities even at 10⁻⁴ M. A conformational analysis and density functional theory calculations indicated that the stable conformation of <b>3</b> differed from that of aplog-1. Since 27-methyl and 27-methoxy derivatives (<b>1</b>, <b>2</b>) without the ability to bind to PKC isozymes exhibited marked anti-proliferative and cytotoxic activities at 10⁻⁴ M, <b>3</b> may be an inactive control to identify the target proteins of aplogs.</p></div

Structure–Activity Studies on the Spiroketal Moiety of a Simplified Analogue of Debromoaplysiatoxin with Antiproliferative Activity

Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (<b>5</b>) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar <i>K</i>_i values, approximately 10–20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (<b>4</b>) had levels of activity similar to those of aplog-1. Interestingly, <b>5</b> showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that <b>5</b> is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins

Total Synthesis and in Vitro Anti-Tumor-Promoting Activities of Racemic Acetophenone Monomers from <i>Acronychia trifoliolata</i>

Six acetophenone derivatives, acronyculatins I (<b>1</b>), J (<b>2</b>), K (<b>3</b>), L (<b>4</b>), N (<b>5</b>), and O (<b>6</b>), were recently isolated from <i>Acronychia trifoliolata</i>, and the structure of the known acronyculatin B (<b>7</b>) was revised. Because of the limited quantities of isolated products as well as their structure similarity, racemic acronyculatins I–L, N, O, and B (<b>1</b>–<b>7</b>) were synthesized to confirm their structures and to obtain sufficient material for biological evaluation. Trihydroxyacetophenone was converted to the target compounds by various sequences of hydroxy group protection, allylation or prenylation, and epoxidation followed by cyclization. <i>C</i>-Prenylations were carried out by direct addition of a prenyl group or through 1,3- or 3,3-sigmatropic rearrangement. The synthesized racemic compounds were evaluated in an anti-tumor-promoting assay using the Epstein–Barr virus early antigen (EBV-EA) activation induced by 12-<i>O</i>-tetradecanoylphorbol-13-acetate in Raji cells. All tested compounds significantly inhibited EBV-EA activation. Especially, racemic acronyculatin I (<b>1</b>) displayed the most potent inhibitory effects, with an IC₅₀ value of 7.3 μM