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

Cytotoxic, antitumour-promoting and inhibition of protein denaturation effects of flavonoids, isolated from <i>Potentilla evestita</i> Th. Wolf

<div><p>This study was designed to evaluate the isolated flavonoids (chrysin <b>1</b>, and umbelliferone <b>2</b>) from <i>Potentilla evestita</i> for cytotoxic, antitumour-promoting and inhibition of protein denaturation activities. The results showed marked cytotoxic effect of compounds <b>1</b> and <b>2</b> in brine shrimp cytotoxic assay at various concentrations with LD₅₀ of 34.5 and 31.8 mg/mL, respectively. In Epstein–Barr-virus early antigen activation assay, both compounds <b>1</b> and <b>2</b> illustrated significant antitumour-promoting effect with IC₅₀ values of 462 and 308 mol ratio/32 pmol TPA, respectively. The cytotoxic and antitumour-promoting effects of compounds were strongly supported by inhibition of protein denaturation activity with IC₅₀ of 119 and 112 μg/mL, respectively. In conclusion, both compounds possess strong cytotoxic, antitumour-promoting and inhibition of protein denaturation activities.</p></div

Structural optimization of 10-methyl-aplog-1, a simplified analog of debromoaplysiatoxin, as an anticancer lead

<div><p>Aplog-1 is a simplified analog of debromoaplysiatoxin (DAT) with potent tumor-promoting and proinflammatory activities. Aplog-1 and DAT exhibited anti-proliferative activities against several human cancer cell lines, whereas aplog-1 did not have tumor-promoting nor proinflammatory activities. We have recently found 10-methyl-aplog-1 (<b>1</b>) to have strong anti-proliferative activity compared with aplog-1. To further investigate the structural factors involved in the tumor-promoting, proinflammatory, and anti-proliferative activities, two dimethyl derivatives of aplog-1 (<b>2</b>, <b>3</b>) were synthesized, where two methyl groups were installed at positions 4 and 10 or 10 and 12. 10,12-Dimethyl-aplog-1 (<b>2</b>) had stronger inhibitory effects on the growth of several human cancer cell lines than <b>1</b> and DAT, but exhibited no tumor-promoting and proinflammatory activities. In contrast, 4,10-dimethyl-aplog-1 (<b>3)</b> displayed weak tumor-promoting and proinflammatory activities along with anti-proliferative activity similar to that of <b>1</b> and DAT. Compound <b>2</b> would be the optimized seed for anticancer drugs among the simplified analogs of DAT.</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

Absolute Configuration of Dihydro-β-agarofuran Sesquiterpenes from <i>Maytenus jelskii</i> and Their Potential Antitumor-Promoting Effects

Chemoprevention of human cancer appears to be a feasible strategy for cancer control, especially when chemopreventive intervention is involved during early stages of the carcinogenesis process. As a part of our ongoing research program into new chemopreventive agents, herein are reported the isolation, structural elucidation, and biological evaluation of 10 new (<b>1</b>–<b>10</b>) and three known (<b>11</b>–<b>13</b>) sesquiterpenes with a dihydro-β-agarofuran skeleton from the leaves of <i>Maytenus jelskii</i> Zahlbr. Their stereostructures have been elucidated by means of spectroscopic analysis, including 1D and 2D NMR techniques, ECD studies, and biogenetic considerations. The isolated metabolites and eight previously reported sesquiterpenes (<b>14</b>–<b>21</b>) were screened for their antitumor-promoting activity using a short-term in vitro assay for Epstein–Barr virus early antigen (EBV-EA) activation induced by 12-<i>O</i>-tetradecanoylphorbol-13-acetate (TPA). Six compounds from this series (<b>4</b>, <b>5</b>, <b>11</b>, and <b>13</b>–<b>15</b>) were found to exhibit higher efficacies than β-carotene, used as reference inhibitor for EBV-EA activation. In particular, promising antitumor activity was observed for compound <b>5</b>, exhibiting inhibition even at the lowest concentration assayed (10 mol ratio/TPA). Preliminary structure–activity relationship analysis revealed that the acetate, benzoate, and hydroxy groups are the most desirable substituents on the sesquiterpene scaffold for activity in the EBV-EA activation assay

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