Cancer preventive agents 10. Prenylated dehydrozingerone analogs as potent chemopreventive agents

Dehydrozingerone analogs and related compounds were screened as potential antitumor promoters by using the in vitro short-term 12-O-tetradecanphorbol-13-acetate (TPA)-induced Epstein-Barr virus early antigen (EBV-EA) activation assay. Among 40 synthesized compounds, the prenylated analogs 16 and 34–36 showed the most significant and promising activity (100% inhibition of activation at 1×10 3 mol ratio/TPA, and 82–80%, 37–35%, 13–11% inhibition at 5×102, 1×102, 1×10 mol ratio/TPA, respectively) in this screening. Their activity profiles were comparable to that of the reference standard curcumin. While a prenyl moiety conferred potent chemopreventive activity, an extended prenyl unit such as a farnesyl moiety did not improve activity. Because in vitro inhibitory effects in this assay generally correlate well with in vivo inhibitory effects on tumor promotion, our results strongly suggested that prenylated 16 and 34–36 are likely to be promising antitumor promoters

Cancer preventive agents 9. Betulinic acid derivatives as potent cancer chemopreventive agents

C-3 Esterifications of betulinic acid (BA, 1) and its A-ring homolog, ceanothic acid (CA, 2), were carried out to provide sixteen terpenoids, 4-19, including nine new compounds (4-12). All synthesized compounds were evaluated in an in vitro antitumor-promoting assay using the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Among them, compounds 4-6, 11-14, 16, and 17 displayed remarkable inhibitory effects of EBV-EA activation. BA analog 6, which contains a prenyl-like group, showed the most potent inhibitory effect (100, 76, 37, and 11% inhibition of EBA activation at 1000, 500, 100 and 10 mol ratio/TPA, respectively, with IC50 value of 285 mol ratio/32pmol TPA). Compound 6 merits further development as a cancer preventive agent

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

Design, synthesis and experimental validation of novel potential chemopreventive agents using random forest and support vector machine binary classifiers

Compared to the current knowledge on cancer chemotherapeutic agents, only limited information is available on the ability of organic compounds, such as drugs and/or natural products, to prevent or delay the onset of cancer. In order to evaluate chemical chemopreventive potentials and design novel chemopreventive agents with low to no toxicity, we developed predictive computational models for chemopreventive agents in this study. First, we curated a database containing over 400 organic compounds with known chemoprevention activities. Based on this database, various random forest and support vector machine binary classifiers were developed. All of the resulting models were validated by cross validation procedures. Then, the validated models were applied to virtually screen a chemical library containing around 23,000 natural products and derivatives. We selected a list of 148 novel chemopreventive compounds based on the consensus prediction of all validated models. We further analyzed the predicted active compounds by their ease of organic synthesis. Finally, 18 compounds were synthesized and experimentally validated for their chemopreventive activity. The experimental validation results paralleled the cross validation results, demonstrating the utility of the developed models. The predictive models developed in this study can be applied to virtually screen other chemical libraries to identify novel lead compounds for the chemo-prevention of cancers

A-ring modified betulinic acid derivatives as potent cancer preventive agents

Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7–15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1 × 103 mol ratio/TPA and 73. 4%, 35. 9%, and 8. 4% inhibition at 5 × 102, 1 × 102, and 1 × 10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay

Total synthesis of plagiochin G and derivatives as potential cancer chemopreventive agents

A new and efficient total synthesis has been developed to obtain plagiochin G (22), a macrocyclic bisbibenzyl, and four derivatives. The key 16-membered ring containing biphenyl ether and biaryl units was closed via an intramolecular SNAr reaction. All synthesized macrocyclic bisbibenzyls inhibited Epstein-Barr virus early antigen (EBVEA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and, thus, are potential cancer chemopreventive agents