To replace animal testing and improve the prediction of skin sensitization, significant attention has been directed to the use of alternative methods. The direct peptide reactivity assay (DPRA), the regulatory agencies’ approved alternative in chemico method, has been applied for understanding the sensitization capacity of activated ascaridole. Ascaridole, the oxidative metabolite of α-terpinene, is considered to be one of the components responsible for the contact allergy associated with essential oils derived from Chenopodium and Melaleuca species. The recently developed high-throughput screening based on the dansyl cysteamine (HTS-DCYA) method was applied to understand the reported enhanced reactivity of activated ascaridole and possibly to identify the resulting elusive radical or other reactive species. For the first time, a substituted cyclohexenone was identified as a potential electrophilic intermediate resulting in higher depletion of nucleophilic DCYA, along with several nonreactive byproducts of ascaridole via a radical degradation mechanism. Formation of electrophilic species via radical degradation is one of the possible pathways should be considered for the peptide reactivity of in aged tea tree oil or oils rich in terpinenes along with commonly believed reactants, allylic-epoxides and allylic-peroxides.

Laurenditerpenol is the first marine natural product shown to inhibit hypoxia-inducible factor 1 (HIF-1) activation. Preclinical studies support that the inhibition of HIF-1 is one of the molecular targets for antitumor drug discovery. The synthetically challenging molecular architecture of laurenditerpenol, its absolute stereostructure, and the biological activity of several diastereoisomers were accomplished by our group in 2007 by diastereoselective synthesis. Herein, we report enantioselective syntheses of both enantiomers of laurenditerpenol involving sequential Michael addition and remote homoallylic hydroxyl group-directed asymmetric hydrogenation at ambient temperature and pressure as key reaction steps. The current approach is elegant and overall more efficient than the ones previously reported in the literature.

In addition to lowering blood pressure, telmisartan, an angiotensin (AT1) receptor blocker, has recently been shown to exert pleiotropic effects as a partial agonist of nuclear peroxisome proliferator-activated receptor γ (PPARγ). On the basis of these findings and docking pose similarity between telmisartan and rosiglitazone in PPARγ active site, two classes of benzimidazole derivatives were designed and synthesized as dual PPARγ agonist/angiotensin II antagonists for the possible treatment of metabolic syndrome. Compound 4, a bisbenzimidazole derivative showed the best affinity for the AT1 receptor with a Ki = 13.4 nM, but it was devoid of PPARγ activity. On the other hand 9, a monobenzimidazole derivative, showed the highest activity in PPARγ transactivation assay (69% activation) with no affinity for the AT1 receptor. Docking studies lead to the designing of a molecule with dual activity, 10, with moderate PPARγ activity (29%) and affinity for the AT1 receptor (Ki = 2.5 μM).

•Botanical estrogens are marketed to midlife women as an aide to healthy aging.•The efficacy of the botanical estrogen S-equol to alter cognition was assessed.•Middle-aged ovariectomized (OVX) rats were treated with S-equol.•Rats were tested on a prefrontal working memory or hippocampal place learning task.•S-equol treatment did not alter learning and memory on these tasks.The use of over-the-counter botanical estrogens containing isolated soy isoflavones, including genistein and daidzein, has become a popular alternative to traditional hormone therapies. Menopausal women use these products as an aide in healthy aging, including for the maintenance of cognitive function. The safety and efficacy of many of these commercial preparations remain unknown. Previous research in our lab found that treatment of ovariectomized (OVX) female Long-Evans rats with genistein impaired working memory in an operant delayed spatial alternation (DSA) task and response learning in a plus-maze, but enhanced place learning assessed in the plus-maze. The present study further examined the effects of isolated isoflavones on working memory and place learning by treating middle-aged (12–13 month old) OVX female Long-Evans rats with S-equol, the exclusive enantiomer produced by metabolism of daidzein in the mammalian gut. S-equol binds selectively to ERβ with an affinity similar to that of genistein but has low transcriptional potency. For DSA testing, S-equol at 1.94, 0.97 mg, or 0 mg (sucrose control) was orally administered to animals daily, 30 min before behavioral testing, and again both 4 and 8 hours after the first treatment. Rats were tested on the DSA task following the first, morning dose. For place learning, rats received 0.97 mg S-equol every 4 hours during the light portion of the cycle beginning 48 hours prior to behavioral testing (total exposure 8.7 mg S-equol). S-equol treatment was largely without effect on the DSA and place learning tasks. This is the first study to test the behavioral effects of isolated S-equol in OVX rodents, and shows that, unlike genistein or estradiol, repeated daily treatment with this isoflavone metabolite does not alter learning and memory processes in middle-aged OVX rats.