Pauline Chiu

Alisol B, a Novel Inhibitor of the Sarcoplasmic/Endoplasmic Reticulum Ca2+ ATPase Pump, Induces Autophagy, Endoplasmic Reticulum Stress, and Apoptosis

Emerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B–treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G1 phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B–treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound. Mol Cancer Ther; 9(3); 718–30

Pseudolaric Acid B, a Novel Microtubule-Destabilizing Agent That Circumvents Multidrug Resistance Phenotype and Exhibits Antitumor Activity In vivo

Purpose: Pseudolaric acid B (PAB) is the major bioactive constituent in the root bark of Pseudolarix kaempferi that has been used as an antifungal remedy in traditional Chinese medicine. Previous studies showed that PAB exhibited substantial cytotoxicity. The aims of this study were to elucidate the molecular target of PAB, to examine its mechanism of action, and to evaluate the efficacy of this compound in vivo. Experimental Design: The effect of PAB on cell growth inhibition toward a panel of cancer cell lines was assayed. Cell cycle analysis, Western blotting, immunocytochemistry, and apoptosis analysis were carried out to examine the mechanism of action. Tubulin polymerization assays were conducted to examine the interaction between PAB and tubulin. A P-glycoprotein–overexpressing cell line was used to evaluate the efficacy of PAB toward multidrug-resistant phenotypes. In vivo efficacy of PAB was evaluated by the murine xenograft model. Results: PAB induces cell cycle arrest at G2-M transition, leading to apoptosis. The drug disrupts cellular microtubule networks and inhibits the formation of mitotic spindles. Polymerization of purified bovine brain tubulin was dose-dependently inhibited by PAB. Furthermore, PAB circumvents the multidrug resistance mechanism, displaying notable potency also in P-glycoprotein–overexpressing cells. Finally, we showed that PAB is effective in inhibiting tumor growth in vivo. Conclusions: We identified the microtubules as the molecular target of PAB. Furthermore, we showed that PAB circumvents P-glycoprotein overexpression-induced drug resistance and is effective in inhibiting tumor growth in vivo. Our work will facilitate the future development of PAB as a cancer therapeutic.

Inter- and intramolecular [4 + 3] cycloadditions using epoxy enol silanes as functionalized oxyallyl cation precursors

Using epoxy enol triethylsilanes as oxyallyl cation precursors, [4 + 3] cycloadditions with various dienes occur under catalysis by silyl triflates and acids in good yields. The intramolecular [4 + 3] cycloaddition proceeds under mild conditions and generate hydroxylated cycloadducts with high diastereoselectivity and yields. Enantiomerically pure epoxy enol silanes have been shown to give excellent yields of the optically pure cycloadduct bearing multiple stereocenters.

A CONJUGATE REDUCTION-INTRAMOLECULAR ALDOL STRATEGY TOWARD THE SYNTHESIS OF PSEUDOLARIC ACID A

Abstract An unprecedented tandem conjugate reduction-intramolecular aldol cyclization using Strykers reagent produced diastereomers of 5 from the ketoester precursor 8 . Compound 5c with the trans -fused perhydroazulene carboskeleton as in pseudolaric acid A was formed as a minor isomer, while the all- cis 5b was obtained as the major product. The structures of the two diastereomers have been determined by X-ray crystallography.

An expeditious asymmetric synthesis of the pentacyclic core of the cortistatins by an intramolecular (4+3) cycloaddition

A concise, asymmetric synthesis of the pentacyclic framework of the cortistatins has been accomplished in 12 steps from commercially available starting materials, employing a highly diastereoselective intramolecular (4+3) cycloaddition of epoxy enolsilanes as the key step.

Pseudolaric acids: isolation, bioactivity and synthetic studies

The pseudolaric acids are diterpenoids isolated from the root bark of Pseudolarix amabilis, or the golden larch. Pseudolaric acids A and B are the major antifungal and anti-angiogenic congeners of this family of compounds. This review presents the results of the isolation, biological and synthetic studies of these natural products. 127 references are cited.

An expedient preparation of Stryker's reagent

Abstract A convenient and efficient preparation of Strykers reagent, [Ph3PCuH]6, under homogeneous conditions using silanes as the reducing agent is detailed. The reaction time can be reduced to 1–2 h, and high yields of Strykers reagent can be routinely achieved. The same method has been extended to the synthesis of [Ph3PCuD]6 using Ph2SiD2.

Asymmetric (4+3) Cycloadditions of Enantiomerically Enriched Epoxy Enolsilanes

employed, thus resulting in bicyclic adducts which are useful synthetic intermediates. Compared with the (4+2) reaction, however, asymmetric (4+3) cycloadditions remain underdeveloped. Other than two examples of asymmetric catalysis, the majority of asymmetric versions of (4+3) cycloadditions rely on chiral auxiliaries or incorporate chiral elements into the reacting cation or the diene. 6] On the basis of the seminal work by Eguchi et al. , we have developed a silyl-triflate-catalyzed intramolecular (4+3) cycloaddition reaction of furan-tethered epoxy enolsilanes such as 1, and it affords the cycloadduct 2 in excellent yield and diastereoselectivity (Scheme 2). The corresponding intermolecular (4+3) cycloadditions with epoxy enolsilanes such as 3a have also been observed to generate endo and exo cycloadducts with facial selectivity (Scheme 2). In both cases, the reactions with optically active epoxy enolsilanes generate cycloadducts with high conservation of the enantiomeric excess. 10] Each of these cycloadducts has inherited one stereocenter (* in Scheme 2) from the epoxide precursor, so the observed selectivity could be understood as a diastereoselective cycloaddition of chiral oxyallyl cations, similar to the previously reported asymmetric (4+3) cycloadditions involving chiral cations. In contrast, for intermolecular (4+3) cycloadditions of simpler enolsilanes such as the optically pure 5 a (Scheme 3), the corresponding oxyallyl cation would be expected to be

Application of the tandem Stryker reduction–aldol cyclization strategy to the asymmetric synthesis of lucinone

Abstract The tandem conjugate reduction–aldol cyclization using Strykers reagent has been employed as the key-step in an asymmetric total synthesis of lucinone.

Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library

Amentoflavone has been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library. In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo. Molecular modeling and kinetic experiments suggested that the analogues may function as Type II inhibitors of JAK2.