Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23 interaction.

HER2 overexpression significantly contributes to the aggressive nature and recurrent patterns observed in various solid tumors, notably gastric cancers. Trastuzumab, HER2-targeting monoclonal antibody drug, has shown considerable clinical success; however, readily emerging drug resistance emphasizes the pressing need for improved interventions in HER2-overexpressing cancers. To address this, we proposed targeting the protein-protein interaction (PPI) between ELF3 and MED23 as an alternative therapeutic approach to trastuzumab.

Stereoselective total synthesis of (3)- and (3)-elatenynes.

We describe here the highly stereoselective total synthesis of the C acetogenins (3)- and (3)-elatenynes having a 7,12-dibromo-6,9--10,13- adjacent bis-tetrahydrofuran (THF) core. The present synthesis features a highly stereoselective, protecting group-dependent, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 7-hydroxy-6,7--6,9--THF intermediate 10, deployment of the sequential ate complex (-BuLi/DIBAL-H) reduction/Keck allylation/cross metathesis (CM) protocol for the stereoselective introduction of the C(10)-C(15) unit, a sequential Sharpless asymmetric dihydroxylation (SAD)/intramolecular Williamson etherification for the construction of the 10,13--THF ring, and a modified Nakata chloromethanesulfonate-mediated S2 displacement for the 7,12-dibromo functionality. Furthermore, our strategy based on chelate-controlled IAEA methodology would provide access to any member of the C adjacent bis-THF acetogenin class.

Total Synthesis and Structure Confirmation of (-)-Asimitrin, a C Annonaceous Acetogenin with a Hydroxylated Adjacent Bis-Tetrahydrofuran Core.

The total synthesis and structure confirmation of the potent cytotoxic agent (-)-asimitrin (), a C annonaceous acetogenin having a hydroxylated adjacent bis-tetrahydrofuran (THF) core, are described. The present synthesis features a highly stereoselective, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 17-hydroxy-16,17--16,19--THF , our direct ketone synthesis/l-Selectride reduction protocol for stereoselective introduction of the C(21)-C(34) unit, Sharpless asymmetric dihydroxylation (SAD), and internal Williamson etherification for construction of the 20,23--THF ring.

Prenylated Chrysin Derivatives as Partial PPARγ Agonists with Adiponectin Secretion-Inducing Activity.

Decreased circulating adiponectin levels are associated with an increased risk of human metabolic diseases. The chemical-mediated upregulation of adiponectin biosynthesis has been proposed as a novel therapeutic approach to managing hypoadiponectinemia-associated diseases. In preliminary screening, the natural flavonoid chrysin () exhibited adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs).

Highly Stereodivergent Construction of a C-Symmetric ,- and ,-2,6-Dioxabicyclo[3.3.0]octane Framework by Double Intramolecular Amide Enolate Alkylation: Total Synthesis of (+)-Laurenidificin and (+)-Aplysiallene.

The highly stereoselective construction of C-symmetric ,- and ,-2,6-dioxabicyclo[3.3.0]octane (fused -tetrahydrofuran) skeletons and has been accomplished via a novel stereodivergent double intramolecular amide enolate alkylation of common cyclization substrate through the judicious choice of "chelate" versus crown ether-promoted "nonchelate" control.

Interrupting specific hydrogen bonds between ELF3 and MED23 as an alternative drug resistance-free strategy for HER2-overexpressing cancers.

Introduction: HER2 overexpression induces cancer aggression and frequent recurrences in many solid tumors. Because HER2 overproduction is generally followed by gene amplification, inhibition of protein-protein interaction (PPI) between transcriptional factor ELF3 and its coactivator MED23 has been considered an effective but challenging strategy.

Objectives: This study aimed to determine the hotspot of ELF3-MED23 PPI and further specify the essential residues and their key interactions in the hotspot which are controllable by small molecules with significant anticancer activity.

Galangin 3-benzyl-5-methylether derivatives function as an adiponectin synthesis-promoting peroxisome proliferator-activated receptor γ partial agonist.

The upregulation of adiponectin production has been suggested as a novel strategy for the treatment of metabolic diseases. Galangin, a natural flavonoid, exhibited adiponectin synthesis-promoting activity during adipogenesis in human bone marrow mesenchymal stem cells. In target identification, galangin bound both peroxisome proliferator-activated receptor (PPAR) γ and estrogen receptor (ER) β.

Asymmetric Total Synthesis and Determination of the Absolute Configuration of (+)-Srilankenyne via Sequence-Sensitive Halogenations Guided by Conformational Analysis.

This first asymmetric total synthesis of (+)-srilankenyne (), a halogenated C15 tetrahydropyran acetogenin isolated from , features a sequence-sensitive process guided by conformational analysis to solve the challenging problem of introducing halogens. A competing semipinacol rearrangement during the installation of C(12)-bromide was suppressed by our A strain-controlled bromination protocol with support from X-ray crystallographic and computational studies. The C(10)-chloride was then placed by the Nakata chloromesylate-mediated chlorination.

Sensitization of lung cancer cells by altered dimerization of HSP27.

Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain.

Synthesis and biological effect of chrom-4-one derivatives as functional inhibitors of heat shock protein 27.

Heat Shock Protein 27 (HSP27) is a member of small heat shock proteins with a highly-conserved α-crystalline domain. It inhibits aggregation of damaged proteins through a complex structural systems of phosphorylation-dependent oligomerization and self-assembly. It has been demonstrated that HSP27 is involved in a variety of pathophysiological pathways with negative or positive protective activities.

Synthesis and topoisomerases inhibitory activity of heteroaromatic chalcones.

The critical role of nuclear topoisomerase enzymes during cell proliferation process guided topoisomerases to be one of the major targets for anticancer drug development. We have designed and synthesized 22 heteroaromatic ring incorporated chalcone derivatives substituted with epoxide or thioepoxide. Topoisomerase enzyme inhibitory activity and cytotoxic tests were also conducted to evaluate compounds' pharmacological efficacy.

Synthesis and biological evaluation of C1-O-substituted-3-(3-butylamino-2-hydroxy-propoxy)-xanthen-9-one as topoisomerase IIα catalytic inhibitors.

Topoisomerase II poison blocks the transitorily generated DNA double-strand breaks (DSBs) from religation, thereby causes severe DNA damage and gene toxicity. While topoisomerase II catalytic inhibitor does not form cleavable DNA-enzyme complex because its function attributes to inhibition of the catalytic steps of the enzyme such as before generating DNA DSBs or in the last step of the catalytic cycle after religation. It has been reported that the stabilizing effect of etoposide on transient cleavable DNA-topoisomerase IIβ complex attributes to its secondary malignancy.

Overcoming HSP27-mediated resistance by altered dimerization of HSP27 using small molecules.

Heat shock protein 27 (HSP27, HSPB1) is an anti-apoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. The biochemical properties of HSP27 rely on a structural oligomeric and dynamic organization that is important for its chaperone activity. Down-regulation by small interfering RNA or inhibition with a dominant-negative mutant efficiently counteracts the anti-apoptotic and protective properties of HSP27.

Neuroprotective effect of synthetic chalcone derivatives as competitive dual inhibitors against μ-calpain and cathepsin B through the downregulation of tau phosphorylation and insoluble Aβ peptide formation.

A series of chalcone derivatives were synthesized and evaluated for their μ-calpain and cathepsin B inhibitory activities. Among the tested chalcone derivatives, two compounds, 7 and 11, showed potent inhibitory activities against μ-calpain and cathepsin B and were selected for further evaluation. Compounds 7 and 11 showed enzyme inhibitory activities at the cellular level and displayed neuroprotective effects against oxidative stress-induced apoptosis in SH-SY5Y cells, a human neuroblastoma cell line.