A Small Molecule Inhibits Deregulated NRF2 Transcriptional Activity in Cancer

NRF2 serves as the master regulator of oxidative stress resistance in mammalian cells. Although NRF2 activation decreases tumorigenic events in normal cells, accumulating evidence suggests that cancers have broadly selected for NRF2-activating mutations to promote anabolic growth and chemoresistance. Small molecules which inhibit NRF2 activity may therefore offer promise as an alternative anticancer treatment in NRF2 dependent cancers. We have used a high throughput screen to identify small molecules which decrease NRF2 transcriptional activity at antioxidant response element sites. One such molecule, termed AEM1, is capable of broadly decreasing the expression of NRF2 controlled genes, sensitizing A549 cells to various chemotherapeutic agents, and inhibiting the growth of A549 cells <i>in vitro</i> and <i>in vivo</i>. Profiling of multiple cell lines for their responsiveness to AEM1 revealed that AEM1’s activities are restricted to cell lines harboring mutations which render NRF2 constitutively active

Stereoselective Synthesis of 7-<i>epi</i>-Incarvilline

The enantioselective synthesis of 7-<i>epi</i>-incarvilline for formal syntheses of (−)-incarvilline, (+)-incarvine C, and (−)-incarvillateine is described. The key features of our synthesis involve (1) stereoselective construction of the optically active bicyclic lactone utilizing Pd(0)-catalyzed allylic alkylation, (2) efficient transformation of the bridged bicyclic lactone to the key bicyclic lactam skeleton, and (3) stereoselective elaborations of two stereocenters via a substrate-controlled catalytic hydrogenation and a 1,4-addition

Asymmetric Syntheses of 1-Deoxy-6,8a-di-<i>epi</i>-castanospermine and 1-Deoxy-6-<i>epi</i>-castanospermine

Asymmetric syntheses of both 1-deoxy-6,8a-di-<i>epi</i>-castanospermine and 1-deoxy-6-<i>epi</i>-castanospermine, polyhydroxylated indolizidine alkaloids that act as selective glycosidase inhibitors, have been accomplished in seven steps. The key feature of our unique syntheses includes the stereoselective introduction of the C-3 and C-4 hydroxyl groups utilizing the aza-Claisen rearrangement-induced ring expansion of 1-acyl-2-alkoxyvinyl pyrrolidine and a substrate-controlled stereoselective transannulation of the resulting azoninone intermediate

Stereoselective Synthesis of 1,4,5-Tri-<i>cis</i>-guaiane Sesquiterpene: First Total Synthesis of (−)-Dendroside C Aglycon

The first total synthesis of (−)-dendroside C aglycon, consisting of a 1,4,5-tri-<i>cis</i>-guaiane skeleton, from a versatile hydroazulene intermediate has been accomplished. The key features of the syntheses include the stereoselective preparation of the unusual <i>cis</i>-hydroazulene core via a sequence of a unique Dieckmann condensation of the bicyclic lactone system, which was concisely prepared by the tandem conjugate addition and intramolecular allylic alkylation of a butenolide precursor, and construction of the characteristic tricyclic skeleton by a carbene-mediated cyclopropanation

Identification and Validation of Cryptochrome Inhibitors That Modulate the Molecular Circadian Clock

Circadian rhythms, biological oscillations with a period of about 24 h, are maintained by a genetically determined innate time-keeping system called the molecular circadian clockwork. Despite the physiological and clinical importance of the circadian clock, the development of small molecule modulators that directly target the core clock machinery has only been recently initiated. In the present study, we aimed to identify novel small molecule modulators influencing the molecular feedback loop of the circadian clock by applying our two-step cell-based screening strategy based on E-box-mediated transcriptional activity to test more than 1000 drug-like compounds. A derivative of 2-ethoxypropanoic acid designated as compound <b>15</b> was selected as the most promising candidate in terms of both efficacy and potency. We then performed pull-down assays with the biotinylated compound and find out that both cryptochrome (CRY)­1 and 2 (CRY1/2), key negative components of the mammalian circadian clock, as molecular targets of compound <b>15</b>. In accordance with the binding property, compound <b>15</b> enhanced E-box-mediated transcription in a CRY1/2-dependent manner, and more importantly, it attenuated the circadian oscillation of Per2-Luc and Bmal1-dLuc activities in cultured fibroblasts, indicating that compound <b>15</b> can functionally inhibit the effects of CRY1/2 in the molecular circadian clockwork. In conclusion, the present study describes the first novel chemical inhibitor of CRY1/2 that inhibits the repressive function of CRY1/2, thereby activating CLOCK-BMAL1-evoked E-box-mediated transcription. Further optimizations and subsequent functional studies of this compound may lead to development of efficient therapeutic strategies for a variety of physiological and metabolic disorders with circadian natures

Asymmetric Total Synthesis of (+)-Intricenyne via an Endocyclization Route to Oxocane Skeleton

The first total synthesis of (+)-intricenyne consisting of an oxocane skeleton was achieved via an extremely selective endocyclization strategy. The key features of the synthesis include a regio- and diastereoselective epoxide opening reaction, concise elaboration of oxocane cores via abnormally selective endocyclization ether ring formation, and versatile incorporation of the labile functional groups

Asymmetric Total Synthesis of (+)-(3<i>E</i>)‑Pinnatifidenyne via Abnormally Regioselective Pd(0)-Catalyzed Endocyclization

The asymmetric total synthesis of the marine natural product (+)-(3<i>E</i>)-pinnatifidenyne was accomplished. The key features of the synthesis involve the construction of an eight-membered cyclic ether by the abnormally regioselective Pd(0)-catalyzed cyclization, the installation of a double bond in the oxocene skeleton by sequential <i>in situ</i> deconjugative isomerization, and the efficient introduction of the crucial chloride mediated by the substrate-controlled diastereoselective reduction

Redirection of Genetically Engineered CAR‑T Cells Using Bifunctional Small Molecules

Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) provide a potent antitumor response and have become a promising treatment option for cancer. However, despite their efficacy, CAR-T cells are associated with significant safety challenges related to the inability to control their activation and expansion and terminate their response. Herein, we demonstrate that a bifunctional small molecule “switch” consisting of folate conjugated to fluorescein isothiocyanate (folate-FITC) can redirect and regulate FITC-specific CAR-T cell activity toward folate receptor (FR)-overexpressing tumor cells. This system was shown to be highly cytotoxic to FR-positive cells with no activity against FR-negative cells, demonstrating the specificity of redirection by folate-FITC. Anti-FITC-CAR-T cell activation and proliferation was strictly dependent on the presence of both folate-FITC and FR-positive cells and was dose titratable with folate-FITC switch. This novel treatment paradigm may ultimately lead to increased safety for CAR-T cell immunotherapy

Ligand-Based Design, Synthesis, and Biological Evaluation of 2-Aminopyrimidines, a Novel Series of Receptor for Advanced Glycation End Products (RAGE) Inhibitors

Using the approach of ligand-based drug design, we discovered a novel series of 4,6-disubstituted 2-aminopyrimidines as RAGE inhibitors. In transgenic mouse models of AD, one of the 4,6-bis­(4-chlorophenyl)­pyrimidine analogs, <b>59</b>, significantly lowered the concentration of toxic soluble Aβ in the brain and improved cognitive function. SPR analysis confirmed the direct binding of <b>59</b> with RAGE, which should contribute to its biological activities via inhibition of the RAGE–Aβ interaction. We also predicted the binding mode of the 4,6-bis­(4-chlorophenyl)­pyrimidine analogs to the RAGE V-domain through flexible docking study