1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar,
strongly hydrogen
bond-donating solvent that has found numerous uses in organic synthesis
due to its ability to stabilize ionic species, transfer protons, and
engage in a range of other intermolecular interactions. The use of
this solvent has exponentially increased in the past decade and has
become a solvent of choice in some areas, such as C–H functionalization
chemistry. In this review, following a brief history of HFIP in organic
synthesis and an overview of its physical properties, literature examples
of organic reactions using HFIP as a solvent or an additive are presented,
emphasizing the effect of solvent of each reaction.
Cyclic 2-alkyl-1,3-alkanediones are ubiquitous structural motifs in many natural products of biological importance. Reported herein is an AlCl·MeNO-mediated Dieckmann cyclization reaction of general synthetic utility that enables direct access to complex 2-alkyl-1,3-dione building blocks from readily available dicarboxylic acid and acid chloride substrates. This new strategy enables direct synthetic access to the chiloglottone plant pheromones from commercial material in a single synthetic transformation.
The development of acid chlorides as formal dianion linchpin reagents that enable access to cyclic 2-alkyl- and 2-acyl-1,3-alkanediones from dicarboxylic acids is described herein. Mechanistic experiments relying on C-labeling studies confirm the role of acid chlorides as carbon dianion linchpin reagents and have led to a revised reaction mechanism for the aluminum(III)-mediated Dieckmann cyclization of dicarboxylic acids with acid chlorides.
New Avenues for the Synthesis of ent-Kaurene Diterpenoids -[92 refs. + subrefs.]. -(RIEHL, P. S.; DEPORRE, Y. C.; ARMALY, A. M.; GROSO, E. J.; SCHINDLER*, C. S.; Tetrahedron 71 (2015) 38, 6629-6650, http://dx.
The RNA-binding protein Hu antigen R (HuR) is a post-transcriptional
regulator critical in several types of diseases, including cancer,
making it a promising therapeutic target. We have identified small-molecule
inhibitors of HuR through a screening approach used in combination
with fragment analysis. A total of 36 new compounds originating from
fragment linking or structural optimization were studied to establish
structure–activity relationships in the set. Two top inhibitors, 1c and 7c, were further validated by binding
assays and cellular functional assays. Both block HuR function by
directly binding to the RNA-binding pocket, inhibit cancer cell growth
dependence of HuR, and suppress cancer cell invasion. Intraperitoneal
administration of inhibitor 1c inhibits tumor growth
as a single agent and shows a synergistic effect in combination with
chemotherapy docetaxel in breast cancer xenograft models. Mechanistically, 1c interferes with the HuR–TGFB/THBS1 axis.
Chemotherapy remains the standard treatment for triple‐negative breast cancer (TNBC); however, chemoresistance compromises its efficacy. The RNA‐binding protein Hu antigen R (HuR) could be a potential therapeutic target to enhance the chemotherapy efficacy. HuR is known to mainly stabilize its target mRNAs, and/or promote the translation of encoded proteins, which are implicated in multiple cancer hallmarks, including chemoresistance. In this study, a docetaxel‐resistant cell subline (231‐TR) was established from the human TNBC cell line MDA‐MB‐231. Both the parental and resistant cell lines exhibited similar sensitivity to the small molecule functional inhibitor of HuR, KH‐3. Docetaxel and KH‐3 combination therapy synergistically inhibited cell proliferation in TNBC cells and tumor growth in three animal models. KH‐3 downregulated the expression levels of HuR targets (e.g., β‐Catenin and BCL2) in a time‐ and dose‐dependent manner. Moreover, KH‐3 restored docetaxel's effects on activating Caspase‐3 and cleaving PARP in 231‐TR cells, induced apoptotic cell death, and caused S‐phase cell cycle arrest. Together, our findings suggest that HuR is a critical mediator of docetaxel resistance and provide a rationale for combining HuR inhibitors and chemotherapeutic agents to enhance chemotherapy efficacy.
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