A 3 + 2 formal cycloaddition reaction using aza-oxyallyl cation as a synthetic synthon was developed to construct the pyrroloindololine core. With this novel method, a variety of C3-substituted ...indoles were readily converted into the corresponding pyrroloindoline analogues at room temperature in the mixed solvents. To further demonstrate the utility of this method, a synthetic approach to the total synthesis of (±)-minfiensine was developed in quite concise fashion.
(±)-Minfiensine (1) was synthesized in 10 steps in 26% overall yield with the 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole core constructed through a 3+2 cycloaddition reaction between indole and an ...azaoxyallylic cation.
The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number ...of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03-69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03-69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03-69. Transcription profiling identified the upregulation of proapoptotic
gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03-69 led to an in vivo compatible compound MYF-03-176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.
Fragment-based drug discovery has recently drawn great attention from both industry and academia. Fragment library design is critical to success in this field. Herein we report our facile access to ...pyrazole derivatives via a cascade reaction involving a double C(sp3)–H functionalization and dehydrogenative aromatization sequence. Based on the newly developed method, we completed the synthesis of the Indian herbal medicine, withasomnine, in only two steps. In addition, inspired by the different biological activities of withasomnine, this cascade reaction sequence enables us to quickly build up a natural product-based fragment library. The compounds in this fragment library exhibit a variety of biological activities and demonstrate high hit rates on initial biological screening against COX-2.
A novel transition‐metal‐free method to construct N‐hydroxy oxindoles by an aza‐Nazarov‐type reaction involving azaoxyallyl cation intermediates is described. A variety of functional groups were ...tolerated under the weak basic reaction conditions and at room temperature. A one‐pot process was also developed to make the reaction even more practical. This method provides alternative access to oxindoles and their biologically active derivatives.
A bit weak: In the title reaction, a variety of functional groups are tolerated under weakly basic reaction conditions and at room temperature. This method provides alternative access to oxindoles and their biologically active derivatives. FG=functional group, HFIP=1,1,1,3,3,3‐hexafluoro‐2‐propanol.
A direct oxidative cyanation of arenes under FeII catalysis with 3,5‐di(trifluoromethyl)phenyl(cyano)iodonium triflate (DFCT) as the cyanating agent has been developed. The reaction is applicable to ...wide range of aromatic substrates, including polycyclic structures and heteroaromatic compounds.
Direct facile cyanation today! A direct cyanation of aryl CH bonds with 3,5‐di(trifluoromethyl)phenyl(cyano)iodonium triflate (DFCT) under FeII catalysis was successfully applied to a wide range of aromatic substrates, including polycyclic structures and heteroaromatic compounds (see scheme). The reaction proceeded efficiently under mild conditions.
We present the anhydride-based decarboxylative alkylation of aryl iodides catalyzed by nickel. This method of decarboxylative coupling works with a broad scope of aliphatic carboxylic anhydrides and ...tolerates synthetically useful aromatic substituents. Assisted by a redox system of pyridine N-oxide and zinc additives, the current reaction occurs under mild conditions and without the assistance of photocatalyst. Notably, this method features high chemoselectivity toward alkyl migration with mixed aliphatic/aromatic anhydrides. Thus, it provides a powerful synthetic tool to modify high-valued aliphatic carboxylic acids by converting them into mixed anhydrides using readily available aryl carboxylic acids such as p-toluic acid. We propose a catalytic cycle that involves the key steps of free radical-based decarboxylation and subsequent alkyl transfer to nickel that precedes an oxidatively induced C–C reductive elimination from Ni(III).
Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers
. Independent studies have identified cell death pathways that ...eliminate cells for the good of the organism
. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse large B cell lymphoma, in which the transcription factor B cell lymphoma 6 (BCL6) is deregulated
. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression
. We produced TCIPs by covalently linking small molecules that bind BCL6 to those that bind to transcriptional activators that contribute to the oncogenic program, such as BRD4. The most potent molecule, TCIP1, increases binding of BRD4 by 50% over genomic BCL6-binding sites to produce transcriptional elongation at pro-apoptotic target genes within 15 min, while reducing binding of BRD4 over enhancers by only 10%, reflecting a gain-of-function mechanism. TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC
of 1-10 nM in 72 h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription. The TCIP concept also has therapeutic applications in regulating the expression of genes for regenerative medicine and developmental disorders.
We report herein a transition-metal-free coupling reaction of arylboronic acids with benzyl halides and mesylates for the construction of C(sp2)C(sp3) bonds. A unique feature of this coupling ...reaction is the formation regioisomers in some cases. Mechanistic studies suggest that this reaction may proceed via an unprecedented Friedel–Crafts-type reaction pathway under base conditions with the assistance of boronic acid moiety.
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We report herein a metal-free cross-coupling of diazirines with arylboronic acids under oxidative conditions. The reaction affords a series of substituted olefins. It is proposed that the interaction ...between the nitrogen on diazirine with arylboronic acid plays a key role in this transformation.
