RESUMO
Preparation of a range of enantioenriched ß-fluoro amines (α,ß-disubstituted) is described in which the nitrogen and fluorine atoms are attached to sp3-hybridized carbons. The key finding is a chiral bifunctional Brønsted acid/base catalyst that can deliver ß-amino-α-fluoro nitroalkanes with high enantio- and diastereoselection. A denitration step renders the nitro group "traceless" and delivers secondary, tertiary, or vinyl alkyl fluorides embedded within a vicinal fluoro amine functional group. A synthesis of each possible stereoisomer of a ß-fluoro lanicemine illustrates the potential ease with which fluorinated small molecules relevant to neuroscience drug development can be prepared in a stereochemically comprehensive manner.
RESUMO
Carbon dioxide exhibits many of the qualities of an ideal reagent: it is nontoxic, plentiful, and inexpensive. Unlike other gaseous reagents, however, it has found limited use in enantioselective synthesis. Moreover, unprecedented is a tool that merges one of the simplest biological approaches to catalysis-Brønsted acid/base activation-with this abundant reagent. We describe a metal-free small molecule catalyst that achieves the three component reaction between a homoallylic alcohol, carbon dioxide, and an electrophilic source of iodine. Cyclic carbonates are formed enantioselectively.
Assuntos
Ácidos/química , Álcalis/química , Dióxido de Carbono/química , Etilenodiaminas/química , Compostos Organometálicos/química , Bibliotecas de Moléculas Pequenas/síntese química , Catálise , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , EstereoisomerismoRESUMO
The finding by scientists at Hoffmann-La Roche that cis-imidazolines could disrupt the protein-protein interaction between p53 and MDM2, thereby inducing apoptosis in cancer cells, raised considerable interest in this scaffold over the past decade. Initial routes to these small molecules (i.e., Nutlin-3) provided only the racemic form, with enantiomers being enriched by chromatographic separation using high-pressure liquid chromatography (HPLC) and a chiral stationary phase. Reported here is the first application of an enantioselective aza-Henry approach to nonsymmetric cis-stilbene diamines and cis-imidazolines. Two novel mono(amidine) organocatalysts (MAM) were discovered to provide high levels of enantioselection (>95% ee) across a broad range of substrate combinations. Furthermore, the versatility of the aza-Henry strategy for preparing nonsymmetric cis-imidazolines is illustrated by a comparison of the roles of aryl nitromethane and aryl aldimine in the key step, which revealed unique substrate electronic effects providing direction for aza-Henry substrate-catalyst matching. This method was used to prepare highly substituted cis-4,5-diaryl imidazolines that project unique aromatic rings, and these were evaluated for MDM2-p53 inhibition in a fluorescence polarization assay. The diversification of access to cis-stilbene diamine-derived imidazolines provided by this platform should streamline their further development as chemical tools for disrupting protein-protein interactions.
Assuntos
Amidinas/química , Diaminas/química , Imidazolinas/química , Estilbenos/química , Apoptose , Catálise , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Polarização de Fluorescência , Humanos , Estrutura Molecular , Fenômenos de Química Orgânica , Domínios e Motivos de Interação entre Proteínas , EstereoisomerismoRESUMO
Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TEAD complex formation and transcriptional activity. We report the discovery and characterization of a novel YAP1/TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TEAD activity. In vivo, MRK-A showed a favorable tolerability profile in mice and demonstrated pharmacokinetics suitable for twice daily oral dosing in preclinical efficacy studies. Importantly, monotherapeutic targeting of YAP1/TEAD in preclinical models generated regressions in a mesothelioma CDX model; however, rapid resistance to therapy was observed. RNA-sequencing of resistant tumors revealed mRNA expression changes correlated with the resistance state and a marked increase of hepatocyte growth factor (HGF) expression. In vitro, exogenous HGF was able to fully rescue cytostasis induced by MRK-A in mesothelioma cell lines. In addition, co-administration of small molecule inhibitors of the MET receptor tyrosine kinase suppressed the resistance generating effect of HGF on MRK-A induced growth inhibition. In this work, we report the structure and characterization of MRK-A, demonstrating potent and specific inhibition of YAP1/TAZ-TEAD-mediated transcriptional responses, with potential implications for treating malignancies driven by altered Hippo signaling, including factors resulting in acquired drug resistance.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Resistencia a Medicamentos Antineoplásicos , Fator de Crescimento de Hepatócito , Proteínas Proto-Oncogênicas c-met , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Fator de Crescimento de Hepatócito/metabolismo , Animais , Fatores de Transcrição/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição de Domínio TEA , Proliferação de Células/efeitos dos fármacosRESUMO
Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure-activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.
RESUMO
Late-stage derivatization of pharmaceutically relevant scaffolds relies on the availability of highly functional-group tolerant reactions. Reactions that increase the sp3 character of molecules enable the pursuit of more selective and well-tolerated pharmaceuticals. Herein, we report the use of sp3-sp2 cross-electrophile reductive couplings to modify a generic ATP-competitive kinase inhibitor with a broad range of primary and secondary alkyl halide coupling partners.
Assuntos
Hidrocarbonetos Bromados/química , Preparações Farmacêuticas/química , Inibidores de Proteínas Quinases/química , Estrutura Molecular , Oxirredução , Preparações Farmacêuticas/síntese química , Inibidores de Proteínas Quinases/síntese químicaRESUMO
Site-specific functionalization of unprotected native peptides and biomolecules remains a useful transformation in synthetic design and chemical biology, yet until recently, advancements in transition metal-catalyzed methods, which have prevailed in organic synthesis, have been relatively ineffective when applied to large and structurally complex biomolecules. Here, the mechanistically distinct, Ni/photoredox-catalyzed arylation of unprotected, native thiols (e.g., cysteine residues) is reported - a process initiated through a visible light-promoted, hydrogen atom transfer (HAT) event under ambient conditions. Sub-stoichiometric loadings of the dual-catalyst system (≤5 mol%) are employed, granting excellent site-specificity, broad substrate scope, and low chemical waste. Reaction scalability (from µg to grams) has been achieved through modest reagent adjustments, and high throughput experimentation (HTE) demonstrates the ease of reaction setup, enabling prompt screening of aryl halide coupling partners and conditions. Scores of thiol substrates and aryl entities were examined and effectively conjugated, suggesting further diverse, practical applications.
RESUMO
Alkyl xanthate esters are perhaps best known for their use in deoxygenation chemistry. However, their use in cross-coupling chemistry has not been productive, which is due, in part, to inadequate xanthate activation strategies. Herein, we report the use of O-benzyl xanthate esters, readily derived from alcohols, as radical pronucleophiles in Csp3-Csp2 cross-couplings under Ni/photoredox dual catalysis. Xanthate (C-O) cleavage is found to be reliant on photogenerated (sec-butyl) radical activators to form new carbon-centered radicals primed for nickel-catalyzed cross-couplings. Mechanistic experiments support the fact that the key radical components are formed independently, and relative rates are carefully orchestrated, such that no cross reactivity is observed.
RESUMO
The attractive field of iterative cross-coupling has seen numerous advances, although almost exclusively in the union of sp2-hybridized partners. Conspicuously absent from this useful synthetic manifold is the inclusion of sp3-hybridized pronucleophiles that can undergo transmetalation under mild conditions. Described here is the use of primary and secondary ammonium alkylsilicates, which undergo facile C(sp3)-C(sp2) cross-coupling with borylated aryl bromide partners under photoredox/nickel dual catalysis conditions. This operationally simple procedure allows the production of alkylated small molecules possessing boronate ester (BPin, Bneopentyl, BMIDA) functional handles. Because of the extremely mild reaction conditions and the innocuous byproduct generated upon fragmentative oxidation of silicates, the corresponding borylated compounds were isolated in good to excellent yields. Aryl bromides bearing unprotected boronic acids are also generally tolerated for the first time and prove useful in multistep syntheses. Unlike many previously reported photoredox/Ni dual cross-couplings, the C(sp3)-C(sp2) bonds were forged using a transition metal-free photocatalyst, allowing a substantial increase in sustainability as well as a cost reduction. Because the developed Ni-catalyzed cross-coupling does not require discrete boron speciation control, as in many popular orthogonal Pd-based methods, this protocol represents a significant advance in atom- and step-economy.
RESUMO
Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations.
Assuntos
Azepinas/administração & dosagem , Dano ao DNA/efeitos dos fármacos , Imidazóis/administração & dosagem , Melanoma/tratamento farmacológico , Piperazinas/administração & dosagem , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirrolidinas/administração & dosagem , para-Aminobenzoatos/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azepinas/farmacologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Replicação do DNA/efeitos dos fármacos , Células HCT116 , Humanos , Imidazóis/farmacologia , Melanoma/genética , Camundongos , Piperazinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , para-Aminobenzoatos/farmacologiaRESUMO
A Ni/photoredox dual catalytic cross-coupling is disclosed in which a diverse range of (hetero)aryl bromides are used as electrophiles, with 1,4-dihydropyridines serving as precursors to Csp3-centered alkyl radical coupling partners. The reported method is characterized by its extremely mild reaction conditions, enabling access to underexplored cores.
RESUMO
Chiral diamine-derived hydrogen-bond donors were evaluated for their ability to effect stereocontrol in an intramolecular hetero-Diels-Alder (HDA) reaction hypothesized in the biosynthesis of brevianamides A and B. Collectively, these results provide proof of principle that small-molecule hydrogen-bond catalysis, if even based on a hypothetical biosynthesis construct, holds significant potential within enantioselective natural product synthesis.