RESUMEN
A mild and efficient method for photoredox-catalyzed bromonitroalkylation of alkenes is described herein. In this reaction, bromonitromethane serves as a source of both nitroalkyl and bromine for direct and regioselective formation of C-Br and C-C bonds from alkenes, and additional cyclization provides C-C bonds to the cyclopropylamine core as an LSD1 inhibitor.
RESUMEN
A mild and efficient three-component thio(seleno)cyano-difluoroalkylation of simple alkenes is demonstrated using an iridium(ruthenium) photocatalyst. This protocol provides a direct and regioselective installation of both C-S(Se)CN [thio(seleno)cyanation] and C-CF (difluoroalkylation) bonds.
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In order to deliver chemotherapeutics more efficiently, small-molecule-drug conjugates (SMDCs) and antibody-drug conjugates (ADCs) have been synthesized and explored. These conjugates not only provide selective delivery but also improve the therapeutic index of toxins. By merging this conjugate concept with target protein degradation (TPD), the degrader-antibody conjugate (DAC) field has emerged, and clinical trials have even begun in recent years. In this Perspective, we provide the concepts, applications, and recent advances in the area of DACs.
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Antineoplásicos , Inmunoconjugados , Inmunoconjugados/uso terapéutico , Preparaciones Farmacéuticas , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: The dysregulation of melanin production causes skin-disfiguring ultraviolet (UV)-associated hyperpigmented spots. Previously, we found that the activation of c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase (MAPK), inhibited melanogenesis. METHODS: We selected BCI-215 as it may modify MAPK expression via a known function of a dual-specificity phosphatase (DUSP) 1/6 inhibitor. B16F10 melanoma cells, Mel-ab cells, human melanocytes, and a coculture were used to assess the anti-melanogenic activity of BCI-215. The molecular mechanisms were deciphered by assaying the melanin content and cellular tyrosinase activity via immunoblotting and RT-PCR. RESULTS: BCI-215 was found to suppress basal and cAMP-stimulated melanin production and cellular tyrosinase activity in vitro through the downregulation of microphthalmia-associated transcription factor (MITF) protein and its downstream enzymes. The reduction in MITF expression caused by BCI-215 was found to be due to all three types of MAPK activation, including extracellular signal-regulated kinase (ERK), JNK, and p38. The degree of activation was greater in ERK. A phosphorylation of the ß-catenin pathway was also demonstrated. The melanin index, expression of MITF, and downstream enzymes were well-reduced in UVB-irradiated ex vivo human skin by BCI-215. CONCLUSIONS: As BCI-215 potently inhibits UV-stimulated melanogenesis, small molecules of DUSP-related signaling modulators may provide therapeutic benefits against pigmentation disorders.
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Interfaces Cerebro-Computador , Fosfatasas de Especificidad Dual , Hiperpigmentación , Línea Celular Tumoral , Fosfatasas de Especificidad Dual/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Hiperpigmentación/metabolismo , Melaninas , Melanocitos/metabolismo , Monofenol Monooxigenasa , PigmentaciónRESUMEN
Inhibition of translation initiation has emerging implications for the development of mechanism-based anticancer therapeutics. Phosphorylation of eIF2α is recognized as a key target that regulates the translation initiation cascade. Based on the bioisosteric replacement of urea-derived eIF2α phosphorylation activator 1, a novel series of N-aryl-N'-[4-(aryloxy)cyclohexyl]squaramide derivatives was designed and synthesized; their effects on the activation of eIF2α phosphorylation was assessed systematically. A brief structure-activity relationship analysis was established by stepwise structural optimization of the squaramide series. Subsequently, the antiproliferative activities of the selected analogues were determined in human leukemia K562 cells. We then identified 10 potent eIF2α phosphorylation activators with considerable anticancer activity. The most promising analogues 19 and 40 possessed higher cancer cell selectivity (SI = 6.16 and 4.83, respectively) than parent 1 (SI = 2.20). Finally, protein expression analysis revealed that compounds 19 and 40 induced eIF2α phosphorylation and its downstream effectors ATF4 and CHOP.
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Factor 2 Eucariótico de Iniciación , Quinina , Humanos , Fosforilación , Quinina/análogos & derivados , Relación Estructura-ActividadRESUMEN
Nuclear receptor-binding SET domain (NSD) proteins are a class of histone lysine methyltransferases (HKMTases) that are amplified, mutated, translocated, or overexpressed in various types of cancers. Several campaigns to develop NSD inhibitors for cancer treatment have begun following recent advances in knowledge of NSD1, NSD2, and NSD3 structures and functions as well as the U.S. FDA approval of the first HKMTase inhibitor (tazemetostat, an EZH2 inhibitor) to treat follicular lymphoma and epithelioid sarcoma. This perspective highlights recent findings on the structures of catalytic su(var), enhancer-of-zeste, trithorax (SET) domains and other functional domains of NSD methyltransferases. In addition, recent progress and efforts to discover NSD-specific small molecule inhibitors against cancer-targeting catalytic SET domains, plant homeodomains, and proline-tryptophan-tryptophan-proline domains are summarized.
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Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Neoplasias/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Antineoplásicos/química , Inhibidores Enzimáticos/química , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Estructura Molecular , Neoplasias/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Psiguadial B (8), and its fluoro- (8a), chloro- (8b), and bromo- (8c) derivatives were synthesized using a sodium acetate-catalyzed single step coupling of three components: ß-caryophyllene (5), diformylphloroglucinol (11), and benzaldehyde (12). These compounds efficiently and dose-dependently decreased H2O2-induced cell death, a quantitative marker of cell death, in primary cultures of mouse cortical neurons. Psiguadial B also decreased neuronal death and accumulation of ROS induced by FeCl2 in cortical cultures. The in vitro effects of these compounds in lipopolysaccharide (LPS)-induced expression of nitric oxide (NO), and TNF-α and IL-6 by suppressing the NF-κB pathway in immune cells demonstrated their antioxidative and anti-inflammatory activity. The present findings warrant further research on the development of psiguadial B-based neuroprotective agents for the treatment of neurodegenerative diseases, acute brain injuries and immunological disorders.
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Antiinflamatorios/química , Antioxidantes/química , Fármacos Neuroprotectores/química , Terpenos/química , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Compuestos Ferrosos/farmacología , Halogenación , Peróxido de Hidrógeno/farmacología , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacología , Óxido Nítrico/metabolismo , Psidium/química , Psidium/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Rpn13 is one of several ubiquitin receptors in the 26S proteasome. Cys88 of Rpn13 has been proposed to be the principal target of RA190, an electrophilic small molecule with interesting anti-cancer activities. Here, we examine the claim that RA190 mediates its cytotoxic effects through engagement with Rpn13. We find no evidence that this is the case. In vitro, RA190 is has no measurable effect on any of the known interactions of Rpn13. In cellulo, we see no physical engagement of Rpn13 by RA190, either on C88 or any other residue. However, chemical proteomics experiments in two different cell lines reveal that dozens of other proteins are heavily engaged by RA190. Finally, increasing or reducing the level of Rpn13 in HeLa and melanoma cells had no effect on the sensitivity of HeLa or melanoma cells to RA190. We conclude that Rpn13 is not the physiologically relevant target of RA190.
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Compuestos de Bencilideno/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Compuestos de Bencilideno/síntesis química , Compuestos de Bencilideno/química , Células Cultivadas , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Estructura MolecularRESUMEN
Estrogen-related receptor gamma (ERRγ) is the NR3B subgroup of associated transcription factors. In this report, a new generation of a potent and selective ERRγ inverse agonist (25) with good biocompatibility was proposed. We also explored the potential of the newly developed compound 25 in the PDTC model to expand the original indications from ATC. In addition, an X-ray crystallographic study of the ligand and ERRγ co-complex showed that 25 completely binds to the target protein (PDB 6KNR). Its medicinal chemistry, including a distinctive structural study to in vivo results, denotes that 25 may be directed towards the development of a pivotal treatment for ERRγ-related cancers.
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Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Agonismo Inverso de Drogas , Radioisótopos de Yodo/uso terapéutico , Receptores de Estrógenos/antagonistas & inhibidores , Neoplasias de la Tiroides/tratamiento farmacológico , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Disponibilidad Biológica , Línea Celular Tumoral , Humanos , Simulación del Acoplamiento Molecular , Conformación Proteica , Receptores de Estrógenos/química , Receptores de Estrógenos/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/radioterapiaRESUMEN
One of the three subtypes of the peroxisome proliferator-activated receptor (PPAR) functioning as a transcription factor is the PPARß or PPARδ. PPARδ is crucial to pathophysiological processes, including metabolic disorders, liver diseases, and cardiovascular diseases. In the past, the clinical development of PPARδ-selective agonist drugs has been stalled due to potential safety-related issues. Despite the elusiveness of such a drug, efforts continue in developing drugs that target PPARδ due to advances in the knowledge of the PPARδ receptor's structure and functions. While several preclinical and clinical studies are reported on PPARδ agonists, there is limited data with no clinical evidence available for PPARδ-selective antagonists. In this review, we mainly focus on the challenges of PPARδ selectivity and the medicinal chemistry of most active agonists discovered by different pharmaceutical companies and institutes. With this in mind, we also provide an update on the development status of PPARδ agonists that are undergoing clinical trials and their therapeutic promise for the treatment of various diseases.
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Compuestos Orgánicos/uso terapéutico , PPAR delta/agonistas , Animales , Química Farmacéutica , Humanos , Estructura Molecular , Compuestos Orgánicos/química , Compuestos Orgánicos/farmacología , PPAR delta/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The development of faster and less expensive methods to discover bioactive small molecules remains a high priority in chemical biology. This article discusses one alternative to traditional high-throughput screening: the synthesis and screening of one bead one compound (OBOC) libraries. Protocols are provided to create and screen libraries of peptoid displayed on TentaGel beads, which is a cheap and relatively straightforward process for the identification of selective protein ligands. However, peptoids bind to proteins with modest affinity in most cases. Therefore, we also describe protocols to create libraries of stiffer oligomers called PICCOs (peptoid-inspired, conformationally constrained oligomers) that have proven to be a superior source of high affinity ligands.
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Técnicas Químicas Combinatorias/métodos , Peptoides/síntesis química , Peptoides/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Ligandos , Microesferas , Modelos Moleculares , Peptoides/química , Proteínas/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Técnicas de Síntesis en Fase Sólida/métodos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodosRESUMEN
Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.
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Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Diseño de Fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Neovascularización Retiniana/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Benceno/química , Benceno/farmacología , Benceno/uso terapéutico , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Ratones , Solubilidad , Relación Estructura-Actividad , Agua/químicaRESUMEN
The first total synthesis of (-)-dendroside C aglycon, consisting of a 1,4,5-tri-cis-guaiane skeleton, from a versatile hydroazulene intermediate has been accomplished. The key features of the syntheses include the stereoselective preparation of the unusual cis-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.
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The first total syntheses of the bioactive cyclodepsipeptides ohmyungsamycinâ A and B are described. Key features of our synthesis include the concise preparation of a linear cyclization precursor that consists of N-methyl amides and non-proteinogenic amino acids, and its macrolactamization from a bent conformation. The proposed structure of ohmyungsamycinâ B was revised based on its synthesis. The cyclic core of the ohmyungsamycins was shown to be responsible for the excellent antituberculosis activity, and ohmyungsamycin variants with truncated chains were evaluated for their biological activity.
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Péptidos Cíclicos/síntesis química , Modelos Moleculares , Conformación Molecular , Péptidos Cíclicos/químicaRESUMEN
We demonstrate that the Knoevenagel condensation can be exploited in combinatorial synthesis on the solid phase. Condensation products from such reactions were structurally characterized, and their Michael reactivity with thiol and phosphine nucleophiles is described. Cyanoacrylamides were previously reported to react reversibly with thiols, and notably, we show that dilution into low pH buffer can trap covalent adducts, which are isolable via chromatography. Finally, we synthesized both traditional and DNA-encoded one-bead, one-compound libraries containing cyanoacrylamides as a source of cysteine-reactive reversibly covalent protein ligands.
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Acrilamidas/síntesis química , Técnicas Químicas Combinatorias/métodos , ADN/química , Nitrilos/síntesis química , Técnicas de Síntesis en Fase Sólida/métodos , Cisteína/química , Biblioteca de Genes , Ligandos , Estructura Molecular , Fosfinas/química , Proteínas/química , Compuestos de Sulfhidrilo/químicaRESUMEN
The asymmetric total synthesis of the marine natural product (+)-(3E)-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 in situ deconjugative isomerization, and the efficient introduction of the crucial chloride mediated by the substrate-controlled diastereoselective reduction.
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The enantioselective total synthesis of (+)-brasilenyne has been accomplished. The key features of the synthesis include the convergent preparation of a highly functionalized endocyclization precursor via selective epoxide opening, the construction of an oxonene skeleton through perfect regioselective Pd(0)-catalyzed endocyclization, and the installation of a 1,3-cis,cis-diene unit via a decarboxylative photophenylselenylation and site-selective selenoxide elimination sequence.
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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.
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Chiral vinylogous ß-amino acids (VBAA) were synthesized using enantioselective Mannich reactions of aldehydes with in situ generated N-carbamoyl imines followed by a Horner-Wadsworth-Emmons reaction. The efficiency with which these units could be incorporated into oligomers with different moieties on the C- and N-terminal sides was established, as was the feasibility of sequencing oligomers containing VBAAs by tandem mass spectrometry. The data show that VBAAs will be useful building blocks for the construction of combinatorial libraries of peptidomimetic compounds.