RESUMEN

The pyrimidine heterocycle plays an important role in anticancer research. In particular, the pyrimidine derivative families of uracil show promise as structural scaffolds relevant to cervical cancer. This group of chemicals lacks data-driven machine learning quantitative structure-activity relationships (QSARs) that allow for generalization and predictive capabilities in the search for new active compounds. To achieve this, a dataset of pyrimidine and uracil compounds from ChEMBL were collected and curated. A workflow was developed for data-driven machine learning QSAR using an intuitive dataset design and forwards selection of molecular descriptors. The model was thoroughly externally validated against available data. Blind validation was also performed by synthesis and antiproliferative evaluation of new synthesized uracil-based and pyrimidine derivatives. The most active compound among new synthesized derivatives, 2,4,5-trisubstituted pyrimidine was predicted with the QSAR model with differences of 0.02 compared to experimentally tested activity.

Asunto(s)

Antineoplásicos , Proliferación Celular , Pirimidinas , Relación Estructura-Actividad Cuantitativa , Uracilo , Uracilo/química , Uracilo/análogos & derivados , Uracilo/farmacología , Uracilo/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Aprendizaje Automático , Línea Celular Tumoral

RESUMEN

The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13-18)(a-d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7-12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a-d)) under microwave irradiation at 150-170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC50 values lower than 5 µM, and for four of them (16a, 18b, 18c and 18d), IC50 ≈ 1 µM. Additionally, all compounds with IC50 < 10 µM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC50 > 100 µM, and the other thirteen behaving as double inhibitors.

Asunto(s)

Inhibidores Enzimáticos , L-Lactato Deshidrogenasa , Simulación del Acoplamiento Molecular , Pirimidinas , Humanos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/metabolismo , L-Lactato Deshidrogenasa/química , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Relación Estructura-Actividad

RESUMEN

Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC50 values ranging from 0.042 µM to 7.530 µM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC50 values of 0.031 µM and 0.094 µM, being about 4.3-fold superior to EFV (EC50 = 0.132 µM) and 1.9-fold superior to NVP (EC50 = 0.181 µM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC50 = 27.9 µM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure-activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections.

Asunto(s)

Aminoácidos , Fármacos Anti-VIH , Diseño de Fármacos , Transcriptasa Inversa del VIH , VIH-1 , Pirimidinas , Inhibidores de la Transcriptasa Inversa , Tiofenos , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Humanos , Tiofenos/farmacología , Tiofenos/química , Tiofenos/síntesis química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/síntesis química , Relación Estructura-Actividad , Aminoácidos/química , Simulación del Acoplamiento Molecular

RESUMEN

A series of pyrimidine-2,4-diamine analogues were designed and synthesized. Their anticancer activity and the underlying mechanism against colorectal cancer (CRC) HCT116 cells and non-small cell lung cancer (NSCLC) A549 cells were investigated. The results demonstrated that the active compound Y18 significantly inhibited cancer cell proliferation by inducing robust cell cycle arrest and cell senescence through the persistence of DNA damage. Additionally, Y18 exhibited significant inhibitory effects on the adhesion, migration and invasion of cancer cells in vitro. Mechanistically, Y18 achieved these anticancer activities by suppressing GTSE1 transcription and expression. Y18 also effectively inhibited tumor growth in vivo with minimal side effects. Furthermore, Y18 exhibited a suitable half-life and oral bioavailability (16.27%), with limited inhibitory activity on CYP isoforms. Taken together, these results suggested that Y18 could be a potential chemotherapeutic drug for cancer treatment, particularly in cases of GTSE1 overexpressed cancers.

Asunto(s)

Antineoplásicos , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Pirimidinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Animales , Descubrimiento de Drogas , Ratones , Movimiento Celular/efectos de los fármacos , Diaminas/química , Diaminas/farmacología , Diaminas/síntesis química , Ratones Desnudos

RESUMEN

The rapid emergence of drug resistance severely reduces the clinical response of human immunodeficiency virus-1 (HIV-1) to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, a series of 2,4,6-trisubstituted pyrimidine derivatives was designed and synthesized, with the aim to identify novel anti-HIV-1 agents with improved drug resistance profiles. The antiviral activity results demonstrated that all compounds showed excellent potency to wild-type (WT) HIV-1 strain (EC50 = 3.61-15.5 nM). Moreover, 13c was proved to be the most potent inhibitor against the whole tested viral panel, with EC50 ranging from 4.68 to 229 nM. In addition, 13c yielded moderate HIV-1 RT inhibition with IC50 value of 0.231 µM, which demonstrated it was a classical NNRTI. Molecular docking was further conducted to illustrate its binding mode with HIV-1 RT. These encouraging results indicated that 13c can be used as a lead compound for further study.

Asunto(s)

Fármacos Anti-VIH , Transcriptasa Inversa del VIH , VIH-1 , Simulación del Acoplamiento Molecular , Pirimidinas , Inhibidores de la Transcriptasa Inversa , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/síntesis química , VIH-1/efectos de los fármacos , VIH-1/enzimología , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , Relación Estructura-Actividad , Humanos , Estructura Molecular , Pruebas de Sensibilidad Microbiana , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas

RESUMEN

Rho-associated coiled-coil kinase (ROCK) is involved in multiple cellular activities regulating the actin cytoskeleton, such as cell morphology, adhesion, and migration. The inhibition of ROCK is a feasible strategy to suppress breast cancer metastasis. Herein, based on Belumosudil, a series of pyrazolo[1,5-a]pyrimidine derivatives as selective ROCK2 inhibitors were designed and synthesized. Through systematic investigation of SARs, the piperazine analog 7u was identified with optimum ROCK2 inhibitory activity (IC50 = 36.8 nM) and excellent selectivity over the isoform protein ROCK1 (>250-fold). Intriguingly, upon treatment with 7u, the arrangement of the MDA-MB-231 cytoskeleton was affected accompanied by the alteration of morphology. Furthermore, cell scratch and transwell assays indicated that 7u inhibited MDA-MB-231 cell migration and invasion in a dose-dependent manner. Ultimately, the binding model of 7u with ROCK2 well accounted for the superior activities of 7u as a promising ROCK2 inhibitor with the potential application in breast cancer metastasis treatment.

Asunto(s)

Antineoplásicos , Neoplasias de la Mama , Movimiento Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Proteínas Quinasas , Pirazoles , Pirimidinas , Quinasas Asociadas a rho , Humanos , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo , Movimiento Celular/efectos de los fármacos , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Femenino , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Descubrimiento de Drogas , Simulación del Acoplamiento Molecular

RESUMEN

Targeted covalent inhibitors (TCIs) directing cysteine have historically relied on a narrow set of electrophilic "warheads". While Michael acceptors remain at the forefront of TCI design strategies, they show variable stability and selectivity under physiological conditions. Here, we show that the 2-sulfonylpyrimidine motif is an effective replacement for the acrylamide warhead of Ibrutinib, for the inhibition of Bruton's tyrosine kinase. In a few iterations, we discovered new derivatives, which inhibit BTK both in vitro and in cellulo at low nanomolar concentrations, on par with Ibrutinib. Several derivatives also displayed good plasma stability and reduced off-target binding in vitro across 135 tyrosine kinases. This proof-of-concept study on a well-studied kinase/TCI system highlights the 2-sulfonylpyrimidine group as a useful acrylamide replacement. In the future, it will be interesting to investigate its wider potential for developing TCIs with improved pharmacologies and selectivity profiles across structurally related protein families.

Asunto(s)

Acrilamida , Agammaglobulinemia Tirosina Quinasa , Inhibidores de Proteínas Quinasas , Pirimidinas , Humanos , Acrilamida/química , Acrilamida/farmacología , Adenina/química , Adenina/análogos & derivados , Adenina/farmacología , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Piperidinas/química , Piperidinas/farmacología , Piperidinas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Relación Estructura-Actividad

RESUMEN

The P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Aδ-primary afferent neurons, has been proposed as a drug target for neurological inflammatory diseases, e.g., neuropathic pain, and chronic cough. Aiming to develop novel, selective P2X3R antagonists, tetrazolopyrimidine-based hit compound 9 was optimized through structure-activity relationship studies by modifying the tetrazole core as well as side chain substituents. The optimized antagonist 26a, featuring a cyclopropane-substituted triazolopyrimidine core, displayed potent P2X3R-antagonistic activity (IC50 = 54.9 nM), 20-fold selectivity versus the heteromeric P2X2/3R, and high selectivity versus other P2XR subtypes. Noncompetitive P2X3R blockade was experimentally confirmed by calcium influx assays. Cryo-electron microscopy revealed that 26a stabilizes the P2X3R in its desensitized state, acting as a molecular barrier to prevent ions from accessing the central pore. In vivo studies in a rat neuropathic pain model (spinal nerve ligation) showed dose-dependent antiallodynic effects of 26a, thus presenting a novel, promising lead structure.

Asunto(s)

Microscopía por Crioelectrón , Antagonistas del Receptor Purinérgico P2X , Pirimidinas , Receptores Purinérgicos P2X3 , Triazoles , Animales , Antagonistas del Receptor Purinérgico P2X/farmacología , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/síntesis química , Relación Estructura-Actividad , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Ratas , Receptores Purinérgicos P2X3/metabolismo , Humanos , Triazoles/farmacología , Triazoles/química , Triazoles/síntesis química , Sitio Alostérico , Masculino , Neuralgia/tratamiento farmacológico , Descubrimiento de Drogas , Ratas Sprague-Dawley

RESUMEN

Tuberculosis (TB) remains a major public health challenge, with research on new anti-TB drugs crucial for global TB elimination efforts. Here, we report a novel class of anti-TB agents. Especially, compounds 5b and 5j exhibited the highest activity [minimum inhibitory concentration (MIC) H37Rv: 0.16 and 0.12 µg/mL]. Chiral resolution was performed on compounds 5b and 5j; the isomers were evaluated for their activity and safety, confirming that the R-isomer 5bb and 5jb displayed significant anti-TB activity (MIC H37Rv: 0.03-0.06 µg/mL; MDR-Mtb: 0.125-0.06 µg/mL) and low hERG toxicity. Further evaluations on 5bb and 5jb demonstrated good metabolic stability, favorable kinetic parameters and oral bioavailability (F: 56.7 and 63.8%, respectively). The results of in vivo activity assessment indicate that 5bb and 5jb exhibit protective and therapeutic effects on zebrafish larvae and adult zebrafish infected with Mycobacterium marinum. Based on these results, compounds 5bb and 5jb are considered promising candidates for further in-depth studies.

Asunto(s)

Antituberculosos , Diseño de Fármacos , Pruebas de Sensibilidad Microbiana , Pez Cebra , Antituberculosos/farmacología , Antituberculosos/síntesis química , Antituberculosos/farmacocinética , Antituberculosos/química , Animales , Relación Estructura-Actividad , Mycobacterium tuberculosis/efectos de los fármacos , Pirimidinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacocinética , Humanos , Mycobacterium marinum/efectos de los fármacos , Estructura Molecular

RESUMEN

Toll-like receptors 7 and 8 are involved in modulating the adaptive and innate immune responses, and their activation has shown promise as a therapeutic strategy in the field of immuno-oncology. While systemic exposure to TLR7/8 agonists can result in poor tolerance, combination therapies and targeted delivery through antibody-drug conjugates (ADCs) can help mitigate adverse effects. Described herein is the identification of a novel and potent series of pyrazolopyrimidine-based TLR7/8 agonists with tunable receptor selectivity. Representative agonists from this series were successfully able to induce the production of various proinflammatory cytokines and chemokines from human peripheral blood mononuclear cells. Anti-HER2-25 and anti-HER2-26 ADCs made from this class of payloads demonstrated mechanism-based activation of TLR7/8 in a THP1/N87 coculture system.

Asunto(s)

Diseño de Fármacos , Inmunoconjugados , Receptor Toll-Like 7 , Receptor Toll-Like 8 , Humanos , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 8/agonistas , Receptor Toll-Like 8/metabolismo , Inmunoconjugados/farmacología , Inmunoconjugados/química , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Relación Estructura-Actividad , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Citocinas/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Pirazoles/farmacología , Pirazoles/química

RESUMEN

Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.

Asunto(s)

Aminopiridinas , Antineoplásicos , Inhibidores de Histona Desacetilasas , Pirimidinas , Humanos , Animales , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Aminopiridinas/farmacología , Aminopiridinas/síntesis química , Aminopiridinas/química , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Pirimidinas/uso terapéutico , Relación Estructura-Actividad , Ratones , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/patología , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/metabolismo , Descubrimiento de Drogas , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos Antitumorales , Ratones Desnudos

RESUMEN

Herein, we designed and synthesized a series of novel 2-methylthieno [3,2-d]pyrimidine analogues as tubulin inhibitors with antiproliferative activities at low nanomolar levels. Among them, compound DPP-21 displayed the most potent anti-proliferative activity against six cancer cell lines with an average IC50 of ∼6.23 nM, better than that of colchicine (IC50 = 9.26 nM). DPP-21 exerted its anti-cancer activity by suppressing the polymerization of tubulin with an IC50 of 2.4 µM. Furthermore, the crystal structure of DPP-21 in complex with tubulin was solved by X-ray crystallography to 2.94 Å resolution, confirming the direct binding of DPP-21 to the colchicine site. Moreover, DPP-21 arrested the cell cycle in the G2/M phase of mitosis, subsequently inducing tumor cell apoptosis. Additionally, DPP-21 was able to effectively inhibit the migration of cancer cells. Besides, DPP-21 exhibited significant in vivo anti-tumor efficacy in a B16-F10 melanoma tumor model with a TGI of 63.3 % (7 mg/kg) by intraperitoneal (i.p.) injection. Notably, the combination of DPP-21 with NP-19 (a PD-L1-targeting small molecule inhibitor reported by our group before) demonstrated enhanced anti-cancer efficacy in vivo. These results suggest that DPP-21 is a promising lead compound deserving further investigation as a potential anti-cancer agent.

Asunto(s)

Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Pirimidinas , Tiofenos , Moduladores de Tubulina , Humanos , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/química , Moduladores de Tubulina/síntesis química , Proliferación Celular/efectos de los fármacos , Animales , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ratones , Tiofenos/química , Tiofenos/farmacología , Tiofenos/síntesis química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Apoptosis/efectos de los fármacos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Descubrimiento de Drogas , Tubulina (Proteína)/metabolismo , Línea Celular Tumoral , Inmunoterapia , Ratones Endogámicos C57BL , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/química , Inhibidores de Puntos de Control Inmunológico/síntesis química , Melanoma/tratamiento farmacológico , Melanoma/patología , Modelos Moleculares

RESUMEN

To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR L858R/T790M/C797S inhibitor (IC50 = 0.053 µM) but had a weak effect on EGFRWT (IC50 = 1.05 µM). 11eg significantly inhibited the proliferation of the non-small cell lung cancer (NSCLC) cells harboring EGFRL858R/T790M/C797S with an IC50 of 0.052 µM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing apoptosis of NSCLC cells with mutant EGFRC797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFRC797S to guide in-depth structural optimization.

Asunto(s)

Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Resistencia a Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Mutación , Inhibidores de Proteínas Quinasas , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Animales , Relación Estructura-Actividad , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Ratones Desnudos , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química

RESUMEN

USP7 is one of the most studied deubiquitinating enzymes, which is involved in the regulation of multiple cell signaling pathways and has been shown to be associated with the occurrence and progression of a variety of cancers. Inhibitors targeting USP7 have been studied by several teams, but most of them lack selectivity and have low activities. Herein, we reported a serious of pyrrole[2,3-d]pyrimidin-4-one derivatives through scaffold hopping of recently reported 4-hydroxypiperidine compounds. The representative compound Z33 (YCH3124) exhibited highly potent USP7 inhibition activity as well as anti-proliferative activity against four kinds of cancer cell lines. Further study revealed that YCH3124 effectively inhibited the downstream USP7 pathway and resulted in the accumulation of both p53 and p21 in a dose-dependent manner. Notably, YCH3124 disrupted cell cycle progression through restricting G1 phase and induced significant apoptosis in CHP-212 cells. In summary, our efforts provided a series of novel pyrrole[2,3-d]pyrimidin-4-one analogs as potent USP7 inhibitors with excellent anti-cancer activity.

Asunto(s)

Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Pirimidinas , Pirroles , Peptidasa Específica de Ubiquitina 7 , Humanos , Peptidasa Específica de Ubiquitina 7/antagonistas & inhibidores , Peptidasa Específica de Ubiquitina 7/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Pirroles/farmacología , Pirroles/química , Pirroles/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Línea Celular Tumoral , Estructura Molecular , Relación Dosis-Respuesta a Droga , Apoptosis/efectos de los fármacos , Descubrimiento de Drogas , Pirimidinonas/farmacología , Pirimidinonas/química , Pirimidinonas/síntesis química , Ciclo Celular/efectos de los fármacos

RESUMEN

The P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5 µM (IC50 = 27.00 nM, RF = 247.40) and 10 µM (IC50 = 10.07 nM, RF = 663.44). Compound 16q could effectively bind and stabilize ABCB1, and does not affect the expression and subcellular localization of ABCB1 in MCF-7/ADR cells. Compound 16q inhibited the function of ABCB1, thereby increasing PTX accumulation, and interrupting the accumulation and efflux of the ABCB1-mediated Rh123, thus resulting in exhibiting good reversal effects. In addition, due to the potent reversal effects of compound 16q, the abilities of PTX to inhibit tubulin depolymerization, and induce cell cycle arrest and apoptosis in MCF-7/ADR cells under low-dose conditions were restored. These results indicate that compound 16q might be a promising potent reversal agent capable of revising ABCB1-mediated MDR, and pyrazolo [1,5-a]pyrimidine might represent a novel scaffold for the discovery of new ABCB1-mediated MDR reversal agents.

Asunto(s)

Subfamilia B de Transportador de Casetes de Unión a ATP , Antineoplásicos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Pirazoles , Pirimidinas , Humanos , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Resistencia a Antineoplásicos/efectos de los fármacos , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Estructura Molecular , Paclitaxel/farmacología , Paclitaxel/química , Células MCF-7 , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos

RESUMEN

Due to the emerging global epidemic of obesity, developing safe and effective agents for anti-obesity is urgently needed. Our previous study found that 2-pyrimidinylindole derivative Wd3d exhibited potential anti-obesity activity. Herein, to further optimize the potential moiety, structural modifications were proceeded for two rounds in this study. Firstly, we designed, synthesized, and evaluated 36 new derivatives of 2-pyrimidinylindole scaffold with different substituents on the indole ring and pyrimidine ring to investigate their structure-activity relationship (SAR). Then, analogs with potent activity had the aldehyde group replaced with the acylhydrazone group to reduce cytotoxicity and improve metabolic stability. Detailed SAR studies and animal evaluation experiments led to the discovery of the compound 9ga, which significantly reduced TG accumulation with an EC50 value of 0.07 µM and showed relatively low cytotoxicity with an IC50 value of around 24 µM. Oral administration of 9ga effectively prevented the excessive growth of body weight and lessened fat mass as well as liver mass, decreased lipid accumulation in the liver and blood, and improved the heart injury parameter in the diet-induced obesity mouse model significantly better than Wd3d. A mechanism study showed that 9ga regulated the lipid metabolism during early adipogenesis by inhibiting PPARγ pathway. In conclusion, our study further highlights the anti-obesity potential of 2-pyrimidinylindole derivatives in diet-induced obesity.

Asunto(s)

Fármacos Antiobesidad , Diseño de Fármacos , Indoles , Obesidad , Relación Estructura-Actividad , Animales , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Ratones , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Obesidad/tratamiento farmacológico , Administración Oral , Estructura Molecular , Masculino , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Relación Dosis-Respuesta a Droga , Ratones Endogámicos C57BL , Humanos , Células 3T3-L1

RESUMEN

The JAK-STAT signalling pathway is primarily involved in cytokine signalling and induces various factors namely, erythropoietin, thrombopoietin, interferons, interleukins, and granulocyte colony-stimulating factors. These factors tremendously influenced understanding human health and illness, specifically cancer. Inhibiting the JAK/STAT pathway offers enormous therapeutic promises against cancer. Many JAK inhibitors are now being studied due to their efficacy in various cancer treatments. Further, the Nitrogen-heterocyclic (N-heterocyclic) scaffold has always shown to be a powerful tool for designing and discovering synthetic compounds with diverse pharmacological characteristics. The review focuses on several FDA-approved JAK inhibitors and their systematic categorization. The medicinal chemistry perspective is highlighted and classified review on the basis of N-heterocyclic molecules. Several examples of designing strategies of N-heterocyclic rings including pyrrolo-azepine, purine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrazole, thieno[3,2-d] pyrimidine, and, pyrimidine-based derivatives and their structure-activity relationships (SAR) are discussed. Among the various N-heterocyclic-based JAK inhibitors pyrimidine-containing compound 1 exhibited excellent inhibition activity against JAK2WT and mutated-JAK2V617F with IC50 of 2.01 and 18.84 nM respectively. Amino pyrimidine-containing compound 6 and thiopheno[3,2-d]pyrimidine-containing compound 13 expressed admirable JAK3 inhibition activity with IC50 of 1.7 nM and 1.38 nM respectively. Our review will support the medicinal chemists in refining and directing the development of novel N-heterocyclic-based JAK inhibitors.

Asunto(s)

Antineoplásicos , Compuestos Heterocíclicos , Inhibidores de las Cinasas Janus , Animales , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/química , Inhibidores de las Cinasas Janus/síntesis química , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Estructura Molecular , Neoplasias/tratamiento farmacológico , Nitrógeno/química , Relación Estructura-Actividad , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacología

RESUMEN

In the upcoming decades, the incidence and mortality rates of cancer are expected to rise globally, with colorectal and prostate cancers among the most prevalent types. Despite advancements in molecular targeted therapy, platinum-based chemotherapies remain the cornerstone of treatment, especially for colorectal and prostate cancer, with oxaliplatin and cisplatin being extremely effective due to their DNA-targeting capabilities. In our pursuit of new platinum-based chemotherapeutics that are potentially less toxic and more effective, we have explored the combination of the Pt-binding groups of the diaminocyclohexane ring used in oxaliplatin, with the stable amino-pyrimidine hemicurcumin moiety. This new derivative exhibit improved stability in physiological conditions and increased solubility in aqueous media, demonstrating promising effects on cell proliferation of both colorectal and prostate cells. We report herein the complete synthesis and chemical characterization in solution of the new derivative [(1R,2R)-N1-(3-(4-((E)-2-(2-Amino-6-methylpyrimidin-4-yl)vinyl)-2-methoxyphenoxy) propyl) cyclohexane-1,2-diamine] (MPYD). Our analysis includes an examination of its acid-base equilibria, speciation and stability in physiological conditions. The synthesis and in situ formation of Pt(II) complexes were investigated by nuclear magnetic resonance spectroscopy, while density functional theory calculations were employed to elucidate the chemical structure in solution. Results on the biological activity were obtained through cell viability assays on different colorectal and prostate cell lines (HCT116, HT29, PC3 and LNCaP).

Asunto(s)

Antineoplásicos , Cisplatino , Pirimidinas , Humanos , Cisplatino/farmacología , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/química , Compuestos Organoplatinos/síntesis química

RESUMEN

Two series of C-Mannich base derivatives were synthesized and evaluated through the reaction of formaldehyde, two thiazolo-pyrimidine compounds, and various 2°-amines. The chemical structures and inherent properties of the synthesized compounds were authenticated using a variety of spectroscopic techniques. The aseptic bactericidal potential of the compounds was assessed alongside five common bacterial microbes, with Ampicillin employed as the reference drug. Compounds 9b and 9d demonstrated comparable antibacterial activity to ampicillin against Bacillus subtilis and Bacillus megaterium, respectively, at 100 µg/mL. Furthermore, compounds 9f and 10f exhibited noteworthy action against Staphylococcus aureus (MIC: 250 µg/mL). Compounds 10b and 10f displayed excellent efficacy versus Escherichia coli, boasting (MIC: 50 µg/mL). Molecular docking studies elucidated the necessary connections and energies of molecular entities with the E. coli DNA gyrase B enzyme, a pivotal target in bacterial DNA replication. Further thermodynamic stability of the ligand-receptor complex of 10b and 10f were further validated though 200 ns molecular dynamics simulation. The findings highlight the potential of these synthesized derivatives as effective antibacterial agents and provide valuable insights into their mechanism of action.

Asunto(s)

Antibacterianos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Pirimidinas , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Bacillus subtilis/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Tiazoles/síntesis química , Pruebas de Sensibilidad Microbiana , Escherichia coli/efectos de los fármacos , Girasa de ADN/metabolismo , Girasa de ADN/química

RESUMEN

Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure-activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.

Asunto(s)

Inhibidores de Proteínas Quinasas , Pirazoles , Pirimidinas , Receptor trkA , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Humanos , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad , Receptor trkA/antagonistas & inhibidores , Receptor trkA/metabolismo , Receptor trkA/genética , Receptor trkB/antagonistas & inhibidores , Receptor trkB/metabolismo , Receptor trkC/antagonistas & inhibidores , Receptor trkC/genética , Receptor trkC/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química