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Background: Hepatocellular carcinoma (HCC) is a common malignancy. Ferroptosis and cuproptosis promote HCC spread and proliferation. While fewer studies have combined ferroptosis and cuproptosis to construct prognostic signature of HCC. This work attempts to establish a novel scoring system for predicting HCC prognosis, immunotherapy, and medication sensitivity based on ferroptosis-related genes (FRGs) and cuproptosis-related genes (CRGs). Methods: FerrDb and previous literature were used to identify FRGs. CRGs came from original research. The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases included the HCC transcriptional profile and clinical information [survival time, survival status, age, gender, Tumor Node Metastasis (TNM) stage, etc.]. Correlation, Cox, and least absolute shrinkage and selection operator (LASSO) regression analyses were used to narrow down prognostic genes and develop an HCC risk model. Using "caret", R separated TCGA-HCC samples into a training risk set and an internal test risk set. As external validation, we used ICGC samples. We employed Kaplan-Meier analysis and receiver operating characteristic (ROC) curve to evaluate the model's clinical efficacy. CIBERSORT and TIMER measured immunocytic infiltration in high- and low-risk populations. Results: TXNRD1 [hazard ratio (HR) =1.477, P<0.001], FTL (HR =1.373, P=0.001), GPX4 (HR =1.650, P=0.004), PRDX1 (HR =1.576, P=0.002), VDAC2 (HR =1.728, P=0.008), OTUB1 (HR =1.826, P=0.002), NRAS (HR =1.596, P=0.005), SLC38A1 (HR =1.290, P=0.002), and SLC1A5 (HR =1.306, P<0.001) were distinguished to build predictive model. In both the model cohort (P<0.001) and the validation cohort (P<0.05), low-risk patients had superior overall survival (OS). The areas under the curve (AUCs) of the ROC curves in the training cohort (1-, 3-, and 5-year AUCs: 0.751, 0.727, and 0.743), internal validation cohort (1-, 3-, and 5-year AUCs: 0.826, 0.624, and 0.589), and ICGC cohort (1-, 3-, and 5-year AUCs: 0.699, 0.702, and 0.568) were calculated. Infiltration of immune cells and immunological checkpoints were also connected with our signature. Treatments with BI.2536, Epothilone.B, Gemcitabine, Mitomycin.C, Obatoclax. Mesylate, and Sunitinib may profit high-risk patients. Conclusions: We analyzed FRGs and CRGs profiles in HCC and established a unique risk model for treatment and prognosis. Our data highlight FRGs and CRGs in clinical practice and suggest ferroptosis and cuproptosis may be therapeutic targets for HCC patients. To validate the model's clinical efficacy, more HCC cases and prospective clinical assessments are needed.
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Background: Ferroptosis and cuproptosis play a crucial role in the progression and dissemination of hepatocellular carcinoma (HCC). The primary objective of this study was to develop a unique scoring system for predicting the prognosis and immunological landscape of HCC based on ferroptosis-related genes (FRGs) and cuproptosis-related genes (CRGs). Methods: As the training cohort, we assembled a novel HCC cohort by merging gene expression data and clinical data from The Cancer Genome Atlas (TCGA) database, and Gene Expression Omnibus (GEO) database. The validation cohort consisted of 230 HCC cases taken from the International Cancer Genome Consortium (ICGC) database. Multiple genomic characteristics, such as tumor mutation burden (TMB), and copy number variations were analyzed concurrently. On the basis of the expression of CRGs and FRGs, patients were classified into cuproptosis and ferroptosis subtypes. Then, we constructed a risk model using least absolute shrinkage and selection operator (LASSO) analysis and Cox regression analysis based on ferroptosis and cuproptosis-related differentially expressed genes (DEGs). Patients were separated into two groups according to median risk score. We compared the immunophenotype, tumor microenvironment (TME), cancer stem cell index, and treatment sensitivity of two groups. Results: Three subtypes of ferroptosis and two subtypes of cuproptosis were identified among the patients. A greater likelihood of survival (P<0.05) was expected for patients in FRGcluster B and CRGcluster B. After that, a confirmed risk signature for ferroptosis and cuproptosis was developed and tested. Patients in the low-risk group had significantly higher survival rates than those in the high-risk group, according to our study (P<0.001). There was also a strong correlation between the signature and other variables including immunophenoscore, TMB, cancer stem cell index, immunological checkpoint genes, and sensitivity to chemotherapeutics. Conclusions: Through this comprehensive research, we identified a unique risk signature associated with HCC patients' treatment status and prognosis. Our findings highlight FRGs' and CRGs' significance in clinical practice and imply ferroptosis and cuproptosis may be therapeutic targets for HCC patients.
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Natural quinones and their analogues have attracted growing attention because of their novel anticancer activities. A series of novel isothiazoloquinoline quinone analogues were synthesized and evaluated for antitumor activities against four different kind of cancer cells. Among them, isothiazoloquinolinoquinones inhibited cancer cells proliferation effectively with IC50 values in the nanomolar range, and isothiazoloquinolinoquinone 13a induced the cell apoptosis. Further exploration of possible mechanism of action indicates that 13a not only activates ROS production through NQO1-directed redox cycling but also inhibits the phosphorylation of STAT3. These findings indicate that 13a has potential use for the development of new skeleton drug candidate as an efficient substrate of NQO1 and STAT3 inhibitor.
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Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , NAD(P)H Deshidrogenasa (Quinona)/antagonistas & inhibidores , Quinonas/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Oxidación-Reducción , Quinonas/síntesis química , Quinonas/química , Factor de Transcripción STAT3/metabolismo , Relación Estructura-ActividadRESUMEN
A series of DLC (delocalized lipophilic cation) modified spinosyn derivatives were synthesized and evaluated for antitumor efficacies both in vitro and in vivo. Cancer cell based antiproliferative assays indicated that the more lipophilic derivatives had stronger inhibitory effects on the tested cancer cell lines. Compound 7b and 8b exhibited strong anti-OXPHOS and apoptosis inducing ability. Notable antitumor efficacies of 7b (5 mg/kg) and 8b (2.5 mg/kg) were observed in the in vivo tumor xenograft experiments, however, lethal toxicities were observed on higher dosages. Our findings indicated that DLC modification is a viable strategy to enhance the anti-OXPHOS and antitumor efficacies of spinosyn derivatives.
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Macrólidos/síntesis química , Macrólidos/farmacología , Mitocondrias/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Animales , Antineoplásicos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A convenient Fe-catalyzed four-component radical dual difunctionalization and ordered assembly of two alkenes with aromatic/aliphatic aldehydes and TBHP to provide chain elongated ß,δ-functionalized ketones via a one-pot procedure has been developed. Aldehydes were homolytically cleavaged to produce acyl radicals and subsequently allowed for the successive construction of C(sp2)-C(sp3), C(sp3)-C(sp3), and C(sp3)-O bonds via dual radical insertions and radical-radical coupling, following the intrinsic nucleo/electrophilic reactivity of both the radicals and alkenes.
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In order to enhance the mitochondria-targeting ability of spinosad. A series of quartenary ammonium spinosyn derivatives was designed and synthesized. Some of the derivatives displayed greatly enhanced antiproliferative ability towards tested human cancer cell lines. The structure activity relationship study indicated that lipophilicity has a great influence on the antiproliferative effects of these derivatives. The most active compound 11d exhibited remarkably enhanced OXPHS inhibition and apoptosis inducing ability than spinosyn A.
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Antineoplásicos/farmacología , Macrólidos/farmacología , Compuestos de Amonio Cuaternario/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Macrólidos/síntesis química , Macrólidos/química , Mitocondrias/metabolismo , Estructura Molecular , Fosforilación Oxidativa/efectos de los fármacos , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/química , Relación Estructura-ActividadRESUMEN
BACKGROUND: The heptaprotective flavonolignan silibinin and dehydrosilibinin have exhibited moderate antiproliferative activities toward many cancer cell lines. Considering of the nontoxic profile of these natural products, chemical modification to enhance the anticancer potentials is promising. METHOD: A series of 7-O-aminoalkyl-2,3-dehydrosilibinin derivatives were synthesized and evaluated for their antiproliferative activities against several cancer cell lines. RESULTS: A number of the synthesized dehydrosilibinin derivatives exhibited greatly enhanced potency with 50% growth inhibition at low micromolar concentrations. Structure activity study indicated that the distance between N and 7-O on the side chain has a limited influence on the antiproliferative activity, while the presence of a morpholino group decreases the antiproliferative activities dramatically. Flow cytometry based assays on human colon cancer HCT116 cells revealed that 6a and 6c, two of the most potent derivatives, effectively arrested the cell cycle in the G2 phase and stimulated cell apoptosis. CONCLUSION: Our findings suggest that attaching an appropriate tertiary amino alkyl side chain through 7-Oalkylation on 2,3-dehydrosilibinin, would be a viable strategy for the development of silibinin derivatives as anticancer agents.
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Antineoplásicos/farmacología , Silibina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Silibina/síntesis química , Silibina/química , Relación Estructura-ActividadRESUMEN
An iodine-catalyzed multiple C-H bond functionalization of isoquinolines with methylarenes via a successive benzylic sp3 C-H iodination/N-benzylation/amidation/double sp2 C-H oxidation sequence is developed. This reaction utilizes un-functionalized isoquinolines and readily available methylarenes as starting materials, proceeds under metal-free conditions, and avoids a multi-step experimental operation, to make it an efficient and practical method for the synthesis of N-benzyl isoquinoline-1,3,4-triones.
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OBJECTIVE: To study the chemical constituents in roots of Caragana sinica. METHOD: The constituents were isolated by silica gel column chromatography, and their structures were identified by spectroscopic methods. RESULT: Seven compounds were identified as (+) - stenophyllol B (1), 4-hydroxybenzoic acid (2), odoratin (3), resveratrol (4), cararosinol A (5), leachinol C (6), carasinaurone (7) respectively. CONCLUSION: Compound 1 was a new compound which was the enantiomer of stenophyllol B. Compounds 2-6 were obtained from the plant for the first time.
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Caragana/química , Medicamentos Herbarios Chinos/química , Raíces de Plantas/química , Cromatografía en Gel , Medicamentos Herbarios Chinos/análisis , Estructura Molecular , Parabenos/análisis , Parabenos/química , Resveratrol , Estilbenos/análisis , Estilbenos/químicaRESUMEN
Biotransformations of a number of racemic beta-hydroxy and beta-amino nitrile derivatives were studied using Rhodococcus erythropolis AJ270, the nitrile hydratase and amidase-containing microbial whole cell catalyst, under very mild conditions. The overall enantioselectivity of nitrile biotransformations was governed predominantly by the amidase whose enantioselectivity was switched on remarkably by an O- and a N-benzyl protection group of the substrates. While biotransformations of beta-hydroxy and beta-amino alkanenitriles gave low yields of amide and acid products of very low enantiomeric purity, introduction of a simple benzyl protection group on the beta-hydroxy and beta-amino of nitrile substrates led to the formation of highly enantioenriched beta-benzyloxy and beta-benzylamino amides and acids in almost quantitative yield. The easy protection and deprotection operations, high chemical yield, and excellent enantioselectivity render the nitrile biotransformation a useful protocol in the synthesis of enantiopure beta-hydroxy and beta-amino acids.
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Amidas/química , Amidohidrolasas/química , Aminoácidos/química , Nitrilos/química , Biotransformación , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Espectrometría de Masas/métodos , Rhodococcus/enzimología , EstereoisomerismoRESUMEN
[Structure: see text] Catalyzed by the Rhodococcus erythropolis AJ270 whole cell catalyst, the O-benzylated beta-hydroxy alkanenitriles underwent remarkably high enantioselective biotransformations, whereas the biotransformations of free beta-hydroxy alkanenitriles gave very low enantioselectivity. The easy manipulations of O-protection and O-deprotection, excellent chemical and enantiomeric yields of biotransformations, along with the scalability render this enzymatic transformation attractive and practical for the synthesis of highly enantiopure beta-hydroxy alkanoic acids and their amide derivatives.
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Derivados del Benceno/química , Ácidos Carboxílicos/síntesis química , Nitrilos/química , Rhodococcus/metabolismo , Amidas/química , Biotransformación , Catálisis , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A new resveratrol dimer, carasiphenol A (1), and a new resveratrol trimer, carasiphenol B (2), have been isolated from the aerial parts of Caragana sinica. Their structures have been elucidated from spectroscopic evidence, especially HMBC and NOE experiments. The relative configuration of the known dimer pallidol (6) was confirmed by X-ray diffraction.