ABSTRACT
Sophoridine is a quinolizidine natural product and the exploration of its derivatives has been carried out, and the potent anticancer compound IMB-HDC was acquired. Although previous studies have revealed that some sophoridine derivatives could induce DNA breakage, the underlying mechanisms of inhibition of DNA damage repair (ATR inactivation) and the apoptosis independent of p53, have not been elucidated. Our research reveals a novel DNA response mechanism different from general DNA-damaging agents, and that sophoridine derivate inhibits the phosphorylation of Tyr694 and Ser780 of STAT5a to induce the lessened shuttle from the cytoplasm to the nucleus, and leads to the decreased nuclear STAT5a and subsequently inhibits the expression of STAT5a target gene RAD51 that contributes to the checkpoint activation, thus inhibiting ATR activation. Meanwhile, IMB-HDC that induced the diminished expression of STAT5a target gene contributes to proliferation and leads to apoptosis. More importantly, we give the first evidence that promoting the effect of Tyr694 phosphorylation on nuclear location and subsequent STAT5a target gene transcription depends on Ser780 increased or unchanged phosphorylation and was not correlated with Ser726 phosphorylation.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Quinolizidines/pharmacology , STAT5 Transcription Factor/antagonists & inhibitors , Tumor Suppressor Proteins/antagonists & inhibitors , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , DNA Damage , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Phosphorylation/drug effects , Quinolizidines/chemistry , STAT5 Transcription Factor/genetics , STAT5 Transcription Factor/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Traumatic brain injury (TBI) has high morbidity and mortality rates. The mechanisms underlying TBI are unclear and may include the change in biological material in exosomes. Circular ribonucleic acids (circRNAs) are enriched and stable in exosomes, which can function as microRNA (miRNA) sponges to regulate gene expression levels. Therefore, we speculated that circRNAs in exosomes might play an important role in regulating gene expression after TBI and then regulate specific signaling pathways, which may protect the brain. We first isolated exosomes from the brain extracellular space in mice with TBI by digestion. We then investigated the alterations in circRNA expression in exosomes by high-throughput whole transcriptome sequencing, analyzed the data by gene ontology (GO) and pathway analysis, and constructed the circRNA-miRNA network. In this study, we identified 231 significantly and differentially expressed circRNAs, including 155 that were upregulated and 76 that were downregulated. GO analysis showed that these differentially expressed circRNAs might be related to the growth and repair of neurons, the development of the nervous system, and the transmission of nerve signals. The most highly correlated pathways that we identified were involved primarily with glutamatergic synapse and the cyclic guanosine monophosphate-protein kinase G signaling pathway. The circRNA-miRNA network predicted the potential roles of these differentially expressed circRNAs and the interaction of circRNAs with miRNAs. Our study broadens the horizon of research on gene regulation in exosomes from the brain extracellular space after TBI and provides novel targets for further research on both the molecular mechanisms of TBI and the potential intervention therapy targets.
Subject(s)
Brain Chemistry , Brain Injuries, Traumatic/metabolism , Exosomes/metabolism , Extracellular Space/metabolism , RNA/biosynthesis , Animals , Brain Injuries, Traumatic/genetics , Extracellular Space/chemistry , Gene Expression Regulation , High-Throughput Screening Assays , Male , Mice , Mice, Inbred C57BL , TranscriptomeSubject(s)
Antineoplastic Agents/toxicity , Autophagy/drug effects , Antineoplastic Agents/therapeutic use , Humans , Medicine, Chinese Traditional , Neoplasms/drug therapy , Neoplasms/pathology , Nitrogen Mustard Compounds/chemistry , Nitrogen Mustard Compounds/therapeutic use , Nitrogen Mustard Compounds/toxicityABSTRACT
A series of monobactam derivatives were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative strains, taking Aztreonam and BAL30072 as the leads. Six conjugates (12a-f) bearing PIH-like siderophore moieties were created to enhance the bactericidal activities against Gram-negative bacteria based on Trojan Horse strategy, and all of them displayed potencies against susceptible Gram-negative strains with MIC ≤ 8 µg/mL. SAR revealed that the polar substituents on the oxime side chain were beneficial for activities against resistant Gram-negative bacteria. Compounds 19c and 33a-b exhibited the promising potencies against ESBLs-producing E. coli and Klebsiella pneumoniae with MICs ranging from 2 µg/mL to 8 µg/mL. These results offered powerful information for further strategic optimization in search of the antibacterial candidates against MDR Gram-negative bacteria.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , Monobactams/chemistry , Monobactams/pharmacology , Anti-Bacterial Agents/chemical synthesis , Aztreonam/analogs & derivatives , Aztreonam/chemical synthesis , Aztreonam/pharmacology , Drug Design , Escherichia coli/drug effects , Humans , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests , Models, Molecular , Monobactams/chemical synthesis , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
A novel series of N-benzenesulfonyl matrinic amine/amide and matrinic methyl ether analogues were designed, synthesized and evaluated for their in vitro anti-coxsackievirus B3 (CVB3) activities. The structure-activity relationship (SAR) studies revealed that introduction of a suitable amide substituent on position 4' could greatly enhance the antivirus potency. Compared to the lead compounds, the newly synthesized matrinic amide derivatives 21c-d and 21j exhibited stronger anti-CVB3 activities with lower micromolar IC50 from 2.5 µM to 2.7 µM, and better therapeutic properties with improved selectivity index (SI) from 63 to 67. The SAR results provided powerful information for further strategic optimization, and these top compounds were selected for the next evaluation as novel enterovirus inhibitors.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Enterovirus B, Human/drug effects , Structure-Activity Relationship , Animals , Chemistry Techniques, Synthetic , Chlorocebus aethiops , Drug Evaluation, Preclinical/methods , Enterovirus B, Human/pathogenicity , Vero Cells/drug effects , Vero Cells/virologyABSTRACT
Using sophoridine (1) as the lead compound, a series of new N-substituted sophoridinic acid derivatives were designed, synthesized and evaluated for their cytotoxicity. SAR analysis indicated that introduction of a chlorobenzyl on the 12-nitrogen atom of sophoridinol might significantly enhance the antiproliferative activity. Of the newly synthesized compounds, sophoridinol analogue 9k exhibited a potent effect against six human tumor cell lines (liver, colon, breast, lung, glioma and nasopharyngeal). The mode of action of 9k was to inhibit the DNA topoisomerase I activity, followed by the G0/G1 phase arrest. It also showed a moderate oral bioavailability and good safety in vivo. Therefore, compound 9k has been selected as a novel-scaffold lead for further structural optimizations or as a chemical probe for exploring anticancer pathways of this kinds of compounds.
Subject(s)
Antineoplastic Agents/pharmacology , DNA Topoisomerases, Type I/metabolism , Quinazolines/chemistry , Quinazolines/pharmacology , Topoisomerase I Inhibitors/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , Hep G2 Cells , Humans , Injections, Intravenous , KB Cells , MCF-7 Cells , Male , Mice , Mice, Inbred ICR , Models, Molecular , Molecular Structure , Quinazolines/administration & dosage , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Topoisomerase I Inhibitors/administration & dosage , Topoisomerase I Inhibitors/chemistryABSTRACT
A series of new 1,13-cycloprotoberberine derivatives defined through variations at the 9-position were designed, synthesized and evaluated for their cytotoxicities in human HepG2 (hepatoma), HT1080 (fibrosarcoma) and HCT116 (colon cancer) cells. The preliminary structure-activity relationship (SAR) revealed that the replacement of 9-methoxyl with an ester moiety might significantly enhance the antiproliferative activity in vitro. Notably, compound 7f demonstrated equipotent cytotoxicity activity against breast cancer MCF-7 (parent) and doxorubicin (DOX)-resistant MCF-7 (MCF-7/ADrR) cells, indicating a mode of action different from that of DOX. Further mechanism study showed that 7f significantly inhibited activity of DNA topoisomerase I (Top I) and Top II. G2/M phase arrest and tumor cell growth reduction was observed thereafter. Thus, we consider cycloprotoberberine analogues to be a new family of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.
Subject(s)
Berberine Alkaloids/chemistry , Berberine Alkaloids/pharmacology , Drug Discovery , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Berberine Alkaloids/chemical synthesis , Binding Sites , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Cyclization , Drug Resistance, Neoplasm/drug effects , Humans , Inhibitory Concentration 50 , MCF-7 Cells , Models, Biological , Molecular Docking Simulation , Molecular StructureABSTRACT
BACKGROUND: The emergence of multi-drug resistant tuberculosis (MDR-TB) has heightened the need for new chemical classes and innovative strategies to tackle TB infections. It is urgent to discover new classes of molecules without cross-resistance with currently used antimycobacterial drugs. RESULTS: Eighteen new 8-substituted protoberberine derivatives were synthesized and evaluated for their anti-mycobacterial activities against Mycobacterium tuberculosis (M. tuberculosis) strain H37Rv. Among them, compound 7g was the most effective antitubercular agent with minimum inhibitory concentration (MIC) of 0.5 µg/mL. Moreover, it also afforded a potent antitubercular effect against clinically isolated MDR strains of M. tuberculosis with MICs ranging from 0.25 to 1.0 µg/mL, suggesting a novel mode of action. CONCLUSIONS: The structure-activity relationship (SAR) analysis revealed that introduction of a substituent at the 8-position in pseudoprotoberberine, especially an n-decyl, could significantly enhance the anti-TB activity. We consider 8-n-decylberberines to be a novel family of anti-tubercular agents with an advantage of inhibiting MDR strains of M. tuberculosis.
ABSTRACT
Heat-stress cognate 70 (Hsc70) is a host factor that helps hepatitis C virus (HCV) to complete its life cycle in infected hepatocytes. Using Hsc70 as a target for HCV inhibition, a series of novel N-substituted benzyl matrinic/sophoridinic acid derivatives was synthesized and evaluated for their anti-HCV activity in vitro. Among these analogues, compound 7c possessing N-p-methylbenzyl afforded an appealing ability to inhibit HCV replication with SI value over 53. Furthermore, it showed a good oral pharmacokinetic profile with area-under-curve (AUC) of 13.4 µM·h, and a considerably good safety in oral administration in mice (LD50>1000 mg/kg). As 7c suppresses HCV replication via an action mode distinctly different from that of the marketed anti-HCV drugs, it has been selected as a new mechanism anti-HCV candidate for further investigation, with an advantage of no or decreased chance to induce drug-resistant mutations.
Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Down-Regulation/drug effects , HSC70 Heat-Shock Proteins/metabolism , Hepacivirus/drug effects , Hepacivirus/physiology , Quinolizines/chemistry , Quinolizines/pharmacology , Virus Replication/drug effects , Alkaloids/adverse effects , Alkaloids/pharmacokinetics , Animals , Antiviral Agents/adverse effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Cell Line , Humans , Male , Mice , Mice, Inbred ICR , Quinolizines/adverse effects , Quinolizines/pharmacokinetics , Safety , Structure-Activity Relationship , MatrinesABSTRACT
A series of cycloberberine derivatives were designed, synthesized and evaluated for their anti-cancer activities in vitro. Among these analogs, compounds 6c, 6e and 6g showed strong inhibition on human HepG2 cells. They afforded a potent effect against DOX-resistant MCF-7 breast cells as well. The primary mechanism showed that cell cycle was blocked at G2/M phase of HepG2 cells treated with 6g using flow cytometry assay. It significantly inhibited the activity of DNA Top I at the concentration of 0.1 mg mL-1. Our results provided a basis for the development of this kind of compounds as novel anti-cancer agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Berberine/analogs & derivatives , Berberine/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Berberine/chemistry , Berberine/pharmacology , Cell Cycle/drug effects , Cell Proliferation/drug effects , DNA Topoisomerases, Type I/metabolism , Doxorubicin/pharmacology , Drug Resistance, Neoplasm , Hep G2 Cells , Humans , MCF-7 Cells , Molecular Structure , Structure-Activity RelationshipABSTRACT
Currently there is no approved medicine for the treatment of metabolic syndrome. A series of new derivatives of berberine (BBR) or pseudoberberine (1) was synthesized and evaluated for their activity on AMP-activated protein kinase (AMPK) activation and up-regulatory low-density-lipoprotein receptor (LDLR) gene expression, respectively. In addition, the four major metabolites of BBR in vivo were also examined for their activity on AMPK in order to further understand the chemical mechanisms responsible for its glucose-lowering efficacy. Among those BBR analogues, compound 1 exhibited the potential effect on AMPK activation and LDLR up-regulation as compared with BBR. The results suggested that compound 1 might be a multiple-target agent for the treatment of metabolic syndrome, and thus was selected as a promising drug candidate for further development.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Berberine Alkaloids/chemical synthesis , Berberine/analogs & derivatives , Receptors, LDL/metabolism , AMP-Activated Protein Kinases/genetics , Berberine/chemical synthesis , Berberine/pharmacology , Berberine Alkaloids/chemistry , Berberine Alkaloids/pharmacology , Hep G2 Cells , Humans , Receptors, LDL/genetics , Structure-Activity Relationship , Up-Regulation/drug effectsABSTRACT
Twenty-eight new 13-n-octylberberine derivatives were synthesized and evaluated for their activities against drug-susceptible Mycobacterium tuberculosis (M. tuberculosis) strain H(37)Rv. Among these compounds, compound 16e was the most effective anti-tubercular agent with a MIC value of 0.125 µg/mL. Importantly, compound 16e exhibited more potent effect against rifampicin (RIF)- and isoniazid (INH)-resistant M. tuberculosis strains than both RIF and INH, suggesting a new mechanism of action. Therefore, it has been selected as a drug candidate for further investigation, or as a chemical probe for identifying protein target and studying tuberculosis biology. We consider 13-n-octylberberine analogs to be a promising novel class of antituberculars against multi-drug-resistant (MDR) strains of M. tuberculosis.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Berberine/analogs & derivatives , Berberine/chemical synthesis , Berberine/pharmacology , Chemistry Techniques, Synthetic , Mycobacterium tuberculosis/drug effects , Anti-Bacterial Agents/chemistry , Berberine/chemistry , Drug Resistance, Bacterial/drug effects , Structure-Activity RelationshipABSTRACT
A series of novel N-(2-arylethyl) isoquinoline derivatives were designed, synthesized and evaluated for their anti-cancer activities. Among these analogs, compound 9a exhibited the potential anti-cancer activities on HepG2 and HCT116 cells with IC50 values of 2.52 and 1.99 microg x mL(-1), respectively. Cell cycle was blocked at S phase of HepG2 cells treated with 9a by flow cytometry detection. Our results provided a basis for the development of a new series of anti-cancer candidates.
Subject(s)
Antineoplastic Agents/chemical synthesis , Isoquinolines/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Cell Proliferation/drug effects , HCT116 Cells , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Isoquinolines/chemistry , Isoquinolines/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
Sophoridine (1), a natural anticancer drug, has been used in China for decades. A series of novel N-substituted sophoridinic acid derivatives were synthesized and evaluated for their cytotoxicity with 1 as the lead. The structure-activity relationship indicated that introduction of an aliphatic acyl on the nitrogen atom might significantly enhance the anticancer activity. Among the compounds, 6b bearing bromoacetyl side-chain afforded a potential effect against four human tumor cell lines (liver, colon, breast, and lung). The mechanism of action of 6b is to inhibit the activity of DNA topoisomerase I, followed by the S-phase arrest and then cause apoptotic cell death, similar to that of its parent 1. We consider 6b promising for further anticancer investigation.
Subject(s)
Alkaloids/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Quinolizines/pharmacology , Alkaloids/chemical synthesis , Alkaloids/chemistry , Antineoplastic Agents/chemistry , Cell Death/drug effects , Chemistry Techniques, Synthetic , DNA Topoisomerases, Type I/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Neoplasms/enzymology , Neoplasms/pathology , Quinolizines/chemical synthesis , Quinolizines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Heat-stress cognate 70 (Hsc70) is a host protein required for hepatitis B virus (HBV) replication, and oxymatrine (1) suppresses Hsc70 expression. Taking Hsc70 as a target against HBV, 22 analogues of 1 defined with substituents at position 1, 13, or 14 were synthesized and evaluated for their activity on Hsc70 mRNA expression. The SAR revealed that (i) the oxygen atom at the 1-position was not essential, (ii) increasing electron density on the ring D reduced the activity, and (iii) introducing a proper substituent at the 13- and/or 14-position(s), especially electron-withdrawing groups, might enhance the activity. Among the analogues, 6b possessing 13-ethoxyl afforded an increased activity in respect to 1. Importantly, it was active for either wild-type or lamivudine-resistant HBV, as its target is host Hsc70 but not viral enzymes. LD(50) of 6b in mice was over 750 mg/kg in oral route. We consider compound 6b promising for further investigation.