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Marine Drugs Apr 2018The recent development of analogs of brefeldin A (BFA), a fungal metabolite, for the improvement of BFA apoptosis-inducing activity is described. BFA has been isolated... (Review)
Review
The recent development of analogs of brefeldin A (BFA), a fungal metabolite, for the improvement of BFA apoptosis-inducing activity is described. BFA has been isolated from various soil or, more recently, marine fungi and has shown versatile beneficial activities. More importantly, the apoptosis-inducing activity of BFA in cancer cells highlights the possibility of further developing this natural product as an anticancer agent. Besides its biological importance, its structural features have also gathered tremendous interest from both medicinal and synthetic chemists. By a medicinal chemistry and total synthesis approach, numerous analogs from BFA have been developed to improve its inferior bioavailability and its antiproliferative ability. In this review, the recent medicinal chemistry efforts in relation to the production of BFA analogs are extensively presented.
Topics: Antineoplastic Agents; Apoptosis; Biological Availability; Brefeldin A; Cell Proliferation; Humans
PubMed: 29670019
DOI: 10.3390/md16040133 -
European Journal of Medicinal Chemistry Oct 2022Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and ranks third in mortality rate worldwide. Brefeldin A (BFA, 1), a natural Arf1 inhibitor,...
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and ranks third in mortality rate worldwide. Brefeldin A (BFA, 1), a natural Arf1 inhibitor, qualifies extremely superior antitumor activity against HCC while its low aqueous solubility, poor bioavailability, and high toxicity have greatly hindered its translation to the clinic. Herein, a series of BFA-cinnamic acid ester derivatives was rationally designed and synthesized via introducing active cinnamic acid and its analogues into the structure of 1. Their in vitro cytotoxic activities on five cancer cell lines, including HepG2, BEL-7402, HeLa, Eca-109 and PANC-1, were evaluated using MTT assay. As expected, favorable cytotoxic activity was observed on majority of the mono-substituted derivatives. Especially, the most potent brefeldin A 4-O-(4)-dimethylaminocinnamate (CHNQD-01269, 33) with improved aqueous solubility, demonstrated the strong cytotoxic activity against HepG2 and BEL-7402 cell lines with IC values of 0.29 and 0.84 μM, respectively. More importantly, 33 performed low toxicity on normal liver cell line L-02 with the selectivity index (SI) of 9.69, which was more than 17-fold higher than that of 1. Results from mechanistic studies represented that 33 blocked the cell cycle in the G1 phase, and induced apoptosis via elevating reactive oxygen species (ROS) production and increasing expression of apoptosis-related proteins of HepG2 cells. Docking experiment also suggested 33 a promising Arf1 inhibitor, which was confirmed by the cellular thermal shift assay that 33 displayed a significant effect on the stability of Arf1 protein. Furthermore, 33 possessed high safety profile (MTD >100 mg/kg, ip) and favorable pharmacokinetic properties. Notably, the superior antiproliferative activity was verified in HepG2 tumor-bearing xenograft model in which 33 markedly suppressed the tumor growth (TGI = 46.17%) in nude mice at a dose of 10 mg/kg once a day for 16 d. The present study provided evidence of exploiting this series of highly efficacious derivatives, especially 33, for the treatment of HCC.
Topics: Animals; Antineoplastic Agents; Apoptosis; Brefeldin A; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cinnamates; Drug Screening Assays, Antitumor; Esters; Humans; Liver Neoplasms; Mice; Mice, Nude; Structure-Activity Relationship
PubMed: 35849940
DOI: 10.1016/j.ejmech.2022.114598 -
Cell Apr 1999
Review
Topics: ADP-Ribosylation Factors; Animals; Brefeldin A; GTP-Binding Proteins; Golgi Apparatus; Guanosine Diphosphate; Models, Molecular; Mutation
PubMed: 10219235
DOI: 10.1016/s0092-8674(00)80724-2 -
Autophagy Sep 2016Two topics that have attracted recent attention in the field of autophagy concern the source of the membrane that is used to form the autophagosome during macroautophagy...
Two topics that have attracted recent attention in the field of autophagy concern the source of the membrane that is used to form the autophagosome during macroautophagy and the role of noncanonical autophagic pathways. The 2 topics may converge when considering the intersection of autophagy with viral infection. We suggest that noncanonical autophagy, which is sensitive to treatment with brefeldin A, may converge with the infectious cycles of certain DNA and RNA viruses that utilize membrane from the ER and cis-Golgi.
Topics: Animals; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Beclin-1; Brefeldin A; Cell Membrane; Coronavirus; Coronavirus Infections; Ebolavirus; Endoplasmic Reticulum; Golgi Apparatus; Humans; Microtubule-Associated Proteins; Virus Diseases
PubMed: 27439673
DOI: 10.1080/15548627.2016.1203489 -
American Journal of Physiology. Cell... Aug 2021Endothelial hyperpermeability is the hallmark of acute respiratory distress syndrome (ARDS). Laborious efforts in the investigation of the molecular pathways involved in...
Endothelial hyperpermeability is the hallmark of acute respiratory distress syndrome (ARDS). Laborious efforts in the investigation of the molecular pathways involved in the regulation of the vascular barrier shall reveal novel therapeutic targets toward that respiratory disorder. Herein, we investigate in vitro the effects of the α-1,2-mannosidase 1 inhibitor kifunensine (KIF) and brefeldin A (BFA) in the lipopolysaccharides (LPS)-induced endothelial breakdown. Our results suggest that BFA opposes the deteriorating effects of KIF [unfolded protein response (UPR) suppressor] toward the lung microvasculature. Since KIF is a UPR suppressor, and brefeldin A is a UPR inducer, we suggest that a carefully devised UPR manipulation may deliver novel therapeutic avenues in diseases related to endothelial barrier dysfunction (e.g., ARDS and sepsis).
Topics: Alkaloids; Animals; Brefeldin A; Cattle; Endothelial Cells; Endothelium, Vascular; Humans; Lipopolysaccharides; Lung; Microvessels; Permeability; Respiratory Distress Syndrome
PubMed: 34161151
DOI: 10.1152/ajpcell.00142.2021 -
Biochemical and Biophysical Research... Sep 2020Arf proteins are small Ras-family GTPases which recruit clathrin and COPI coats to Golgi membranes and regulate components of the membrane trafficking machinery. It is...
Arf proteins are small Ras-family GTPases which recruit clathrin and COPI coats to Golgi membranes and regulate components of the membrane trafficking machinery. It is believed membrane association and activity of Arfs is coupled to GTP binding, with GTP hydrolysis required for vesicle uncoating. In humans, four Arf proteins (Arf1, Arf3, Arf4 and Arf5) are Golgi-associated. Conflicting reports have suggested that HA-GFP-tagged Class II ARFs (Arf4 and Arf5) are recruited to membrane independently of the brefeldin A sensitive exchange factor GBF1, suggesting regulation fundamentally different from the Class I Arfs (Arf1, Arf3), or alternately that the GTPase cycle of GFP-tagged Class II Arfs is similar to other Arfs. We show that these results depend on the fluorescent tag, with Arf4-HA-GFP tag resistant to brefeldin, but Arf4-GFP acting similarly to Arf1-GFP in brefeldin-sensitivity and photobleach assays. Arf4-HA-GFP could be partially reverted to the behavior of Arf4-GFP by mutation of two aspartic acids in the HA tag to alanine. Our results, which indicate a high sensitivity of Arf4 to tagging, can explain the discrepancies between previous studies. We discuss the implications of this study for future work with tagged Arfs.
Topics: ADP-Ribosylation Factor 1; ADP-Ribosylation Factors; Brefeldin A; Golgi Apparatus; Guanine Nucleotide Exchange Factors; HeLa Cells; Humans
PubMed: 32828303
DOI: 10.1016/j.bbrc.2020.07.001 -
Plant Physiology Nov 2002
Review
Topics: Biological Transport; Brefeldin A; Endoplasmic Reticulum; Golgi Apparatus; Plant Cells; Plants
PubMed: 12427977
DOI: 10.1104/pp.011569 -
Chemistry & Biodiversity Oct 2022From the deep-sea-derived Fusarium sp. ZEN-48, four known compounds were obtained. Their structures were established by extensive analyses of the NMR, HR-ESI-MS, and the...
From the deep-sea-derived Fusarium sp. ZEN-48, four known compounds were obtained. Their structures were established by extensive analyses of the NMR, HR-ESI-MS, and the X-ray crystallographic data as brefeldin A (BFA, 1), brevianamide F (2), N-acetyltryptamine (3), and (+)-diaporthin (4). Although BFA was extensively investigated for its potent bioactivities, its role on TNFα-induced necroptosis was incompletely understood. In this study, BFA showed significant inhibition on TNFα-induced necroptosis by disrupting the necrosome formation and suppressing the phosphorylation of RIPK3 and MLKL (IC =0.5 μM). While, it had no effect on TNFα-induced NF-κB/MAPKs activation and apoptosis. The finding raised significant implications of BFA for necroptosis-related inflammatory disease therapy and new drug development from marine fungi.
Topics: Necroptosis; Tumor Necrosis Factor-alpha; Brefeldin A; Fusarium; Necrosis; NF-kappa B; Apoptosis
PubMed: 36000162
DOI: 10.1002/cbdv.202200696 -
Phytochemistry Aug 2022Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is one of the most important carcinogenic factors in many solid tumors, which leads to the poor prognosis and...
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is one of the most important carcinogenic factors in many solid tumors, which leads to the poor prognosis and therapy resistance of cancer. In order to develop direct or indirect KRAS inhibitors, one unique asymmetric dicyclopentenone penipentenone A, three undescribed brefeldin A (BFA) derivatives, and five known BFA derivatives were discovered from the endophytic fungus Penicillium brefeldianum guided by LC-MS/MS and cytotoxic activities. Their structures were elucidated by optical rotation, mass spectrometry, and NMR spectroscopic data. The absolute configurations of four undescribed compounds were elucidated by comparison of the experimental and calculated ECD spectra. The antiproliferative activities of obtained compounds against three KRAS mutant tumor cell lines and two BFA derivative-sensitive cell lines were evaluated. Besides 4-epi-15-epi-brefeldin A, the other compounds showed significant inhibitory activities against those tumor cell lines with IC values ranging from 0.82 to 18.87 μM. Intriguingly, penipentenone A selectively inhibited KRAS mutant cancer cells SW620 (KRAS) and ASPC-1 (KRAS). BFA and four derivatives showed potent cytotoxic activities against all selected tumor cell lines H358 (KRAS), SW620 (KRAS), ASPC-1 (KRAS), PC-3, and HepG-2. These findings will provide undescribed lead compounds for developing drugs that target KRAS mutations.
Topics: Antineoplastic Agents; Brefeldin A; Cell Line, Tumor; Chromatography, Liquid; Neoplasms; Penicillium; Proto-Oncogene Proteins p21(ras); Tandem Mass Spectrometry
PubMed: 35577124
DOI: 10.1016/j.phytochem.2022.113243 -
Anti-cancer Agents in Medicinal... 2022Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by BCR-ABL oncoprotein. Tyrosine kinase inhibitors have been developed to inhibit the activity of...
BACKGROUND
Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by BCR-ABL oncoprotein. Tyrosine kinase inhibitors have been developed to inhibit the activity of BCR-ABL; however, drug resistance and side effect occur in clinic application. Therefore, it is urgent to find novel drugs for CML treatment. Under the guidance of cytotoxic activity, crude extracts of 55 fungal strains from the medicinal mangrove Acanthus ilicifolius were evaluated, and one potent cytotoxic natural compound, brefeldin A (BFA), was discovered from Penicillium sp. (HS-N-29).
OBJECTIVE
This study was aimed to determine the cytotoxic activity of BFA and the effect on the activation and expression of BCR-ABL in K562 cells.
METHODS
We evaluated cytotoxic activity by MTT assay and soft agar clone assay; apoptosis and cell cycle distribution by Muse cell analyzer. The protein level of BCR-ABL and signaling molecules was detected by western blotting, and the mRNA level of BCR-ABL was determined by RT-PCR.
RESULTS
BFA inhibited cell proliferation, induced G2/M cell cycle arrest, and stimulated cell apoptosis in K562 cells. Importantly, for the first time, we revealed that BFA inhibited the activation of BCR-ABL and consequently inhibited the activation of its downstream signaling molecules in K562 cells. Moreover, we found BFA degraded BCR-ABL without affecting its transcription in K562 cells, and BFA-induced BCR-ABL degradation was related to caspase activation, while not to autophagy or ubiquitinated proteasome degradation pathway.
CONCLUSION
Our present results indicate that BFA acts as a dual functional inhibitor and degrader of BCR-ABL, and BFA is a potential compound for chemotherapeutics to overcome CML.
Topics: Antineoplastic Agents; Apoptosis; Brefeldin A; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 34102989
DOI: 10.2174/1871520621666210608110435