A5076577365- Microbial Natural Products and Biosynthesis
- Marine Sponges and Natural Products
- Synthetic Organic Chemistry Methods
- Chemical Synthesis and Analysis
- Chronic Lymphocytic Leukemia Research
- Radiopharmaceutical Chemistry and Applications
- Vitamin C and Antioxidants Research
- Polyomavirus and related diseases
- Lanthanide and Transition Metal Complexes
- BRCA gene mutations in cancer
- RNA Interference and Gene Delivery
- PARP inhibition in cancer therapy
- Cancer Mechanisms and Therapy
- Advanced biosensing and bioanalysis techniques
- Endometrial and Cervical Cancer Treatments
- Genetic factors in colorectal cancer
- Biotin and Related Studies
- Cancer therapeutics and mechanisms
- Ovarian cancer diagnosis and treatment
- Ubiquitin and proteasome pathways
- Immunotherapy and Immune Responses
- Cell death mechanisms and regulation
- Lymphoma Diagnosis and Treatment
- Quinazolinone synthesis and applications
- Biosimilars and Bioanalytical Methods
National Institutes of Health
2021-2025
National Cancer Institute
2019-2024
Target (United States)
2019-2024
Center for Cancer Research
2020-2024
Leidos (United States)
2019-2024
Frederick National Laboratory for Cancer Research
2019-2024
Leidos Biomedical Research Inc. (United States)
2021-2022
Memorial Sloan Kettering Cancer Center
2004-2020
University of Cincinnati
2012
Merck & Co., Inc., Rahway, NJ, USA (United States)
2010
Abstract Vitamin C is an antioxidant vitamin that has been hypothesized to antagonize the effects of reactive oxygen species–generating antineoplastic drugs. The therapeutic efficacy widely used drugs doxorubicin, cisplatin, vincristine, methotrexate, and imatinib were compared in leukemia (K562) lymphoma (RL) cell lines with without pretreatment dehydroascorbic acid, commonly transported form C. effect on viability, clonogenicity, apoptosis, P-glycoprotein, species (ROS), mitochondrial...
Methotrexate is known to synergize with cytarabine [1-beta-D-arabinofuranosylcytosine (ara-C)] in a schedule-dependent manner. The purpose of this article compare and contrast the activity pralatrexate (10-propargyl-10-deazaminopterin)/gemcitabine standard combination methotrexate/ara-C determine if schedule dependency important lymphoma.Cytotoxicity assays using trypan blue exclusion assay were used explore vitro gemcitabine against panel lymphoma cell lines. Both severe combined...
Abstract Cholangiocarcinoma (CCA) is a highly aggressive malignancy that arises from the biliary tree, and often presents with advanced stage disease. For patients disease arising intrahepatic bile ducts, genomic analyses have revealed targetable mutations. Unfortunately, these mutations are exceedingly rare in extrahepatic (eCCA), limiting therapeutic options. It therefore necessary to investigate functional crosstalk resulting different signal transduction pathways identify new treatment...
Pyrrole-containing natural products form a large group of structurally diverse compounds that occur in both terrestrial and marine organisms. In the present study formation trideuteromethylated artifacts pyrrole-containing was investigated, focusing on discorhabdins. Three deuterated discorhabdins, 1, 3, 5, were identified to be isolation procedure caused by presence DMSO-d6 during NMR sample preparation handling. additional semisynthetic derivatives, 7–9, made investigation mechanism...
A high throughput screen performed to identify catalytic inhibitors of the oncogenic fusion form cAMP-dependent protein kinase subunit alpha (J-PKAcα) found an individual fraction from organic extract marine soft coral
Abstract Purpose: To determine whether the combination of proteasome inhibitor bortezomib and bcl-2 antisense molecule oblimersen can sensitize human lymphoma to cyclophosphamide. Experimental Design: Cytotoxicity assays were conducted if there was any additive or synergistic interaction between combinations bortezomib, oblimersen, cyclophosphamide using a standard trypan blue exclusion assay. Based on these experiments, in vivo experiments severe combined immunodeficiency beige mice done...
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer. Two new prenylated indole 2,5-diketopiperazine alkaloids, brevianamides E1 (
A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) viability. The set included five new natural products compounds whose structures were elucidated with NMR, HRMS, ECD techniques. Several averaged sub-micromolar potency against the MCC lines tested most active showed selectivity towards virus-positive lines. An investigation structure–activity relationships resulted in an expanded understanding crucial structural...
Bioassay-guided separation of an extract from a Dictyosporium sp. isolate led to the identification six new compounds, 1–6, together with five known 7–11. The structures compounds were primarily established by extensive 1D and 2D NMR experiments. absolute configurations 3–6 determined comparison their experimental electronic circular dichroism (ECD) spectra DFT quantum mechanical calculated ECD spectra. Compounds 3–5 possess novel structural scaffolds, biochemical studies revealed that...
Abstract Activating mutations in RAS are found approximately 30% of human cancers, resulting the delivery a persistent signal to critical downstream effectors that drive tumorigenesis. RAS-driven malignancies respond poorly conventional cancer treatments and inhibitors target directly limited; therefore, identification new strategies and/or drugs disrupt signaling tumor cells remains pressing therapeutic need. Taking advantage live-cell bioluminescence resonance energy transfer (BRET)...
The DNAJB1–PRKACA oncogenic gene fusion results in an active kinase enzyme, J-PKAcα, that has been identified as attractive antitumor target for fibrolamellar hepatocellular carcinoma (FLHCC). A high-throughput assay was used to identify inhibitors of J-PKAcα catalytic activity by screening the NCI Program Natural Product Discovery (NPNPD) prefractionated natural product library. Purification agent from a single fraction Aplidium sp. marine tunicate led discovery two unprecedented alkaloids,...
High-throughput siRNA screens are now widely used for identifying novel drug targets and mapping disease pathways. Despite their popularity, there remain challenges related to data variability, primarily due measurement errors, biological variance, uneven transfection efficiency, the efficacy of sequences, or off-target effects, consequent high false discovery rates. Data variability can be reduced if performed in replicate. Running a large-scale screen replicate is difficult, however,...
A new dimeric alkaloid plakoramine [(±)-1] was identified from a marine sponge Plakortis sp. Chiral-phase HPLC separation of (±)-1 led to the purified enantiomers (+)-1 and (-)-1 which both potently inhibited CBL-B E3 ubiquitin ligase activities. The absolute configurations were determined by quantum chemical calculations. Scrutinization purification conditions revealed previously undescribed, nonenzymatic route form via photochemical conversion its naturally occurring monomeric counterpart,...
Two new cyclic depsipeptides named swinhopeptolides A (1) and B (2) have been isolated from the marine sponge Theonella swinhoei cf. verrucosa, collected Papua New Guinea. They each contain 11 diverse amino acid residues 13-carbon polyketide moieties attached at N-terminus. Compounds 1 2 exist as two conformers in DMSO-d6 due to cis/trans isomerism of proline residue, their structures were successfully assigned by extensive NMR analyses complemented chemical degradation derivatization...
An extract of the coralline demosponge
The transfer of the small protein ubiquitin to a target is an intricately orchestrated process called ubiquitination that results in modulation function or stability. Proper regulation essential, and dysregulation this implicated several human diseases. An example cascade central signaling node important disease-associated pathways CBLB [a homolog viral oncogene Casitas B-lineage lymphoma (CBL) from Cas NS-1 murine retrovirus], RING finger ligase (E3) whose substrates include number...
An extract of a Sinularia sp. soft coral showed inhibitory activity against the E3-ubiquitin ligase casitas B-lineage lymphoma proto-oncogene B (Cbl-b). Subsequent bioassay-guided separation provided series terpenoid-derived spermidine and spermine amides that were named sinularamides A–G (1–7). Compounds 1–7 represent new natural products; however, sinularamide A (1) was previously reported as synthetic end product. The structures (1–7) elucidated by analysis spectroscopic spectrometric...
The recent demonstration that adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent protein kinase A (PKA) plays an oncogenic role in a number of important cancers has led to renaissance drug development interest targeting this kinase. We therefore have established suite biochemical, cell-based, and structural biology assays for identifying evaluating new pharmacophores PKA inhibition. This discovery process started with 384-well high-throughput screen more than 200,000 substances, including...
A new 11 amino acid linear peptide named roseabol (1) and the known compound 13-oxo-trans-9,10-epoxy-11(E)-octadecenoic (2) were isolated from fungus Clonostachys rosea. Combined NMR MS analysis revealed that contained residues characteristic of peptaibol family peptides such as isovaline, α-aminoisobutyric acid, hydroxyproline, leucinol, an N-terminal isovaleric moiety. The sequence was established by a combination studies tandem fragmentation analyses, absolute configurations constituent...
Toll-like receptors (TLR) are pattern recognition that play a pivotal role in the initiation of immune responses. Here we report murine mammary carcinoma 4T1 constitutively expressed genes encoding TLR2, 3, 4 and 5. Moreover, treatment cell line with peptidoglycan (PGN), polyinosinic-polycytidylic acid (Poly(I:C)) or lipopolysaccharide (LPS), agonists for 3 respectively, induced nuclear translocation NFκB secretion CCL2, CCL5 CXCL1 dose dependent manner. Although treating tumor cells TLR did...
Merkel cell carcinoma (MCC) is a rare, but aggressive skin cancer the incidence of which has increased significantly in recent years. The majority MCCs have incorporated polyomavirus (VP-MCC) while remainder are virus-negative (VN-MCC). Although variety therapeutic options shown promise treating MCC, there remains need for additional therapeutics as well probes better understanding MCC. A high-throughput screening campaign was used to assess ability > 25,000 synthetic and natural product...