A5038741616- Chemical Synthesis and Analysis
- RNA Research and Splicing
- Conflict of Laws and Jurisdiction
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Inorganic and Organometallic Chemistry
- DNA and Nucleic Acid Chemistry
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Organometallic Complex Synthesis and Catalysis
- Legal Issues in South Africa
- Cancer therapeutics and mechanisms
- Crystallography and molecular interactions
- Influenza Virus Research Studies
- Chemical Synthesis and Reactions
- Computational Drug Discovery Methods
- Advanced Chemical Physics Studies
- Comparative and International Law Studies
- Metal complexes synthesis and properties
- Stress Responses and Cortisol
- Receptor Mechanisms and Signaling
- Carbohydrate Chemistry and Synthesis
- Asymmetric Hydrogenation and Catalysis
- European and International Law Studies
- Legal principles and applications
Glenfield Hospital
2022
University of Leicester
2022
NIHR Leicester Biomedical Research Centre
2022
SRI International
2014-2020
University of California, Santa Cruz
2018-2020
Menlo School
2015-2019
St. Jude Children's Research Hospital
2006-2018
University of Kentucky
2017
University of Tennessee Health Science Center
2012
ChemBridge (United States)
2000-2008
Renal cell carcinomas (RCC) commonly retain wild-type but functionally inactive p53, which is repressed by an unknown dominant mechanism. To help reveal this mechanism, we screened a diverse chemical library for small molecules capable of restoring p53-dependent transactivation in RCC cells carrying p53-responsive reporter. Among the compounds isolated were derivatives 9-aminoacridine (9AA), including antimalaria drug quinacrine, strongly induced p53 function and other types cancer cells....
The structure of thallium dicyanoargentate(I) has been determined crystallographically. crystal shows an Ag-Ag distance 3.11 Å. This is the shortest reported for any silver dicyanide salt whose determined. Raman spectra compound show four nu(C)(-)(N) peaks that are well-resolved in 10-80 K temperature range. result agrees well with group theory analysis. Extended Hückel calculations using relativistic wave functions have carried out two models which describe interactions between Ag(CN)(2)(-)...
Two unrelated bacterial natural products, FR901464 and pladienolide B, have previously been shown to significant antitumor activity in vivo. These compounds target the SF3b subunit of spliceosome, with a derivative (E7107) entering clinical trials for cancer. However, due structural complexity these molecules, their research development has significantly constrained. We generated set novel analogues (Sudemycins) that possess pharmacophore is common pladienolide, via flexible enantioselective...
Emerging influenza viruses are a serious threat to human health because of their pandemic potential. A promising target for the development novel anti-influenza therapeutics is PA protein, whose endonuclease activity essential viral replication. Translation mRNAs by host ribosome requires mRNA capping recognition and binding, necessary caps cleaved or “snatched” from pre-mRNAs endonuclease. The structure-based inhibitors that now possible with recent crystal structure catalytic domain. In...
To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These identified the plant homeodomain (PHD)-finger domain protein PHF5A as differentially required for GSC expansion, compared with untransformed neural (NSCs) fibroblasts. Given PHF5A's known involvement facilitating interactions between U2 snRNP complex ATP-dependent helicases, examined...
Abstract Somatic mutations in spliceosome genes are detectable ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring gene have increased sensitivity to pharmacological perturbation the spliceosome. focus on mutant U2AF1 and utilize sudemycin compounds modulate pre-mRNA splicing. find haematopoietic expressing U2AF1(S34F), including primary patient cells, an vitro treatment relative controls. In vivo U2AF1(S34F) transgenic mice alters splicing reverts...
ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTDesign and Synthesis of a Series Non-Peptide High-Affinity Human Corticotropin-Releasing Factor1 Receptor AntagonistsChen, Raymond Dagnino, Errol B. De Souza, Dimitri E. Grigoriadis, Charles Q. Huang, Kyung-Il Kim, Zhengyu Liu, Terry Moran, Thomas R. Webb, Jeffrey P. Whitten, Yun Feng Xie, James McCarthyView Author Information Neurocrine Biosciences, 3050 Science Park Road, San Diego, California 92121 Cite this: J. Med. Chem. 1996, 39, 22,...
Influenza viruses have been responsible for the largest pandemics in previous century. Although vaccination and prophylactic antiviral therapeutics are primary defense against influenza virus, there is a pressing need to develop new agents circumvent limitations of current therapies. The endonuclease activity virus PA(N) protein essential replication promising target novel anti-influenza drugs. To facilitate discovery inhibitors, we developed high-throughput fluorescence polarization (FP)...
Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. treated drug praziquantel (PZQ), which has proved therapeutic mainstay for over three decades use. However, molecular target(s) PZQ remain undefined. Here we identify target antischistosomal eutomer - (R)-PZQ functions as partial agonist human serotoninergic...
// Sílvia Xargay-Torrent 1, * , Mónica López-Guerra 2, Laia Rosich 1 Arnau Montraveta Jocabed Roldán Vanina Rodríguez Neus Villamor 2 Marta Aymerich Chandraiah Lagisetti 3 Thomas R. Webb Carlos López-Otín 4 Elias Campo Dolors Colomer Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Hematopathology Unit, Department of Pathology, Hospital Clinic, University Center for Chemical Biology, Biosciences...
We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at 3-position bicyclic nucleus was designed to reduce lipophilicity from initial leads such as 7. Here, we showed these 3-pyridyl compounds exhibited CRF(1) Moreover, hydrophilic moiety increased water solubility some...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAutomated synthesis of peptide C-terminal aldehydesAileen M. Murphy, Raymond Dagnino Jr., Pureza L. Vallar, Anthony J. Trippe, Shannon Sherman, Richard H. Lumpkin, Susan Y. Tamura, and Thomas R. WebbCite this: Am. Chem. Soc. 1992, 114, 8, 3156–3157Publication Date (Print):April 1, 1992Publication History Published online1 May 2002Published inissue 1 April...
This paper reports details of the synthesis oligodeoxynucleotides containing modified base 5-methyl-N4,N4-ethanocytosine (Ce). The 9-fluorenylmethoxycarbonyl group is used as a protecting for exocyclic amines dA and dC. can be removed rapidly under very mild conditions. Oligomers Ce form cross-link when hybridized to their complementary deoxyoligonucleotides. Some scope limitations these forming oligonucleotides are reported.
Sudemycin E is an analog of the pre-messenger RNA splicing modulator FR901464 and its derivative spliceostatin A. causes death cancer cells through unknown mechanism. We found that similar to A, sudemycin binds U2 small nuclear ribonucleoprotein (snRNP) component SF3B1. Native chromatin immunoprecipitations showed snRNPs physically interact with nucleosomes. induces a dissociation decreases their interaction To determine effect on gene expression, we performed genome-wide array analysis....
Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease that affects hundreds millions. Treatment schistosomiasis depends almost entirely on drug praziquantel (PZQ). Though essential to treating and controlling major limitation PZQ is it not active against immature mammalian-stage schistosomes. Furthermore, there are reports field isolates with heritable reductions in susceptibility, researchers have selected for PZQ-resistant schistosomes laboratory....
The spliceosome regulates pre-mRNA splicing, which is a critical process in normal mammalian cells. Recently, recurrent mutations numerous spliceosomal proteins have been associated with number of cancers. Previously, natural product antitumor agents shown to interact one the that subject (SF3B1). We report optimization class tumor-selective modulators demonstrate significant vivo activity. This culminated discovery sudemycin D6, shows potent cytotoxic activity melanoma line SK-MEL-2 (IC50 =...
Herboxidiene is a natural product that has previously been shown to exhibit antitumor activity by targeting the spliceosome. This makes herboxidiene valuable starting point for development of anticancer drugs. Here, we report an improved enantioselective synthesis and first its biologically active totally synthetic analog: 6-norherboxidiene. The tetrahydropyran moiety utilizes novel application inverse electron-demand Diels–Alder chemistry Ferrier-type rearrangement as key steps. We report,...
The recent identification of compounds that interact with the spliceosome (sudemycins, spliceostatin A, and meayamycin) indicates these molecules modulate aberrant splicing via SF3B1 inhibition. Through whole transcriptome sequencing, we have demonstrated treatment Rh18 cells sudemycin leads to exon skipping as predominant event. This was also observed following reanalysis published RNA-seq data sets derived from HeLa after A exposure. These results are in contrast previous reports indicate...
Significance The endonuclease domain within the influenza virus heterotrimeric replication machinery is essential and represents an attractive drug target. It important to understand structural basis of potential inhibitor resistance, design appropriate inhibitors prioritize candidates that are unlikely cause rapid development clinically-relevant resistance mutations. Using a prototypical (L-742,001), we used mutagenesis select for competent resistant mutants studied functional observed...