Category: Schaus, Scott
Until now, there has been no effective, systemic treatment for liver cancer (hepatocellular carcinoma), the fifth most common cancer worldwide. Writing in the Proceedings of the National Academy of Science (PNAS), Professor Scott Schaus (Chemistry) and Professor Ulla Hansen (Biology and Molecular Biology, Cell Biology & Biochemistry) have reported their discovery of a new protein target for chemotherapy in the treatment of liver cancer — the transcription factor LSF. LSF occurs at high levels in the tumor tissue of patients with liver cancer and is known to promote the development of cancer (oncogenesis) in studies using laboratory rodents.
The co-investigators have identified small molecules that effectively inhibit LSF cellular activity, which in turn slows the growth of the cancer. In particular, they found that one such molecule, Factor Quinolinone Inhibitor 1 (FQI1), derived from a lead compound, inhibits the ability of LSF to bind DNA both in extracts (in vitro, as determined by electrophoretic mobility shift assays) and in cells. Consistent with inhibiting LSF activity, FQI1 also eliminates the ability of LSF to turn up transcription. While FQI1 quickly causes cell death in LSF-overexpressing cells, including liver cancer cells, healthy cells are unaffected by the treatment. This phenomenon has been called oncogene addiction, where tumor cells are “addicted” to the activity of an oncogenic factor for their survival, but normal cells can do without it. This characteristic is very encouraging for use
of such compounds clinically.
Following in vitro trials, the researchers tested the efficacy of FQI1 in inhibiting liver cancer tumor growth by injecting HCC cell lines into rodent models. FQI1 was observed to significantly inhibit tumor growth with no observable side effects (general tissue cytotoxicity). These dramatic findings support the further development of LSF inhibitors as a promising new chemotherapy treatment for liver cancer.
Citation: T.J. Grant, J. A. Bishop, L.M. Christadore, G. Barot, H.G. Chin, S. Woodson, J. Kavouris, A. Siddiq, R. Gedler, X-N. Shen, J. Sherman, T. Meehan, K. Fitzgerald, S. Pradhan, L.A. Briggs, W.H. Andrews, D. Sarkar, S.E. Schaus, and U. Hansen, “Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma,” Proc. Natl. Acad. Sci. U.S.A., March 20, 2012, Vol. 109, No. 12, 4503-4508.
BU Chemistry has dramatically improved the undergraduate organic chemistry laboratory by giving students access to major research instrumentation and state-of-the-art technology. By enabling more modern experimentation, these resources foster critical thinking and problem solving skills that prepare undergraduates for graduate and pre-professional schools or for careers in industry. Advanced experimentation also enables more sophisticated student-designed research-type projects.
Renovations and instrumentation
Renovations in the Metcalf Center for Science and Engineering (Summer 2011) have transformed our organic chemistry instructional laboratories into an 6,350 sq. ft. suite with fume hoods and bench areas for each student, auxiliary support space, and a chemical stockroom. Space has been dedicated for an undergraduate instrumentation center for with fully automated high field nuclear magnetic resonance (NMR), ultra-performance liquid chromatography–mass spectrometry (UPLC-MS), Fourier transform infrared spectroscopy (FT-IR), and gas chromatography-mass spectrometry (GC-MS). Microwave reactors allow for rapid reaction rates, enabling multistep syntheses to be undertaken in a single day.
Advanced Technology in the Laboratory Curriculum
The entire laboratory curriculum of our sophomore-level organic chemistry sequence has been transformed with the adoption of the “paperless laboratory” through the use of electronic laboratory notebooks. Spearheaded by Professor John Snyder and Professor Scott Schaus and Postdoctoral Faculty Fellow, Seann Mulcahy, integration of these technology resources have enabled the creation of an open-access repository of laboratory protocols, design of laboratory experiments that facilitate sharing of data between students and between disciplines, exposure to automated NMR, GC-MS, and UPLC-MS, and remote download and manipulation of spectroscopic data.
- Fast Forward to the 21st Century -The new instrumentation advances undergraduate capabilities well beyond those in traditional sophomore organic textbooks that repeat traditional experiments. Instead, we have designed novel, research-oriented, exploratory experiments that have applicability to modern organic chemistry. These include cross-coupling experiments, olefin metathesis, and many others. Experiment protocols are available on BU’s Digital Common site (DCommon), an open-access online repository that is accessible not only by our students, but by outside instructors as well. Users can be granted upload privileges to deposit modified or new protocols thereby creating a rich resource to the worldwide research community. In addition, a DCommon collection of NMR and UPLC-MS spectra is being compiled as a teaching tool for organic chemistry courses.
- Major Instrumentation – BU is unique in using the latest instrumentation for routine, hands-on training at the sophomore level. The laboratory’s state-of-the-art instrumentation also allows comprehensive characterization of synthetic material prepared in each experiment. Students now routinely run 1H and 13C NMR (and 2D COSY), UPLC/MS, GC/MS, and FT-IR on their own samples and to obtain a set of data which approaches the quality needed for publication.
- Into the Cloud – Our students are now using fully electronic laboratory notebooks, which they populate on their laptops with reaction details, procedural notes, and safety protocols. Analytic data and spectra (manipulated and interpreted remotely) are uploaded into the notebook and serve as part of their final laboratory reports.
The Research Internship in Science & Engineering Program (RISE) provides academically motivated high school seniors the opportunity to conduct university-level research in state-of-the-art laboratories.
In the summer of 2011, Joshua Kubiak, a senior from the Louisiana School for Math, Science and the Arts (Natchitoches, LA), joined the laboratory of Professor Scott Schaus to conduct research for 3 months on Asymmetric Conjugate Addition of Ortho-Quinone Methides as a Pathway to Communesin Analogs.
Under the mentorship of Professor Schaus and graduate student, Yi Luan, Joshua made a molecular scaffold which can then be built upon to create chemical compounds with potential medicinal applications. The quality of his research has been recognized by a Siemens Foundation Award.
Joshua is the first student from his school to be named a Regional Finalist in the Siemens Competition, and he plans to pursue a career in drug design and development.
ScienceDaily, has featured the research of a team of Boston University scientists in which they identified a novel compound that inhibits viruses from replicating.
The findings, which were published online in the Journal of Virology, could lead to the development of highly targeted compounds to block the replication of poxviruses, such as the emerging infectious disease, Monkeypox.
Investigators from the Boston University School of Medicine (Dr. Ken Dower and Dr. John Connors) teamed with Professor Scott Schaus to use a library of chemicals from the CMLD-BU to identify compounds that could stop vaccinia from replicating inside human cells.
Professor Schaus is Associate Professor in the Boston University Department of Chemistry. The Center for Chemical Methodology and Library Development at Boston University (CMLD-BU) is an National Institutes of Health Funded Center of Excellence in the area of chemical methodology and library development.
Read the ScienceDaily article at:
Published in PNAS in July 2011, the paper represents their collaborative work with researchers in the BU Department of Mathematics and Statistics, Professor Eric Kolaczyk and Graduate Student Lisa Pham.
It reports on the effectiveness of their novel method, latent pathway identification analysis (LPIA), in providing insights into systemic biological pathways and key cellular mechanisms that dictate disease states, drug response, and altered cellular function. The work was supported by NIH, NSF, and DOD.
Dr. Philip Moquist has received a postdoctoral research fellowship from the Alexander von Humboldt Foundation to study in Germany with Professor Gerhard Erker at the Westfaelische Wilhelms-Universitaet Muenster Organisch-Chemisches Institut in Muenster.
His research proposal is to work on the asymmetric activation of hydrogen using electron deficient boron complexes. The Humboldt Foundation aims to promote academic cooperation between German scientists and researchers from other countries.
Dr. Moquist received his B.S. in Chemistry at the University of California, San Diego. In 2010, he recieved his Ph.D. in Chemistry under the guidance of Professor Scott Schaus at Boston University. His work at BU included the development of enantioselective boronate reactions.
Due to the large number of e-mails that Dr. Moquist has received, we request that you do NOT contact Dr. Moquist for assistance in applying for the Fellowship.
The National Institute of General Medical Sciences (NIGMS) is continuing its support of the CMLD-BU as one of five Centers of Excellence addressing the problem of how to develop small molecule libraries and techniques for making them that meet all the needs of pharmaceutical and biomedical scientists.
The CMLD-BU was originally established in 2002. The renewal is for another 5 years (through 2013) and is worth more than $11.5 million. The first year’s funding, $2.6 million, will be used to develop microfluidics and other strategies to synthesize small molecules for application by the biological community. The program is highly collaborative. Professor John A. Porco, Jr., who is the Director and Principal Investigator, is joined by Co-PI’s Professors Jim Panek, Scott Schaus, John Snyder, and Corey Stephenson, who are leaders in the field of organic chemistry.
The goal of the Center is to develop cutting-edge technologies to generate, analyze, and optimize chemical libraries and synthesize thousands of novel chemical entities using high-throughput techniques. It is also making these methods and libraries broadly available for biomedical research and drug discovery. The CMLD’s PI’s are collaborating with biologist, Professor Tom Gilmore, to determine the physiological activities of new molecules.
Chemical & Engineering News: Science & Technology (5/19/08) reports in a “Highlight” that Sha Lou and Scott E. Schaus have developed the first asymmetric catalytic version of the reaction.
It uses chiral biphenol catalysts to convert alkenyl boronates, secondary amines, and glyoxylates to chiral α-amino acid esters with good yields and high enantiomeric ratios (J. Am. Chem. Soc., DOI: 10.1021/ja8018934). The advance eliminates the need for stoichiometric chiral starting materials and opens the way to a broader range of products.
The work was done through the NIN-funded Boston University Chemical Methodology and Library Development Center
CMLD-BU Scientists Awarded National Institutes of Health Grant in Pilot-Scale Libraries for High-Throughput Screening Program
Co-investigators of the Boston University Chemical Methodology and Library Development Center (CMLD-BU) (http://cmld.bu.edu) have been awarded a three-year grant for their joint proposal “Generation of Stereochemically and Structurally Complex Chemical Libraries.” The goal of the work by Professors Porco, and co-Principal Investigators Panek, Schaus, and Snyder, is to generate a number of stereochemically and structurally complex chemical libraries for inclusion in the National Institutes of Health (NIH) Molecular Repository (http://mlsmr.glpg.com/MLSMR_HomePage/index.html). They will develop five library projects that are distinct from ongoing and planned CMLD-BU library projects, but which utilize novel chemistries previously developed in their laboratories. Target pilot libraries include complex dihydropyrimidones, azaphilone-derived libraries, tetracyclic alkaloid-type libraries, exo-methylene scaffolds and derived spirocycles, and macrocyclic lactams. In addition, all planned libraries have been designed to include unique structures that do not overlap in chemical space with molecules currently in the PubChem database. Data will be shared using an internet-based structure-searchable database of synthesis protocols.
The Molecular Libraries and Imaging Initiative is a component of the “New Pathways to Discovery” theme of the NIH Roadmap, which seeks to enable the rapid transformation of new scientific knowledge into tangible benefits for public health. While high-throughput screening (HTS) of small-molecule libraries is widespread in the pharmaceutical industry, the goal of the Molecular Libraries (ML) Roadmap Initiative is to facilitate the use of HTS and chemical libraries within the academic community. It is anticipated that the ML initiative will produce research tools (including novel small-molecule modulators of cellular function and phenotypic assays) to facilitate studies of biology and physiology (http://nihroadmap.nih.gov/molecularlibraries). It is anticipated that the initiative will complement private sector drug development efforts by contributing to the identification and validation of novel drug targets, as well as molecular structure classes with potential for development into therapeutics. The initiative promises benefits to public health, especially for rare or marginalized disorders.
From Chemical & Engineering News (Vol 83, p. 13):
The asymmetric construction of monastrol and other dihydropyrimidones has been a challenge for some time. The compounds are generally produced as racemates by the Biginelli reaction, developed in 1893, and single enantiomers are obtained by chiral resolution.
Assistant professor of chemistry Scott E. Schaus and coworkers at Boston University’s Center for Chemical Methodology & Library Development have now devised the first highly asymmetric synthesis of Biginelli reaction products (J. Am. Chem. Soc. 2005, 127, 11256). The addition reaction provides a direct catalytic route to highly enantiopure chiral dihydropyrimidones.
Read the complete article.