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Synthetic and Biopolymer Chemistry Core

Synthetic and Biopolymer Chemistry Core
Director:
David Horne, Ph.D.
626-256-4673, ext. 67310
 
The Synthetic and Biopolymer Chemistry Core (SBCC) has evolved over three decades to its current state where it provides both biopolymer and small-molecule synthetic services to scientists at City of Hope. These services would not be available from commercial sources.

 

The lab was originally established in 1974 under the leadership of Dr. Bruce Kaplan to facilitate the synthesis of enzyme substrates and carbohydrates. The laboratory synthesized the starting materials that were utilized in thepioneering work on solid phase DNA synthesis, which led to the bioengineering of synthetic insulin (Humulin) by Dr. Art Riggs and Dr. Keiichi Itakura.This important pharmaceutical is still being used today worldwide by millions of people with diabetes. With the arrival of Dr. Piotr Swiderski in 1989 the laboratory was able to provide synthetic RNA and DNA/RNA chimeras to theCity of Hoperesearch community. In 1990 there were only three labs making RNA in the US.

 

The general capabilities of the core include the design and synthesis of highly specialized biopolymers, including siRNA-aptamers, DNA-peptide hybrid derivatives, and peptides. The core is capable of handling the synthesis of very complex molecules, as well as the synthesis of small-molecule agonists and antagonists, imaging agents, affinity ligands, nanoparticles, and focused combinatorial libraries. An important new goal of the SBCC is on cancer drug discovery in the area of molecular-targeted therapeutics. These compounds are used for chemical biology, generation of lead compounds for drug discovery, and ultimately optimization of new drugs for preclinical evaluation.

 

The SBCC is capable of handling the synthesis of all structural classes of small to large organic molecules.A unique strength of the SBCC is in total synthesis of natural products and derivatives. State-of-the-art organic synthesis and the use of modern synthetic methodologies are used for the efficient construction of molecular agents and ligands.

 

The SBCC provides an affordable means and knowledge to access chemistry technology that cannot be supported by individual labs. The centralized intellectual and technical resources of the SBCC can assist the researcher in designing and conducting the proper experiment, preparing the appropriate samples for analysis, and analyzing them in the most appropriate manner.The core can assist in correctly interpreting results in conjunction with the PI.Core staff scientists also provide essential technical support for the operation and maintenance of highly specialized instruments, such as nuclear magnetic resonance (NMR) and mass spectroscopy (MS) equipment.

 

SBCC General Capabilities:

 

  • Provide expertise, consultations, and experience in the area of chemical synthesis and designof biopolymers.
 
  • Provide broad expertise in the custom synthesis of essentially any organic-based compound with particular emphasis on complex natural products and developing improved synthetic routes.
 
  • Provide scale-up protocols for pure materials for pre-clinical and clinical investigations.
 
  • Facilitate collaborations among molecular biologists, chemists, structural biologists, pharmacologists and clinicians.
 
  • Support small-molecule drug discovery for chemical biology and cancer therapeutics development.
 
  • Provide synthesis of radiolabeled compounds and biologicals, such as imaging agents and antibody conjugates.
 
  • Facilitate sharing of instruments, methodologies, and chemical insights with project investigators throughout City of Hope Comprehensive Cancer Center.
 
Research reported in this publication included work performed in the Synthetic and Biopolymer Chemistry Core supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
 

Equipment

The Synthetic and Biopolymer Chemistry Core (SBCC) equipment is comprehensive in both small and large molecule synthesis capabilities and state-of-the-art spectroscopic instrumentation for structural characterization. In addition, the lab is equipped with in-house custom-built instruments adapted for specialized applications in the area of biopolymer synthesis.
 
Biopolymer Synthesis
The Synthetic and Biopolymer Chemistry Core maintains several nucleic acid and peptide synthesizers that are adapted for both routine andhighly specialized custom syntheses. These include:
 
Two Automated DNA/RNA Synthesizers. These machines are fully adaptable for custom synthesis to include modified bases as well as other non-natural base and sugar analogs.
 
 
Two Semi-Automated Peptide Synthesizers. These are state-of-the-art, in-house designed and built, semi-automated peptide synthesizers. These custom instruments provide much greater mechanical flexibility and efficiency in the coupling processes that allow for the introduction of difficult-to-incorporate modified amino acid derivatives. Long polypeptides containing >100 amino acids have been synthesized on these instruments, which were unachievable by commercial vendors.
   
Waters HPLC Instrumentation. The HPLC system is specifically adapted for purification of small to relatively large amounts of DNA/RNA and peptides.
Small Molecule Synthesis
 
Virtually all of the small molecule projects involve custom synthesis to varying degrees. A full array of state-of-the-art small molecule instrumentation is available for complete structural characterization. These include:
 
Agilent Analytical and Preparatory HPLCs. In addition to the standard features, these instruments possess chiral separation capabilities that enable the purification and resolution of racemic material providing single enantiomers with high purity.
   
Varian High-Field 400 MHz NMR. This instrument is capable of one- and two-dimensional data analysis with cryoprobe capability for added sensitivity. Higher field NMR instrumentation (500 and 600 MHz) also exists on campus when the need for greater magnet strength arises.
   
JEOL AccuTOF™-DART™ Mass Spectrometer. This new MS design is capable of exact mass measurements under atmospheric conditions with no sample preparation and instantaneous detection. The precision of this new instrument is unmatched for the determination of small-molecule molecular mass of virtually all compound classes.
   
FTIR, UV/VIS and Polarimeter. Spectroscopic instrumentation used for the structural identification of organic functional groups, chromophores, and optical rotation measurements, respectively.
 
 

Pricing

Prices and availability vary.
 
For more information, please contact:
 
David Horne, Ph.D., Director
dhorne@coh.org
626-256-4673, ext. 67310.
 
If you are a City of Hope employee, please click here for pricing.
 

Quality Control

The efficient output of high-quality materials by the Synthetic and Biopolymer Chemistry Core (SBCC) is second to none. The high caliber of scientific core staff members and years of experience ensures efficiency, accuracy, and product reliability. The SBCC is in a unique position to fulfill not only “routine” requests but also deliver novel and custom chemical entities. All materials undergo the utmost stringent purification and structural characterization protocols to ensure high purity and identification. For small molecule work, all compounds are subjected to extensive nuclear magnetic resonance and mass spectroscopy characterization as well as infrared, ultraviolet and combustion analyses. Investigators also receive valuable design and execution input from the SBCC scientists. These discussions often result in the development of better alternatives that are significantly different from the original approach.
 
The Synthetic and Biopolymer Chemistry Core has implemented a series of informatics programs and standard operating procedures (SOP) to ensure proper management of information and data it handles regularly. These steps will also allow for efficient information exchange between the core, its users as well as other Cancer Center cores and shared resources on campus.
 
  • LIMS: The SBCC has in place a comprehensive centralized database, built upon a Laboratory Information Management System (LIMS).
 
  • Information Tracking: eNotebook records daily experiments
 
  • Compound Registration: All compounds including biopolymers, regardless of source, are entered into the database and assigned a unique ID #. The unique ID# facilitates tracking of the compound as it passes through various reactions, assays, and analysis. In addition, chemical properties, source (including link to eNotebook) and structural data are linked to the ID # and are readily accessible.
 
  • Barcoding: Reagents and chemicals have barcode identification for inventory purposes that greatly facilitates ETS compliance.
 
  • Quality Control: All spectral data such as 1H and 13C NMR, mass spec, IR, UV, and HPLC traces are stringently analyzed and deposited in the LIMS for each completed and approved compound.
 

Scientific Accomplishments

Since its inception, the original DNA/RNA and Peptide Synthesis Core has had significant impact on the successful execution and completion of a number of research projects. This core has a long history of scientific achievement and innovation. Dr. Kaplan and co-workers were among the early developers and users of automated DNA and peptide synthesis, having designed and built early prototypes upon which current commercial instruments are based.
 
The biopolymer synthesislaboratory provides a variety of custom oligonucleotides to the research community of City of Hope Comprehensive Cancer Center. The DNA and RNA may be synthesized with many reagents containing modified bases and sugars. In addition, a variety of labels and linkers can be incorporated into the oligomer. Some of the reagents are commercially available but some have to be synthesized in our laboratory. In addition, the facility has produced synthetic reagents that allows for the introduction of cis and 6-4 TT photodimers into an oligonucleotide. The biopolymer lab is capable of synthesizing peptides in excess of 100 amino acids. The laboratory has successfully synthesized peptides with phospho-Thr and -Ser, as well as peptides with biotin and acroyl groups attached to the amino terminus.
 
The facility has recently added the production of fluorescently-labeled peptides to its repertoire and has pioneered the synthesis of chimeric DNA/RNA/DNA molecules for use as anti-sense drugs. As a significant portion of these technologies is developed “in-house” to meet a specific research demand, they have been successfully applied to a myriad of City of Hope Comprehensive Cancer Center projects.
 

Services

The SBCC facility is capable of handling the synthesis of all small to large organic molecules as well as biopolymers such as DNA, RNA and peptides.

In each of these areas, the appropriate SBCC co-director will engage the research PI and staff regarding consultation and formulation of the initial design and subsequent execution to ensure the successful completion of the project.
 
State-of-the-art organic synthesis and the use of modern synthetic methodologies are employed for the efficient construction of molecular agents and ligands. The SBCC is committed to advancing collaborative research efforts through creation of a multidisciplinary team approach to chemical biology and drug discovery.
 
The following is a list of specific services and capabilities currently supported by the Synthetic and Biopolymer Chemistry Core facility:
 
  • Synthesis of DNA and RNA Oligonucleotides. This includes synthesis of commercially unavailable reagents such as derivatives of modified and/or labeled nucleosides.
 
  • Synthesis of Biopolymer Conjugates. Examples include specialized covalent and none-covalent (Watson-Crick) conjugates of variousbiopolymers, for example: siRNA-aptamers or DNA-peptide hybrid derivatives.
 
  • Synthesis of Custom Peptides. Examples include peptides containing phosphorylated serine/threonine/tyrosine residues, acetylated lysines, as well as biotin, fluorescein, D-amino acids, 13C and 15N labeled amino acids and other unusual moieties.
 
  • Development of Novel Purification Techniques. This is particularly applicable for the production and isolation of large amounts of very pure RNA and DNA.Examples include chimeric ribozymes andsiRNAsmodified with cholesterol, which are used in animal studies, as well as large amounts of DNA for NMR structural studies.
 
  • Design and Synthesis of All Small Molecule Structural Classes. This encompasses natural and non-natural analogs of carbocycles, heterocycles, carbohydrates, terpenoids, steroids, small peptides, and peptide mimetics as well as nanoparticle derivatives.
 
  • Design and Execute SAR Studies for Lead Optimization. This is accomplished in close collaboration with the HTS Core and structural biophysical groups in the City of Hope Cancer Center that include NMR, X-ray, and molecular modeling.
 
  • Isolation and Structural Identification of Bioactive Natural Products and Drug Metabolites. An international collaborative effort is underway in conjunction with the Strathclyde Institute (Scotland, UK) to identify anti-cancer natural products from terrestrial sources around the world (vida infra).
 
  • Design and Scale-up Synthesis. Full in-house capabilities are in place for scale-up synthesis of optimized lead candidates for use in chemical biology studies and pre-clinical evaluation.
 
  • Design and Synthesis of Radiolabeled Compounds. This will be accomplished in conjunction with the pharmacology group for metabolic identification studies.
 
  • Design and Synthesis of Structural Diversity-Oriented Combinatorial Libraries for HTS. Libraries are used for the identification and optimization of lead compounds.
 
  • Design, Synthesis, and Development of Novel Fluorescent-Based Substrates for Enzymatic Assays. The objective is to work in close collaboration with biologists toward new and improved enzyme/protein assay development yielding more efficient, accurate, and reliable results.
 
  • Design, Synthesis, and Development of Novel Metal Chelator-Antibody Bioconjugates and Ligands for Use in Tumor Imaging. This includes the design and synthesis of new ligands and thesynthesisof radiolabeled substrates in conjunction with cancer immunotherapeutics researchers.
 
Research Shared Services

City of Hope embodies the spirit of scientific collaboration by sharing services and core facilities with colleagues here and around the world.
 

Recognized nationwide for its innovative biomedical research, City of Hope's Beckman Research Institute is home to some of the most tenacious and creative minds in science.
City of Hope is one of only 41 Comprehensive Cancer Centers in the country, the highest designation awarded by the National Cancer Institute to institutions that lead the way in cancer research, treatment, prevention and professional education.
Learn more about City of Hope's institutional distinctions, breakthrough innovations and collaborations.
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Media Inquiries/Social Media

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800-888-5323
dgrignetti@coh.org

 

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213-241-7160
ssprester@coh.org

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213-241-7112
cnassr@coh.org

 
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