Our work is accomplished by designing and executing efficient and economical chemical syntheses of entities that are not readily available. The facility works primarily with investigators from Memorial Sloan Kettering. However, we occasionally extend our services to neighboring institutions when possible. The facility enjoys a successful track record of achievements through service, collaborations, and interdisciplinary interactions.
- The chemical synthesis of compounds which are not readily available.
- Phase 1- enabling work grade batch syntheses for clinical trials
- Phase 1 grade syntheses of radiotracer and radio-therapeutic precursors for positron-emission tomography (PET) as well as targeted and non-targeted radioisotope-based therapies
- Synthesis of modified nucleosides, nucleotides, as well as modified oligonucleotides (modified siRNAs, miRNAs, and damaged synthetic DNA)
The synthesis of assay development tools and reagents:
- Fluorescently labeled compounds
- Affinity labeled intermediates
- Cross linker-tethered molecules
- Cold-labeled (13C, 2H, 15N) compounds
- Precursors for radiolabeling experiments, as well as radio-labeled (11C, 3H, 125I, 32P â€¦etc.) compounds for preclinical and clinical pharmacological evaluations in collaboration with the Cyclotron-Radiochemistry Core Facility.
- Activity-based purification of active intermediates from extracts, and scale up purification of active intermediates.
- Structure determination of unknown active entities be they natural or unnatural products.
- Large-scale chemical synthesis of compounds with demonstrated activity in primary bioassays in order to provide sufficient quantities for continued testing.
- The synthesis of modified and unmodified compounds in amounts that permit their availability for in vitro and in vivo assays and for secondary assays. Some of the modifications that could be introduced will address such properties of molecules to render them more versatile. More precisely, we could introduce alterations that improve solubility, affinity, and specificity.
- Perform structure-activity relationship (SAR) studies on validated pharmacophores to optimize targeting, specificity, and bioavailability, while minimizing toxicity.
- Molecular modeling, homology modeling, and “in-silico” screening of virtual chemical libraries. This is backed by follow up organic synthesis of hits.
- Submission of requests Investigators submit their requests to the core head, Dr. Ouerfelli, along with all available information. A typical request could be a molecule, an enzyme inhibitor, a hit from a screen, a scale-up of a lead, a reagent for an assay or readout, an idea to be chemically addressed/developed, etc. The project will then be thoroughly examined in terms of antecedent work and chemical feasibility. A formal meeting is then scheduled with the investigator to discuss the specifics of the synthesis request and establish its nature (complexity, length, etc.) and to consider easier, less time consuming alternative routes when possible. At this point, a cost estimate and a potential timeframe for synthesis and delivery will be determined. The availability of adequate funding with clear provision for chemistry work, project scheduling in the context of other ongoing investigational requests in facility workload, and the availability of testing tools (activity assay, readout, tissue culture model, etc) post-synthesis are key factors that will be considered prior to request execution. Last but not least, the scale and length of the synthesis sequence (number of steps), and number of personnel required will also be examined.
- The Prioritization Committee This is an internal scientific prioritization panel composed of the following members: Drs. Derek Tan (Chair), David Scheinberg, Nikola Pavletich, Marilyn Resh, and Samuel J. Danishefsky (Honorary Member) and Ouathek Ouerfelli. It is primarily concerned with the scientific merit of each project, and scheduling of retained projects based on the complexity of the synthesis and the timeframe of need by the user.
- The Synthesis Following prioritization committee decision, selected requests would be looked at in terms of the actual chemistry involved by evaluating the chemical literature in combination with round table discussions with other Faculty Chemists when necessary. Because of the high level of synthetic expertise currently in the Organic Synthesis Core Facility, original synthetic methods may be developed within the facility to accomplish the project in a timelier, efficient, safe, and cost effective manner.
- Delivery The compounds that are produced by the Synthesis Core are delivered directly to the end users along with a certificate illustrating all quality control steps as well as an LC-MS profile of the product insuring high-level purity. Within this process, the compound, user name, amount of compound synthesized, its spectral identity (NMR, IR, UV… etc.), amount of compound delivered, compound ID and Lot number, and the date of delivery are recorded for future reference.
- Development Based on the biological results of the delivered compounds, a consultation with different parties would be scheduled to assess the state of the project and decide the way to proceed. Should further synthetic work be warranted, the above process would be reiterated.
Personnel & Resources of the Organic Synthesis Core
The facility excels in all areas of chemistry that interface with biology and medicine. This is not possible without a translational mind and an understanding of biological problems. Together, facility personnel have expertise that spans all aspects of organic synthesis. These include but are not limited to complex carbohydrate vaccine synthesis and development, combinatorial chemistry, high throughput synthesis and purification, Chemical library design and synthesis, virtual screening, molecular modeling, natural and unnatural product synthesis, natural product extraction/fractionation and structure determination. Recent projects in the facility pushed synthesis limits to reach nanotechnology and inorganic complex synthesis.
We provide advice/consulting in chemical problems free of charge to all of Memorial Sloan Kettering.