8:00 am Registration and Breakfast
9:00 Organizer's Welcome
George O’Doherty, Professor of Chemistry, Northeastern University
George O’Doherty was born in Kilkenny Ireland in 1966 and received his undergraduate education from RPI with Professor Alan R. Cutler in 1987. After earning his Ph.D. with Professor Leo A. Paquette at OSU in 1993 he pursued postdoctoral studies with first Professor Barry M. Trost at Stanford and the Anthony G. M. Barrett. He began his independent career at University of Minnesota in 1996 and in 2002, he moved to West Virginia University. He moved again in 2010, to Northeastern University where he has risen to the rank of Professor. His laboratory is interested in the use of asymmetric catalysis for the synthesis and medicinal chemistry study of biological important carbohydrate and natural products. These stereodivergent asymmetric syntheses enable novel Stereochemical-Structure Activity Relationship (S-SAR) studies of natural structures that nature does not provide.
9:10 Morning Chair's Remarks
9:15 Morning Session
10:35 Coffee Break with Poster Viewing of Even-Numbered Presenters
11:15 KEYNOTE PRESENTATION: Stereoelectronic Effects in Protein-Ligand Interaction
Laura Kiessling, Novartis Professor of Chemistry, MIT
12:15 pm Networking Lunch with Poster Viewing
1:30 Afternoon Chair's Remarks
Brian Liau, Assistant Professor of Chemistry and Chemical Biology, Harvard University
1:35 Afternoon Session, Part 1
2:55 Refreshment Break with Poster Viewing of Odd-Numbered Presenters
3:30 Afternoon Session, Part 2
4:10 KEYNOTE PRESENTATION: New Activities for Cereblon Modulators
Phil Chamberlain, Senior Director, Structural and Chemical Biology, Celgene
5:10 Closing Remarks
Mike Ellis, Executive Director, Chemistry, Celgene
Mike Ellis is Executive Director, Chemistry at Celgene, where he leads an interdisciplinary team of scientists at the Cambridge, MA and San Diego, CA sites. The group’s expertise in medicinal chemistry, chemical biology, and synthesis & enabling technologies is deployed across the Celgene portfolio supporting therapeutic opportunities within epigenetics, immunology & inflammation, immuno-oncology, neuroscience, and protein homeostasis. Prior to joining Celgene, Mike began his professional career at Merck Research Laboratories in Boston, MA as an individual contributor, people manager, and program lead within the areas of immunology, neuroscience, and oncology. Mike has contributed to the discovery of multiple enabling tools, development candidates, and clinical assets over the course of his career. Mike obtained a Bachelor of Science in Chemistry with honors, magna cum laude, from Wake Forest University, and a Ph.D. in Chemistry from the University of North Carolina at Chapel Hill under the mentorship of Professor Michael T. Crimmins. Following a Ruth L. Kirschstein National Institutes of Health Postdoctoral Fellowship in the laboratory of Professor Larry E. Overman, Mike transitioned to the biopharmaceutical industry.
5:20 Networking Reception with Poster Viewing
6:30 Close of BSOBC 2019
Copper Hydride-Catalyzed Enantioselective Synthesis of Axially Chiral 1,3-Disubstituted Allenes
Liela Bayeh-Romero, Stephen Buchwald Group, Massachusetts Institute of Technology
Axially chiral allenes constitute a synthetically intriguing class of compounds represented in a variety of natural products, bioactive molecules and synthetic intermediates. Despite their prevalence and distinct reactivity, catalytic methods to access chiral 1,3-disubstituted allenes with high levels of selectivity from prochiral starting materials remains a goal in chemical synthesis. We have developed a mild and general strategy for the direct asymmetric semi-reduction of 1,3-enynes utilizing copper hydride catalysis and water. An assortment of chiral 1,3-disubstituted allenes are obtained in up to 98% yield and 99% enantioselectivity and further applications of this protocol are demonstrated for the synthesis of enantioenriched 2,5-dihydropyrroles and monodeuterated allenes.
Enantioselective α-Amino C–H Functionalization by Cooperative Actions of B(C6F5)3 and Chiral Mg–PyBOX Complex
Jessica Chan, Masayuki Wasa Group, Boston College
Catalytic enantioselective transformations of α-amino C–H bonds furnish valuable α-substituted amines that are prevalent in pharmaceuticals and natural products. However, there are few catalyst systems that can promote stereo- and regio-selective transformations of amino C–H bonds. We present an efficient enantioselective coupling of N-alkylamines and α,β-unsaturated compounds, promoted through concerted action of two Lewis acid catalysts, B(C6F5)3 and a chiral Mg–PyBOX complex. The use of a sterically encumbered N-alkylamine substrate and hindered Lewis acid catalysts circumvents the formation of a “classic” Lewis adduct. Instead, B(C6F5)3 abstracts a hydride from N-alkylamine to generate an ion pair comprised of iminium ion and borohyride. Subsequent borohydride reduction of the Mg–PyBOX-activated α,β-unsaturated compound affords a Mg-enolate. The in situ-generated iminium ion and enolate undergo stereoselective C–C bond formation to afford β-amino carbonyl compounds, under redox neutral conditions and with complete atom economy.
Using the Chloroalkane Cell Penetration Assay (CAPA) to Study the Cytosolic Localization of RNA Therapeutics
Kirsten Deprey, Joshua Kritzer Group, Tufts University
A critical obstacle for RNA therapeutics is the lack of understanding of the characteristics that affect cell uptake, cytosolic localization, and intracellular trafficking. RNA with specific chemical modifications are able to access the cytosol without an external delivery method, but the mechanisms by which these molecules penetrate the cell membrane are unknown. Current methods for measuring the cellular uptake of RNA are imprecise and largely qualitative, which severely limits our understanding of, and control over, this therapeutic strategy. The drawbacks of existing methods highlight the importance of a quantitative and high throughput assay to uncover information about the cytosolic access of therapeutically-relevant molecules. To solve this problem, the Kritzer lab has developed the chloroalkane penetration assay (CAPA), which can quantitatively compare the cytosolic penetration of exogenously added molecules. We have previously used CAPA to examine the relative cytosolic access of peptides, and here we apply CAPA to RNA for the first time. CAPA provides cell penetration profiles for therapeutically relevant RNA molecules, and we are using it to screen for structural changes that improve RNA penetration. We present CAPA as a means to study the mechanism of uptake, degree of endosomal escape, and subcellular localization of therapeutic RNA molecules. Enhancing cell penetration would improve the therapeutic effect of biologically active molecules. Better control over the cellular fate of RNAs would be transformative in the design of new therapies for currently untreatable genetic diseases.
A Divergent Total Synthesis of Streptothricin F
Matt Dowgiallo, Roman Manetsch Group, Northeastern University
Streptothricin F is an antibiotic that was discovered over 70 years ago by Waksman and Woodruff that displays an impressive activity spectrum against otherwise resistant Gram-negative pathogens. Initial concerns around toxicities and the availability of alternative antibiotics precluded its development, although a total synthesis was performed in 1982 by Kusumoto. While this natural product has largely been forgotten, its activity remains constant as resistance towards antimicrobials continues to grow. In this talk, I will demonstrate a novel total synthesis for streptothricin F designed for medicinal chemistry to generate several derivatives. Through a divergent total synthetic approach, we pursue SAR exploration of the three primary molecular constituents of this natural product.
A Medicinal Chemistry Approach to Optimize a Functional Virus Conjugate
Sarah Erickson, Abhishek Chatterjee Group, Boston College
Numerous genetic diseases, where the pathogenicity arises from absence/attenuation of a gene function remain refractory to traditional therapeutic approaches. Curing such diseases would require restoring the necessary gene function in appropriate cells. Engineered human viruses provide a highly attractive route to deliver such ‘gene therapeutics’ into patients but often, properties of natural viruses (suboptimal cell specificity, immune activation, etc.) are not optimally suited for therapeutic application. Adeno-Associated Virus (AAV), small nonpathogenic human virus, has emerged as the leading candidate for human gene therapy; three AAV-based therapeutics have already been clinically approved. However, all current trials use the natural serotypes of AAV, which offer suboptimal cell-tropism and immune response. The ability to ‘rewrite’ the cell-specificity of AAV vectors will greatly expand its potential for gene therapy. The complex and multifunctional capsid proteins of AAV are challenging to engineer using the traditional genetic route (e.g., fusion of protein/peptide tags), frequently causing perturbation of native function. We have developed a precise chemical approach to alter the cell-specificity of AAV through site-specific incorporation of unnatural amino acids (UAAs) into the AAV capsid. Owing to their small footprint, UAAs are well tolerated on the AAV capsid. Incorporating UAAs with bioorthogonal conjugation handles enables subsequent functionalization of the resulting virus capsid with unprecedented precision. I have shown that AAV can be retargeted to distinct cell-lines by attaching synthetic receptor targeting groups on its capsid. Furthermore, by systematically optimizing the site and stoichiometry of attachment, I was able to fine-tune the function of such virus conjugates – similar to how medicinal chemists transform a lead molecule into a drug through structure-activity relationship. The unprecedented degree of control in creating virus conjugates with novel properties using our chemical approach could be key for developing next-generation viral vectors.
The Asymmetric Petasis Reaction Affording Chiral β-Amino Alcohols
John Kavouris, Scott Schaus Group, Boston University
Chiral β-amino alcohols are found in a range of synthetically and industrially useful compounds, including drugs, natural products, and organocatalysts. However, despite their prevalence, synthetic methods to generate this chiral building block are underreported. The Schaus lab has developed a methodology to address this, employing chiral 3,3’-substituted BINOL catalysts in the asymmetric Petasis reaction of amines, boronic acids, and glycolaldehyde. Products are obtained in excellent yields and selectivities (up to 92% yield, up to >99:1 er). Furthermore, this reaction can easily be scaled to decagram quantities, maintaining good yields and selectivities, with high catalyst recovery, all via chromatography-free purifications.
Scalable Synthesis and In Vivo Activity of a Novel Lincosamide Antibiotic
Jeremy Mason, Andrew Myers Group, Harvard University
The lincosamides are an underexplored class of antibiotics including a single clinically relevant member, clindamycin, which has been in use since 1970. A new lead lincosamide featuring a trans-fused oxepinoproline moiety has been discovered via a fully synthetic approach. This compound exhibits excellent in vitro activity against a variety of gram-positive bacteria, including several multidrug-resistant clinical isolates. A convergent, gram-scale synthesis of this molecule will be presented, along with the results of preliminary efficacy studies in mice.
Strain-Promoted Cycloadditions for DNA-Encoded Library Synthesis
Matthias Westphal, Stuart Schreiber Group, The Broad Institute
DNA-encoded libraries (DEL) have emerged as rich sources of small molecules interacting with targets of interest. However, the limited arsenal of DNA-compatible reactions required for library generation naturally translates into an overrepresentation of sp2-rich architectures and peptidomimetics. For the synthesis of complementary libraries, chemical transformations that enable access to more complex, sp3-rich entities are therefore highly desirable. Despite the successful history of strain-promoted cycloaddition reactions in the field of chemical biology (i.e. in the presence of water and biopolymers), there has been no report on the use of this concept in DEL synthesis. Strained allenes for example, usually generated under anhydrous conditions, are known to exhibit various reactivity modes when allowed to react with activated olefins ([2+2]), 1,3-dipoles ([3+2]) or dienes ([4+2]), and the resulting sp3-rich products exhibit high structural diversity. We document the successful in-situ generation and trapping of DNA-conjugated strained allenes in the presence of various coupling partners. The significance of our findings for future libraries is demonstrated by two-step diversification of DNA-linked substrates involving strain-promoted cycloadditions and N-capping reactions. Due to the mild conditions and general applicability, the process is thought to be an attractive addition to existing on-DNA bond forming reactions.
Iron Withholding by the Innate Immune Protein Calprotectin
Emily Zygiel, Elizabeth Nolan Group, Massachusetts Institute of Technology
Most microbial pathogens have a metabolic iron requirement, necessitating the acquisition of this nutrient in the host. In response to pathogen invasion, the human host limits iron availability. Although canonical examples of nutritional immunity are host strategies that limit Fe(III), little is known about how the host restricts access to another biologically relevant oxidation state of this metal, Fe(II). This redox species is prevalent at certain infection sites and is utilized by bacteria during chronic infection, suggesting that Fe(II) withholding by the host may be an effective but unrecognized form of nutritional immunity. We have reported that human calprotectin (CP, S100A8/S100A9) inhibits iron uptake by several bacterial pathogens by sequestering Fe(II) at its unusual His6 site. Our work indicates that CP induces iron starvation responses and affects the expression of virulence traits, including the biosynthesis of secondary metabolites, in Pseudomonas aeruginosa and other bacterial pathogens. Furthermore, our work has shown that P. aeruginosa secondary metabolites can affect CP-mediated Fe(II) sequestration by (i) phenazine-mediated reduction of Fe(III) to Fe(II) or (ii) stabilization of the Fe(III) redox state by siderophores. This work implicates Fe(II) sequestration by CP as a novel component of nutritional immunity, and highlights the role of bacterial metabolites in affecting the iron-withholding capabilities of CP.