UCLA

Chem 278: Special Inorganic Chemistry Seminar - Dr. Benjamin E. R. Snyder
2022-02-08 16:00 (America/Los_Angeles)
“Iron and Copper Active Sites in Porous Materials and Their Correlation to Metalloenzymes”

Strategic Bond Construction and Cleavage Enabled by Photocatalytic Radical Transformations
2022-02-09 10:30
Abstract: Radical chemistry is an important class of reactions in modern organic synthesis, due to the high reactivity and versatile bond formation and cleavage events that can happen with radical intermediates. One of the current challenges in radical chemistry is to generate these reactive open-shell intermediates from accessible starting materials under mild conditions. We have developed several powerful strategies to homolytically cleave strong X–H bonds and generate the corresponding X• radical via proton-coupled electron transfer (PCET). In this talk, I will present a photocatalytic intermolecular anti-Markovnikov hydroamination reaction of sulfonamides, and a remote C–H alkylation reaction of amides, enabled by the amidyl radicals generated via PCET. Moreover, we also developed a photocatalytic condition to conduct various carbocation reactions via mesolytic cleavage of alkoxyamine compounds. Lastly, to understand the remarkable chemoselectivity and improve the quantum efficiency of a set of photocatalytic hydroamination reactions, we performed detailed mechanistic studies, using advanced spectroscopic and electroanalytical tools to unveil the origin of the chemoselectivity of this reaction, and also improved the reaction quantum yields. Based on these studies, gram-scale synthesis of several dialkylamines were performed in a flow reactor.

Chem 278: Prof. Robert Macfarlane
2022-02-09 16:00
“Macroscopic Materials from Nanoparticle Assembly”

James Gaynor, Postdoc Fellow, University of California, Berkeley Seminar
2022-02-10 12:00
Stories of Coherence: From Vibronic to Electronic Phenomena
A robust understanding of chemical reactivity in excited states is essential for designing and discovering new ways of harnessing energy flow at the atomic and molecular level. Photo-induced coherent processes, which utilize atomic or molecular motions moving with a well-defined phase relationship, may enhance control over important photochemical events. This presentation explores a wide range of timescales over which coherence and decoherence occur in solution phase molecules, gas phase atoms, and in “atomic-like” excitations of a crystalline ionic solid. We will begin with a new perspective on the first two picoseconds of excited state charge transfer involving coupled electronic and vibrational (i.e., “vibronic”) motions in solution phase solar cell dye molecules. Next, pure electronic coherences in a noble gas are investigated in the absence of vibrational or environmental perturbations, lasting for hundreds of femtoseconds. Finally, we return to the condensed phase in the solid form, where many-body electron correlations appear to cause core-excited state dephasing on sub-10 femtosecond timescales.

Battery-Inspired Strategies for Electrocatalytic C–C and C–N Bond-Forming Reactions
2022-02-10 16:00
Abstract: The seminar will describe our efforts towards the development of scalable, mild, and general electrosynthetic methodologies for C–C and C–N/X coupling reactions. These electrosynthetic methodologies are largely possible because of a synergy between redox-active mediators developed by the energy storage community and transition metal catalysts. It will be shown that yields from electrocatalytic reactions are greatly improved by the incorporation of co-catalytic quantities of soluble battery compounds that mediate electron transfer with the coupling catalyst or protect the coupling catalyst from over-oxidation/reduction and degradation.
Employing mediators with properly tuned redox potentials and electron-transfer kinetics, we demonstrate electrocatalytic cross-electrophile coupling reactions of (hetero) aryl halides and alkyl halides that represent the state of the art in the area. Additionally, we demonstrate a broad scope for Chan-Lam coupling of amines and arylboronic acids in the absence of a chemical oxidants. Our studies reveal unique mechanisms that are only accessible under electrochemical conditions that enable cross coupling of tertiary electrophiles or arylchlorides: challenging substrates that are currently incompatible with any form of reductive activation.

Chem 268 - David Moffet
2022-02-11 15:30
“Untangling Amyloid: Slowing the Progression of Type 2 Diabetes”

Chem 228: David Pine
2022-02-14 16:00
“Self-assembly of colloidal diamond for photonics”

Chemical Strategies for Regulating DNA-Interactive Proteins: Targeting APOBEC Cytosine Deaminases and the N-Myc Transcription Factor
2022-02-15 16:00
Abstract: Our laboratory focuses on the development of small molecule ligands and enzymatic inhibitors of proteins that interact with nucleic acids. We utilize biophysical and biochemical assays to screen chemical libraries to discover protein-binding ligands, which are then optimized using iterative rounds of molecular design, synthesis, and biological evaluation. Our overarching goals are to develop chemical probes to enable the discovery of new biology by the biomedical research community, as well as develop novel and patentable therapeutic compounds for clinical development by a pharmaceutical partner. In this vein, two programs from our laboratory, the discovery of APOBEC inhibitors and N-Myc degraders, will be presented.
APOBEC enzymes are a family of 7 human DNA cytosine-to-uracil deaminases that degrade foreign DNA as part of the innate immune response to pathogen infection. However, APOBEC enzymes have been shown to contribute C-to-U/T mutations that enable virus and cancer cell genomic mutations that confer resistance to drug therapies. Consequently, small molecule APOBEC inhibitors may have utility as “anti-mutation” therapies that slow or prevent the evolution of resistance mutations that defeat targeted drug therapies. Our work to develop first-in-class APOBEC inhibitors will be presented.
The Myc family of transcription factors are master regulators of proliferation in the majority of human cancers. In the case of childhood neuroblastomas, which are the most prevalent cancer in children under 1-year of age, N-Myc is a validated therapeutic target and molecular diagnostic. A vulnerability of N-Myc in many neuroblastomas is that N-Myc is stabilized from proteolytic degradation by Aurora kinase A (Aurora-A). We have developed novel chemical degraders of Aurora-A, such as HLB-0532259, that elicit the degradation of Aurora-A and the concomitant degradation of N-Myc. HLB-0532259 also exhibits potent antiproliferative activity in neuroblastoma cells and xenograft mouse models. Our work to develop novel N-Myc degraders will be presented.

Investigating Selectivity in Complex Systems: from Total Synthesis to Glycan Labeling
2022-02-16 10:30
Abstract: The indole diterpenoids constitute a family of natural products that exhibit potent and selective Big Potassium (BK) ion channel inhibition. We have developed a unified synthetic strategy towards the indole diterpenoid class, culminating in the total synthesis of several representative congeners, including paspaline A and emindole PB. Density functional theory calculations are utilized to interrogate a simplifying key bond formation in a predictive capacity to aid in the selection of the most favorable precursor substrate. This work highlights how retrosynthetic design can be augmented with quantum chemical calculations to reveal energetically feasible synthetic disconnections, minimizing time- consuming and expensive empirical evaluation. Furthermore, these studies provide modular entry to privileged indole diterpenoid class of natural products, enabling their application as tool compounds for interrogating BK channel dynamics, as well as therapeutic leads for channelopathies linked to BK channel dysregulation.
Glycans are ubiquitous and play important biological roles, yet chemical methods for probing their structure and function within cells remain limited. Strategies for studying other biomacromolecules, such as proteins, often exploit chemoselective reactions for covalent modification, capture, or imaging. Unlike amino acids that constitute proteins, glycan building blocks lack distinguishing reactivity because they are composed primarily of polyol isomers. Moreover, encoding glycan variants through genetic manipulation is complex. To address these limitations, we have developed a new, generalizable strategy for monomer-selective glycan modification that exploits the reactivity of cellular glycosyltransferases by designing reagents with bioorthogonal handles that function as substrate surrogates. Further, we demonstrate the utility of these labeling reagents by using them to study the biosynthesis, localization, and dynamics of cell wall glycans in mycobacteria.

Special Biochem/PChem Seminar - Eitan Lerner
2022-02-16 14:00
“Structure-function relationship of an unstructured protein – the alpha-Synuclein case”

Chem 278: Prof. Thomas Kempa
2022-02-16 16:00
“Precision Synthesis of Quantum Material Building Blocks”

Dr. Joonho Lee. Postdoctoral Fellow, Columbia University/Google Quantum AI Seminar
2022-02-17 12:00
Challenging Problems in Quantum Chemistry: How to Diagnose Them and How to Tackle Them
Quantum chemistry has become an indispensable tool in revealing the microscopic details of molecules and materials such as barrier heights, interaction energies, and correlation functions. The nature of electronic correlation is sometimes controversial, obscuring the optimal choice of quantum chemistry methods with minimal computational effort and the desired accuracy. First, I will discuss a computational framework that addresses this question using regularized perturbation theory. Second, I will also discuss several challenging problems beyond the scope of such perturbation theory. I will argue that these problems can be tackled by methods based on auxiliary-field quantum Monte Carlo. Lastly, I will present my latest development of a new quantum-classical hybrid algorithm in this context, which represents the largest quantum computation of chemical systems on a quantum computer to date.

Searching for Selective Catalytic Reactions in Complex Molecular Environments
2022-02-17 16:00
Abstract: This lecture will describe recent developments in our efforts to develop catalysts for asymmetric reactions, in particular for the preparation of densely functionalized, stereochemically complex structures. Over time, our foci have been on enantioselectivity, site-selectivity and chemoselectivity. In much of our current work, we are studying issues of enantioselectivity as a prelude to the extrapolation of catalysis concepts to more complex molecular settings where multiple issues are presented in a singular substrate. Mechanistic paradigms, and their associated ambiguities – especially in light of catalyst or substrate conformational dynamics – will figure strongly in the lecture, raising analogies to enzymes. Finally, several interesting – and often unexpected – collaborations with colleagues in industry will be discussed.

Chem 268 - Jennifer Niven Shepherd
2022-02-18 15:30
“Characterization of RquA – a novel enzyme used in microbial rhodoquinone biosynthesis”

Chemistry at the Biomedicine Interface: Synthesis and Catalysis
2022-02-22 10:30
Abstract: Chemical reactivity can be utilized in many ways, including to improve synthetic access to new molecules and to devise tools to advance biomedicine. ‘Synthesis and catalysis’ are two themes interwoven throughout this presentation, which describes 1) the development of short synthetic routes to (–)-picrotoxinin, (–)-picrotin, and 5-methyl-picrotoxinin enabled by a late-stage strong-bond activation strategy for the long term goal of interrogating GABAa receptor combinatorial diversity, 2) the development of three methods for alkene hydrofunctionalization using Mn- and Co- hydrogen atom transfer chemistry, and 3) two studies in catalysis centered on one-carbon metabolism which improve understanding of how one-carbon metabolites contribute to health and disease.

Chem 278: Prof. Sara Skrabalak - MilliporeSigma Inorganic Nano-Materials Lecture
2022-02-23 16:00
“Multimetallic Nanomaterials by Design”

Insight-Driven Strategies in Catalysis for Selective Functionalizations
2022-02-24 16:00
Abstract: Detailed understanding of catalytic transformations is key to designing better catalysts and overcome pertinent challenges in synthesis. This talk will give insights on case studies and reactivity designs recently undertaken in our laboratory. The focus will be on multinuclear metal catalysis for the chemoselective and modular construction of molecules, the exploration of organogermanes in catalysis, and the development of synthetic strategies towards novel fluorinated motifs. Experimental and computational tools were applied in these studies.

Chem 268 - Hung Ton-That
2022-02-25 15:30
“Sortase-catalyzed surface assembly in monoderm bacteria”

Chem 248 - Organic Chemistry Student Seminar
2022-02-28 15:00
Harnessing Bifunctional Ligands for Regioselective C–H Bond Functionalization

Chem 228: Robijn Bruinsma
2022-02-28 16:00
“Physics and the HIV-1 virus”

Chem 228: Prof. Denis Usvyat
2022-03-01 11:00
“High-accuracy Theoretical Treatment of Defects in Periodic Systems”

NSF Center for Integrated Catalysis Webinar Series
2022-03-01 13:00
“2D Particle Surfactants and Pickering Emulsions for Reagent Compartmentalization”

Special Organic Colloquium - Prof. Stuart Conway
2022-03-01 16:00
“The development and targeting of epigenetic drugs for therapeutic benefit”
Abstract: The talk will comprise two interconnected parts describing the development and targeting of epigenetic drugs for the treatment of disease.
The development of bromodomain ligands for the treatment of disease: bromodomains, protein modules that ‘read’ of lysine acetylation state, have emerged as important therapeutic targets for indications including oncology. I will describe our work on the design and synthesis of inhibitors for the BET and CREBBP/EP300 bromodomains, their biological effects, and their role as leads for cancer drug discovery. While the function of some human bromodomain-containing proteins (BCPs) has been heavily investigated, little is known about the role of these proteins in other species. I will describe work to identify 22 BCPs in Schistosoma mansoni (schistosomiasis/bilharzia). We have annotated one of these proteins as SmBRD3, in analogy to human BRD3, a member of the BET bromodomain family. I will discuss the design, synthesis, and validation of high affinity ligands for SmBRD3 and the use of these ligands in phenotypic studies on S. mansoni.
Targeting and imaging tumour hypoxia: Tumor hypoxia (low oxygen) is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, which target oxygen-deficient cells, represent a promising treatment strategy. We have demonstrated the pre-clinical efficacy of NI-Pano, a novel hypoxia-activated pro-drug of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano is stable in normoxic (21% oxygen) conditions and undergoes NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (<0.1% oxygen). NI-Pano exhibited growth delay effects as a single agent in mouse tumor xenografts. Pharmacokinetic analysis confirmed the presence of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Our preclinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors. Work to develop complementary imaging agents for hypoxia will also be discussed.

2022 M. Frederick Hawthorne Lecture
2022-03-02 16:00
“Releasing, or capturing, that is the question. Porous molecular materials”
Porous materials are one important class where the shape and distribution of “empty” space throughout the framework is a main determinant for the resulting functionality. For instance, zeolites are available with many different pore size and geometries, which is the fundament of their wide spread use in industry, e.g. as absorbents and catalysts. Drug delivery applications with porous inorganic materials are in the focus of several investigations all over the world. Following supramolecular principles, i.e., incorporating dynamically covalent bonds into a silica framework, we have reported a “break on-demand” of the silica structure. Recently we have developed disulfide-bridged organosilica nanoparticles with cage-like morphology, and assessed in detail their bioaccumulation in vivo.[1] Interestingly their lung accumulation and their ability to escape macrophage filtering open new promises for their use as drug delivery systems.
In addition they are able to stabilize out of equilibrium species and transport them inside cells were they can be released and evolve towards the equilibrium state.[2] But controlling the shape and the “emptiness”, of porous systems can allow the capture, and not release, of specific molecules, biomarkers. In particular a novel class of fluorescent artificial receptors (FAR) is introduced that can bind the neurotransmitters serotonin and dopamine in a bio-relevant concentration range with unprecedented affinity and selectivity.[3] The fully synthetic receptors are based on zeolites and rapid responding and thus enable instantaneous neurotransmitter detection through cost economic and facile absorbance- and emission-based assays. Their potential for high-throughput diagnostics in urine and for monitoring of important enzymatic reactions is shown.
Finally amongst the most studied porous systems in medicine are hydrogels, which are inherently more disordered porous system than the aforementioned inorganic host materials. An example of hybrid injectable hydrogels will be given for the treatment of fistula.[4]
References
[1] P. Picchetti et al. ACS Nano 2021, 15, 9701–9716
[2] P. Picchetti, L. De Cola et al. J. Am. Chem. Soc. 2021, 143, 7681-7687.
[3] F. Biedermann, L. De Cola et al. Adv. Mater. 2021, 33, 2104614.
[4] E. Piantanida, Materials Today Bio, 2021, 10, 100109

Organic Colloquium - Prof. Ross Denton
2022-03-03 12:00
“Phosphorus-Oriented” Method Development and Total Synthesis
Abstract: The lecture will describe the design, development and applications of new synthetic methods based upon phosphorus(V) reagents and catalysts. Topics will include catalytic halogenation, hydroxyl activation and the total synthesis of polychlorinated and trimeric phenol-derived natural products.

Postponed - Chem 218: Student Exit Seminar - Samuel Lilak
2022-03-03 12:00

Chem 248 - Organic Chemistry Student Seminar
2022-03-07 15:00
Recent Advancements in the Employment of Pd/Ni Catalyzed C-N Amide Cross-Coupling

Chem 228: Stephen Quake
2022-03-07 16:00
“The Cell is a Bag of RNA”

Chem 278: Prof. James McCusker
2022-03-09 16:00
“Ultrafast Synthesis: Leveraging Time-resolved Spectroscopy for Targeted Synthetic Control of Ultrafast Dynamics in Transition Metal-based Chromophores”
Abstract: The interconversion of light and chemical energy is one of the most fundamental processes on Earth. Research on solar energy conversion, for example – which will ultimately lead to the next generation of solar energy technologies – has sought to replicate Nature’s solution through the realization of artificial constructs that mimic various aspects of photosynthesis. Whether it is the creation of potential gradients to generate current (i.e., photovoltaics) or more recent efforts coupling photo-generated electrons and holes to catalysts (e.g., photoredox catalysis), the critical first step is the absorption of light and the subsequent separation of charge. Transition metal-based chromophores are particularly well-suited for use in such schemes by virtue of the charge-transfer excited-states that a majority of them possess. Indeed, tremendous advances have been made through use of compounds such as [Ru(bpy)3]2+ and Ir(ppy)3 in areas ranging from solar energy conversion to photoredox catalysis. Despite the obvious advantages of ruthenium- and iridium-based chromophores, the fact that these elements are among the rarest in the earth’s crust raises legitimate questions concerning cost and scalability of processes reliant on such chromophores. Such issues, coupled with the possibility of unlocking new chemistry, has motivated exploring the possibility of replacing these compounds with chromophores based on earth-abundant first-row transition metals that can carry out analogous excited-state reaction chemistry. With these opportunities come significant challenges due to inherent differences in the electronic structures of first- versus second- and third-row metal complexes that profoundly impact the ability of such compounds to engage in the desired chemistry. The focus of our research program is therefore to understand the factors that determine the dynamics associated with charge-transfer excited-states of first-row transition metal-based chromophores, with the ultimate goal of circumventing and/or redefining their intrinsic photophysics in order to make feasible their use in a variety of light-driven applications. This seminar will outline the key scientific issues defining this challenge as well as discuss recent examples from our lab illustrating how these challenges can be met and, ultimately, overcome.

Chem 218: Student Exit Seminar
2022-03-10 12:00
“Choosing the right lens: Energy surfaces and chemical identity in the photodissociation of Na2+ in different solvent environments”
