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Open Access Publications from the University of California

Scholarly Works (52 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2022)

This dissertation describes how modern organic chemistry can be used to improve thetoolbox of fluorine-18 (18F) labeled prosthetic groups for thiol radiolabeling. Herein, I report two new prosthetic groups (4-[18F]fluorovinylsulfonyl benzene ([18F]FVSB) and a [18F]fluoroaryl gold(III) complex), their syntheses, scope, and stability.

Chapter One provides a popular science background for those currently outside of thesynthetic chemistry and radiochemistry communities. This is meant to serve as a broad and brief overview of the work detailed in this dissertation while requiring little background knowledge.

Chapter Two provides a brief overview of positron emission tomography (PET) molecularimaging technology and why fluorine-18 is the radioisotope of choice for clinical applications. This chapter details a variety of radiofluorination methods to prepare 18F-labeled arenes as well as a range of 18F-labeled prosthetic groups and their respective reactivities.

Chapter Three discloses the development of [18F]FVSB, an 18F-labeled vinyl sulfone thatis rapidly synthesized via an 18F-deoxyfluorination method. This chapter details the broad scope of [18F]FVSB to radiolabel free thiols in aqueous media while also demonstrating high stability of the 18F-labeled bioconjugates, produced under a variety of conditions.

Chapter Four details the precise operations involved in the manual and fully-automatedradiosynthesis of [18F]FVSB and subsequent peptide labeling, including many minute specifics as well as troubleshooting advice for those who may use this method. Chapter Five demonstrates the design and development of the first gold mediated 18Farylation reagent for thiol-containing substrates. The robust 18F-gold complex is able to rapidly label free thiols in aqueous environments and furnish stable thioaryl bioconjugates.

    Cover page: Novel Methodologies for Site-selective Fluorine-18-Labeling of Thiol Containing Molecules via Chemoselective Cysteine Functionalization
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2016)
    Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3+2) cycloadditions with N-phenyl sydnone with the rate constant of up to 1.46 M-1 s-1. Most signifcantly, the sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions were predicted to be mutually orthogonal. This was validated experimentally and used for highly selective fluorescence labeling of two proteins simultaneously.
      Cover page: Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2016)
      Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3 + 2) cycloadditions with N-phenyl sydnone with the rate constant of up to 1.46 M-1 s-1. Most significantly, the sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions were predicted to be mutually orthogonal. This was validated experimentally and used for highly selective fluorescence labeling of two proteins simultaneously.
        Cover page: Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening.
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2020)
        Acute myeloid leukemia (AML) is an aggressive clonal bone marrow cancer characterized by high rates of relapse and mortality. A middle-aged woman with AML relapsed twice after achieving complete remission with induction therapy and subsequent salvage therapy. She was then enrolled in a clinical trial with the bromodomain extraterminal inhibitor (BETi) mivebresib and achieved complete remission with incomplete count recovery (CRi) with monotherapy. Subsequently, she relapsed and was transitioned to combination therapy with mivebresib plus venetoclax and achieved CR again. The patient required eltrombopag to decrease platelet dependence in both arms of the trial and exhibited less myelosuppression with the combination therapy. The exceptional response to mivebresib demonstrated by this patient underscores the therapeutic potential of mivebresib.
          Cover page: Prolonged Response of a Patient with Relapsed Acute Myeloid Leukemia to a Novel Oral Bromodomain Extraterminal Inhibitor (BETi)Creative Commons 'BY' version 4.0 license
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2022)
          The 18F labeling of unprotected peptides and sugars with a Au(III)-[18F]fluoroaryl complex is reported. The chemoselective method generates 18F-labeled S-aryl bioconjugates in an aqueous environment in 15 min with high radiochemical yields and displays excellent functional group tolerance. This approach utilizes an air and moisture stable, robust organometallic Au(III) complex and highlights the versatility of designer organometallic reagents as efficient agents for rapid radiolabeling.
            Cover page: An Organometallic Gold(III) Reagent for 18F Labeling of Unprotected Peptides and Sugars in Aqueous Media
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2017)
            A practical method for radiofluorination of anilines with [18 F]fluoride via N-arylsydnone intermediates is described. These precursors are stable, easy to handle and facilitate direct and regioselective 18 F-labeling to prepare [18 F]fluoroarenes. The value of this methodology is further highlighted by successful application to prepare an 18 F-labeled neuropeptide.
              Cover page: Synthesis of [<sup>18</sup> F]Fluoroarenes by Nucleophilic Radiofluorination of N-Arylsydnones.
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2018)
              A new class of bioorthogonal reagents based on the cyclopentadiene scaffold is described. The diene 6,7,8,9-tetrachloro-1,4-dioxospiro[4,4]nona-6,8-diene (a tetrachlorocyclopentadiene ketal, TCK) is ambiphilic and self-orthogonal with remarkable stability. The diene reacts rapidly with a trans-cyclooctene and an endo-bicyclononyne, but slowly with dibenzoazacyclooctyne (DIBAC), allowing for tandem labeling studies with mutually orthogonal azides that react rapidly with DIBAC. TCK analogues are synthesized in three steps from inexpensive, commercially available starting materials.
                Cover page: Readily Accessible Ambiphilic Cyclopentadienes for Bioorthogonal Labeling
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2017)

                Background

                To prospectively evaluate the progression of cognitive-behavioral function in amyotrophic lateral sclerosis (ALS) and examine the association of cognitive-behavioral deficits with disease progression, patient quality of life (QOL), and caregiver burden.

                Methods

                We evaluated cognitive-behavioral function using the Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen at enrollment and after 7 months in a cohort of patients with ALS. Paired t tests were used to evaluate the change in the 2 assessments. Linear regression and Kruskal-Wallis tests were applied to investigate how initial cognitive or behavioral status related to outcomes.

                Results

                The mean test-retest interval was 6.8 months (SD 1.6). Cognitive status of the study population (n = 49) overall did not change over the study period (p = 0.06) despite progression of motor weakness (p < 0.001), though small subsets of the sample demonstrate cognitive change. Patients initially classified as behaviorally normal showed increased behavioral problems over time (t = -2.8, p = 0.009). Decline in cognitive (β = -1.3, p = 0.03) and behavioral (β = -0.76, p = 0.002) status predicted increasing caregiver burden. Behavioral abnormalities predicted decline in forced vital capacity and ALS Functional Rating Scale-Revised score (p = 0.008, 0.012) in the study population and patient QOL in the most severely affected group (t = 4.3, p = 0.003).

                Conclusions

                Cognitive-behavioral change is a key aspect of disease heterogeneity in ALS. Executive function in ALS overall remains stable over 7 months as detected by an administered screening tool. However, patients may develop caregiver-reported behavioral symptoms in that time period. Screening for caregiver-reported symptoms has a particular utility in predicting future clinical decline, increased caregiver burden, and worsening patient QOL.
                  Cover page: Progression and effect of cognitive-behavioral changes in patients with amyotrophic lateral sclerosis
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2013)
                  A practical, palladium-catalyzed synthesis of aryl fluorides from arylboronic acid derivatives is presented. The reaction is operationally simple and amenable to multigram-scale synthesis. Evaluation of the reaction mechanism suggests a single-electron-transfer pathway, involving a Pd(III) intermediate that has been isolated and characterized.
                    Cover page: Palladium(III)-Catalyzed Fluorination of Arylboronic Acid Derivatives
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2023)
                    Significant evidence suggests that the failure of clinically tested epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (e.g. erlotinib, lapatinib, gefitinib) in glioblastoma (GBM) patients is primarily attributed to insufficient brain penetration, resulting in inadequate exposure to the targeted cells. Molecular imaging tools can facilitate GBM drug development by visualizing drug biodistribution and confirming target expression and localization. To assess brain exposure via PET molecular imaging, we synthesized fluorine-18 isotopologues of two brain-penetrant EGFR tyrosine kinase inhibitors developed specifically for GBM. Adapting our recently reported radiofluorination of N-arylsydnones, we constructed an ortho-disubstituted [18F]fluoroarene as the key intermediate. The radiotracers were produced on an automated synthesis module in 7-8% activity yield with high molar activity. In vivo PET imaging revealed rapid brain uptake in rodents and tumor accumulation in an EGFR-driven orthotopic GBM xenograft model.
                      Cover page: 18 F-Labeled brain-penetrant EGFR tyrosine kinase inhibitors for PET imaging of glioblastoma
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