Efficient construction of C-N bonds and nitrogen-containing heterocycles is instrumental in synthesizing chemical building blocks with direct applicability to the pharmaceutical industry. Three projects incorporating this theme to address unmet scientific challenges are reported herein: quinolinone inhibitors of LSF, pyrazolopyrrolidnones for the treatment of leishmaniasis, and an asymmetric Petasis reaction to synthesize chiral 1,2-amino alcohols. Quinolinone inhibitors of LSF, an oncogenic transcription factor overexpressed in several liver cancers, were previously reported as potential cancer therapies, however; they exhibited poor oral bioavailability, and the series was optimized for improved pharmacokinetics. Newly synthesized analogs demonstrate nanomolar potency against liver cancer cells in vitro with improved pharmacokinetic properties. Furthermore, the synthetic route was optimized to deliver lead compounds in multi-gram quantities, and to establish regio-control over the final intramolecular Friedel-Crafts cyclization. A series of pyrazolopyrrolidinones was developed to address an unmet medical need for new treatments against the parasitic disease leishmaniasis. Over 200 analogs were generated via parallel synthesis, which were assayed in a high-throughput phenotypic screen and many demonstrated low-micromolar to nanomolar potency against Leishmania parasites in vitro. SAR trends and in vivo pharmacokinetic and efficacy studies identified a critical balance between physiochemical properties (solubility, lipophilicity, plasma protein binding) and potency that appear to limit expected in vivo efficacy. These trends informed subsequent analog design to further optimize the physiochemical properties for in vivo efficacy, with further studies pending. Chiral 1,2-amino alcohols are valuable building blocks found in drugs, natural products, and organocatalysts. To enable their synthesis, an asymmetric multicomponent Petasis reaction was developed using boronic acids or boronates, primary or secondary amines, and glycolaldehyde, catalyzed by chiral biphenols. The reactions are run in ethanol or trifluorotoluene with commercially available starting materials, accommodate electron deficient and electron rich boron reagents, and afford products in up to 99% yield and >99:1 er. The reaction is scalable to generate decagram quantities of product, and an extractive purification procedure allows for chromatography-free product isolation and catalyst recovery. / 2022-06-04T00:00:00Z

Flavoenzymes comprise a group of biological molecules that utilize the flavin cofactor to catalyze a large variety of oxidation and reduction reactions. The protein constituent of these redox-active enzymes regulates the activity of the flavin apoenzyme, mainly through non-covalent interactions. Some of these non-covalent interactions that have been previously isolated and investigated include hydrogen bonding, π-π aromatic stacking, dipolar and steric effects. We have focused our efforts in gaining better understanding on hydrogen bonded interactions utilizing a combination of 1H-NMR, electrochemistry, SEEPR and B3LYP computational techniques. In the present manuscript we have studied the interplay between hydrogen bond formation and redox activity in redox-active model systems. Specifically, we have used cyclic voltammetry and chemical modification of the flavin cofactor to understand better the influence of hydrogen bonding on the redox properties of the flavin cofactor. We have concluded that hydrogen bond formation at the N(3)-H position of the cofactor modulates the reduction potential by 80 mV (1.8 kcal/mol), making the flavin harder to reduce. This effect is similar in effect and magnitude to methylating the N(3) position of the cofactor. Our next goal was to investigate how far the electronic modulation is transmitted from the binding site. For this project we have utilized the flavin cofactor and a group of chemically related triazine hosts with different functionality and electronic donating and withdrawing capabilities. We analyzed the effects of the electronic requirements of the functional groups on the association constants between flavin and 5 different triazine-based complexes. Further insight on the systems under study was obtained through DFT-B3LYP computational studies. Our results show that electronic modulation extend more than 11 Å from the binding site, providing further knowledge useful in designing molecular wires and sensing devices. Finally, we have utilized the redox-active compound 1,8-naphthalimide and two chemically related hosts to study the recognition-controlled modulation in hydrogen bond formation. In this project we have employed diaminotriazine and diaminopyridine hosts to examine the interplay between polarizability and electrostatic interactions on the formation of hydrogen bonds. We have concluded that in the naphthalimide-triazine pair, the recognition is mainly driven by electrostatic interaction. However, in the naphthalimide-diaminopyridine complex, the hydrogen bond formation is due to polarization of the N-H bonds.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a large family of natural products with highly oxygenated and densely functionalized frameworks and broad range of biological activities. Due to these features, PPAP natural products have drawn significant synthetic attention in organic synthesis. The dissertation research herein describes the efforts towards the asymmetric synthesis of two series of PPAP natural products: 1) the type A PPAPs (–)-nemorosone and (–)-6-epi-garcimultiflorone A and 2) the spirocyclic polyprenylated acylphloroglucinol (spiro-PPAP) natural products hyperbeanols and their precursor hypercalin B. Regiodivergent photocyclization of dearomatized acylphloroglucinol substrates has been investigated and developed to produce type A PPAP structures using an excited- state intramolecular proton transfer (ESIPT) process. Using this strategy, we achieved the enantioselective total syntheses of the type A PPAPs (–)-nemorosone and (–)-6-epi- garcimultiflorone A. Diverse photocyclization substrates have also been investigated leading to divergent photocyclization processes as a function of tether length. Also, considerable progress has been made in achieving the first total synthesis of spiro-PPAP natural products and one precursor hypercalin B. The synthetic pathway utilized Cu(I)-mediated coupling of a dienone synthon to rapidly build the critical C-C bond, and stereoselective intramolecular radical cyclization/oxygen trapping cascade to construct the spirocyclic motif. / 2024-03-07T00:00:00Z

Bibliography: pages 91-96. / Different synthetic approaches to tertiary mixed phosphoric-carboxylic imides(III) are discussed. The preparation of (III) via the N-acylation of phosphoramidates was investigated. The reaction of PhC(O)X (X = Br, Cl, F) with the conjugate base of (EtO)₂P(O)NHMe (IX) yields three products: PhCO₂Et (4), PhC(O)NHMe (5) and (PhCO)₂NMe (6). (5) and (6) are formed via the initial rapid formation of (EtO)₂P(O)-NMe-C(O)Ph (IIIe), while (4) results from the E1cB related reaction of (EtO)₂P(O)NMe involving electrophilic assistance by PhC(O)X. The attack of various nucleophilic species at the mixed-imide (IIIe) was studied, and the possible mechanisms of the P-N bond cleavage, followed by the N-methyl transfer from the phosphoryl to the carbonyl centre are discussed.

Bibliography: p. 84-86. / The acid catalysed hydrolysis of a number of ring alkyl substituted dimethyl N-aryl phosphoramidates, (MeO)2P(0)NHAr, has been studied by measuring the rates of hyd~olysis with the aid of a UV spectrophotometer. These rates have been correlated with the pKa values of the corresponding ani I inium iOhs and the slope of this reactivitybasicity relationship for phosphoramidate with ortho substituents (6 = 0~85) is found to differ from that for substrates with meta and para substituents (S = 0,36). Determination of the thermodynamic parameters indicates that the entropy of activation is approximately constant for the substrates studied and the strongly negative values ~ -I -I (~S = 155,4 - 17,5 J mole K ) are consistent with an A2 type mechanism.

Abstract not available

In an attempt to overcome the inherent problems of poor selectivity for tumor cells and toxicity to normal tissues which plague most current chemotherapeutic regimens, heterosubstituted quinone propanoic acid derivatives designed to be used as hypoxia-selective bioreductive drug delivery agents were prepared. It is believed that the heterosubstitution will provide both negative reduction potentials similar to that of the known antitumor agent mitomycin C and acceptable aqueous solubilities. Alkoxy- and aminoquinone propanoic acids were prepared initially and the quinone-drug conjugates were obtained as amides or thioesters by reaction of the corresponding in situ generated symmetric quinone acid anhydrides with the known cytotoxic agents bis(2-chloroethyl)amine, 4-(3-methyltriazeno) toluene, 4-(methyltriazeno)imidazole-5-carboxamide, 5-fluorouracil, and 6-mercaptopurine. These agents are designed to be selectively reduced at an oxygen deficient hypoxic tumor site to the transient hydroquinone amides or thioesters which then should cyclize to the related lactones with concurrent release of the cytotoxic drugs. The controlled release should result in the selective kill of tumor cells with minimal toxic effects in normal tissues. This approach is based upon studies of similar quinone-based antitumor compounds which are thought to operate via initial bioreductive activation. Tests on both model quinone amides and the quinone-drug conjugates show that under reductive conditions lactonization and drug release does indeed occur. Biological testing of the various quinone derivatives prepared is currently in progress in several laboratories.

No description available.

Post-translational modifications (PTMs) allot versatility to the biological functions of highly conserved proteins. Recently, modifications to non-histone proteins such as methylation, acetylation, phosphorylation, glycosylation, ubiquitination, and many more have been linked to the regulation of pivotal pathways related to cellular response and stability. Due to the broad spectrum of pathways PTMs are associated with, their dysregulation is often linked to oncogenesis and various autoimmune diseases. Proteins involved in the incorporation (writers), removal (erasers) and recognition (readers) of PTMs, and substrate proteins, are regarded as important biomarkers and potential therapeutic targets as a result of their role in detrimental pathways. Current methodologies to monitor PTM substrates rely on alkyne/azide-based chemical proteomics, which are inefficient due to their bulky nature. This steric hindrance has been shown to limit the metabolic incorporation of alkyne/azide tags via PTM writers on to substrate proteins and has limited the use of these chemical reporters to enzymes containing large active sites. One portion of this dissertation will focus on the development of a steric-free biorthogonal chemical tagging platform utilizing a fluorine-thiol displacement reaction. Fluorinated PTM cofactors/precursors are steric free and could be easily recognized and metabolized by PTM enzymes. Reaction development identified thiophenols as a suitable partner for the displacement reaction to convert fluorine to other useful functionalities, allowing for the labeling and enrichment of multiple acetylation substrates in cell lysates. Another goal of this dissertation was the synthesis of novel stapled peptide therapeutics with this FTDR platform. A library of unprotected peptides were cyclized with this methodology, and were found to promote sufficient levels of alpha helical stability. Biological evaluation of FTDR-based stapled peptides showed that this methodology produced compounds with enhanced stabilities, which were a significant upgrade to ring-closing metathesis-based peptides in regard to solubility and cell permeability. The final goal of this dissertation focuses on the synthesis of a novel PET imaging probe. Immuno-PET imaging is a rising field in cancer prognosis and therapy, yet current probes utilize full-length IgGs and random conjugation methods, that lead to conjugates with random stabilities and activities. In conjunction with biologist in our lab, a 64Cu chelating NOTA linker, tethered to a BCN moiety was site-specifically conjugated to Fab fragments. The smaller unnatural amino acid containing Fab fragments, specifically mutated with p-azidophenylalanine (pAzF), boasted improved pharmacokinetic profiles and allowed for site-specific conjugation via strain-promoted cycloaddition. / Chemistry

No description available.