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1. 1,3,3-триметил-5-метокси-6´-бром-8´-[(Е)-2-(1´´,3´´,3´´-триметил-5-метокси-3Н-индолий-2´´-ил)винил]-спиро[индолин-2,2´-2Н-хромен]йодид. 2. 1,3,3-триметил-5-метокси-6´-бром-8´-[(Е)-2-(1´´,3´´,3´´-триметил-5-метокси-3Н-индолий-2´´-ил)винил]-спиро[индолин-2,2´-2Н-хромен] йодид по п. 1, обладающий фотохромными свойствами

Aim: This thesis is focused on the synthesis of new pyridine-based 1,2,3-triazoles to be employed as potential scaffolds for drug discovery and for diverse applications in organic chemistry such as C-H activation and organocatalysis. In particular, this thesis will focus on the biological importance of the synthesised pyridine-based triazoles as potential inhibitors of the KAT2A protein and on their transformations through copper- and palladium- catalysed C-H activations into potentially active compounds. Moreover, it is also described the attempted synthesis of proline-based organocatalysts, enclosing a triazole moiety in their backbone, that will be further evaluated for future applications in organocatalytic reactions such as aldol condensations, Mannich and Michael reactions.

The green synthesis of nanoparticles has been a vital aspect in the search for novel antimicrobial agents. This research aimed at biosynthesis, characterization and preliminary evaluation of the antibacterial properties of silver nanoparticles (AgNPs) from the back extract of Annona senegalensisis. The bark of Annona senegalensis was scraped from the stem, washed, air-dried, pulverised and extracted. Four millilitre (4 ​ml) of the extract was pipetted into 36 ​mL (36 ​ml) of silver nitrate solution (5 ​mM AgNO3) in a conical flask. The resulting solution was subjected to magnetic stirring at room temperature (28 ​°C ​± ​2) till AgNPs were formed. The synthesized AgNPs were filtered, washed with deionized water and dried in oven at 40 ​°C. Fourier transform infrared (FTIR) analysis was carried out on the synthesized AgNPs. The AgNPs synthesized was also characterized with UV–visible spectrophotometer (UV), scanning electron microscope (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray (EDX) spectroscopy to ascertain the physico-chemical and morphological properties of the AgNPs. The antimicrobial investigation was carried out following standard method. The observation of colour change (pale yellow to dark brown) during the synthesis and maximum absorbance at wavelength 431.19 ​nm in the UV spectrum confirmed the formation of AgNPs. The FTIR analysis showed that the biomolecules responsible for the reduction of silver ion contain O–H functional groups. The electron microscopy studies indicated that the AgNPS are spherical in shape with nanoparticles sizes of 11–24.76 ​nm. EDX analysis showed that the AgNPs contain high amount of silver and few other elements. The antimicrobial study showed high zones of inhibition 22.75–33.75 against tested bacteria. The simplicity of the synthesis of AgNPs from the extract of the stem bark of Annona senegalensisis and relatively high zones of inhibitions shown by the AgNPs are strong evidences of the possible application of Annona senegalensisis in the synthesis of novel therapeutic agent against infections from bacteria and fungi.

Peptide biomaterials have drawn great attention in recent decades owing to their tunability and biocompatibility. Coiled-coils specifically have become a well-studied scaffold with a clear sequence-to-structure relationship. As such, the Chmielewski lab has extensively studied peptide assemblies based on the GCN4 leucine zipper. First, we present the peptide TriCross, where nitrilotriacetic acid (NTA) and di-histidine ligands are installed at the N- and C-terminus, respectively, and a bipyridine ligand installed at a central, solvent exposed position. Through strategic placement of these metal-binding ligands, TriCross assembled into a three-dimensional (3D) mesh in the presence of zinc ions and dissembled following mild ethylenediaminetetraacetic acid (EDTA) treatment. These properties created a 3D network capable of encapsulating cells for extended periods of time (>1 week) and releasing cells upon metal-chelation. Next, we describe a stabilized nanotube and enhanced crystal assembly through a heterocoiled-coil assembly. Nanotubes composed of the coiled-coil peptide TriNL that assembled likely through ionic interactions rapidly degraded in phosphate buffered saline (PBS). To improve stability, a peptide with metal-binding ligands, p2L, was introduced through thermal annealing of the two peptides. Low levels of p2L (up to 10:1 TriNL:p2L) retained nanotube morphology while simultaneously introducing NTA and di-histidine ligands. Upon addition of metal, metal-ligand interactions were established within the nanotube and increased stability of the material. Higher levels of p2L (2:1 TriNL:p2L) led to hexagonal crystals similar to p2L but now without the use of metal ions. These crystals expanded the scope of protein inclusion by removing the requirement for His-tags on proteins to be incorporated within the material. Finally, a self-replicating and self-assembling coiled-coil peptide is reported. The coiled-coil TriNL was cysteine modified (N20C) to create a peptide capable of native chemical ligation. At low concentrations, the N20C FL peptide acted as a template for the cysteine and thioester fragments while high concentrations led to fibrillar structures. The size of the fibrils was controlled through the addition of preassembled seeds into the native chemical ligation system.

This dissertation focuses on the development of amine-boranes and their novel monotrifluoroacetoxy-derivatives as efficient and environmentally friendly reagents for reductive amination. Trimethyl borate, as a lewis acid, is shown to improve the chemoselectivity of amine-boranes while promoting faster imine formation. Refinement of amine-boranes via reaction with trifluoroacetic acid provides mono trifluoroacetoxyborane-amine (TFAB-amine) complexes. This new class of reagents serves as mild, chemoselective agents for the direct reductive amination of aldehydes and ketones. Among these, TFAB-NEt3 is established as superior, compared to widely-used reductive amination reagents, with improved yields even for challenging substrates. The application of the monotrifluoroacetoxy-derivatives has been extended for the synthesis of lactams from keto-acids and amino-acids via a tandem reductive amination amidation protocol.

This thesis explores distinct but overlapping approaches to contemporary drug discovery. PROTAC drugs are an emerging therapeutic approach where molecules hijack the ubiquitin-proteasome system to degrade disease-implicated proteins. Fragment-based and structure-based drug design principles were applied to develop PROTACs targeting two target proteins − BRD4, a prominent cancer target and Mpro, a critical enzyme for SARS-CoV-2 replication. Mpro-degrading PROTACs were developed that may provide a new paradigm for drug development against SARS-CoV-2 and other viral infectious diseases. Lastly, the concept of phenotypic drug discovery and open-source research was enacted for the development of novel antifungal agents.

1. 1,3,3-триметил-5-метокси-6´-бром-8´-[(Е)-2-(1´´,3´´,3´´-триметил-5-метокси-3Н-индолий-2´´-ил)винил]-спиро[индолин-2,2´-2Н-хромен]йодид. 2. 1,3,3-триметил-5-метокси-6´-бром-8´-[(Е)-2-(1´´,3´´,3´´-триметил-5-метокси-3Н-индолий-2´´-ил)винил]-спиро[индолин-2,2´-2Н-хромен] йодид по п. 1, обладающий фотохромными свойствами

DNA nanotechnology has rendered programmable, bottom-up self-assembly of nanostructures in various morphology, versatile functionalization, and atomic level precision over the last forty years. DNA nanostructures are usually assembled in solution by the thermodynamic process in a specific solution. In recent years, DNA two-dimensional (2D) structures on the surface have been widely applied in semiconductors, electronic devices, and biomedical studies. My research mainly focused on novel DNA nanostructures assembly on the surface and their applications. I have developed an equilibrium-enabled flexibly curved DNA homopolymer. I have further developed a novel method to determine the interhelical angle of DNA secondary structure by DNA 2D-array. In this thesis, I have envisioned a strategy to prepare DNA linear polymers with flexible curvature and further assembled them into spiral or concentric rings on the surface. In DNA double crossover-like (DXL) homopolymers, an aromatic chemical group was introduced to the 3'-end in each strand. The planar group could stack into the DNA homopolymer, which increases the length on one side of the DXL polymer and further bend the structure by uneven-length stress. Moreover, the stacking in is under the equilibrium with flipping out, endowing the dynamic change and flexibility to the curvature of the DNA homopolymer, which could be a benefit in the surface-assisted construction of spirals or concentric rings. With the appropriate design, DNA could be self-assembled on the surface into 2D crystals in a certain periodicity. Such a structure could be applied in nucleic acid secondary structure determination as a crystallography-like method. In this work, I have successfully incorporated the 10-23 DNAzyme, a common-used RNA-cleavage DNA sequence into DNA 2D arrays. In the brick-wall-like DNA 2D arrays, the repeating distance determined the interhelical angle of the 10-23 DNAzyme flanks. By 2D fast Fourier transform (FFT), this repeating distance could be measured and calibrated, following the deduction of the target angle. This approach had been validated with well-known DNA secondary structures.

Noscapine is a naturally occurring opiate compound that has been shown to have weak anti-cancer properties. The work in this thesis demonstrates many different ways in which chemical modifications can be made to the molecular scaffold of noscapine resulting in retention, or increases, in anti-cancer activity.

Cyclopropanes are found in an array of synthetic and natural products. The Simmons–Smith reaction has been one of the most common methods used to synthesize cyclopropanes since it was first discovered in the 1950s. The Simmons–Smith reaction entails the transfer of a carbene (:CH2) from a zinc carbenoid to an alkene, forming a cyclopropane. However, there are still many limitations to the Simmons–Smith method, including poor functional group tolerance and poor regioselectivity in polyalkene substrates. To address the weaknesses in the Simmons–Smith reactions, we have pursued a transition metal-catalyzed method. Our group has reported a cobalt pyridinediimine (PDI) catalyst system to carry out cyclopropanation reactions using gem-dichloroalkanes and gem-dibromoalkanes in order to access nonstabilized carbenes. This method also offers an advantage over diazo transfer chemistry since diazo chemistry requires a stabilizing group to be present in most cases. This established work has demonstrated a complimentary reactivity to the Simmons–Smith reaction. In this work, we demonstrate that we could expand upon the existing methods of dimethylcyclopropanation to access spirocyclopropanated products by changing the identity of the dichloroalkane. In addition to this reactivity, an enantiopure catalyst that is able to catalyze an enantioselective cyclopropanation was found. We were able to show a broad scope of this new reaction, and mechanistic experiments are carried out in order to probe the mechanism of this reaction. Overall, this thesis offers a new way to access enantiopure dimethylcyclopropane and spirocyclopropanated products.

1. 1,3,3-триметил-5-метокси-6´-бром-8´-[(Е)-2-(1´´,3´´,3´´-триметил-5-метокси-3Н-индолий-2´´-ил)винил]-спиро[индолин-2,2´-2Н-хромен]йодид. 2. 1,3,3-триметил-5-метокси-6´-бром-8´-[(Е)-2-(1´´,3´´,3´´-триметил-5-метокси-3Н-индолий-2´´-ил)винил]-спиро[индолин-2,2´-2Н-хромен] йодид по п. 1, обладающий фотохромными свойствами

This thesis involves three different published manuscripts (Chapter 2 submitted to peer review, Chapters 3 and 4 published) and unpublished data (Chapter 5) in the area of organocatalysis and Phase-Transfer Catalysis: mechanistic insights, synthetic applications and new catalyst syntheses are reported. These chapters are preceded by an introductory overview (Chapter 1) of the two common themes found throughout the projects: Phase-Transfer Catalysis (PTC) and Sulfonic Acids. PTC is the most exploited organocatalysis due to its benefits such as simple experimental procedures, mild reaction conditions, inexpensive and environmentally benign reagents and solvents, and possible scale-up. Among the chiral catalysts used for asymmetric PTC reactions, Cinchona alkaloid derivatives are undoubtedly the most common because of their efficiency and convenience. Alongside their development carried out in recent decades, many theories and studies have arisen to shed light upon the nature of their interaction with the substrates of a reaction, which leads to the enantioselective outcomes of reactions. In Chapter 2, we report a deep mechanistic insight into this interaction, revealing a crucial role played by the N+CHs of the quaternary catalyst. When observed in solution and with neutral species, thanks to 1H-NMR titrations of Cinchona alkaloid PTC bromides with different neutral hydrogen bond acceptors, the interactions between catalyst and substrates were elicited as H-bonds. The correspondent BArF salts were also titrated, showing a different pattern of H-bonding. When studied in solution and in solid state with negatively charged substrates, thanks to 1H-NMR and X-ray data of probes bearing ammonium and sulfonate or enolate groups within the same framework, catalyst and substrate surrogates interacted via ion-dipole interactions. The high directionality exerted by both H-bonds and ion-dipole interactions between catalysts and substrates could rationally explain how these interactions are pivotal to the enantioselectivity. The findings were further confirmed by appropriate computational studies. In Chapter 3 and Chapter 4 two examples of synthetic applications of asymmetric organocatalyses are reported, involving the use of bifunctional thiourea catalysts and Cinchona-alkaloid PTCs respectively. In Chapter 3, the mild procedure previously reported by Adamo’s group for the asymmetric addition of sodium bisulfite to olefins catalysed by Cinchona-thiourea catalysts, was exploited. This allowed us to synthesise for the first time enantioenriched ginge and shogasulfonic acids in natural and unnatural configurations. These compounds are recognised as the active principles of Ginger rhizome, exhibiting antiemetic and stomach protecting effects. The same sulfonylation methodology was also involved in Chapter 2 for synthesising the ammonium-sulfonate probe. In Chapter 4, a new procedure for the enantioselective synthesis of 3,4-dihydropyran-2-ones is reported. The optimized reaction proceeded via PTC addition-cyclisation of acetylacetone to cinnamic thioesters, catalysed by N-phenylquininium bromide and the system base/phenol. Mechanistic insights concerning the catalytic cycle of reaction are also indicated. Finally, we decided to synthesise a new class of potential PTCs that could combine the main features of the most efficient catalysts reported in the literature: chiral ammonium betaine scaffold, Cinchona alkaloid derivatization, and ammonium-sulfonate interaction. The synthetic approaches and the characterization of the final designer products are reported in Chapter 5. Complete abstracts of the projects are reported as distinct paragraphs in each chapter.

A new practical method for synthesizing 4-aryl-6-cycloamino-1,3,5-triazine-2-amines and bis(1,3,5-triazine-2,4-diamines) was developed. This method is suitable for generating combinatorial libraries of potentially bioactive compounds. Initially, 94 compounds with the 4-aryl-6-cycloamino-1,3,5-triazine-2-amine scaffold were prepared and screened for their antileukemic activity using Jurkat T-cell lines. This method was then successfully extended to the synthesis of bis(1,3,5-triazine-2,4-diamines).

Phosphine organocatalysis opens the door for the discovery of novel reactions and methodologies. Here two distinct modes of reactivity are examined using these catalysts in conjunction with amines and allenes forming a wide range of N-heterocycles with a wealth of investigation of the mechanism for their formation.

A historically important reaction, the Ueno-Stork reaction promotes, through the use of toxic organotin species, the cyclization of a haloacetal onto an alkene generating bicyclic acetals. This reaction has been used over the years in several total syntheses of biologically relevant natural products, especially the prostaglandin class of natural products. Herein, will be described the development of a novel nickel-catalyzed Ueno-Stork cyclization reaction, which no toxic organotin and radical promoters are used, and instead a greener, operationally friendly, and non-toxic earth abundant nickel catalyst is applied. Optimization studies, substrate scope, scalability, relative stereochemistry of the bicyclic acetals, as well as derivatization of the products were studied. Furthermore, the newly developed reaction was applied on the total synthesis of tricyclic-PGDM Methyl ester, a prostaglandin D2 metabolite of important clinical relevance that currently suffers from material supply issues. Cyclopropanol ring opening reactions have different reactivity modes. Either a metal homoenolate species or a b-keto radical species can be formed after ring opening depending on the reaction conditions applied. More specifically, hydroxycyclopropanols have been studied to access several important motifs present in an array of natural products and medicinally important molecules. The Dai group has used this strategy to access several motifs through intramolecular trapping of the homoenolate species with and without the presence of carbon monoxide to generate oxaspirolactones, THF/THP-fused bicyclic lactones, and disubstituted THF/THP heterocycles. Herein, it will be discussed the application of similar concepts to access new classes of heterocycles 4-ketovalerolactones and 3-furanones. The optimization of two reaction conditions to selectively synthesize each product starting from the same starting material was studied. Furthermore, the substrate scope, scale-up, and derivatization studies of each motif will be disclosed.

The aim of this project is based on the optimization of new route of synthesis of phenyl alkyl halides, in particular benzylic bromides that are considered versatile intermediates in organic synthesis and often employed in the preparation of bioactive materials. Though this project, we have provided an innovative method that is alternative to methodologies based on phosphorous (III) and (V) for the preparation of bromides having EWG group in β position. This procedure allowed to by-pass the methodologies based on the oxygen-based leaving group and their significant drawnbacks, such as bromide product racemisation and undesired alkene side product arising from elimination of sensitive bromides. Moreover, we have showed that the oxidative activation of sulphide via SN2 could be useful for the development of C-X bond forming reactions. We showed how alkyl bromides and chlorides could be employed for the preparation of Carbon-Oxygen bond in bioactive molecules such as API with an aryl propanamine core. For example, a full synthesis of five steps is showed for the synthesis of Atomoxetine, anti-depressant known as Strattera.

The work presented in this thesis will focus on the formation of carbocycles and N-heterocycles promoted by gold(I) catalysis. It will rely on the unique reactivity of 1,n-enyne and -diynes esters when subjected to the gold(I) complex to access compounds of potential biological interest in an atom-economical manner under mild conditions. These studies will allow the formation of complex ring structure in a single pot reaction, starting from readily accessible materials.

This thesis examines catalysis involving novel reactivity of N-heterocyclic carbenes leading to the synthesis of nitrogen and oxygen containing heterocycles.

Streptomyces bacteria use γ-butyrolactone (GBL) hormones to signal biosynthesis of natural products, many of which are useful as medicines, agricultural chemicals, and chemical tools. These GBL hormones have been the target of synthetic efforts for over a decade due to their promising potential to unlock novel natural products that can aid in the fight against cancer, fungal infections, bacterial infections, and more. However, previous syntheses of the Streptomyces coelicolor GBLs suffer from lengthy syntheses, low yields, low enantioselectivity or diastereoselectivity, or lack of diversifiability. The work described herein bypasses each of these issues. The synthesis is shorter than previous efforts, accessing the final molecules in six steps while also having high enantioselectivity, diastereoselectivity, and overall yield. In addition, work has begun to create derivatives of these natural GBLs using five-membered lactam and thiolactone cores, which could have greater stability than the traditional lactone GBL core.

Synthesis of biologically relevant compounds or compounds that probe biological entities with the purpose of creating potential drug candidates

Pincer ligands are a cornerstone of modern transition metal catalysis. An increasing interest in bimetallic catalysis motivated us to develop binucleating variants of these mononucleating ligands. Expanded variants of the PDI and PyBOX ligands were targeted, leading to the development of the Naphthyridine Diimine (“NDI”) and Naphthyridine Bisoxazoline (“NapBOX”) ligands, respectively. Metalation of NDI with appropriate metal precursors yielded Fe2, Co2 and Ni2 complexes which exhibited unique stoichiometric and catalytic reactivity. Metalation of the NapBOX ligand with nickel carboxylate salts yielded Ni2 complexes which were capable of catalyzing an asymmetric intermolecular [4+1] cycloaddition reaction between 1,1-dichloroalkene-derived vinylidenes and 1,3-dienes. Each of these processes were studied experimentally and computationally in order to understand the fundamental reactivity of organic substrates across metal-metal bonds.

The work presented in this thesis deals initially with the synthesis of rigid polyalicyclic dienes and dienophiles with pyrimidine moieties inbuilt in a rigid fashion (building BLOCKS). This work has allowed the production of a new class of ribbon molecules with precisely defined size, shape and position of the pyrimidine ring. In the second stage of the project, an assessment of their ability to participate in cycloaddition reactions as pyrimidine building BLOCK* components was investigated. 2,4-Dimethoxy-1,3-diazaanthracene (I) has acted as the pyrimidine transfer reagent for preparing building BLOCKs. The Diels-Alder adducts IV and V (Scheme I), prepared by reaction of I with norbomadiene, are new pyrimidine dienophilic BLOCKs. Both I and 2,4-dichloro-1,3-diazaanthracene (II) were active in photochemical [4π+4π] cycloaddition reactions with cyclopentadiene to form a second class of building BLOCKs VII and VIII (Scheme I). In addition, the photodimerisation of I and II was studied and structures IX-XII assigned on the basis of spectral and X-ray method. The 2,4-dichloro-photoadduct VIII is of particular importance for this work since it is easily hydrolysed (2M NaOH, 60 °C, overnight) to the corresponding uracil XIII In contrast, thermal adducts IV and V were very difficult to hydrolyse (NaOH fusion) to uracils XIV and XV (Figure I). The availability of pyrimidine BLOCKs which contain a reactive π-bond, e.g. (IV, V, VII and VIII) has enabled us to employ 3,6-di(2'-pyridyl)-s-tetrazine (XVI) and ACE (Alkene plus Cyclobutene Epoxide) coupling methods to obtain precisely functionalised ribbon molecules in a direct, convergent synthetic strategy. The synthesis of the bis-pyrimidines by coupling norbornene reagents using 3,6-di(2'-pyridyl)-s-tetrazine is illustrated in Scheme II. In the first step, s-tetrazine XVI was reacted with pyrimidine BLOCK V under basic conditions to generate the dihydropyridazine XVII. This diaza-1,3-diene was reacted with a further equivalent of V under high pressure conditions to yield the bis-pyrimidines XVIII and XIX, which were separated by radial chromatography. The same procedure was used to link pyrimiclines to other effectors by using alternative alkenes in the second step. The ACE coupling protocol is illustrated by the reaction of alkene VIII with the dimethoxynaphthalene-containing epoxide XX (Scheme III). The reaction can be conducted under thermal or photochemical conditions and is considered to proceed via 1,3-dipolar intermediate formed by ring-opening of the epoxide C-C bond of XX (See Chapter 4). Each class of coupled adduct could be hydrolysed to the corresponding uracil by using either acid (XXII) or base (XXIII) hydrolysis conditions, the choice depending on the structure of the molecule in question and its substituents. The work presented in this thesis involves a deal of new work and has been instrumental in the development of the Lego®-based BLOCK assembly protocol for ribbon molecules construction.

Neuropathic pain is a debilitating condition affecting 7-8% of the population. Current treatment options, which include anticonvulsants, antidepressants and opioids, offer minimal relief. This project was focused on the development of analgesics, which act at the N- and T-type calcium channels involved in pain transmission. Sixty-three novel compounds were rationally designed, synthesised and tested for activity using a Fluorescence Image Plate Reader bioassay. The stability of the compounds in plasma and their cytotoxic properties were assessed. The sulfonamide derivatives were identified as drug leads due to their stability in plasma, low toxicity profile and high potency for both calcium channels.

Delayed fracture healing is a major health issue involved with aging. Therefore, strategies to improve the pace of repair and prevent non-union are needed in order to improve patient outcomes and lower healthcare costs. In order to accelerate bone fracture healing noninvasively, we sought to develop a drug delivery system that could safely and effectively be used to deliver therapeutics to the site of a bone fracture. We elected to pursue the promising strategy of using small-molecule drug conjugates that deliver therapeutics to bone in an attempt to increase the efficacy and safety of drugs for treating bone-related diseases.This strategy also opened the door for new methods of administering drugs. Traditionally, administering bone anabolic agents to treat bone fractures has relied entirely on local surgical application. However, because it is so invasive, this method’s use and development has been limited. By conjugating bone anabolic agents to bone-homing molecules, bone fracture treatment can be performed through minimally invasive subcutaneous administration. The exposure of raw hydroxyapatite that occurs with a bone fracture allows these high-affinity molecules to chelate the calcium component of hydroxyapatite and localize primarily to the fracture site.Many bone-homing molecules (such as bisphosphonates and tetracycline targeting) have been developed to treat osteoporosis. However, many of these molecules have toxicity associated with them. We have found that short oligopeptides of acidic amino acids can localize to bone fractures with high selectivity and with very low toxicity compared to bisphosphonates and tetracyclines.We have also demonstrated that these molecules can be used to target peptides of all chemical classes: hydrophobic, neutral, cationic, anionic, short, and long. This ability is particularly useful because many bone anabolics are peptidic in nature. We have found that acidic oligopeptides have better persistence at the site of the fracture than bisphosphonate-targeted therapeutics. This method allows for a systemic administration of bone anabolics to treat bone fractures, which it achieves by accumulating the bone anabolic at the fracture site. It also opens the door for a new way of treating the prevalent afflictions of broken bones and the deaths associated with them.We further developed this technology by using it to deliver anabolic peptides derived from growth factors, angiogenic agents, neuropeptides, and extracellular matrix fragments. We found several promising therapeutics that accelerated the healing of bone fractures by improving the mineralization of the callus and improving the overall strength. We optimized the performance of these molecules by improving their stability, targeting ligands, linkers, dose, and dosing frequency.We also found that these therapeutics could be used to accelerate bone fracture repair even in the presence of severe comorbidities (such as diabetes and osteoporosis) that typically slow the repair process. We found that, unlike the currently approved therapeutic for fracture healing (BMP2), our therapeutics improved functionality and reduced pain in addition to strengthening the bone. These optimized targeted bone anabolics were not only effective at healing bone fractures but they also demonstrated that they could be used to speed up spinal fusion. Additionally, we demonstrated that acidic oligopeptides have potential to be used to treat other bone diseases with damaged bone.With these targeted therapeutics, we no longer have to limit bone fracture healing to casts or invasive surgeries. Rather, we can apply these promising therapeutics that can be administered non-invasively to augment existing orthopedic practices. As these therapeutics move into clinical development, we anticipate that they will be able to reduce the immobilization time that is the source of so many of the deadly complications associated with bone fracture healing, particularly in the elderly.

Niemann-Pick Type C (NPC) disease is a rare lysosomal storage disorder that occurs in about 1/89,000 to 1/120,000 live births and is characterized by an aberrant accumulation of cholesterol within the late endosome/lysosome of cells. Symptoms of this disease include splenomegaly, neurological deterioration, and often death before adulthood. Mutations in the membrane bound NPC1 or luminal NPC2 proteins lead to a decrease in cholesterol efflux within the lysosomes by which excess cholesterol crystallizes within membranes resulting in cell death. It has been demonstrated that increasing the amount of the lysosomal specific phospholipid Bis(monoacylglycerol)phosphate (BMP), also known as Lysobisphosphatidic acid (LBPA), in cells increases the rate of cholesterol transport in npc1-/- cells, but not in npc2-/- cells, indicating a strong synergistic relationship between the NPC2 protein and the lysosomal membranes. Increasing the amount of phosphatidyl glycerol (PG), a hypothesized precursor to BMP, has also shown an increase in cholesterol egress. While it is hypothesized that the increase in cholesterol clearance in the latter is due to the biosynthesis of LBPA from PG, there is no study to directly confirm this phenomenon. Therefore, we set out to synthesize diastereochemically pure PG containing isotopically labeled oleyl acyl chains to examine LBPA levels using lipidomic analysis of npc1-/- cells post treatment with PG. Initially, efforts centered around the use of phosphoramidite methodology commonly encountered in DNA oligonucleotide synthesis. While this route proved to be successful in making PG in modest yield (52%), reproducibility of this route with consistent yields was hindered due to the use of tetrabutylammonium fluoride (TBAF) in the final global deprotection step. Thus, we set out to discover a phosphorylated intermediate that did not require TBAF in the final step or contain easily hydrolysable protecting groups. It was discovered that H-phosphonate methodology using diphenyl phosphite for phosphorylation of the glycerol headgroup and backbone proved to be robust enough for PG synthesis. In this strategy, PG can be isolated in two steps from the final protected intermediate by first oxidizing the H-phosphonate from PIII to PV followed by deprotection of the glycerol head group under acidic conditions. Additionally, the H-phosphonate strategy also allowed us to omit headgroup modification prior to phosphorylation which reduced the number of synthetic steps from 11 steps to 7 steps. As a result, we were able to synthesize diastereochemically pure PG more consistently than the previous route in 75% yield. The route was further modified further to incorporate asymmetric acyl chains allowing the selective installation of a labeled acyl chain on the sn-1 or sn-2 positions of the phosphoglycerol backbone. The results from the lipidomic experiments indicate that increased LBPA concentrations in cells rise upon incubation with labeled PG. Additionally, increases in lyso-PG and acyl-PG are also observed leading to several hypotheses on how LBPA might be synthesized from PG. Future directions on this effort include identification of phospholipid species made from PG containing asymmetrically labeled acyl chains. Synthesis of photoaffinity labeled PG is also underway to determine the protein partners involved in PG metabolism.

Multidrug resistance is a major issue in treatment and eradication of diseases. There are many mechanisms by which pathogens develop multi drug resistance. Here we focus on the ability of pathogens to evade drug treatment by establishing multi drug resistant reservoirs. In the case of HIV, the virus is able to evade drug treatment and forms both latent and active replicating reservoirs throughout the body. In the case of many bacterial pathogens, multidrug resistance reservoirs are established within mammalian cells, such as macrophages. Many classes of antibiotics are unable to penetrate mammalian cells, making intracellular bacteria difficult to clearPreviously our research group has developed a Trojan horse strategy to deliver antivirals to HIV cellular reservoirs. Ester based prodrug dimers of abacavir, a reverse transcriptase inhibitor, acted to both inhibit efflux transporters at the BBB and revert to the monomeric therapy in the reducing environments of the cell. Herein we present a new group of sterically hindered carbonate based disulfide linkers that shows improved payload delivery of abacavir and maintain the stability of prodrug molecules towards hydrolysis. We employed these linker molecules to synthesize prodrug dimers of the HIV latency reversal agent prostratin with the hope of targeting latent HIV reservoirs. Payload release studies as well as latency reversal experiments with a latently infected T-helper cell model confirmed that the prostratin carbonate homodimers (ProS2Me2 and ProS2Me4) were able to revert to monomeric prostratin and reverse HIV latency. We next sought to synthesize a prostrain-protease inhibitor heterodimer. While our initial study of a prostratin-lopinavir heterodimer employing this linker strategy (ProLpvS2Me2) did not show significant HIV latency reversal activity, we hope to expand our heterodimer studies to achieve dual therapeutic molecules that can both reverse HIV latency and deliver antivirals to HIV reservoirs.In order to combat intracellular bacteria our group has focused on development of a novel class of cell penetrating peptides with intrinsic broad spectrum antimicrobial activity that are based on a repeating amino acid triad which forms a cationic amphiphilic polyproline helix (CAPH) scaffold. The first member of this class, P14LRR, exhibited clearance of intracellular bacteria and concentration dependent co-localization within mammalian cells. In efforts to optimize antimicrobial activity we have expanded the CAPHs library by adjusting the chain length between the proline backbone and the guanadinium groups of the cationic amino acids. The first peptide from this expanded library, P14GAP showed much greater cell penetration and antimicrobial activity against a wide range of pathogenic bacteria. However, P14GAP also showed greater toxicity towards mammalian cells, increased hemolysis, and greater membrane binding with mammalian cells as compared to P14LRR. Here we describe the design and synthesis of P14GAP-C1, which contains a methylene between the proline backbone and the guanadinium group. This new analogue decreased the hemolysis activity as compared to P14GAP, although similar membrane binding with mammalian cells was observed. This improvement in hemolysis activity and a slight improvement in cell viability may allow us to use higher concentrations of peptide to treat multidrug resistant bacterial infections.

This document is the culmination of four years of research facilitated through the graduate program in the School of Materials Engineering as part of the Purdue Energetics Research center. It includes four manuscripts and one review that were peer-reviewed and published in the journals: Chemistry Open, Organic Letters, RSC Advances, Journal of Inorganic and General Chemistry and Engineering. It also includes work with annulated systems and a new oxidizer for propellants, that will be submitted for publication to peer-reviewed journals in the near future. Discussed here is a brief history of energetic materials as a field, main requirements of energetic materials based on their specific applications, methods of obtaining those requirements, and characterization of energetic materials. Specific topics include: 1,2,3-triazoles as energetic materials, zwitterionic energetic materials, improved synthesis of an energetic material, energetic salts of a fused-ring system, a new oxidizer for propellants, pentazoles, and the future of high-nitrogen energetic materials.

Neuropathic pain is a type of chronic pain that responds poorly to traditional pain therapies. We worked on developing new molecules capable of blocking calcium channels involved in the transmission of these pain signals. Advanced molecular modelling was used to aid in the design of these compounds; they were then produced using efficient and flexible synthetic routes. A series of highly promising drug candidates was thus discovered, with high activity against the target, low clearance in blood and metabolic stability assays, and well-balanced physicochemical properties.

The aim of this thesis is to enable incorporation of a dually-functionalized molecular apparatus that can be assembled within a nanoparticle for selective and controlled release of both payloads in the acidic environment of a solid tumour. For proof of concept, a variety of acylhydrazone-based dual release molecular frameworks are designed and synthesized, and their hydrolytic stability are tested at various pH values. We successfully obtain a diverse set of novel linkers with different scaffolds that can undergo rapid cleavage and dual payload release in fine increments from pH 4.5 all the way to pH 7.4.

Breast cancer is a commonly diagnosed form of cancer. A person is 6-times more likely to develop breast cancer if they have inherited mutations to the BRCA-1 gene. One potential means of preventing this is by inhibiting a protein called 53BP1. This work details the synthesis and testing of over 1000 potential drug-like compounds against 53BP1. It also demonstrates one of the first applications of a novel workflow hoped to expedite drug discovery called REFiL – the Rapid Elaboration of Fragments into Leads. In under 3 years, 7 promising leads were identified against this potential new anti-cancer target.

This PhD thesis describes the use of hypervalent sulfur(IV) for the development of new synthetic methodologies to prepare much sought alkyl bromides and fluorides.In order to frame the context of the work and rationalise the results obtained we present, in the first chapter of this thesis, a literature review of sulfur(IV) and (VI) hypervalent compounds detailing their preparation and application in organic synthesis.In the second chapter of this thesis, we describe a novel procedure to prepare alkyl fluorides in up to 77% isolated yields and 35% enantiomeric excess. The reaction made use of electrophilic fluorinating reagent N-fluorobenzenesulfonimide (NFSI) to achieve desulfurative fluorination of alkyl sulfides under mild conditions and in short (10-120 minutes) reaction times. Moreover, the presence of hypervalent sulfur(IV) intermediates was observed via NMR analysis.In the third chapter of this thesis, we report other means to achieve enantioselective desulfurative fluorination of chiral thia-Michael derived alkyl sulfides. Though no conditions suitable for the production of highly enantioenriched alkyl fluorides have been found, three different sets of fluorinating conditions have been identified for the efficient production of thia-Michael derived alkyl fluorides in excellent isolated yields (up to 92% yield) and short reaction times. Moreover, an unexpected and unprecedented methodology to form carbon–carbon bonds has been discovered.In the fourth and final chapter of the thesis, we present the first example of an on-water enantiospecific synthesis of alkyl bromides. This procedure allowed the conversion of secondary activated alkyl sulfides to benzylic alkyl bromides, in 80-99% isolated yields and excellent enantioselectivity (up to 92% ee; 94% es). The conditions identified required no temperature control, made use of no solvent and did not employ liquid-liquid organic extraction on a multigram-scale.

Ammonia is future fuel and required electrochemical systems to support, i. e. water electrolyser and nitrogen reduction reaction (NRR) cell. That requests active and sustainable catalyst to operate the process at required conditions. So far, the composite of cobalt- bismuth-tin oxide has been shown promising in term of stability for oxidation side of the water electrolyser. And lithium supported NRR process is outperformed and delivers better rate and selectivity of ammonia production compared to other approaches.

Zaragozic acids (ZAs) are a family of fungal natural products exhibiting strong inhibition of squalene synthase (SS), the first enzyme involved in the synthesis of cholesterol. This thesis examined new synthetic approaches to construct the framework of ZAs and the marine-derived thermochromic heterocycle polyandrocarpamide D.

This thesis outlines two key approaches to antimicrobial synthesis. The first is through the attempts at the synthesis of analogues of a known antibiotic, virginiamycin MII. The second is through reaction design targeted towards a natural product with antimicrobial activity, hisunic acid. The reaction design revolves around the application of organocatalysis, specifically N-heterocyclic carbenes.

Acute myeloid leukemia (AML) is a type of bone marrow cancer, with a low survival rate, and leukemia stem cells (LSC) is a major factor in the development of AML. Histone acetyltransferase (HAT) enzymes are essential for a wide range of normal cellular processes, including cell proliferation and DNA replication. Specifically, two HAT enzymes, MOZ and HBO1, have been identified as critical regulators for the maintenance of LSC. My project is focused on the synthesis, and biological testing of small drug molecules to inhibit MOZ and HBO1 as epigenetic targets, as a potential treatment for AML and other chronic diseases.

The aim of the research presented in this thesis was to study the self-assembly of amphiphilic block copolymers in continuous flow and, to create standardized parameters to tune particle shape and size. The thesis focuses on 2 main components: the creation of a reliable and simple flow platform for the self-assembly process, and the investigation of the effects certain variables will have on the self-assembly process in flow. In addition, the process was applied to a bio-imaging topic with the delivery of a dye to show the validity and versatility of the setup.

Positron emission tomography (PET) is a sensitive nuclear imaging technique that can highlight physiological and biochemical processes in vivo. If we extend the current utility of PET, we can both diagnose disease earlier, and improve our understanding of disease evolution. This thesis represents an investigation into PET applications in HIV and cancer, with new targeting vectors, and with novel chemical scaffolds.

The use of silicon-based reagents in organic synthesis has received significant attention and has been an ever-growing area of focus in recent years. Since Hosami and Sakurai first described the fluoride-initiated reaction of allytrimethylsilane to aldehydes, there have been several advancements in the field. Alternative sources of silicon activation have been developed such as tBu-P4 and proazaphosphotrane bases as well as work completed by my research group into the tetrabutylammonium controlled addition to aldehydes under mild conditions for a wide variety of substituted trimethylsilanes. It was recognized that these reaction conditions could be further developed through the tailoring of tetrabutylammonium activators for use with specific trimethylsilane substrates, to provide mild and efficient routes to β-hydroxy esters and α,β-unsaturated esters. Conditions for tetrabutylammonium controlled addition and olefination reactions of ethyl 2-(trimethylsilyl)acetate were developed under both batch and continuous flow conditions, employing catalytic amounts of activator at ambient temperature. The synthesis of a diverse range of β-hydroxy esters was achieved through the addition reactions of various aromatic, heteroaromatic, aliphatic aldehydes and ketones to ethyl 2-(trimethylsilyl)acetate using of catalytic amounts of Bu4NOAc. In parallel, conditions for the batch synthesis of the corresponding α,β-unsaturated esters using catalytic amounts of Bu4NOTMS were developed by another member of my research group. A stepwise reaction pathway to the α,β-unsaturated ester was demonstrated via formation of the silylated β-hydroxy ester and subsequent elimination reaction. The use of a specific tetrabutyl ammonium activator was key to the desired product formation. The weaker acetate activator was unable to effect the elimination, whereas it’s trimethylsilyloxide counterpart effectively completed the elimination reaction to provide α,β-unsaturated esters. In both cases, the tetrabutylammonium counterion was shown to play a vital role in the effectiveness of the reaction. The synthesis of these β-hydroxy esters and α,β-unsaturated esters were achieved using mild conditions without the specialized precautions associated with other organometallic synthesis. To further develop these conditions, the reactions were transferred from traditional batch style synthesis methods to continuous flow. The time required to achieve full conversion was significantly reduced for both addition and olefination reactions, from the one hour required for batch to one minute for continuous flow, while maintaining the employment of catalytic amounts of activator and the use of ambient temperature. Teaming this reduction in reaction time with the improved process safety that flow chemistry offers, highlights the significant benefits of adapting pharmaceutical synthesis from batch to continuous flow.

This thesis aims to better understand at the cellular level the behaviour of beta-blockers, which decrease the heart rate and are used daily in the treatment of cardiovascular diseases and anxiety. Some medicines in this class can both decrease and increase the heart rate depending on the amount used. To study this, we developed new molecules based on a known beta-blocker with this effect and evaluated their behaviour in cell lines. We identified molecular features that modulate this peculiar effect. In future, the understanding of this behaviour may contribute to an improved profile of beta-blockers leading to less side effects.

Students studying organic chemistry often have difficulty applying prior knowledge from general chemistry in their thinking about organic reaction mechanisms. In the United States, electrophilic aromatic substitution (EAS) mechanisms can be taught towards the end in a second-semester course of organic chemistry, providing students with almost two-semesters' worth of experience with organic chemistry reactions before solving problems on synthesis of substituted aromatic compounds.Little research has been done on how, or if, instructors consider their students' prior knowledge or understanding of these concepts in EAS in their teaching activities. The purpose of this study was to describe how students reason through EAS synthesis problems and to identify concepts or gaps in understanding that inhibit students from successfully solving these types of problems. Participants were interviewed using a think-aloud protocol in which they were asked to describe the reactants and mechanisms necessary to synthesize di- and tri-substituted benzenes using EAS. The interviews were transcribed and analyzed using a qualitative inquiry approach and the data interpreted in terms of the ACS Examinations Institute's Anchoring Concepts Content Maps for general and organic chemistry.The findings from this study indicated that while students correctly applied their knowledge of substituent effects to solve these types of problems, they relied on rote-memorization of these effects, resulting in inflexibility when applying them to novel situations. Additionally, students exhibited gaps in understanding of fundamental concepts in resonance theory and Lewis structures, differentiating and utilizing Friedel-Crafts reactions, and recognizing when to use oxidation/reduction reactions in their syntheses.Another component of this study focused on instructors of organic chemistry from a range of institutions in the United States. The purpose of this study was to describe how organic chemistry instructors perceived their students' reasoning about these types of problems, and to describe the characteristics of each instructors' topic-specific pedagogical content knowledge (TS-PCK) and the three general knowledge domains (GKDs) instructors draw upon to inform their TS-PCK. These knowledge domains are knowledge of students, subject matter knowledge, and pedagogical knowledge. These participants were remotely-interviewed using a think-aloud protocol in which they were asked to describe their classroom practices and teaching strategies when teaching EAS, and to describe how they would synthesize the same aromatic compounds as their students (a selection of which were interviewed in the previous study). Participants were asked to consider how their students would approach the syntheses and to specify what parts of the syntheses their students would find challenging, and why. The interviews were transcribed and analyzed using a qualitative inquiry approach. The findings from this study indicated that the instructors were aware of their students' tendencies to use rote-memorization without understanding in the course, but there was still a mis-alignment between how instructors' perceived their students' reasoning through EAS synthesis problems and the reasoning the students actually used. The instructors believed that their students would only rely on the directing effects of substituents in their reasoning, but the students demonstrated they were aware of the activating and deactivating effects too. Additionally, instructors believed their students would not be hindered by an understanding of resonance or Lewis structures in their syntheses.Finally, there are some recommendations for addressing the students' propensity for rote-memorization by providing a visual way to represent directing and activating/deactivating effects of substituents using electrostatic potential maps. There are also suggestions for further building on this work.

Infectious diseases caused by bacteria, fungi, and plasmodium parasites are a huge global health problem which ultimately leads to millions of deaths annually. The emergence of strains that exhibit resistance to nearly every class of antimicrobial agents, and the inability to keep up with these resistance trends has brought to the fore the need for new therapeutic agents (antibacterial, antifungal, and antimalarial) with novel scaffolds and functionalities capable of targeting microbial resistance. A novel class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically relevant strains of methicillin-resistant Staphylococcus aureus (MRSA). Synthesis, structure-activity relationship (SAR) studies, and biological investigations have led to lead molecules that exhibit anti-MRSA inhibitory activity as low as 1 – 2 µM. The most potent compounds have also been shown to have low toxicity against mammalian cells and exhibit in vivo efficacy in MRSA skin and thigh infection mouse models. The novel aryl isonitriles have also been evaluated for antifungal activity. This study examines the SAR of aryl isonitrile compounds and showed the isonitriles as compounds that exhibit broad spectrum antifungal activity against species of Candida and Cryptococcus. The most potent derivatives are capable of inhibiting growth of these pathogens at concentrations as low as 0.5 µM. Notably, the most active compounds exhibit excellent safety profile and are non-toxic to mammalian cells up to 256 µM. Beyond the antibacterial and antifungal activities, structure-antimalarial relationship analysis of over 40 novel aryl isonitrile compounds has established the importance of the isonitrile functionality as an important moiety for antimalarial activity. Of the many isonitrile compounds exhibiting potent antimalarial activity, two have emerged as leads with activity comparable to that of Artemisinin. The SAR details presented in this study will prove essential for the development new aryl isonitrile analogues to advance them to the next step in the antimalarial drug discovery process. 17-nor-Excelsinidine, a zwitterion monoterpene indole alkaloid isolated from Alstonia scholaris is a subject of synthetic scrutiny. This is primarily due to its intriguing chemical structure which includes a bridged bicyclic ammonium moiety, and its anti-adenovirus and anti-HSV activity. Herein we describe a six-step total synthesis of (±)-17-nor-Excelsinidine from tryptamine. Key to the success of this synthesis is the use of palladium-catalyzed carbonylative heck lactamization methodology which built the 6, 7-membered ring lactam in one step. The resulting pentacyclic product, beyond facilitating the easy access to (±)-17-nor-Excelsinidine, could also serve as a precursor to other related indole alkaloids.

Refereed/Peer-reviewed