Master of Science / Department of Chemistry / Sundeep Rayat / Compounds containing the tetrazole scaffold have wide variety of applications in medicine, food industry, automobile industry, photography, agriculture. As a result, the structure and reactivity of these compounds have been studied. However, the related tetrazolethione scaffold has not been studied well. In our work presented in Chapter-1 (part-1), the synthesis, photochemical properties and reactivities of 1,4-disubstituted tetrazolethione analogs 20a-d are described. The solvent effects on the photochemistry of compounds are discussed and; the rates and quantum yields for the photodecomposition of compounds are documented. The photodecomposition products for the photolysis of 20a-d were analyzed by LCMS, GCMS and NMR spectroscopy; the results pertaining to their identification are also reported. Further, the multiphoton excitation of THF solution of 1-methyl-4-(4-nitrophenyl)-1H-tetrazol-5(4H)-thione 20d with Ti: Sapphire laser was also performed; however, the experiment was not successful. In Chapter-2 (part-1), the cytoxicity of the 1-methyl-4-(4-chlorophenyl)-1H-tetrazol-5(4H)-thione 20c against human breast cancer cell is documented. MTT assays were performed for a time dependent study of the cytoxicity. In part-2 which consists of Chapter-3, the synthesis of 2-(2-phenylimino)vinyl)benzonitirle is described. This was as a step towards our laboratory's goal of synthesizing a series of mono-, di- and tri- azaenyne-allenes and studying their Myers-Saito and Schmittel cyclizations. In future, if our cyclization studies are successful, these cyclizations could be employed for synthesis of heteroaromatic rings found in many compounds of biological importance.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / (+)-Myriceric acid A, [(+)-1.1], is a natural product isolated in 0.01% yield from the southern bayberry, myrica cerifera twigs. It is a specific ETA receptor antagonist because it selectively inhibits the endothelin-1 (ET-1) induced increase in [Ca2+] (IC50 = 11 + 2 nM) and antagonizes the binding of ET-1 (Ki = 66 + 15 nM), in rat aortic smooth muscle cells. ET-1 is a potent vasoconstrictor peptide released by the vascular endothelial cell. Over production of this peptide causes vasospasm, which may lead to heart attack, stroke, pulmonary hypertension, and congestive heart failure. My research involved the development of a total synthesis of (+)-myriceric acid A. This is a triterpenoid compound that has five six-member rings, seven stereo-centers, a carboxylic acid group, and a trans-caffeoyl ester side chain. The synthesis was planned to be accomplished by adding the D and E rings to the known ABC ring compound (4a'S,4b'R,8a'R)-1',1',4a',8a'-tetramethyldecahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthren]-8'(3'H)-one [(-)-2.1]. Many model studies, both convergent and linear syntheses, were conducted to determine the best approach to construct the D and E rings. From these studies it was determined that a linear synthesis was best. After the ABCD ring compound (4aR,4bR,6aR,10bR)-1,1,4a,10b-tetramethyl-4,4a,4b,5,6,6a,7,8,10b,11,12,12a-dodecahydro-1H-spiro[chrysene-2,2'-[1,3]dioxolan]-9(3H)-one [(-)-3.41a] was synthesized, several approaches were investigated for the functionalization of the D ring. The best method turned out to be one in which the C14 position of 3.41a was functionalized by a Michael addition of a nitrile group. Conversion of the nitrile to the aldehyde proved to be problematic, but was overcome by the formation of an interesting cyclic hemiiminal which hydrolyzed cleanly to the aldehyde (4aR,4bR,6aR,10aS,10bR,12aR)-1,1,4a,10b-tetramethyl-9-oxohexadecahydro-1H-spiro[chrysene-2,2'-[1,3]dioxolane]-10a-carbaldehyde (4.22) when treated with acid. Herein, the studies that led to the tetra-cyclic aldehyde 4.22, a key intermediate for the synthesis of (+)-myriceric acid A, will be discussed.

Doctor of Philosophy / Department of Chemistry / Stefan Kraft / In the present study, the rescorcin[4]arenes decorated with an alternating arrangement of pyridinium and sulfonate moieties were synthesized to establish a molecular quadrupole. These rescorcin[4]arenes are capable of undergoing conformational changes from a ‘collapsed’ to ‘open’ state. The stability of the two state are controlled by the polarity of the solvent environment. The electrostatic interactions between pyridinium and sulfonates enforced a ‘quadrupolar collapse’ in solvents such as chloroform. While these interactions are disrupted in dimethylsulfoxide. A major synthetic challenge was functionalizing the resorcin[4]arene in a positive/negative/positve/negative pattern was successfully addressed. Comparison to dipolar resorcin[4]arene were undertaken to establish a quantitative measurement of the quadrupolar forces and to address the question of cooperatively provided addition attraction beyond two dipoles. A,C-functionalized-bis sulfonate resorcin[4]arenes and A,C function bis-pyridinium resocin[4]arenes were synthesized independently. Combining these dicationic and dianionic moieties provided an interdigitating dimeric unit with overall quadrupolar charge distribution. Disruption of the quadrupolar salt bridges in CDCl[subscript]3 was accomplished through the addition of DMSO or through dilution. DeltaG[superscript]o, DeltaH[superscript]o, and DeltaS[superscript]o have been determined for the dimer formation. Addition of pyridinium salts led to a disruption of the dimeric capsule. Host-guest binding studies established attractive binding to CS[superscript]2. Larger guests such as toluene, diiodobenzene, dicynanobenzene could not be encapsulated.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first section of this thesis deals with the synthesis of substituted quinolines and its bioactivities against gap junction. Cancer cells are characterized by down regulated or altered gap junction intercellular communication (GJIC) activities; enhancement of GJIC would provide a pathway for the delivery of anticancer drugs. Our computational studies using Autodock found binding interactions between gap junction channels and substituted quionlines (code name PQs). Thus, a serial of PQ compounds were synthesized and their activities against GJIC were tested. Among these synthesized PQs, 6-Methoxy-8-[(3-aminopropyl) amino]-4- methyl-5-(3-trifluoromethyl- phenyloxy)quinoline (PQ1) can specifically enhance GJIC activity of T47D cells without affecting the normal MECs. The PQ1 induced apoptosis can spread throughout the gap juctions, consequently cause the decrease of cell viability and colony growth. PQ1 can attenuate tumor growth of xenograft tumors in Nu/Nu mice. Compound 7 (code PQ11) which has an IC50 of 15.6nM against T47D cancer cell, is a promising candidate for further pharmacological studies. The second section of this thesis deals with the synthesis and anticancer bioactivities of PEG-PEI based nanogels. Nanogels were synthesized, encapsulated with anticancer drugs, and loaded to stem cells. Stem cells can target at the cancer cell and release the nanogel and anticancer drug to kill the cancer cell. The nontoxic PEG-PEI nanogel which can be loaded to stem cells was successfully synthesized by doubly treatment of PEI with activated PEG. Based on this nontoxic nanogel, two other types of nanogels were synthesized. In one type of nanogel, an anticancer drug, SN38 was modified and attached to the nontoxic nanogel via a tetra-peptide linker. This tetra peptide can be recognized and cut by legumain, a protein that highly over expressed in many tumors, to release the drug to tumors. In the other type of nanogel, straptavidin was attached to the nanogel which can bind to biotin and recognized by tumor. The result indicated this type of nanogel can be loaded to stem cells within 15 minutes.

Doctor of Philosophy / Department of Chemistry / Stefan Kraft / Highly toxic aromatic halogenated compounds such as PCB’s, PCDF’s and PCDD’s act as persistent organic pollutants and can bio-accumulate. These compounds are highly stable to oxidation, reduction and thermal degradation. Current remediation technologies are expensive and can cause the formation of even more toxic byproducts. It is clear that an environmentally friendly and inexpensive remediation technology is required. Our goal was the synthesis of dehalogenation catalysts incorporating aromatic side arms for the pre-concentration of the substrates to the catalysts. We envisioned that aromatic side arms would allow the aggregation of catalyst and substrate to form a pre-complex that would enhance rates of dehalogenation. Rapid and stereochemically predictable synthesis of N and C functionalized nickel cyclam complexes were a priority for this project. Synthesis of N-functionalized cyclam molecules and subsequent metal incorporation proceeds smoothly to form trans(III) nickel cyclam complexes. However longer reaction times, initiation periods and short catalyst lifetimes made these complexes unsuitable for long-term study. Cyclization of dipeptides and tetrapeptides using a metal template in basic conditions led to the formation of cyclopeptide nickel complexes with stereochemistry retained from the peptide precursors. Free cyclopeptides could be isolated from the nickel complexes by treatment with HCl. Cyclopeptides are reduced to the cyclam molecules via a LAH reduction in low to moderate yields. Nickel incorporation into the cyclam molecules produced C-functionalized nickel catalysts with stereochemical integrity maintained throughout the synthesis. Intermolecular CH-π interactions can be seen in the solid state for the nickel cyclam complexes with aromatic side arms. Reduction data show that the C-functionalized catalysts do not show improved rates of reduction for several aromatic substrates but small rate enhancements are observed for the reduction of chloronaphthalene over the unfunctionalized catalyst.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / The directed-assembly of small molecular building-blocks into discrete supermolecules or extended networks through non-covalent intermolecular interactions is an on-going challenge in the field of crystal engineering. This synthetic challenge may be overcome by identifying or establishing a hierarchy of intermolecular interactions which, in turn, may facilitate a modular supramolecular assembly process producing final products in high yields. A family of three 3-pyridine/amino-pyrimidine supramolecular reactants (SR’s) was prepared and allowed to react with aromatic carboxylic acids producing nine 1:1 molecular co-crystals and four 1:1 ionic salts through heteromeric O-H···N/N-H···O or charge-assisted N–H+···O-/N–H···O- hydrogen bonds with the amino-pyrimidine binding site. We introduced a Q-value, based on AM1 calculations, to show that the amino-pyrimidine moiety is a superior hydrogen-bond acceptor for an incoming carboxylic acid. The amino-pyrimidine/carboxylic acid synthon resulted 13/13 times (100 % yield) even in the presence of other potentially disruptive intermolecular interactions. However, reacting a 4-pyridine/amino-pyrimidine SR and a carboxylic acid in a 1:2 ratio, resulted in structures containing both acid/amino-pyrimidine and acid/pyridine synthons. The same family of pyridine/amino-pyrimidine SR’s were allowed to react with halogentated benzoic acids in which the amino-pyrimidine/carboxylic acid synthon formed 7/7 times (100 % yield) and halogen bonds (N···I or N···Br) extended the SR/acid dimers into polymeric networks 4/7 times (57 %). These results were rationalized through a hierarchial view of intermolecular interactions consisting of hydrogen and halogen bonds. Four bifunctional 3-pyridine/amino-pyrimidine or amino-pyridine SR’s were reacted with neutral metal complexes producing thirteen crystal structures in which the pyridyl moiety coordinates to the metal center 13/13 times (100 % yield) and amino-pyrimidine···amino-pyrimidine hydrogen bonds link the neighboring metal-ligand complexes 10/13 times (77 % yield) into 1-D or 2-D extended architectures. Finally, we synthesized and characterized a series of tetra-substituted hydrogen bond donor and acceptor functionalized, i.e. pyridyl, amino-pyridine, carboxylic acid, resorcinarene-based cavitands forming deep-walled cavitands through amino-pyridine···carboxylic acid heteromeric synthons and a heterodimeric molecular capsule through pyridyl···carboxylic acid hydrogen bonds. The heterodimeric capsule is only one of three, of its type, characterized crystallographically.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first part of this thesis deals with the syntheses of ovalicin and its analogues. Ovalicin inhibits the endothelial cell proliferation. Apart from being anti-angiogenic it also exhibits antibiotic, antitumor, and immunosuppressive properties. Unlike other syntheses, we started with an acyclic compound, ethyl propiolate (1.66). Our flexible route towards the synthesis used intramolecular Heck cyclization reaction to construct an appropriately functionalized 3-methylene-6-(tert-butyldimethylsilyloxy)cyclohexene (1.63) from 1.66 in four steps. A number of synthetic analogues were synthesized via this strategy. Upon selective epoxidation and dihydroxylation of 1.63, a mixture of diols (3S*,4R*,5S*,6S*)-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octane-4,5-diol (1.107) and (3S*,4S*,5R*,6R*)-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octane-4,5-diol (1.108) were obtained. Subsequent functional group transformations of diols 1.107 and 1.108 gave ketones (3S*,4S*,5R*,6R*)-6-(tert-butyldimethylsilyloxy)-5-methoxy-1-oxaspiro[2.5]octan-4-one (1.112) and (3S*,5S*,6S*)-6-(tert-butyldimethylsilyloxy)-5-methoxy-1-oxaspiro[2.5]octan -4-one (1.117). Addition of vinyl lithium to the ketones followed by functional group transformation gave ovalicin analogues. Several intermediates were subjected to biological activity test for inhibition of growth of T. brucei. Our synthetic efforts towards the synthesis of ovalicin are discussed. The second part of my thesis deals with the synthesis of different tricyclic pyrone (TP) analogues which inhibit the aggregation of Aβ peptides. Alzhemier’s disease (AD) is caused by accumulation of fibrillar amyloid deposits in the AD brain. We synthesized a series of tricyclic pyrone derivatives and evaluated their counteraction on amyloid toxicity. TP analogue, (5aS,7S)-7-[(1R) and (1S)-2-(N3-adenyl)-1-methylethyl]-3-methyl-1H,7H-5a,6,8,9-tetrahyro-1-oxopyranol[4,3 -b] [1] benzopyran (CP2) is nontoxic, small and permeable molecule prevents the death of human neuroblastoma MC65 cells that conditionally expressed SβC gene. We further found that CP2 ameliorates the toxicity and inhibits the formation of Aβ oligomeric complexes. Binding studies using surface plasma resonance and atomic force microscopy studies suggest that CP2 permeates into the cells and interacts with Aβ peptides and inhibits the Aβ oligomerization. To understand the mechanism of Aβ aggregation and toxicity, CP2 and its derivatives are synthesized to evaluate their action. The key intermediate in the synthesis of CP2 is (5aS*,7S*)-7-[(1R*) and (1S*)-2-bromo-1-methylethyl]-3-methyl-1H,7H-5a,6,8,9-tetrahyro-1-oxopyranol[4,3-b][1] benzopyran (2.9), which in turn can be prepared from our previously reported method. Our aim is to synthesize a series of compounds and investigate the biological activities of different TP analogues.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The description of this thesis is divided into three chapters following the chronological events of my research development. In chapter one, a series of new 1,4-anthracenediones were synthesized via functionalizations of the methyl side chain of 6-methyl-1,4-anthracenedione. The new 1,4-anthracenediones were found to exhibit potent cytotoxic activities against human L1210 leukemic and HL-60 cell lines. A key intermediate, 6-bromomethyl-1,4- anthracenedione (1.44), was first synthesized through a sequence of reactions including a double Friedel-Crafts reaction, reductive quinone formation, and selective benzylic bromination. The bromide (1.44) was further converted to other 1,4-anthracenediones via hydrolysis, subsequent oxidation, and reductive amination or nucleophilic substitution. Chapter two deals with a continuous research project aiming at macropolycyclic cyclodecitycene or [10]beltene derivative using Diels-Alder reaction as the key strategy for cyclization. A tetraene, (4aR,5R,7S,7aS,11aR,12R,14S,14aR)-5,7,12,14-tetrahydroxy- 2,3,9,10-tetramethylene-1,4,4a,5,6,7,7a,8,11,11a,12,13,14,14a-tetradecahydro-6,13-obenzenopentacene (2.51), was synthesized by following previous work from this laboratory. Unfortunately, the Diels-Alder reaction of tetraene 2.51 with triptycene bisquinone showed predominantly polymerization over intramolecular cyclization. The use of double activated quinone such as 1,4,5,8-naphthodiquinone (2.64) and 1,2,4,5- tetraethoxycarbonyl-1,4-benzoquinone (2.70) as dienophiles gave monoadducts 2.67 and 2.71 respectively. However, they both failed to cyclize under high dilution conditions at elevated temperature, which may be rationalized by chair conformations adopted in six membered rings causing unfavorable twist for intramolecular cylization. Further study showed tetraene 2.51 underwent an unexpected furan ring forming reaction. In chapter three, an unprecedented substituted cyclododeciptycene, 2,4,6,8,10,12,14,16,18,20,22,24-dodecahydro-9,11,21,23-tetramethoxy-(2,14:4,16:6,18:8, 20:10,22:12,24)-hexa(o-benzeno)-[12]cyclacene-1,3,5,7,13,14,17,19-octaone (3.138), was successfully synthesized based on a successful intramolecular Diels-Alder reaction, which was developed from the above [10]beltene project and previously reported literature work. A series of all cis-iptycenequinones were synthesized as bisdienophile building blocks from a sequence of Diels-Alder reactions, separation of individual Diels- Alder adducts, enolization, and oxidative demethoxylation. It was found that each Diels- Alder adduct isomer shows distinguish [superscript]1HNMR signals inherent to its structure. The characteristic [superscript]1HNMR signals allow the identification of the structures of iptycenequinones derived from the above reactions. A bisdimethoxyanthracene, 6,8,15,17-tetramethoxy-7,16-dihydro-7,16-(o-benzeno)heptacene (3.56), was synthesized as bisdiene building block, which reacted with cis,cis-heptiptycene tetraquinone (3.23). The cycloadduct was transformed to cyclododeciptycene 3.138, whose structure was firmly established by a single-crystal X-ray analysis.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / The ability to predict and control molecular arrangements without compromising the individual molecules themselves still remains an important goal in supramolecular chemistry. This can be accomplished by establishing a hierarchy of intermolecular interactions such as hydrogen and halogen bond, which may facilitate supramolecular assembly processes. Several acetaminopyridine/acetaminomethylpyridine supramolecular reactants (SR’s) were prepared with aliphatic carboxylic acids in order to determine patterns of molecular recognition preferences of the N-H moiety. The results obtained revealed the formation of molecular cocrystals through heteromeric O-H…N/N-H…O hydrogen bonds with the acetaminopyridine/acetaminomethylpyridine binding site. Furthermore, the SR’s also reacted with metal ions resulting in robust 1D and 2D metal-containing architectures. A series of pyridyl/pyrazine mono-N-oxide compounds were synthesized and reacted with a variety of halogenated benzoic acids, in order to assess the ability of these molecules to establish binding selectivity when both a hydrogen and halogen bond donor is present. The results obtained revealed that the pyridyl/carboxylic acid synthon formed 7/7 times and halogen bonds (N-O…I or N-O…Br) extended the SR/acid dimers into 1D and 2D networks. These results were rationalized via charge calculations as well as through the hierarchical view of intermolecular interactions consisting of hydrogen and halogen bonds. Furthermore, a series of thienyl compounds were synthesized and allowed to react with halogen bond donors to determine whether the halogen bond is purely electrostatic or based on the hard and soft acids and bases principles. The results obtained showed that of the 34 reactions between a halogen bond donor and thienyl compounds, the halogen bond is predominantly electrostatic in nature. Finally, as a result of our improved understanding on molecular recognition, we were able to carry out systematic structure-property studies on a series of cocrystals of anti-cancer drug molecules with aliphatic carboxylic acids. This study revealed that systematic changes to the molecular nature of the co-crystallizing agent combined with control over the way individual building blocks are organized within the crystalline lattice makes it possible to establish predictable links between molecular structure and macroscopic physical properties, such as melting behavior, solubility, dissolution rate, etc.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / Supramolecular synthesis relies upon the creative and rational use of the common intermolecular forces and a proper understanding of these forces is critical for design and assembly of molecular building blocks into extended networks. The strength of seven substituted pyridines as hydrogen-bond acceptors was probed using a series of fifteen mono/dicarboxylic acids to demonstrate the interrelationship between the charge on the substrate and its ability to form co-crystals/salts. The higher charge in the acceptor led to proton transfer (100% yield) from the hydrogen bond donor to give a salt, whereas the lower charge led to co-crystals. This specificity observed for small molecules was extended to an investigation of selectivity in ditopic molecules. A series of nineteen hydrogen-bond donors, including fifteen carboxylic acids and four cyanoximes, were tested for binding preferences against ten ditopic ligands with variable charges. The overall supramolecular yield of 82% (9/11) proved a high degree of reliability in terms of best acceptor/donor approach, hence establishing the efficiency of the calculated charges as a guideline for molecular recognition processes. Solubility and thermal properties of pharmaceutical drug mimics were altered via formation of co-crystals/salts. The ligands and their co-crystals/salts with five even-chain dicarboxylic acids were synthesized and their comparative solubility in pure water and in pH 6.8 buffer solution measured. Solubility enhancement to a degree of 9x is observed for pharmaceutical drug haloperidol, whereas decrease in solubility down to 81% is achieved for 2-amino-5-(3-pyridyl)pyrimidine (which has agrochemical significance). Also the thermal and solubility behavior of these co-crystals were shown to reflect the properties of their parent co-crystallizing agents, allowing for a modulation of physical properties. Finally, the specificity and selectivity of the intermolecular interactions observed for small molecules were applied in the synthesis of hydrogen and halogen-bonded capsules. Several resorcinarene-based cavitands were synthesized and their upper rim decorated with acetamidopyridyl, aminopyrazinyl, 3-pyridyl, and 4-pyridyl moieties with hydrogen and halogen-bonding potentials. A homomeric hydrogen-bonded capsule was formed with self-assembly of acetamidoethynylcavitand via N-H···O=C interactions, whereas a heteromeric halogen-bonded capsule, the very first of its kind, was formed with N···I halogen-bonded interaction between 3-pyridylcavitand and tetrafluoroiodo-substituted calixarene.