The quinoline-5,8-diones are an important class of compounds with a wide spectrum of biological activites such as antibacterial, antiasthmatic, antifungal, antitumour and antiparasitic agents. Over the past three decades many variously substituted derivatives of quinoline-5,8-diones have been synthesized and reported. The majority of them dealt with the chemistry of C-6 and/or C-7 substituted quinolinediones and were related to Lavendamycin. Our lab has developed several procedures for the condensation (Knoevenagel) and reduction of aldehydes and ketones with malononitrile. When this reductive alkylation procedure was attempted with quinoline-2-carboxaldehyde, a crude product was observed by NMR spectroscopy. This product rearranged upon attempted purification via recrystallization or column chromatography. The nucleophilic attack of the quinoline N on the C of the nitrile followed by a proton transfer and a tautomerization resulted in the creation of indolizine. We will study the reductive alkylation of a series of quinoline-5,8-diones with carboxaldehydes at the C-2 position with malononitrile. This reaction is carried out in 95% ethanol with no catalysts present. This reaction mixture is then diluted with additional 95% ethanol and then cooled in an ice/water bath before the addition of sodium borohydride (NaBH4) to afford the desired monosubstituted malononitrile. We have also carried out the reactions with a range of other substituted quinoline compounds. In these cases the indolizines were not observed. It is assumed that the indolizine product does not form due to the presence of substituents on the C-8 position. Additional studies will focus on unsubstituted C-8 quinoline rings to prepare other novel indolizines. Otherwise, various reactions are performed to force the formation of indolizine. / Introduction/background -- Preparation of quinoline derivatives and their respective carboxaldehydes -- Preparation of monosubstituted malononitriles and indolizines. / Department of Chemistry

Thesis (Ph. D.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains xv, 275 p. : ill. Includes abstract. Includes bibliographical references (p. 107-113).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1959. / Typescript. Abstracted in Dissertation abstracts, v. 20 (1959) no. 3, p. 875-876. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 70-79).

Thesis (Ph. D.)--West Virginia University, 2005. / Title from document title page. Document formatted into pages; contains xvii, 207 p. : ill. Includes abstract. Includes bibliographical references (p. 97-101).

Malaria is a major health problem, mainly in developing countries, and causes an estimated 1 million deaths per year. Plasmodium falciparum is the major type of human malaria parasite, and causes the most infections and deaths. Malaria drugs, like any other drugs, suffer from possible side effects and the potential for emergence of resistance. Chloroquine, which was a very effective drug, has been used since about 1945, but its use is severely limited by resistance, even though it has mild side effects, and is otherwise very efficacious. Research has shown that there are chloroquine reversal agents, molecules that can reinstate antimalarial activity of chloroquine and chloroquine-like drugs; many such reversal agents are composed of two aromatic groups linked to a hydrogen bond acceptor several bonds away. By linking a chloroquine-like molecule to a reversal agent-like molecule, it was hoped that a hybrid molecule could be made with both antimalarial and reversal agent properties. In the Peyton Lab, such hybrid "Reversed Chloroquine" molecules have been synthesized and shown to have better antimalarial activity than chloroquine against the P. falciparum chloroquine-sensitive strain D6, as well as the P. falciparum chloroquine-resistant strains Dd2 and 7G8. The work reported in this manuscript involves simplifying the reversal agent head group of the Reversed Chloroquine molecules, to a single aromatic ring instead of the two rings groups described by others; this modification retained, or even enhanced, the antimalarial activity of the parent Reversed Chloroquine molecules. Of note was compound PL154, which had IC50 values of 0.3 nM and 0.5 nM against chloroquine-sensitive D6 and chloroquine-resistant Dd2. Compound PL106 was made to increase water solubility (a requirement for bioavailability) of the simplified Reversed Chloroquine molecules. Molecular modifications inherent to PL106 were not very detrimental to the antimalarial activity, and PL106 was found to be orally available in mice infected with P. yoelli, with an ED50 value of about 5.5 mg/kg/d. Varying the linker length between the quinoline ring and the protonatable nitrogen, or between the head group and the protonatable nitrogen, did not have adverse effects on the antimalarial activities of the simplified Reversed Chloroquine molecules, in accord with the trends observed for the original design of Reversed Chloroquine molecules as found from previous studies in the Peyton Lab. The simplified Reversed Chloroquine molecules even tolerated aliphatic head groups (rather than the original design which specified aromatic rings), showing that major modifications could be made on the Reversed Chloroquine molecules without major loss in activity. A bisquinoline compound, PL192, was made that contained secondary nitrogens at position 4 of the quinoline ring (PL192 is a modification of piperaquine, a known antimalarial drug that contains tertiary nitrogens at position 4 of the quinoline ring); this compound was more potent than piperaquine which had an IC50 value of 0.7 nM against CQS D6 and an IC50 of 1.5 nM against CQR Dd2, PL192 had IC50 values of 0.63 nM against chloroquine sensitive D6 and 0.02 nM against chloroquine resistant Dd2. Finally, the mechanism of action of these simplified "Reversed Chloroquines" was evaluated; it was found that the simplified "Reversed Chloroquines" behaved like chloroquine in inhibiting β-hematin formation and in heme binding. However, the simplified "Reversed Chloroquines" were found to inhibit chloroquine transport for chloroquine resistant P. falciparum chloroquine resistance transporter expressed in Xenopus oocytes to a lesser extant than the classical reversal agent verapamil. From these studies it was noted that the simplified "Reversed Chloroquines" may not behave as well as classical reversal agents would in restoring chloroquine efficacy, but they are very potent, and so could be a major step in developing drug candidates against malaria.

No description available.

No description available.

Quinolines have been studied for over a century as an important class of heterocyclic compounds and continue to attract considerable interest due to the broad range of biological activities they possess. The incorporation of the essential structural features of quinolines with a ferrocene moiety could provide new derivatives with unexpected and/or enhanced biological activities since several ferrocene derivatives have already been shown to be active against a number of tumors. For this reason, we investigated the synthesis of ferrocenyl-substituted quinolines, such as 2-ferrocenylquinoline, by employing the molecular iodine catalyzed reaction between enolizable aldehydes and ferrocenyl imines, which were prepared by the condensation reactions of ferrocenecarboxaldehyde with aniline derivatives. As anticipated, these reactions produced 2-ferrocenylquinoline derivatives. By employing this ethodology, we synthesized 2-ferrocenylquinoline, 6-chloro-2-ferrocenylquinoline, 6-bromo-2-ferrocenyl-quinoline, 2-ferrocenyl-7-methylquinoline and 2-ferrocenyl-3,7-dimethylquinoline. Due to the ready availability of ferrocenylimines and aldehydes, this practical onepot method represents a versatile synthesis of ferrocenyl-substituted quinolines.

Master of Science / Department of Diagnostic Medicine/Pathobiology / Thu Annelise Nguyen / Colorectal cancer is one of the most common cancers in the United States with an early detection rate of only 39%. Colorectal cancer cells along with other cancer cells exhibit many deficiencies in cell-to-cell communication, particularly gap junctional intercellular communication (GJIC). GJIC has been reported to diminish as cancer cells progress. Gap junctions are intercellular channels composed of connexin proteins, which mediate the direct passage of small molecules from one cell to the next. They are involved in the regulation of the cell cycle, cell differentiation, and cell signaling. Since the regulation of gap junctions is lost in colorectal cancer cells, the goal of this study is to determine the effect of GJIC restoration in colorectal cancer cells. Overexpression of connexin 43 (Cx43) in SW480 colorectal cancer cells causes a 6-fold increase of gap junction activity compared to control un-transfected cells. This suggests that overexpressing Cx43 can restore GJIC. Furthermore, small molecule directly targeting gap junction channel was used to increase GJIC. Gap junction enhancers, PQs, at 200 nM showed a 4-fold increase of gap junction activity in SW480 cells. Using Western blot analysis, Cx43 isoform expression was seen to shift from P0 to P1 and P2 isoforms after treatment with PQ1 200 nM for 1 hour. Overall, the results show that overexpression of connexin and small molecules such as gap junction enhancers, PQs, can directly increase gap junction activity. The findings provide an important implication in which restoration of gap junction activity can be targeted for drug development.

Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: The work in this dissertation provides structural and kinetic insight into the mechanism of action of quinoline antimalarial drugs which may aid rational drug design. Quinoline antimalarial drug-ferrihaem (Fe(III)PPIX) complexes were investigated. Single crystal Xray diffraction (SCD) structures of the complexes formed between Fe(III)PPIX and the quinoline methanol antimalarials quinine, quinidine and mefloquine have been determined, and are the first observed structures of complexes formed between free Fe(III)PPIX and quinoline antimalarial compounds. Quinine, quinidine and mefloquine are shown to have a three-point binding mode to Fe(III)PPIX, which comprises direct coordination of the drug to the Fe(III) centre through its benzylic alcohol functionality, π-stacking between the drug and porphyrin aromatic systems, and intramolecular hydrogen bond formation between the porphyrin propionate group and the protonated quinuclidine nitrogen atom of the drug in the case of quinine and quinidine, and formation of an intramolecular hydrogen bonding network in the case of mefloquine. Extended X-ray absorption fine structure spectroscopy (EXAFS) was use to elucidate structural information of Fe(III)PPIX-drug complexes in solution, and indicates that coordination persists in solution. The protocol for lipid-mediated formation of β-haematin, where monopalmitic glycerol was used as a model lipid, was successfully modified to incorporate antimalarial drugs into the aqueous layer in order to investigate drug activity under biologically-relevant conditions. Four compounds were chosen, namely chloroquine and amodiaquine, both 4- aminoquinolines and quinine and quinidine. IC50 values for the inhibition of β-haematin formation show good correlation with biological activities determined against a chloroquine-sensitive Plasmodium falciparum strain. The lipid-water interface system was further used to investigate the effects of quinine, quinidine chloroquine and amodiaquine on the kinetics of β-haematin formation. The results led to the development of a kinetic model based on the Avrami equation and the Langmuir isotherm. The data strongly support a mechanism of antimalarial drug action by adsorption to the growing face of haemozoin, with precipitation of Fe(III)PPIX at high drug concentrations accounting for decreased yields. Adsorptions constants (log Kads) determined for each drug show a strong correlation with biological activity. Finally, the first SCD structure of the μ-propionato dimer of Fe(III)PPIX, the structural unit of haemozoin, has been determined as its DMSO solvate. EXAFS suggests that this species is only formed upon nucleation, with the π-π dimer species being favoured in solution. / AFRIKAANSE OPSOMMING: Die werk in die dissertasie verleen struktuur en kinetiese insig in the meganisme van aktiwiteit vir kinolien antimalariamiddels wat kan bydra tot die ontwikkeling van nuwe medisyne. Kinolien antimalariamiddel-ferriheem (Fe(III)PPIX) komplekse was ondersoek. Navorsing is gedoen op die enkelkristal X-straaldiffraksie strukture van die komplekse gevorm tussen Fe(III)PPIX en die kinolien metanol antimalaria middels kinien, kinidien en mefloquine. Die strukture is die eerste komplekse wat waargeneem is tussen vrye Fe(III)PPIX en kinolien antimalariamiddels. Kinien, kinidien en mefloquine het ʼn driepunt bindingsvorm, direkte koördinasie met die Fe(III) deur die bensielalkohol groep, ʼn π- stapel tussen die middel en die porfirien aromatiese sisteem, ʼn intramolekulêre waterstofbinding tussen the porfirienpropionaat funksie en die geprotoneerde kinuklidien stikstofatoom (kinien en kinidien) en ʼn netwerk van intramolekulêre waterstof bindings (mefloquine) insluit. Uitgebreide X-straal absorpsie fyn struktuur spektroskopie (EXAFS) is gebruik om inligting oor Fe(III)PPIX-middel komplekse in oplossing te verkry en het aangedui dat die koördinasie in oplossing voorkom. Deur gebruik te maak van monopalmitiengliserol as die lipid in the lipid-water interfase sisteem, waar antimalariamiddels suksesvol in die buffer geïnkorporeer was, was die middel se aktiwiteit onder biologiese kondisies geondersoek. Vier middels was gekies naamlik, chloroquine en amodiaquine, albei 4-aminokinoliene en kinien en kinidien om die IC50-waarde vir inhibisie van β-hematien vorming te bepaal. Die IC50 waardes het ʼn goeie korrelasie met biologiese aktiwiteite teen die chloroquine-sensitiewe Plasmodium falciparum stam gewys. Die lipid-water interfase-sisteem was ook gebruik om die effek van kinien, kinidien, chloroquine en amodiaquine op die kineties effek op die vorming van β-hematien te ondersoek. Die resultate het gelei to die ontwikkeling van die kinetiese model gebaseer op die Avrami vergelyking en die Langmuir isoterm. Die data ondersteun ʼn meganisme van middel aksie waar die middel teen die groeiende vlak van hemosoïen kristal adsorbeer. Die neerslag van Fe(III)PPIX wat vorm by hoë konsentrasies, het gelei tot laer opbrengste. Die adsorpsiekonstante (log Kads) bepaal vir elke middel, het goeie korrelasie met biologiese aktiwiteit getoon. Enkelkristal X-straaldiffraksie strukture van μ- propionatodimeer van Fe(III)PPIX, die struktuur eenheid van hemosoïen, was bepaal as ʼn DMSO solvaat. EXAFS het aangedui dat die spesie slegs by kernvorming ontstaan en dat die π-π dimeerspesie in oplossing voorkom.