No description available.

Submitted in partial fulfillment for the Degree of Master of Applied Sciences in Biotechnology, Durban University of Technology, Durban, South Africa, 2016. / Coumarins are naturally occurring α-benzopyrone derivatives known for their pharmacological properties such as anticoagulant, antimicrobial, anticancer, antioxidant, anti-inflammatory and antiviral properties. The pharmacological, biochemical, and curative applications of coumarins depend on the substitution around the coumarin core structure. In the present study, seven halogenated coumarins CMRN1 - CMRN7 were synthesized and evaluated for mosquito larvicidal, repellancy , and insecticidal activity against Anopheles arabiensis. Furthermore, the antimicrobial properties of compounds CMRN1 - CMRN7 were evaluated by assessing the bacterial and fungicidal activities using the disc diffusion method. The anti-inflammatory properties were evaluated using the 5-lipoxygenase kit assay. The evaluation of the safe use of the compounds was determined using the Brine shrimp lethal test. The potential carcinogenic properties of the studied compounds was done using the Salmonella mutagenicity test. The anti-cancer property of the studied compounds was evaluated against UACC62 (Melanoma), MCF-7 (Breast cancer), and PBMC (Peripheral blood mononuclear) cell lines using of MTT assay. The apoptotic potential of the synthesized coumarin was evaluated against UACC62 (Melanoma) cell by assessing their morphological changes, membrane change, mitochondria membrane potential, and caspase-3 activity using the Annexin V-PI staining, JC-1, caspase-3 enzyme kits, respectively, on flow cytometer. The results were compared to a known anti-cancer drug, doxorubicin. The results showed that compounds CMRN1, CMRN2, CMRN4, CMRN5 and CMRN7 exerted 100% larval mortality within 24 h of exposure. All halogenated coumarins reversibly knocked down adult mosquitoes but did not kill them after 24 h of exposure. Furthermore, the adulticidal activity of the compounds was considered only mild to moderate. The antimicrobial activity of the synthetized coumarins CMRN1 - CMRN7 were assessed against E. coli, K. pneumoniae, S. marcescens, S. faecalis, B. cereus, B. coagulans, B. stearothermophilus, C. freundii, S. aureus and M. luteus bacteria and three yeast cultures, C. albicans, C. utilis, S. cerevisiae as well as two fungal species, A. flavus and A. niger. Compounds CMRN1 and CMRN2 showed bacterial growth inhibition for all the tested species except K. pneumonia and B. stearothermophilus. Compounds CMRN4 and CMRN7 showed moderate bacterial inhibition against B. cereus, M. luteus and S. aureus. The anti-inflammatory activity of the coumarins analogues showed that 1 mg/mL of the compounds CMRN1, CMRN2, CMRN4 and CMRN5 displayed moderate anti-inflammatory activity when compared to the positive control, 15-lapoxygenase. The cytotoxicity results of the studied synthetized coumarins displayed selective activity towards the cancer cell lines used in this study. Our studies showed that CMRN1, CMRN2, CMRN4, and CMRN5 had significant cytotoxity effect against UACC-62 (Melanoma) and MCF-7 ( Breast) cancer cells with an inhibitory concentration (IC50) which displayed significant cytotoxicity effect, in particular CMRN4 and CMRN5. These compounds CMRN1- CMRN7 showed no toxicity effect against PBMCs cell line. The mechanism of cell death, that is, necrosis or apoptosis induced by the coumarins was investigated against UACC-62 (Melanoma). We found that CMRN1, CMRN2, CMRN4, CMRN5 induced morphological changes, characteristic of apoptosis . Annexin V kit showed that CMRN1, CMRN2 and CMRN5 showed early apopotosis and late apoptosis was particularly higher for compound CMRN4. The disruption of the mitochondria membrane was noticed to be greater in CMRN1 and CMRN5 when compared to the positive control doxorubicin. Compound CMRN4 produced high levels of caspase-3 positive compared to the control. The coumarin compounds showed no mutagenicity and were also found to be non-toxic to brine shrimps. In conclusion, compounds CMRN1, CMRN2, CMRN4, CMRN5 and CMRN7 are potential larvicidal agents because they exhibited close to 100% activity within 24 h. Furthermore, the anti-cancer efficiency of compounds CMRN1, CMRN2, CMRN4, and CMRN5, is enough qualification for them to be optimized for increase anticancer potency. / M

Submitted in complete fulfillment for the Degree of Master of Applied Sciences in Biotechnology, Durban University of Technology, Durban, South Africa, 2016. / Piperidine derivatives are essential heterocyclic compounds that have beneficial roles in the medical and commercial sector. They can be isolated from plant material and can be chemically synthesised using simple cost efficient methods. Piperidines and their derivatives are clinically used to prevent postoperative vomiting, facilitate radiological evaluation, correct gastrointestinal function as well as speed up gastric emptying before anaesthesia. Piperidine derivatives also demonstrate a wide spectrum of biological activities which include; antimicrobial, anticancer, anti- TB, anti-HIV, anti-inflammatory, analgesic, anti-influenza, anti-inflammatory and antitumor activity. The properties of piperidine derivatives depend on the nature of the side chains and their orientation. Based on the promising data that demonstrated the synergistic effects of biological agents with piperidine derivatives, the aim of our research is to determine the pharmacological activities, i.e. (i) antimicrobial activity, (ii) anti-inflammatory, (iii) anti-oxidant activity, (iv) cytotoxicity, and (v) biosafety of six piperidine derivatives, PM1 to PM6. All six piperidine derivatives (PM1-PM6) screened for antimicrobial activity exhibit characteristics of varying degrees of microbial inhibition against some Gram-positive and Gram-negative bacteria (B. cereus, B. subtilis, E. coli, S. aureus, Kl. Pneumonia, M. liuteus and P. aurenginosa) with the exception of B. polymixa, S. marcescens and S. faecalis. Certain piperidine derivatives did not demonstrate high inhibition activity towards the fungal strains, with inhibition only shown against four fungal species; A. niger, A. flavus, C. albicans and S. cerevisiae. Thus it is proposed that minor changes could be made to the structure of the compounds so that they can alter the effect that the compounds have on the specific fungi strains. With regard to antioxidant activity it is noted that the concentrations of the test compounds are directly proportional to the percentage of scavenging capacity. In comparison of the piperidine derivatives (PM1-PM6) to Rutin (reference standard), it was illustrated that Rutin displayed the best antioxidant activity. All six piperidine derivatives (PM1-PM6) showed greater than 50% anti-inflammatory activity, whilst the anti-inflammatory reference standard NCGA displayed the greatest activity in comparison to the piperidine derivatives tested. The safety of the piperidine derivatives was tested by assaying cytotoxicity, against melanoma, MCF7 cancer cells and normal fibroblasts as well as Brine shrimp lethality assay. All piperidine derivatives demonstrated high cytotoxicity activity against both cancer cell lines (melanoma and MCF7) and around 50 – 52% cytotoxicity against healthy cells. Chloro substitution of the phenyl ring increases cytotoxicity of compounds (Aerluri et al., 2012). This compound can be used in the treatment of cancer cells while inhibiting 50% of normal cells. All six piperidine derivatives (PM1-PM6) were also tested for toxicity against Artemia salina in a brine shrimp lethality assay. Piperidine derivatives exhibited varying degree of toxic activity towards the shrimp, with all derivatives displaying ± 50% toxic activity at 1000 µg/mL. These results reveal a directly proportional relationship between concentration of drug and toxicity. It remains a future research objective to modify these piperidine compounds (PM1-PM6) chemically to produce more derivatives for further biological evaluation. All the studied piperidine compounds have possible leads for optimization to carry out pre-clinical trials. We can conclude that the substitution of different side chains on the piperidine nucleus results in varying degree of pharmacological activity. Also, compounds containing the substitution of a chloro group at position 4 and a fluoro group at position 2 on the phenyl ring attached to carbon 2 and 6 on the piperidine nucleus resulted in high pharmacological activity. This good pharmacological activity was also exhibited by compounds containing substitutions of a methoxy group at position 3 on the phenyl ring attached to carbon 1 and 6 on the piperidine nucleus. Compounds containing a methoxy group positioned at carbon 4 on the phenyl ring which is attached to carbon 1 and 4 on the piperidine nuleus presented low pharmacological activity. Low activity was also exhibited by compounds containing substitution of a cyano group at position 4 on the phenyl ring which is attached to carbon 2 and 6 on the piperidine ring and a methyl group at position 4 on the phenyl group attached to a nitrogen at position 1 on the piperidine nucleus. / M

Kathleen Shuk Man Poon. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 93-94). / Abbreviations --- p.v / Lists of Figures --- p.vi / Lists of Schemes --- p.vii / Lists of Tables --- p.viii / Part I / Chapter Chapter 1 --- Introduction --- p.2 / Chapter 1.1 --- Thermal stability of metallacycles --- p.2 / Chapter 1.2 --- General Synthetic methods of Metallacycle --- p.5 / Chapter 1.3 --- Objective of this work --- p.6 / Chapter 1.4 --- Features of Ligands --- p.6 / Chapter 1.5 --- References --- p.10 / Chapter Chapter 2 --- Synthesis of Transfer Reagents --- p.11 / Chapter 2.1 --- Brief Survey of various Transfer Reagents --- p.11 / Chapter 2.2 --- Introduction to metallation reaction --- p.13 / Chapter 2.3 --- Result and Discussion --- p.16 / Chapter 2.3.1 --- Lithiation and Derivatization of Ligand --- p.16 / Chapter 2.3.2 --- Charge Migration --- p.18 / Chapter 2.3.3 --- Characterization of compounds --- p.23 / Chapter 2.4 --- Experimental --- p.27 / Chapter 2.5 --- References --- p.33 / Chapter Chapter 3 --- Synthesis of Metallacycles --- p.35 / Section I --- p.35 / Chapter 3.1 --- Introduction --- p.35 / Chapter 3.2 --- Results and Discussion --- p.36 / Chapter 3.2.1 --- Synthesis of Metallacycles of Group 14 elements --- p.36 / Chapter 3.2.2 --- Characterization of Group 14 metallacycles --- p.42 / Chapter 3.2.3 --- Experimental --- p.57 / Section II --- p.64 / Chapter 3.3 --- Introduction --- p.64 / Chapter 3.4 --- Result and Discussion --- p.65 / Chapter 3.4.1 --- Synthesis of Metallacycles of Group 4 elements --- p.65 / Chapter 3.4.2 --- Experimental --- p.68 / Chapter 3.5 --- Attempted synthesis of Group 12 Metallacycles --- p.70 / Chapter 3.5.1 --- Results and Discussion --- p.70 / Chapter 3.5.2 --- Experimental --- p.71 / Chapter 3.6 --- References --- p.73 / Part II --- p.75 / Chapter Chapter 4 --- Synthesis of Bimetallic Complex --- p.76 / Chapter 4.1 --- Brief Review on Bimetallic Complexes --- p.76 / Chapter 4.2 --- Results and Discussion --- p.80 / Chapter 4.2.1 --- Synthesis of bimetallic complexes --- p.80 / Chapter 4.2.2 --- Characterization of bimetallic complexes --- p.87 / Chapter 4.2.3 --- Experimental --- p.90 / Chapter 4.3 --- References --- p.93 / Appendix I General Experimental Procedure --- p.95

by Yong-li Zhong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (p. 234-246). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

The primary aim of this project was to synthesize new heterocyclic dimers of isoflavones and flavones, and investigate various methodologies for their synthesis. The secondary aim of the project was to synthesize some flavonoid natural products. Dimeric systems were synthesized using various methodologies including acid catalyzed arylation of isoflavanols and flavanols, acid catalyzed dimerization of flavenes, oxidative dimerization, Sonogashira coupling, Ullmann coupling and Suzuki-Miyaura coupling reactions. The acid catalyzed arylation of isoflavanols was found to proceed in a very stereoselective fashion to give trans-4-arylisoflavans in good yield in a single step. However, related flavanols under similar conditions gave mixtures of cis and trans isomers of 4-arylflavans. Interestingly, it was found that appropriately substituted flavenes, upon treatment with acid undergo stereoselective rearrangement and dimerization to give benzopyranobenzopyrans in high yields. A rationale for the rearrangement is proposed and this dimerization was used for the stereoselective synthesis of the natural product dependensin. As part of the project, some polycyclic natural products such as octandrenolone, flemiculosin, 3-deoxy-MS-II and laxichalcone were also synthesized. Oxidative dimerization of activated isoflavones was found to be very regioselective, and novel isoflavone dimeric systems were synthesized. Related flavones however, failed to undergo dimerization under similar conditions. A probable explanation for high regioselectivity in the case of isoflavones and unreactivity of flavones has been presented. Phenol oxidative coupling was used for the one-step synthesis of another natural product kudzuisoflavone-A from daidzein. Sonogashira coupling was utilized for the synthesis of dimeric systems linked via an acetylic linker. A variety of soflavone isoflavone, flavone-flavone and isoflavone-flavone dimers were synthesized in "one-pot" by this methodology and in excellent yields. Although Ullmann coupling was found not to be suitable for the synthesis of isoflavone or flavone dimers, one-pot Suzuki-Miyaura methodology gave flavone dimers and various other heterocyclic dimers in good yields.

The synthesis of 1-methyl-promazine, 4-hydroxymethyl-iminodibenzyl, and 4-bromo-5-trimethylsilyl-iminodibenzyl via dilithiation and ¹H-NMR's are described. Molecular modeling was done for the latter compound. The heat of dissociation was 30.6 kcal/mole for the lowest energy conformer. Rotational energies were examined for three bonds. The IC₅₀ values for inhibition of neurotransmitter uptake by rat brain synaptosomes were determined for a series of 1-substituted promazines, and 4-substituted imipramines. 1-Substituted promazines were fair inhibitors of serotonin uptake with an average IC₅₀ of 2000 nm. Their potency for inhibiting norepinephrine uptake was difficult to assess due to poor assay reproducibility, and the average IC₅₀ was estimated at 200 to 1700 nm. Serotonin, but not norepinephrine, uptake inhibition was increased with additional ring substitution at C(2) with a trifluoromethyl group. The 4-substituted imipramines were equal or slightly decreased in potency to unsubstituted imipramine for uptake inhibition of both neurotransmitters. IC₅₀'s were also reported for imipramine and desipramine.

A summary of tin hydride mediated reactions in generating radicals in organic synthesis is presented, together with some of the many alternative methods now available for conducting radical reactions. Particular attention has been given to the iminyl radical and the development of tin-free organic radical precursors. This introduction is followed by three chapters describing research on the development of two new sources of iminyl radicals and their application in syntheses of aza- heterocyles. O-Phenyl oxime ethers are the first iminyl radical precursors described in the thesis. Microwave thermolyses of oxime ethers released iminyl and phenoxyl radicals under comparatively mild conditions and with short reaction times. Few microwave-assisted synthetic methods, based around radical intermediates, are known. The mild and neutral conditions associated with radical chemistry, and the ability of radicals to perform intramolecular cyclisations, together with the virtues of MAOS, make their combination a very useful tool in syntheses of aza-heterocycles. A comprehensive study of intramolecular additions of iminyl radicals onto several radical acceptors, alkenes, alkynes, phenyl rings and indoles, is described. Furthermore, a wide range of nitrogen heterocyles with potential biological activity was prepared making use of this methodology. Intramolecular iminyl radical cyclisation onto imines via microwave irradiation was another process extensively studied. Microwave assisted syntheses of dihydroquinazolines and quinazolines are described. The precursor O-phenyl oxime ethers enable imine formation to be assimilated with iminyl radical generation before subsequent cyclisation. Clean, fast and high yielding methodology was therefore developed for the syntheses of these highly interesting heterocycles which form the basis of many pharmaceutical products. Dioxime oxalates were the second type of precursor investigated as sources of iminyl radicals. Homolytic cleavage of their N-O oxime bonds occurred on photolysis releasing two molecules of CO₂ and two iminyl radicals in a clean and atom-efficient process. A facile route to dioxime oxalates with a range of radical acceptors in suitable positions is described. ESR spectroscopy was used to demonstrate that dioxime oxalates dissociate on photolysis to give iminyl radicals in the presence of photosensitizer. This technique also confirmed the proposed mechanisms of radical cyclisation onto double bonds and several 2-azacyclopentylmethyl radicals were characterized by ESR spectroscopy. In several instances both the uncyclized iminyl radical, and the cyclised C-radical, could be simultaneously detected, and their concentrations determined. ESR spectroscopy was then profitably used to determine 5-exo-cyclization rate constants of iminyl radicals onto double bonds. Finally, the syntheses of several heterocycles from dioxime oxalates are described. Photolytic dissociation of dioxime oxalates containing alkenyl groups yielded iminyl radicals that ring closed to 3,4-dihydro-2H-pyrroles in toluene solution. The syntheses of phenanthridines, and the natural product trisphaeridine, were also accomplished by UV irradiation of dioxime oxalates containing aromatic rings as the radical acceptor.

Classical methodologies for carbon-carbon bond formation often require stoichiometric amount of reagent to prefunctionalize a C-H bond. Such methods generate a lot of waste and are therefore not atom-efficient. On the other hand, the use of catalysts for the direct use of C-H bond without prior functionalization is a more desirable approach for carbon-carbon formation. For example, an overall addition reaction is 100% atom economical. This thesis focuses on the catalytic addition of the three types of C-H bonds (Csp-H, Csp2-H and Csp3-H) to unsaturated molecules such as conjugated dienes, imines and carbon dioxide to form heterocycles. / The first chapter describes the direct single addition of 1,3-diketones (Csp3- H bond) to conjugated dienes and enol ethers catalyzed by gold(III) chloride and silver(I) trifluoromethanesulfonate. The reaction is highly regioselective, although the overall yields are modest (up to 70%) due to the oxidative nature of the catalysts. Under certain conditions, the addition product undergoes a subsequent cyclization to form dihydrofurans. This tandem addition/cyclization reaction is catalyzed by trifluoromethanesulfonic acid and is discussed in the second part of the chapter. / The second chapter deals with the addition of phenol derivatives (C sp2-H bond) to conjugated dienes catalyzed by gold(III) chloride and silver(I) trifluoromethanesulfonate. The reaction affords dihydrobenzofurans via an intramolecular O-H cyclization. Investigation into the sequence of the reaction shows that the C-C bond is formed before the C-O bond. / The third chapter presents the addition of terminal alkynes (Csp-H bond) to imines catalyzed by cheap copper(I) iodide salt via a three-component coupling of salicylaldehyde derivatives, secondary amines and alkynes. Microwave irradiation is used which considerably shortens the reaction time and eliminate the use of solvents. Dihydrobenzofurans with an exocylic double bond are formed via an intramolecular O-H cyclization. The use of aliphatic alkynes molecules containing a heteroatom is critical to the success of the reaction. / Finally, in the last chapter, the addition of terminal alkynes (C sp-H bond) to carbon dioxide (catalyzed by gold(I) chlorotriphenylphosphine and silver trifluoromethanesulfonate) is applied to the synthesis of arynaphthalene lactones via a multicomponent coupling of phenylacetylene, CO2 and 3-bromo-1-phenyl-1-propyne.

The primary aim of this project was to synthesize new heterocyclic dimers of isoflavones and flavones, and investigate various methodologies for their synthesis. The secondary aim of the project was to synthesize some flavonoid natural products. Dimeric systems were synthesized using various methodologies including acid catalyzed arylation of isoflavanols and flavanols, acid catalyzed dimerization of flavenes, oxidative dimerization, Sonogashira coupling, Ullmann coupling and Suzuki-Miyaura coupling reactions. The acid catalyzed arylation of isoflavanols was found to proceed in a very stereoselective fashion to give trans-4-arylisoflavans in good yield in a single step. However, related flavanols under similar conditions gave mixtures of cis and trans isomers of 4-arylflavans. Interestingly, it was found that appropriately substituted flavenes, upon treatment with acid undergo stereoselective rearrangement and dimerization to give benzopyranobenzopyrans in high yields. A rationale for the rearrangement is proposed and this dimerization was used for the stereoselective synthesis of the natural product dependensin. As part of the project, some polycyclic natural products such as octandrenolone, flemiculosin, 3-deoxy-MS-II and laxichalcone were also synthesized. Oxidative dimerization of activated isoflavones was found to be very regioselective, and novel isoflavone dimeric systems were synthesized. Related flavones however, failed to undergo dimerization under similar conditions. A probable explanation for high regioselectivity in the case of isoflavones and unreactivity of flavones has been presented. Phenol oxidative coupling was used for the one-step synthesis of another natural product kudzuisoflavone-A from daidzein. Sonogashira coupling was utilized for the synthesis of dimeric systems linked via an acetylic linker. A variety of soflavone isoflavone, flavone-flavone and isoflavone-flavone dimers were synthesized in "one-pot" by this methodology and in excellent yields. Although Ullmann coupling was found not to be suitable for the synthesis of isoflavone or flavone dimers, one-pot Suzuki-Miyaura methodology gave flavone dimers and various other heterocyclic dimers in good yields.