No description available.

The syntheses of 7-N-chloroacetyllavendamycin methyl ester (55), 7-N-butyryllavendamycin methyl ester (56), 7-N-chloroacetyldemethyllavendamycin octyl ester (57), 7-N-butyryldemethyllavendamycin octyl ester (58), 7-N-chloroacetyldemethyllavendamycin isoamyl ester (59), and 7-N-butyryldemethyllavendamycin isoamyl ester (61) are described. Incorporation of the Pictet-Spengler condensation of 7-chloroacetamido-2-formylquinoline-5,8-dione (62) or 7butyramido-2-formylquinoline-5,8-dione (63) with B - methyltryptophan methyl ester (11), L-tryptophan octyl ester (64), or L-tryptophan isoamyl ester (65) in xylene directly afforded six lavendamycin analogs.The aldehydes 62 and 63 were prepared according to the following general procedure. Nitration of 8-hydroxy-2methylquinoline (66) yielded 8-hydroxy-2-methyl-5,772, and 73 are also included. 1H NMR and IR are provided compounds 67, and 71, and 1H NMR is provided for compound dinitroquinoline (67). Compound 67 was then hydrogenated and acylated with chloroacetic anhydride (or butyric anhydride) to yield 5,7-bis(chloroacet4mido)-8-hydroxy-2-methylquinoline (69) (or 5,7-dibutyramido-8-butyroxy-2 methylquinoline (71)).Compound 69 (and 71) was oxidized by potassium dichromate to give the corresponding 5,8-dione 70 (and 72). Treatment of 70 (and 72) with selenium dioxide in refluxing 1,4-dioxane afforded compound 62 (and 63). It was also noted that 71 would hydrolyze to its 8-hydroxy derivative 73 in hot methanol-water.Compound 64 was prepared through the neutralization of Ltryptophan octyl ester hydrochloride with a 14 % ammonium hydroxide solution followed by extraction. Compound 65 was synthesized via a Fischer esterification of L-tryptophan with isoamyl alcohol saturated with hydrogen chloride. The synthesis of H-methyltryptophan (44) was accomplished with the method of Snyder and Matteson.The structures of the novel compounds 55, 56, 57, 58, 59, 60, 62, 63, 69, 70, 72 and 73 were confirmed through 1H NMR, IR, EIMS, and HRMS. Elemental analyses of 62, 63, 69, 70,for 44. / Department of Chemistry

The synthesis of 7-acetyl-11'-benzyloxylavendamycin methyl ester (47), 7acetyl-11'-hydroxylavendamycin methyl ester (48), 11'-hydroxylavendamycin methyl ester (49), 11'-benzyloxylavendamycin methyl ester (50), are described. Pictet-Spengler condensation of 7-N-acetyl-2-formylquinoline-5,8-dione (26) with 5-benzyloxytrytophan methyl ester (45) or 5-hydroxytryptophan methyl ester (46) in dry xylene or anisole directly afforded lavendamycin analogs 47 or 48. Compound 49 was obtained by hydrolysis of 48 with 70% H2SO4 - H2Osolution. Compound 50 was obtained by hydrolysis of 47 with sodium carbonate solution.Aldehyde 26 was prepared according to the following general procedure. Nitration of 8-hydroxy-2-methylquinoline (28) yielded 8-hydroxy-2-methyl5,7-dinitroquinoline (29). Compound 29 was then hydrogenated and acylated with acetic anhydride to yield 5,7-bis(diacetamido)-8-hydroxy-2methylquinoline (31). Compound 31 was oxidized to give 5,8- dione 25 by using potassium dichromate. Treatment of compound 25 with selenium dioxide in refluxing 1,4-dioxane yielded compound 26.3 (Isopropylaminoethylidene)-6,7-dimethoxyindole (39) was prepared via the following procedure. Acylation of vanillin (32) with acetic anhydride yielded acetylvanillin (33). Compound 33 was nitrated and hydrolyzed to give 2nitrovanillin (35). Compound 35 was then methylated using dimethyl sulfate to produce 2-nitroveratric aldehyde (36). Condensation of compound 36 with nitromethane yielded 3,4-dimethoxy-2-f3-nitrostyrene (37). Ammonium formate reductive cyclization of compound 37 in refluxing methanol in the presence of a catalytic amount of 10% palladium on charcoal yielded 6,7dimethoxyindole (38). Electrophilic substitution reaction of compound 38 with ethylideneisopropylamine (41) in dry toluene yielded compound 39.Methyl (2RS, 3SR)-2-amino-3-[3-(5-benzyloxyindolyl)]butanoate (45) and methyl (2RS, 3SR)-2-amino-3-[3-(5-hydroxyindolyl)]butanoate (46) were obtained following the procedure described below. Electrophilic substitutionreaction of 5-bezyloxyindole (40) with ethylideneisopropylamine (41) in dry toluene yielded 3-(isopropylaminoethylidene)-5-benzyloxyindole (42). Condensation of compound 42 with methyl nitroacetate (43) in dry toluene gave methyl 3-[3-(5-benzyloxyindolyl)]3-nitrobutanoate (44). Hydrogenation of compound 44 in the presence of Raney nickel and trifluoroacetic acid in ethanol yielded methyl (2RS, 3SR)-2-amino-3-[3-(5-benzyloxyindolyl)] butanoate (45). Hydrogenation of compound 44 in the presence of 10% palladium on charcoal and trifluoroacetic acid in ethanol yielded methyl (2RS, 3SR)-2-amino-3-[3-(5-hydroxyindolyl)] butanoate (46).The structures of the novel compounds were confirmed by 1H NMR, IR, and HRMS or elemental analysis. / Department of Chemistry

The chemistry of quinonline-5,8-dione as a functional group is a developing field because of its various biological aspects. Lavendamycin and streptonigrin are known antibiotic, antitumor agents containing the quinolone-5,8-dione functional group believed to provide their antitumor properties. Most cancer cells show an elevated level of NQO1 enzyme which activates lavendamycin to act as an antitumor agent. The research goal is to explore different synthetic methods and reactions to produce novel quinolone-5,8-dione analogues with unique structural features while keeping the selective cytotoxicity. Lavendamycin contains a β-carboline and streptonigrin has a substituted pyridine connected to the 2-position of the quinolone-5,8-dione. The overall goal of this project will develop synthetic methods to create 1,2,3-triazoles and 1,2-diazoles attached to the quinoline moiety from azides and diazonium salts, respectively. In order to accomplish this, 8-hydroxyquinoline undergoes through a four step synthesis to install an azide at the two position of the quinoline ring. 8-Hydroxyquinoline was oxidized to produce 8-hydroxyquinoline-N-oxide, converted into 8-acetoxy-2-hydroxyquinoline with acetic anhydride, reacted with POCl3 to produce 2-chloro-8-hydroxyquinoline, and treated with sodium azide to form 2-azido-8-hydroxyquinoline. However it was found that the product cyclized to yield 8-hydroxy-tetrazole[1,5-a]quinoline. In the quinoline-5,8-dione synthesis, 7-amidoquinoline-5,8-dione is prepared through a three step synthesis. 8-Hydroxquinoline was nitrated to form 8-hydroxy-5,7-dinitroquinoline, hydrogenated/acylated to give 5,7-diacetamido-8-acetoxyquinoline, and oxidized to yield 7-acetamidoquinoline-5,8-dione. In order to reach the end of this project, the four step tetrazole and the three step quinoline-5,8-dione syntheses required merging. Further research will focus on the optimization of these syntheses. / Synthesis of 8-hydroxy-tetrazole [1,5-a] quinoline -- Synthesis of 7-amino-quinoline-5,8-dione -- Novel synthesis of quinoline-5,8-dione analogues. / Department of Chemistry

No description available.

The synthesis of several 7-substituted analogs of 2-methylquinoline-5,8-dione and their chemistry are described. In this investigation the following compounds were prepared.5,7-Diformamido-8-hydroxy-2-methylquinoline (207), 7-formamido-2methylquinoline-5,8-dione (199), 7-acetamido-2-methylquinoline-5,8-dione (6), 7-isobutyramido-2-methylquinoline-5,8-dione (200), 7-amino-2-methylquinoline-5,8-dione (210), 7-amino-6-chloro-2-methylquinoline-5,8-dione (213), 7-methoxy-2-methylquinoline5,8-dione (214), 7-ethoxy-2-methylquinoline-5,8-dione (215), 7-isopropyloxy-2methylquinoline-5,8-dione (216), 7-amino-5-ethyl-5-hydroxy-2-methylquinoline-8-one (218), 7-acetamido-5-ethyl-5-hydroxy-2-methylquinoline-8-one (220), and 7-chloro-2methylquinoline-5,8-dione (222).Trimetylacetic formic anhydride (206) was prepared according to McGarvy,s 68 method from treatment of sodium formate (204) and trimethylacetyl chloride (203) in the presence of poly (4-vinylpyridine-N-oxide) (205) as catalyst. 7-Formamido-2methylquinoline-5,8-dione (199) was prepared according to the following general procedure. 8-Hydroxy-2-mehylquinoline (5) was reacted with a 70% mixture of HNO3/H2SO4 to produce 5,7-dinitro-8-hydroxy-2-methylquinoline (18). Compound 18 was reduced by H2/Pd-C in the presence of HCl and then the resulting 5,7-diamino-8-hydroxy-2 methylquinolin-5,8-dione hydrochloride salt (198) reacted with trimethylacetic formic anhydride to produce 5,7-diformamido-8-hydroxy-2-methylquinoline-5,8-dione (207). Compound 207 was treated with a solution of potassium dichromate in acetic acid-water mixture to give product 199.7-Acetamido-2-methylquinoline-5,8-dione (6) was prepared from reaction of a solution of 198 with acetic anhydride in the presence of sodium acetate and sodium sulfite followed by oxidation with potassium dichromate in acetic acid-water solution. 7-Isobutyramido-2methylquinoline-5,8-dione (200) was prepared according to following procedure. Treatment of a solution of 198 with isobutyric anhydride in the presence of sodium acetate and sodium sulfite afforded 5,7-diisobutyramido-8-isobutyroxy-2-methylquinoline (212). Partial hydrolysis of 212 in boiling methanol-water mixture gave 5,7-diisobutyramido-8-hydroxy-2methylquinoline (211). Oxidation of 211 by a solution of potassium dichromate in acetic acid-water mixture afforded product 200.7-amino-2-methylquinoline-5,8-dione (210) was prepared from alcoholysis of 7-acylamino-2-methylquinoline-5,8-diones 6, 199,and 200 with methanol and sulfuric acid. 7-Alkoxy-2-methylquinoline-5,8-diones 214, 215, and 216 were prepared from reaction of 7-acetamido compound 6 with alcohols in the presence of sulfuric acid. Reaction of 7-acylamino compounds 6, 199, and 200 with methanol in the presence of hydrogen chloride gas at 60°C afforded 7-amino-6-chloro-2-methylquinoline-5,8-dione (213).Reaction of compound 210 with diethylaluminum cyanide gave 7-amino-5-ethyl-5hydroxy-2-methylquinoline-8-one (218). The same reaction was carried out on compound 6 to give 7-acetamido-5-ethyl-5-hydroxy-2-methylquinoline-8-one (220).1-[(tert-Butyldimethylsilyl)oxy]-2-methyl-l-aza-1,3-butadiene (4) was prepared from treatment of methyl vinyl ketone (210) and t-butylmethylsilylhydroxylamine (202) in dichloromethane in the presence of molecular sieves. Cycloaddition reaction of a solution of 4 in dichloromethane with 2,6-dichloro-1,4-benzoquinone (221) in sealed tube afforded 7-chloro-2-methylquinoline-5,8-dione (222). / Department of Chemistry

The synthesis of 7-N -furoyllavendamycin methyl ester (35), 7-N -furoyl demethyllavendamycin methyl ester (36), 7-N -furoyldemethyllavendamycin ethyl ester (37), 7-N -furoyldemethyllavendamycin propyl ester (38), 7-N -furoyl demethyl lavendamycin butyl ester (39), 7-N -furoyldemethyllavendamycin isoamyl ester (40),7-N -furoyldemethyllavendamycin cyclohexyl ester (41), 7-N -furoyldemethyl lavendamycin octyl ester (42), 7-N -furoyldecarboxydemethyllavendamycin (43), and demethyl lavendamycin isoamyl ester (44) are described. Pictet-Spengler condensation of 7-furoylamino-2-formylquinoline-5, 8-dione (55) with (3-methyltryptophan methyl ester (4), Ltryptophan methyl ester (56), L-tryptophan ethyl ester (57), L-tryptophan propyl ester (58), L-tryptophan butyl ester (59), L-tryptophan isoamyl ester (60), L-tryptophan cyclohexyl ester (61), L-tryptophan octyl ester (62), L-tryptamine (63), in xylene, or anisole afforded ten lavendamycin analogs.Aldehyde 55 was prepared according to the following general procedure.Nitration of 8-hydroxy-2-methylquinoline (30) gave 8-hydroxy-2-methyl-5,7dinitroquinoline (31). Compound 31 was then hydrogenated and acylated with 2-furoyl chloride (or acetic anhydride ) to yield 5,7-difuroylamino-8-hydroxy-2-methylquinoline (53) or 5,7-diacetamino-8-acetoxy-2-methyl- quinoline (33). Compounds 53 and 33 were oxidized by potassium dichromate to give the corresponding 5,8-diones 54, and 27. Treatment of 53, and 27 with selenium dioxide in refluxing wet dioxane afforded compounds 55 and 28.Compound 4 was previously prepared by other members of our group, compounds 56, 57, 59, and 62 were obtained through the neutralization of the corresponding Ltryptophan ester hydrochlorides with a 14% ammonium hydroxide solution followed by extraction. Compounds 58, 60, 61 were synthesized via a Fischer esterification of Ltryptophan with : propyl alcohol, isoamyl alcohol, and cyclohexyl alcohol saturated with hydrogen chloride.The structures of compounds 53, 54, 55, 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44 were confirmed through 1H NMR, IR, EIMS, and HRMS. Elemental analyses of 53, 54, and 55 are also included.The structures of esters 56, 57, 58, 59, 60, 61, 62, and 63 were confirmed by 1H NMR. / Department of Chemistry

Thesis (Ph.D.)--Memorial University of Newfoundland, 1999. / Restricted until November 2000. Bibliography: leaves 170-177.

Novel non-leaving groups were employed in this dissertation to synthesize platinum complexes which can assist in the understanding or improvement of anticancer action. Emphasis was placed on (NS)-chelate and (NN)-chelate platinum complexes. Bidentate (NS)-donor ligands were used as non-leaving ligands in the synthesis of platinum(II) complexes with iodo, chloro, bromo and oxalato groups as leaving groups. These complexes were synthesized and studied since many questions regarding the interaction of sulfur-donors and platinum still exist. These relate to thermodynamic and kinetic factors and their influence on anticancer action. In this dissertation the properties of novel platinum(II) complexes of a bidentate ligand having an aromatic nitrogen-donor atom in combination with a thioethereal sulfur atom capable of forming a five-membered ring with platinum(II) were studied. The general structure of the (NS)-ligands used was 2-((alkylthio)methyl)pyridine. Alkyl groups used were methyl, ethyl, propyl, benzyl and phenyl. Amine complexes of platinum have been studied extensively in the past. However, attention was given to novel aspects of substituted pyridine and imidazole ligands and their corresponding complexes. Amongst these are 2-(2-methylaminoethyl)pyridine, 1-methyl-2-methylaminoethylimidazole and 1-methyl-2-methylaminobenzylimidazole. The leaving groups included chloro, bromo and oxalato. Mononitroplatinum(IV) complexes were prepared using novel synthetic methods. Selected platinum(II) amine complexes were used as starting materials for this synthesis. Some of these compounds exhibit promising anticancer behaviour. (Trans-(R,R)-1,2-diaminocyclohexane)(oxalato)(mononitrochloro)platinum(IV) is a particularly good anticancer agent and has been patented internationally. All these complexes were characterized using mass spectrometry, chromatography, thermogravimetric analysis, kinetic aspects such as ligand exchange rates and finally their anticancer action against three different cancer cell lines was evaluated via cytotoxicity assays. Some of the compounds exhibited particularly good anticancer potential.

The research conducted in this study focussed on advancing the knowledge database of diamineplatinum complexes on two frontiers: 1) the development of novel anticancer complexes, and 2) improvements in their synthetic chemistry. Novel square-planar dichloro and oxalato platinum(II) complexes were synthesized as potential anticancer agents in accordance with a comprehensive set of factors identified as being significant in optimizing such action. The nonleaving ligands consisted of asymmetric chelating chiral diamines of the form 1- (1-R-imidazol-2yl)(R')methanamine (R representing methyl, butyl and R' methyl, phenyl). The complexes were characterized by a host of spectral, thermal and crystallographic techniques. In addition, the stabilities of the complexes were monitored in aqueous and saline solutions. Cytotoxicity screening on three cultured cancer cell lines (MCF-7, HeLa and HT29) indicated the compounds, present as their respective racemates, to have rather modest activities relative to cisplatin; with complexes having the smallest substituents, R,R' = methyl, being most active. In recognition of the limitations of traditional silver-based syntheses of oxalatoplatinum(II) complexes, innovative non-silver methods were developed using the well known cancer drug, oxaliplatin, (trans-R,R-1,2- diaminocyclohexane)oxalatoplatinum(II), as a prototype. These involved direct ligand exchange reactions of the dichloro precursor, (trans-R,R-1,2- diaminocyclohexane)dichloroplatinum(II), with tetrabutylammonium oxalate in essentially non-aqueous solvents. A 90:10 mixture of isoamyl alcohol (3-methyl- 1-butanol):water, proved to be a promising solvent, enabling the recovery of pure oxaliplatin (~98 percent) after 9 hours at 88 °C in yields of up to 86 percent. In light of the perceived unique mode of anticancer action available to mononitroplatinum(IV) complexes (i.e. their STAT3-binding potential), octahedral diamineoxalatoplatinum(IV) complexes containing axially-coordinated nitro and halo co-ligands were synthesized and extensively characterized. Electrochemical studies revealed trends in reduction potential which could be correlated to structural / chemical traits of the coordinated diamine and axial ligands. The similarities of the determined cytotoxicities of the platinum(IV) compounds and their respective platinum(II) analogues, implicated reduction as a means of activation of the platinum(IV) complexes.