Synthesis and characterizations of derivatives of multi-ring cycle systems containing heteroatoms

Cylitol, defined as polyhydroxylated cycloalkanes, is found in most natural products and bioactive molecules. Many cyclitol derivatives play an extremely important role both in medicinal chemistry and in the synthesis of drug-active molecules. One of the important cyclitol derivatives is carbasugar compounds. Carbasugars are sugar-like molecules produced by the replacement of the endocyclic oxygen atom in monosaccharides with carbon, which have the potential to be stronger drug candidates than natural sugars due to their hydrolytically stable structure. These molecules are promising drug candidates in the treatment of diseases such as diabetes, cancer and viral infection, thanks to their carbohydrate biomimicry. On the other hand, conduritols are molecules belonging to a class of polyhydroxylated cyclohexanoids that continue to be investigated in the scientific world due to their potential biological activity. In connection with conduritols, halo-substituted haloconduritols such as –Br, –Cl and –F are key compounds for the synthesis of important cyclitol derivatives. Mono- and dihaloconduritol structures of these compounds have gained increasing importance in recent years. In terms of the biological activities of haloconduritols, the most extensively investigated issue has been glycosidase inhibition. Among the haloconduritols, especially bromoconduritols, is a glucosidase inhibitor that plays an important role in glycoprotein processing. They have also been of interest as potent therapeutic agents against HIV and in the treatment of diseases such as AIDS. Although there are many studies in the literature on these important compounds (cyclitol and haloconduritol derivatives), which are generally mentioned, there is a need to develop new inhibitors with less side effects and increased efficacy. For this reason, the synthesis and biological investigations of these compounds are included in the first part of the thesis. In the first part of the thesis, which consists of two parts, the synthesis of new cyclitol and haloconduritol derivatives, which are not included in the literature, was carried out. In the synthesis stage, firstly, rel-(3aR,4R,7S,7aS)-3a,4,7,7a-tetrahidro-4,7-epoksiizobenzofuran-1,3-dion (KRS-1) was obtained in quantitative yield (97 %) by Diels-Alder addition reaction based on furan and maleic anhydride compounds. Then, by reducing with LiAlH4 reagent in the presence of THF at room temperature, subjecting rel-(1S, 2R, 6S)-6-hidroksisiklohez-3-en-1,2-diildimetanol (KRS-2), this compound to acetylation reaction in the presence of AcO2 and pyridine, the compound rel-(1S, 2R, 6S)-6-asetoksisiklohez-3-en-1, 2-diilbis(metilen)diasetat (KRS-3) was synthesized in 86 % yield. As a result of the epoxidation reaction of KRS-3 compound with m-chloroperbenzoic acid reagent in the presence of dichloromethane (DCM), a mixture of rel-(1R, 2R, 3S, 4S, 6S)-4-asetoksi-7-okza bisiklo [4.1.0] heptan-2, 3-diil bis (metilen) diasetat (KRS-4) and rel-(1S, 2R, 3S, 4S, 6R)-4-asetoksi-7-okzabisiklo [4.1.0] heptan-2,3-diil bis (metilen) diasetat (KRS-5) isomers was obtained and the isomers were successfully purified by column chromatography method. The epoxide ring openings of KRS-4 and KRS-5 compounds were performed in the presence of H2O/H2SO4 at 0 oC rel-(1S, 2R, 3R, 4R, 6S)-6-asetoksi-3,4-dihidroksisiklohekzan-1, 2-diil bis (metilen) diasetat (KRS-8) and rel-(1S, 2R, 3S, 4S, 6S)-6-asetoksi-3, 4-dihidroksisiklohekzan-1, 2-diilbis (metilen) diasetat (KRS-9) compounds were synthesized. As a result of subjecting the triacetate KRS-3 to the osmium (OsO4) catalyzed cis-dihydroxylation reaction, the compound rel-(1S, 2R, 3R, 4S, 6S)-6-asetoksi-3, 4-dihidroksi siklohekzan-1,2-diilbis (metilen) diasetat (KRS-10) was obtained in 87 % yield. After acetate of the KRS-8, KRS-9 and KRS-10 compounds, the obtained compounds were subjected to basic hydrolysis in the presence of NH3(g)/MeOH to produce new cyclitol (carbasugar) derivatives (KRS-14, KRS-15 and KRS-16, respectively). synthesized for the first time. Rel-(1R, 2S, 3R, 6S)-3-asetoksi-6-klorosiklohekz-4-en-1, 2-diilbis(metilen) diasetat (KRS-27) and rel-(1R, 2S, 3S, 6S)-3-asetoksi-6-klorosiklohekz-4-en-1, 2-diilbis (metilen) diasetat (KRS-28) isomers were obtained by subjecting the KRS-26 compound obtained as a result of a series of reactions to the oxo bridge opening reaction with acetyl chloride (AcCl) reagent and purified by column chromatography method. KRS-29, KRS-30 and KRS-31 compounds were successfully obtained by applying oxo bridge opening with acetyl bromide (AcBr) reagent at the same time. Then, these oxo bridging compounds (KRS-27, KRS-29 and KRS-30) were treated with acidic hydrolysis in the presence of HCl(g)/MeOH to produce dibromo- and monochloroconduritol derivatives (KRS-32, KRS-33 and KRS-34, respectively) for the first time was synthesized. KRS-42 compounds were obtained by opening the oxo bridge with BBr3, BCl3 reagents, respectively, and KRS-43 and KRS-44 compounds were obtained, and then the synthesis of amino cyclitol analogs (KRS-45 and KRS-46) was successfully performed by applying acidic hydrolysis processes to these compounds. has been carried out. In the first part, the structures of all synthesized compounds were characterized using spectroscopic methods such as NMR, FT-IR, elemental analysis. The inhibitory potentials of α-glucosidase and α-amylase enzymes of synthesized new inositol carbasugar analogues and new haloconduritol derivative compounds were investigated. Among the compounds examined, it was observed that the compound KRS-2 exhibited good activation against both α-glucosidase (IC50 = 56.88 ± 0.13 µM) and α-amylase (IC50 = 68.20 ± 0.93 µM) compared to acarbose (IC50 = 98.33 ± 1.75 µM). Among the carbasugar analogues, only compound KRS-15 exhibited the best activity against α-glucosidase (IC50 = 36.72 ± 1.27 µM). It was determined that carbasugar derived compounds did not show weak or no effect against α-amylase. Among the newly synthesized haloconduritol compounds, bromo-substituted conduritols (KRS-33 and KRS-34) were found to have better activity against both enzymes than acarbose, which is used as a drug. Chloro-substituted conduritol KRS-32 compound showed good activity against α-glucosidase (IC50 = 53.27 ± 0.24 µM) and weak activity against α-amylase (IC50 = 241.38 ± 1.71 µM). The inhibition types of well-active compounds (KRS-2, KRS-15, KRS-32, KRS-33 and KRS-34) were determined by enzyme kinetic studies. KRS-2, KRS-33 and KRS-34 compounds were found to be mixed inhibitors, and KRS-15 compound to be noncompetitive inhibitors. KRS-32 showed competitive type inhibition like acarbose. Carbazole, an important compound that forms the second part of the thesis, constitutes an important class of aromatic heterocyclic compounds containing electroactive nitrogen atoms. Some synthetic and natural carbazole derivatives have pharmacologically important properties such as anti-tumor, anti-oxidant, anti-bacterial, anti-diabetic and anti-inflammatory in pharmaceutical chemistry. It is known that carbazoles show photoconductivity and luminescence properties due to the electroactive nitrogen atom they contain, and are also strong α-glucosidase inhibitors. Phthalocyanines constitute an important class of tetrapyrrole compounds. The importance of phthalocyanines in various scientific fields and applications continues to attract attention today, thanks to their photochemical properties resulting from their aromatic and strong 18-π electronic structures. Phthalocyanines are among the subjects of interest today due to their strong activity with high singlet oxygen production in photodynamic therapy, enzyme inhibition properties, photophysical and photochemical properties, thanks to the diamagnetic zinc (Zn) metal ion in their core. However, to our knowledge, there is little literature examining the enzyme inhibitory effect of carbazole-substituted phthalocyanine compounds. Based on this information, in the second part of the study, two new zinc-phthalocyanine complexes (KRB-5 and KRB-8) containing carbazole rings were synthesized. Starting from the carbazole compound, ethylene carbonate and the nitrogen atom of the carbazole are protected 2-(9H-karbazol-9-il)etan-1-ol (KRB-1), by the acetate process 2-(3-asetil-9H-karbazol-9-il)etil asetat (KRB-2), by the hydrolysis process 1-(9-(2-hidroksietil)-9H-karbazol-3-il)etan-1-on (KRB-3) and the potassium hydroxide (KOH), benzaldehyde reagents of this compound in the presence ethanol by treatment was obtained the compound (E)-1-(9-(2-hidroksietil)-9H-karbazol-3-il)-3-fenilprop-2-en-1-on (KRB-6). By reacting the obtained KRB-3 and KRB-6 compounds using 4-nitrophthalonitrile reagent, phthalonitrile derivatives 4-(2-(3-asetil-9H-karbazol-9-il)etoksi)ftalonitril (KRB-4) and 4-(2-(3-sinamoil-9H-karbazol-9-il)etoksi)ftalonitril (KRB-7) ligands were synthesized, respectively. Finally, new mono acetate carbazole-based Zn (II) phthalocyanine KRB-5 and mono chalcone carbazole-based Zn (II) phthalocyanine KRB-8, which are the target compounds, were obtained from phthalonitrile derivatives synthesized for the first time. The structures of the synthesized compounds were characterized by spectroscopic methods such as FT-IR, NMR, elemental analysis, MALDI-TOF MS and UV-Vis spectroscopy. Photochemical and photophysical properties and cyclic voltagram studies of novel Zn(II) phthalocyanine complexes have been reported. For in vitro α-glucosidase inhibitory activities of carbazole Zn(II)-complexes (KRB-5 and KRB-8) and ligands (KRB-3, KRB-4, KRB-6 and KRB-7) compared with the standard drug acarbose and the enzyme kinetic studies were carried out. In addition, the inhibitory effects of these new phthalocyanines and their ligands on carbonic anhydrase I (hCA I) and II (hCA II) isoenzymes of human erythrocytes were investigated. Phthalonitrile compounds (KRB-4 and KRB-7) showed the best activity against α–glucosidase enzyme, while new carbazole-based Zn (II) phthalocyanines (KRB-5 and KRB-8) nanomolar (nM) at the level showed the best activity against carbonic anhydrase (I and II). α-Glucosidase enzyme kinetic studies were performed and it was determined that the compounds were competitive inhibitors such as acarbose. In both parts of the thesis study, KRS-33 haloconduritol compound (IC50 = 27.56 ± 0.28 µM) and the KRB-7 phthalonitrile derivative (IC50 = 7.54 ± 0.51 µM) containing chalcone were the compounds exhibiting the strongest activity against α-glucosidase enzyme among the tested compounds.