VIETNAM NATIONAL UNIVERSITY, HANOI OF VIETNAM HANOI UNIVERSITY OF SCIENCE --------------------- DO THAO THUYEN SYNTHESIS AND CYTOTOXICITY OF DITHIAETHER DERIVATIVES MASTER THESIS Hanoi - 2022 VIETNAM NATIONAL UNIVERSITY, HANOI OF VIETNAM HANOI UNIVERSITY OF SCIENCE --------------------- DO THAO THUYEN SYNTHESIS AND CYTOTOXICITY OF DITHIAETHER DERIVATIVES Major: Organic Chemistry Major number: 8440112.02 MASTER THESIS SUPERVISOR: ASSOC. LE TUAN ANH Hanoi - 2022 ACKNOWLEDGEMENTS This research is carried out in Organic Synthesis Lab 2, Faculty ofChemistry, VNU University of Science, Vietnam National University, Hanoi. I would like to express my sincere gratitude to my supervisors Assoc. Le Tuan Anh for your advice, guidance and enthusiatically supporting me during the course of this research.
I am extremely grateful that you took me on as a student and have a faith in me. Thank you to Prof. Peter Huy who spent time reading and giving me a lot of advices. I have benefited greatly from your wealth of knowledge and meticulous editing.
Thank you to Assoc. Tran Thi Thanh Van and Dr. Dao Thi Nhung for encouragement and sharing evaluable experience to me. Thank you to all my colleagues and colaborators who were always willing to help me during the experimental process as well as in my difficult time.
Most importantly, I am gratefull for my family’s unconditional, unequivocal and loving support. TABLE OF CONTENT INTRODUCTION. Crown ether containing piperidone and pyridine heterocyclic …………. Multicomponent condensation reaction.
Hantzsch dihydropyridine synthesis……………………………………. Synthesis of acyclic dithiaether derivatives. Synthesis of 1,5- bis(2-formylphenthio)-3-oxapentane (3). Synthesis of 1,5-bis(2-acetylphenthio)-3-oxapentane (5).
Synthesis of cyclic dithiaether derivatives. Synthesis dithiaether derivatives containing 2,6-diaryl-piperidin-4-one (7a-c). Synthesis of dithiaether derivatives containing γ-aryl-pyridine (9a-e). RESULTS AND DISCUSSIONS.
Synthesis of Thiopodand derivatives 3, 5. Synthesis of thiacrown ethers derivatives 7a-d. Synthesis of thiacrown ethers derivatives 9a-e. Biological evaluation of dithiaether derivatives.46 LIST OF FIGURES Figure 1.
Classes of cyclic and acyclic ligands. Some podands are found in nature. Examples of monopodands. Examples of crown ether.
Dialkyldiaza-18-crown-6 lariat ethers. crown ether ligands were synthezied by Yildiz and co-workers. Pyridine-containing macrocycles exhibiting toxicity to bacteria and fungi. (γ-arylpyridino)dibenzoaza-14-crown-4 ether and cytotoxic activity.
(γ-piperidono)- 1,7-diaza-14-crown-4 ethers and cytotoxic activities. Exemplary thia crown ether (thio-18-crown-5-ether). Thiacrown ether 31 and 32. Macrocyclic thioether–esters 33.
Comparison of ordinary sequential syntheses wirth MCRs. The structure fomular of compound 78a-c. Molecular structure of azacrown-thioether 80e in the representation of atoms by anisotropic displacement ellipsoids. 36 LIST OF SCHEMES Scheme 1.
The synthesis of 1,4,8,11-Tctrathiacyclotetradecane 11. General reaction synthesis off thiacrown ether. Synthesis of thia benzo-crown ethers according to Schneider and co- workers. Examples of MCRs developed over the decades.
Example for a Mannich reaction. General scheme for the Petrenko-Kritschenko piperidone synthesis. Gerneral scheme for the Hantzch reaction. Hantzch reaction in the synthesis poyridine-containing crown ether.
Target structures and synthsis plan for the current work. Synthesis of 1,5- bis(2-formylphenthio)-3-oxapentane 74. Synthesis of 1,5-bis(2-acetylphenthio)-3-oxapentane 76. Synthesis of dithiacrown ether 78a.
Synthesis of dithiacrown ether 78b. Synthesis of dithiacrown ether 78c. Synthesis of dithiacrown ether 78d. Synthesis of dithiacrown ether 80a.
Synthesis of dithiacrown ether 80b. Synthesis of dithiacrown ether 80c. Synthesis of dithiacrown ether 80d. Synthesis of dithiacrown ether 80e.
General synthesis of thiopodand derivatives 74 and 76. General synthesis of thiacrown ether 78a-d .3 The suggested pathway to synthesis of thiacrown ethers 78a-c. The reaction of dialdehyde 74 with benzyl acetoacetate 78d. The suggested mechnism for the formation of compound 78d.
General synthesis of thiacrown ether 80a-e .35 LIST OF TABLE Table 3. The percent of cell survival induced by compounds 74, 76. Results of IC50 tests of compound 74. The percent of cell survival induced by compounds 78a-d.
Result of IC50 test of compound 78c. The percent of cell survival induced by compounds 80a-e .39 LIST OF ABBREVIATION Notion Meaning Comp. Concentration DMF Dimethyl formamide DMSO Dimethyl sulfoxide EtOAc Ethylacetate EtOH Ethanol Hela HeLa cervical cancer cells HEP-G2 Human hepatocellular carcinoma HRMS High resolution mass spectrometry IR Infrared Spectrometry LCMS Liquid chromatography mass spectrometry LU-1 Human lung adenocarcinoma MCF-7 Human breast adenocarcinoma MCRs Multicomponent condensation reaction MIC Minimal inhibitory concentration Mp Melting point NaOEt Sodium ethoxide n-Hex n-Hexane NMR Nulear magnetic resonance RD Human rhabdomyosarcoma Rf Retardation factor Rt Room temperature TLC Thin layer chromatography INTRODUCTION Crown ethers and their open chain analogues (podands) are of considerable interest, because they can be used as functional fragments combined with other groups in organic compounds. Crown ethers constitute one of the most important classes of macrocyclic compounds.
Moreover, when replacing one or more oxygen atom with sulfur, thiacrown ethers result, which have attracted the attention of researchers due to their wide-spread applications in biology, supramolecular chemistry, new materials, medicine and the chemical industry. Indeed, the presence of a piperidone or pyridine moiety in thiacrown ethers as part of a single macrocyclic molecule could increase the potential of biological activity of such derivatives even further. Based on fundamental references along with preparation to initial compounds, in this thesis, the synthesis of dithiaether derivatives including athiapodand and either piperidone or pyridine-containing thiacrown ethers is described. Podands Podands are a family of linear multidentate ligands, which include acyclic polyethers.
The name “podand” was introduced in 1979 by Vogtle and Weber and has been derived from the combination of the combining form “pod” (having a foot) and ligand.[36] Over time, the type of ligands rapidly developed from podands over very flexible macrocyclic “coronands” to bicyclic “cryptands” (Figure 1. Especially, the corodand type of ligands, which are also known as crown ethers, are widely studied and applied today. Classes of cyclic and acyclic ligands Crown ethers and cryptands possess cavities specific for a single size of cation or neutral host molecule. In contrast, the ‘wrap-around’ capability of podands having terminal functionalities allow to adopt the appropriate sizes during complexation with metal cations or neutral molecules in a manner unique among ligands.
This is rationalized by the special structure of their flexible donor atoms containing chain and podand receptor sites, which can form complexes with many cations ranging from alkali and alkaline earth metals to various transition metals. By chemical modification of the arms (e., changing the chain length or the donor atom) and under certain experimental conditions, podand receptors can selectively form complexes with metal ions.[10] As a recognition motif, podand based receptors have been reported to be used successfully as recognition components in electrochemical sensors and optical sensors.[8] In order to construct ionophore model systems, various macrocyclic compounds, such as crown ethers, cryptands, and calixarenes, have been 2 synthesized and structurally characterized. In addition to these macrocyclic compounds, podands have been employed as noncyclic ionophore models.[27] There are excellent podands found in nature such as monensin 1 and lasalocid 2, which are naturally occurring polyether antibiotics (Figure 1. Some podands are found in nature.
Compounds 3 and 4 are examples of monopodands, which are acyclic analogs of crown ethers (Figure 1. Examples of monopodands 1. Thiopodand Thiopodands are obtained by replacing oxygen with sulfur atoms (Figure 1. They have a profound effect on the coordinating ability, which is reasond by the lower electronegativity and therefore increased Lewis-basicity of sulfur.
Nevertheless, the size of the cavity remains approximately unaltered.[7] The classical method for the synthesis of macrocyclic sulfides with four sulfur atoms from 5 and 6 was first described in 1967 (Scheme 1. The synthesis of 1,4,8,11-Tctrathiacyclotetradecane 11 Initally, 1,3-propanedithiol was alkylated by means of 2-chloropropanol under basic conditions. The resulting diol 5 was next reacted with an excess of thiourea under acidic conditions, which effects the formation of a dithiouronium intermediate. Eventually, hydrolysis by means of KOH provides dithiol 6.
The synthetic sequence was complemented by nucleophilic substitution using 1,3-dibromopropaen in the presence of cesium carbonat as base. Among the linear polyether derivatives, podanes containing sulfur have been synthesized and applied in chemical engineering as ligands to separate alkali, alkaline 4 earth and transition metals.[33] In particularly, to protect the environment, thiopodands are harnessed to remove mercury from water. Crownether Crown ethers are organic cyclic compounds that contain several ether functional groups. Common crown ethers are oligomeric macrocycles consisting of ethylene oxide CH2CH2O, of which tetramers (n=4), pentamers (n=5) and hexamers (n=6) are the most important derivatives.
Examples of crown ether. Compound 12 (also known as dibenzo-18-crown-6-ether) has been the frist crown ether described in literature, which has been synthesized by Charles Pederson in 1967, was isolated in a yield of 0.4% after reaction of Catechol and bis(2- chloroethyl) ether in the presence of sodium hydroxide. It was also the firstly reported substance that possesses the ability to form a complex with Na+ ions. [26] The low yield of the macrocyclization showcases, how challenging these stuctures are to prepare.
Since Charles Pedersen’s discovery, the chemistry of crown ethers has achieved considerable advancement. Macrocyclic compounds based on crown ethers proved to be of tremendous interest in biochemistry, phase transfer catalysis, sensor as well as in the design and synthesis of various oriented compound with specific 5 properties and applications. Crown ethers are known to have a high affinity toward alkaline and alkali metal cations with high selectivity, improving the solubility of these cations in non-polar solvent.[14] These ligands are also known for useful biological activities such as anti-fungi, antibacteria, or anti-cancer. A study by Koji Yagi and co-workers indicated the antifungal activity of crown ethers against woodecay fungigi, phytopathogenic fungigi and eumycetes, and Trichophytonspp for the treatment of dermatomycosis.[11] Dialkyldiaza-18-crown-6 lariat ethers having twin n-octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, 1-oxodecyl and 1- oxododecyl sidechains were prepared and studied with regard to their antimicrobial activity on E.
subtilis, and yeast S. Cerevisiae by Leevy et al. Dialkyldiaza-18-crown-6 ethers Yildiz and co-workers synthesized four new crown ether ligands of the Schiff base type, which showed ativity on various microorganisms.[38] All compounds show high anti-yeast activity against the yeast culture and compound 16d is the most effectual compound. Crown ether ligands were synthezied by Yildiz and co-workers McPhee et al.
produced propargylic sulfone-armed lariat crown ethers and bis(propargylic) sulfone crown ethers in order to connect the molecular recognition 6 of specific alkali metal ions to DNA damage under conditions of elevated alkali metal ion levels reported to exist in tumor cells. These compounds have been evaluated on their effect on various cancer cell lines and showed promising abilities to inhibit cell growth.[20] To date, only a few studies regarding the cytotoxicity of crown ethers have been published and they mainly refer to certain specialized functionalized crown ethers. Crown Ether Containing Piperidone and Pyridine Heterocyles Pyridine and piperidone are natural compounds, which have found many applications as pharmaceuticals. A lot of crown ethers comprehending either piperidone or pyridine moieties have been synthesized and evaluated regarding biological activities.
Several pyridine-containing dibenzo macrocycles, which had been synthesized by Zam and al., exhibited biological activities against microbes, as verfied by disk diffusion and by determination of MIC values (Minimal inhibitory concentration).[39] The compounds of type 17 are represented in Fig.8, whereby X is either CH2, CH2CH2, S, SS or CH2-S-CH2. They are distinguished by activities against a wide range of organisms including Staphylococcus aureus (G+), B. pneumonia (G–), Pseudomonas aeru- ginosa (G–), Kluyveromyces fragilis, Rhodotorula rubra, Candida albicans, Hanseniaspora guilliermondii and Debaryomyces hansenii with the MIC ranging from from ~3 to ~ 50 µg/mL. The best overall performace was apparent for the compound with a disulfide bridge (X= SS).
Pyridine-containing macrocycles exhibiting toxicity to bacteria and fungi Fourteenth different (γ-arylpyridino)dibenzoaza-14-crown-4 ethers were successfully synthesized and investigated towards their biological effects such as cytotoxic activity, antifungal activity, antibacterial activity and antioxidant activity. The following compounds have been identified to exhibit good cytotoxic activities on various human cancer cell lines as given (Figure 1. (γ-arylpyridino)dibenzoaza-14-crown-4 ether and cytotoxic activity In a research project of our working group, five (γ-piperidono)-1,7-diaza-14- crown-4 ethers were synthesized.[4] One of them inhibited the Hep-G2 and Lu-1 cell lines with IC50 = 4.