PSU Knowledge Bank Collection:http://kb.psu.ac.th:80/psukb/handle/2553/55192024-03-29T10:46:11Z2024-03-29T10:46:11ZSynthesis of Small and Medium-Sized Ring Fused QuinazolinonesYotsakorn Saebanghttp://kb.psu.ac.th:80/psukb/handle/2016/193442024-01-25T08:22:16Z2023-01-01T00:00:00ZTitle: Synthesis of Small and Medium-Sized Ring Fused Quinazolinones
Authors: Yotsakorn Saebang
Abstract: Quinazolinones are natural alkaloids that play a crucial role in exhibiting a
wide range of biological and pharmacological activities. Among them, ring-fused
quinazolinones are commonly found in various natural alkaloids and synthetic
molecules, showcasing a diverse array of bioactivities. In this study, we focused on
synthesizing tricyclic quinazolinones. Medium and small-sized ring fused
quinazolinones were achieved via direct cyclization of quinazolinone intermediates
having tert-butyl ethylcarbamate and H as nitrogen substituents, respectively. Firstly,
we focused on cyclic amine and urea moieties to fuse with quinazolinone skeletons to
obtain novel 11-membered ring fused quinazolinones. Key intermediates were
prepared through a copper-catalyzed domino reaction. We successfully incorporated
an alkyl side chain with a functionalized amine moiety. The construction of the 11-membered ring urea moiety involved direct cyclization using 1,1'-
carbonyldiimidazole (CDI) of a diamino quinazolinone intermediate, which was
generated through a series of steps including reductive amination and Bocdeprotection. Secondly, we explored the synthesis of deoxyvasicinone derivatives,
which are smaller-sized ring fused quinazolinones. The cyclization process for
forming the smaller-sized ring was carried out under both basic and acidic conditions,
resulting in the formation of two deoxyvasicinone analogues. Under basic conditions,
1-acetyl-2,3-dihydro pyrrolo[2,1-b]quinazolin-9(1H)-one analogues were synthesized
via direct cyclization in the presence of I2. Under acidic conditions, we synthesized 1-
acetylpyrrolo[2,1-b]quinazolin-9(3H)-one analogues through a two-step process
involving α,α-dichlorination followed by intramolecular C–N bond cyclization, with
para-toluene sulfonic acid (PTSA) serving as a catalyst. The developed synthetic
strategies provide valuable insights into the preparation and modification of
quinazolinone derivatives.
Description: Doctor of Philosophy (Chemistry(International Program)), 20232023-01-01T00:00:00ZElectrochemical Biosensors Based on Molecularly Imprinted Polymer Biomimetic ReceptorsWardani, Nur Indahhttp://kb.psu.ac.th:80/psukb/handle/2016/192362023-12-20T06:40:38Z2023-01-01T00:00:00ZTitle: Electrochemical Biosensors Based on Molecularly Imprinted Polymer Biomimetic Receptors
Authors: Wardani, Nur Indah
Abstract: This thesis presents the utilization of molecularly imprinted polymer (MIP) biomimetic receptors as recognition elements in the development of two MIP electrochemical biosensors. One is a MIP cryogel for the direct detection of insulin, performed in a flow system. The other is an electrochemical biosensor with dual MIPs for the simultaneous determination of creatinine and albumin to provide the albumin to creatinine ratio (ACR) value. The insulin sensor was prepared using a gold electrode modified with carboxylated multiwalled carbon nanotubes (f-MWCNTs) to provide a large surface area platform for the high loading of the MIP cryogel and to increase the conductivity of the sensor. The MIP cryogel porous structure provided a large number of the imprinted recognition sites and improved the access of insulin to/from the MIP cavities. In addition, the flow system facilitated the mass transfer and limited the non-specific binding. This MIP cryogel provided a 0.050-1.40 pM linear range and a low limit of detection (LOD) of 33 fM with good stability at room temperature. For the dual MIP sensor, it was prepared on the dual screen-printed carbon electrodes (SPdCEs) modified with f-MWCNTs and redox probes, polymethylene blue (PMB) and ferrocene (Fc). The surface imprinting and electropolymerization were carried out to obtain more controlled imprinted binding sites of the two analytes on the respective electrode. This sensor was able to selectively recognize the two analytes with linear ranges of 5.0-100 ng mL-1 and 100-2500 ng mL-1 for creatinine and 5.0-100 ng mL-1 for albumin with an LOD of 1.5±0.2 ng mL-1 and 1.5±0.3 ng mL-1, respectively. The two MIP electrochemical biosensors exhibited good reusability and the real sample detection results showed comparable performances to the clinically employed standard methods (P 0.05). The good performances of these MIP electrochemical biosensors, i.e., high sensitivity and selectivity, low limit of detection, and high stability indicate their potential as alternative methods for analysis.
Description: Doctor of Philosophy (Chemistry), 20232023-01-01T00:00:00ZSyntheses of 7-O-Methylnigrosporolide, Pestalotioprolide D, Nigrosporolide, Mutolide and (4S,7S,13S)-4,7-Dihydroxy-13-tetradeca-2,5,8-trienolideAticha Thirapornhttp://kb.psu.ac.th:80/psukb/handle/2016/191562023-12-07T07:56:01Z2023-01-01T00:00:00ZTitle: Syntheses of 7-O-Methylnigrosporolide, Pestalotioprolide D, Nigrosporolide, Mutolide and (4S,7S,13S)-4,7-Dihydroxy-13-tetradeca-2,5,8-trienolide
Authors: Aticha Thiraporn
Abstract: 7-O-Methylnigrosporolide (1), pestalotioprolide D (2), nigrosporolide (3), (4S,7S,13S)-4,7-dihydroxy-13-tetradeca-2,5,8-trienolide (4) and mutolide (5) are 14-membered macrolides isolated from various strains of fungi. The core structure of compounds 1 and 3–5 consists of a 14-membered macrolactone with E-olefin at C2–C3 and Z- or E-double bond at C5–C6 and C8–C9 as well as three alcohol stereogenic centers at the 4, 7 and 13 positions. The structure of 2 is nearly identical to 1 but 2 contains one ketone functional group at the C4-position and saturation at C2–C3. Due to the promising biological activities of this class of natural products and unprecedented total syntheses of 1–5, this work involves the syntheses of these natural products to confirm the absolute configurations as well as to further evaluation of biological activities. The key strategy of our synthesis relied on Shiina macrolactonization to assemble 14-membered macrolactone of targets 1–5. The C2–C3 E-olefin moiety of macrolides 1 and 3–5 was constructed via Wittig olefination. The C8–C9 Z- and E-alkenes of 10 and 11 for the synthesis of 1–4 were generated from Lindlar and Red-Al reduction of propargylic alcohol 9, respectively. Propargylic alcohol intermediate 9 was synthesized by addition of the corresponding acetylide of (S)-tert-butyl(hept-6-yn-2-yloxy)dimethylsilane (7) to (Z)-enal 8 to form the C7–C8 bond and install the C7 alcohol stereogenic center. The synthesis of (S)-alkyne 7 was accomplished in 5 steps from (S)-propylene oxide (5), while (Z)-enal 8 was prepared from (S)-benzyl glycidyl ether (6) in 7 steps using Jacobsen hydrolytic kinetic resolution (HKR) to install the stereogenic center at the C4-position and Still–Gennari olefination to generate C5–C6 Z-olefin as the key strategies. The synthesis of mutolide (5) was accomplished via the similar synthetic procedure as that of 4 but the E-double bond at C8–C9 was constructed via cross metathesis between (R)-hept-6-en-2-yl benzoate (13) and chiral allylic alcohol 14. Alkene 13 was synthesized in 2 steps from (R)-propylene oxide (12). Chiral allylic alcohol 14 was prepared in 8 steps via the similar synthetic sequence as (Z)-enal 8 except for the formation of E-alkene at C5–C6, which was achieved via Wittig olefination. Our research group found that the tert-butyldiphenylsilyl (TBDPS) group was a suitable protecting group for the C4 hydroxy group of the macrocyclic intermediates, which allowed for smooth final deprotection. In addition, our synthesis led to the hypothesis that macrolide pestalotioprolide D (2) might be an artifact from a facile 1,2-hydride shift of 7-O-methylnigrosporolide (1). The syntheses of macrolides 1–4 were accomplished in a longest linear sequence of 17 steps and total of 22 steps and 1.7%, 2.6%, 1.8%, 1.1% overall yields, respectively. The synthetic 5 was obtained in a longest linear sequence of 16 steps and a total of 18 steps in 1.5% overall yield. The 1H and 13C NMR spectroscopic data, HRMS data as well as specific rotation of synthetic compounds 1–5 were in excellent agreement with those reported, which confirmed the assigned absolute configurations of the natural products. Cytotoxic activities of synthetic 7-O-methylnigrosporolide (1) and pestalotioprolide D (2) against six human cancer cell lines consisting of two breast adenocarcinoma (MDA-MB-231 and MCF-7), three cervical carcinoma (C33A, HeLa and SiHa) and one colorectal carcinoma (HCT116) cell lines were evaluated. Compound 2 showed more potent cytotoxic activities against these cancer cell lines than 1. Moreover, the SiHa cervical cancer cell line was the most sensitive cell line to synthetic 1 and 2 with IC50 values of 35.17 10.77 M and 8.90 2.51 M, respectively. Synthetic compounds 3–5 were tested for their cytotoxic activities against three cancer cell lines, including HCT116, MCF-7 and Calu-3 lung adenocarcinoma cell lines as well as their inhibitory effect on cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride secretion in human intestinal epithelial (T84) cells. Mutolide (5) showed significant cytotoxic activity against HCT116 colon cancer cells with an IC50 value of ~12 M. Moreover, 5 also exhibited potent CFTR inhibitory effect with an IC50 value of ~1 μM. However, macrolides 3 and 4 displayed no cytotoxic effects on three cancer cell lines and showed inhibitory effects on the CFTR channels with less efficacy compared to 5.
Description: Doctor of Philosophy (Chemistry (International Program)), 20232023-01-01T00:00:00ZOptosensor Based on Nanocomposite Sensing Probes and Composite Adsorbents for the Determination of Trace Organic Compounds in Foods and BeveragesNaphatsakorn Orachornhttp://kb.psu.ac.th:80/psukb/handle/2016/191362023-12-06T02:32:03Z2023-01-01T00:00:00ZTitle: Optosensor Based on Nanocomposite Sensing Probes and Composite Adsorbents for the Determination of Trace Organic Compounds in Foods and Beverages
Authors: Naphatsakorn Orachorn
Abstract: This thesis aimed to develop optosensor using composite sensing probes and composite adsorbents for the determination of trace organic compounds in food and beverage samples. This thesis is composed of two parts including the optosensor and sample preparation method, which are divided into four sub-projects.
The first part focused on the development of optosensor using nanocomposite probes based on the fluorescence quenching of molecularly imprinted polymer (MIP) composited with quantum dots (QDs) for the detection of organic compounds including lomefloxacin, mafenide and sulfisoxazole. Molecularly imprinted polymer was synthesized via a sol-gel polymerization method consisting of template molecules (lomefloxacin, mafenide and sulfisoxazole), a functional monomer (3-aminopropyltriethoxysilane) and a cross-linker (tetraethyl orthosilicate). After template removal from MIP layer, the specific imprinted cavities are generated that are complementary to the templates in terms of functional groups, shape and size. For the first sub-project, the fabricated fluorescent probe combined the high selectivity of molecularly imprinted polymer, excellent sensitivity of cadmium telluride quantum dots (CdTe QDs) and high adsorption ability of polyaniline (PANI) and graphene oxide (GOx). The nanocomposite PANI-GOx-MIP-CdTe QDs probe was successfully fabricated and employed for the detection of lomefloxacin. The fluorescence emission of the developed fluorescent probe was linearly reduced with increasing concentrations of lomefloxacin from 0.10 to 50.0 micrograms per liter, and the developed probe provided a low detection limit of 0.07 micrograms per liter. The developed optosensor can be utilized to detect lomefloxacin in milk, chicken meat and egg samples, and the obtained recoveries ranged from 81.5 to 99.6% with relative standard deviations (RSDs) below 7%. For the second sub-project, dual magnetic composite fluorescent probes were developed and fabricated by incorporating metal organic framework (MIL-101) with graphene quantum dots (GQDs) or cadmium telluride quantum dots into a magnetic molecularly imprinted polymer (MMIP) for the enrichment and simultaneous detection of mafenide and sulfisoxazole. The dual MIL101-MMIP-GQDs and MIL101-MMIP-CdTe QDs probes can detect mafenide and sulfisoxazole at the same time since their fluorescence emission intensities were different at 435 and 572 nm, respectively. Under optimal condition, the emission intensities of dual fluorescent probes were linearly decreased with increasing mafenide and sulfisoxazole concentrations ranging from 0.10 to 25.0 micrograms per liter with low detection limits of 0.10 micrograms per liter. The developed dual probes successfully detected ultra-trace levels of mafenide and sulfisoxazole in milk with satisfactory recoveries of 80.4 to 97.9% and RSDs lower than 5%. In addition, the accuracy of these developed optosensors was confirmed by comparing with that of the high performance liquid chromatography (HPLC) technique. The analytical results produced by the developed optosensor not only agreed well with HPLC method but also exhibited superior sensitivity. The developed optosensor of both sub-projects is a reliable and effective method for the determination of trace lomefloxacin, mafenide and sulfisoxazole in food and beverage samples. The outstanding properties of the developed optosensor are high selectivity, good sensitivity, simple fabrication, short analysis time, uncomplicated measurement and cost-effectiveness.
The second part focused on the development of composite adsorbents for the simultaneous extraction and enrichment of multiple target compounds including phthalate esters and nonsteroidal anti-inflammatory drugs (NSAIDs) coupled with chromatographic analysis. For the third sub-project, a composite adsorbent of graphene oxide, metal organic framework and silica-modified magnetite (Fe3O4-SiO2) incorporated into alginate hydrogel fiber was fabricated and utilized as dispersive magnetic solid-phase extraction (D-MSPE) adsorbent for the extraction, enrichment and determination of four phthalate esters including dibutyl phthalate (DBP), bis(2-ethylhexyl) phthalate (DEHP), benzyl butyl phthalate (BBP) and di-n-octyl phthalate (DNOP). Alginate hydrogel was employed as a non-toxic and biodegradable supporting material, which can be created in various shapes and readily entrap other composite materials. GOx and MIL-101 were utilized as the primary adsorption materials to adsorb phthalate esters through hydrogen bonding, hydrophobic and pi-pi interactions. The Fe3O4-SiO2 nanoparticles incorporated in hydrogel fiber facilitated rapid isolation of adsorbent from sample solution using an external magnet. The applied composite GOx/MIL-101/Fe3O4-SiO2 alginate hydrogel fiber for the extraction of phthalate esters and quantitative analysis by HPLC method exhibited wide linear response in the range of 5.0 to 250.0 micrograms per liter for DEHP and DNOP and 3.0 to 250.0 micrograms per liter for BBP and DBP. The limit of detections were achieved in the range of 3.0 to 5.0 micrograms per liter. The developed method was successfully utilized to extract and determine phthalate esters in tea, water and juice samples, and the acquired recoveries were satisfactory in the range of 80.7 to 89.9% with RSDs below 8%. In addition, the developed composite hydrogel adsorbent had excellent stability which can be reused up to 16 times. The fourth sub-project was a composite magnetic adsorbent of graphene quantum dots, silica-modified magnetite and mesoporous carbon (MPC) embedded into a molecularly imprinted polymer for the extraction of NSAIDs. The composite GQDs/Fe3O4-SiO2/MPC/MIP adsorbent was successfully fabricated and applied as D-MSPE adsorbent for the extraction, enrichment and determination of three NSAIDs. The selectivity of the adsorbent can be enhanced with MIP, which produced specific imprinted cavities for NSAIDs. In addition, GQDs and MPC enabled increasing adsorption ability between the composite adsorbent and NSAIDs via pi-pi stacking, hydrophobic interaction and hydrogen bonding. The extracted NSAIDs were identified and determined by HPLC. Under optimal condition, the developed method exhibited good linearity with ranges of 0.5 to 100.0 micrograms per liter for diflunisal and mefenamic acid and 1.0 to 100 micrograms per liter for flurbiprofen. The limit of detections were acquired from 0.5 to 1.0 micrograms per liter. The satisfactory recoveries of composite magnetic MIP adsorbent for NSAIDs extraction in milk samples were achieved from 81.4 to 93.7% with RSDs lower than 7%. Furthermore, the fabricated GQDs/Fe3O4-SiO2/MPC/MIP adsorbent can be effectively used to extract NSAIDs up to 6 cycles. The distinctive advantages of the developed composite adsorbents are high extraction efficiency, simple preparation, low solvent consumption, good reproducibility and reusability.
In conclusion, the developed optosensor with composite fluorescent probes and the developed D-MSPE with composite adsorbents in this thesis were successfully applied for the determination of trace organic compounds in foods and beverages with good analytical performances. The developed methods have numerous advantages including simple fabrication, good sensitivity, high selectivity, low toxicity, ease of use and cost-effectiveness. In addition, they can be adapted as alternative strategies for the determination of other organic compounds in a variety of complex samples.
Description: Doctor of Philosophy (Chemistry(International Program)), 20232023-01-01T00:00:00Z