Browsing by Author "Bott, Tina"
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- ItemA specific dispiropiperazine derivative that arrests cell cycle, induces apoptosis, necrosis and DNA damage(2023) Liu, Victor P.; Li, Wai-Ming; Lofroth, Jack; Zeb, Mehreen; Patrick, Brian O.; Bott, Tina; Lee, Chow H.Dispiropiperazine compounds are a class of molecules known to confer biological activity, but those that have been studied as cell cycle regulators are few in number. Here, we report the characterization and synthesis of two dispiropiperazine derivatives: the previously synthesized spiro[2′,3]- bis(acenaphthene-1′-one)perhydrodipyrrolo-[1,2-a:1,2-d]-pyrazine (SPOPP-3, 1), and its previously undescribed isomer, spiro[2′,5′] bis(acenaphthene-1′-one)perhydrodipyrrolo-[1,2-a:1,2-d]-pyrazine (SPOPP-5, 2). SPOPP-3 (1), but not SPOPP-5 (2), was shown to have anti proliferative activity against a panel of 18 human cancer cell lines with IC50 values ranging from 0.63 to 13 μM. Flow cytometry analysis revealed that SPOPP-3 (1) was able to arrest cell cycle at the G2/M phase in SW480 human cancer cells. Western blot analysis further confirmed the cell cycle arrest is in the M phase. In addition, SPOPP-3 (1) was shown to induce apoptosis, necrosis, and DNA damage as well as disrupt mitotic spindle positioning in SW480 cells. These results warrant further investigation of SPOPP-3 (1) as a novel anti-cancer agent, particularly for its potential ability to sensitize cancer cells for radiation induced cell death, enhance cancer immunotherapy, overcome apoptosis-related drug resistance and for possible use in synthetic lethality cancer treatments.
- ItemAffinity crystallography: a new approach to extracting high-affinity enzyme inhibitors from natural extracts(2016) Aguda, Adeleke H.; Lavallee, Vincent; Cheng, Ping; Bott, Tina; Meimetis, Labros G.; Law, Simon; Nguyen, Nham T.; Williams, David E.; Kaleta, Jadwiga; Villanueva, Ivan; Davies, Julian; Andersen, Raymond J.; Brayer, Gary D.; Brömme, DieterNatural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach. The traditional approach resulted in the identification of the known inhibitor antipain (1) and its new but lower potency dehydration product 2, while the affinity crystallography approach led to the identification of a new high-affinity inhibitor named lichostatinal (3). The structure and potency of lichostatinal (3) was verified by total synthesis and kinetic characterization. To the best of our knowledge, this is the first example of isolating and characterizing a potent enzyme inhibitor from a partially purified crude natural product extract using a protein crystallographic approach.
- ItemAntimicrobial screening of phytochemicals produced by Albertan invasive weeds(2021) Supina, Brittany; Bott, Tina; Harcombe, KimberleyAntibiotic resistance has rendered many clinically-used antibiotics ineffective, creating an urgent need for new antimicrobial agents. Phytochemicals (secondary metabolites produced by plants) are produced in response to environmental stressors, and can inhibit the growth of bacteria, fungi and surrounding plants. Therefore, these phytochemicals offer an alternative source of antimicrobial compounds. The diversity and abundance of phytochemicals produced by plants can increase during the invasion of new habitats, making invasive weeds strong candidates for antimicrobial discovery. Despite this increase in phytochemical production, invasive plant species are often overlooked in favour of medicinal and edible plants, and few studies have characterized their antimicrobial activity. In this research, we used successive Soxhlet extractions with hexane, ethyl acetate, and methanol to extract the phytochemicals from Albertan invasive weed species collected from the Edmonton area. Using Kirby-Bauer disk diffusion assays, extracts were assessed for their ability to inhibit the growth of tester bacterial species including Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, and Staphylococcus aureus, which represent a range of common pathogens and bacterial types. Preliminary characterizations of extracts from multiple plant species, including common tansy (Tanacetum vulgare) and woolly burdock (Arctium tomentosum), showed promising inhibitory activity against several bacterial species, warranting further investigation. This study provides a starting point for further bioactivity and chemical characterizations of Albertan invasive weeds and highlights these invasive plant species as potential leads for the development of new antimicrobial treatments.
- ItemAzide trapping of metallocarbenes: generation of reactive C-acylimines and domino trapping with nucleophiles(2014) Bott, Tina; Atienza, Bren Jordan; West, F. G.Azide-tethered diazocarbonyl compounds undergo copper-catalyzed conversion to transient C-acylimines. These reactive intermediates can be trapped with a variety of carbon nucleophiles, giving rise to complex 3-indolinone frameworks, including those with adjacent tetra-substituted carbon centers, in a single transformation.
- ItemMethod optimization for the antimicrobial screening of pigmented invasive weed extracts(2020) Supina, Brittany; Giebelhaus, J. Duncan; Bott, Tina; Harcombe, KimberleyNew antimicrobial sources are required to address the growing prevalence of antibiotic-resistant pathogens. Secondary metabolites produced by plants (phytochemicals) are widely studied for their bacteria-inhibiting activity. Although the antimicrobial activity of medicinal and edible plants is well-known, few studies have examined compounds derived from invasive weeds. Invasive weeds produce large amounts of phytochemicals and can affect the bacterial composition of soils, making them a potential source of new bacteria-inhibiting compounds. Previously, the antimicrobial activity of Albertan invasive weeds was analyzed using Kirby-Bauer disk diffusion, broth microdilution, and drop check assays. Although the results showed promising bioactivity, plant pigment molecule interference at 600 nm prevented the accurate quantification of this antimicrobial activity during spectrophotometric analysis of broth microdilution assays. These issues highlighted a need for improved antimicrobial screening methods in the presence of pigmented plant extracts. Using ultraviolet-visible spectrophotometry, this study identified 750 nm as a wavelength that is minimally absorbed by phytochemicals in Albertan invasive weed extracts. As verified by bacterial growth curve analysis, this wavelength detects bacterial growth and may be used in broth microdilution assays to quantify antimicrobial activity. These findings offer a method for resolving pigment interference, improving the accuracy of antimicrobial screening of Albertan invasive weed extracts. These findings may also be applicable to the antimicrobial screening of other pigmented plant extracts and compounds. Overall, this method optimization may assist in the identification of new antimicrobial compounds derived from pigmented plant sources.
- ItemOne-carbon ring expansion of azetidines via ammonium ylide [1,2]-shifts: a simple route to substituted pyrrolidines(2009) Bott, Tina; Vanecko, John A.; West, F. G.Simple N-substituted azetidines were heated with diazocarbonyl compounds in the presence of catalytic Cu(acac)2 to furnish substituted pyrrolidines via Stevens [1,2]-shift. In all but two examples, complete selectivity was seen for ring expansion rather than migration of the other exocyclic group on the azetidinium nitrogen. The two exceptions, observed with ylides substituted with two carbonyl groups and lacking a stabilizing group at the 2-position of the azetidine, underwent exocyclic benzyl migration in preference to ring expansion.
- ItemThe construction of diverse nitrogen-containing heterocycles via the reaction of amines or azides with metallocarbenes(2011) Bott, TinaA fundamental goal in organic chemistry is the development of new and innovative ways of transforming simple building blocks into complex structures. The formation of ylides from the reaction of metallocarbenes with heteroatoms, such as the nitrogen of an amine or azide, is an example of a versatile methodology that is capable of undergoing divergent transformations into a wide variety of nitrogen-containing heterocycles. Azetidines are a class of small, strained amines, which display properties of their smaller and larger ring counterparts, aziridines or pyrrolidines, depending on the nature of their substitution pattern and their chemical environment. Chapter 1 will highlight the recent advances in the synthesis and application of these molecules in the recent literature. In chapter 2, we demonstrate the ability of azetidines to undergo ring expansion to pyrrolidines via the Stevens rearrangement of ammonium ylides. In this methodology, azetidines behave in a manner distinct from equivalent systems lacking ring strain. This investigation allowed for the construction of a range of differently functionalized pyrrolidines in a one step procedure from readily available azetidines and diazocarbonyl compounds. An extension of this successful azetidine ring expansion chemistry, to provide access to more complex heterocyclic ring systems, is described in chapter 3. The goal of this project was to determine the functionality required on the azetidine ring to direct the Stevens rearrangement in an intramolecular fashion. The use of carbonyl and silyl groups as a means of directing the transformation was investigated. These groups were chosen for their ability to be easily removed or transformed after the ring expansion process in order to access a broader range of compounds during later applications. In chapter 4, we describe a new methodology for the formation of C-acylimines through the reaction of organic azides with in situ generated metallocarbenes. Using aryl-tethered diazo-azide substrates allowed for the production of highly reactive C-acylimines, which in the presence of carbon nucleophiles could be subsequently trapped to form highly conjugated indolone derivatives. In contrast, when an alkyl tether was used, we observed the formation of an isolable C-acylimine, which displayed intriguing umpolung chemistry when treated with organozinc reagents.
- ItemUsing essential oils to teach advanced-level organic chemistry separation techniques and spectroscopy(2013) Bott, Tina; Wan, HayleyStudents sometimes have difficulty grasping the importance of when and how basic distillation techniques, column chromatography, TLC, and basic spectroscopy (IR and NMR) can be used to identify unknown compounds within a mixture. This two-part experiment uses mixtures of pleasant-smelling, readily available terpenoid compounds as unknowns to provide upper-division undergraduate students with experience in two major areas common to organic chemistry: (1) separation of mixtures and (2) structure determination. This experiment also encourages students to use deductive reasoning skills in addition to their expanding knowledge of spectroscopy for structure determination purposes.