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Current Science

"If medicine was like software, organic chemistry would be the boot code."

Synthesis of photocaged prodrugs and stereoselective esterification of podophyllotoxin, antiproliferative lignins for targeting cancer

Cytotoxic small molecules such as podophyllotoxin, doxorubicin, and paclitaxel have demonstrated their potential to be potent antitumor agents. However, their toxicity has created problems upon delivery, as the absence of absolute specificity to cancer cells causes damage in non-cancerous tissues. Among the small molecules, podophyllotoxin is an especially valuable candidate for anticancer treatments due to its ability to inhibit cell division by halting tubulin polymerization. Despite being FDA approved and commercially available, its non-specificity upon dosage limits its potential in the clinic. To mitigate these challenges, we introduce a chemically modified, inactive version of podophyllotoxin that can be released into active cytotoxic form upon photochemical release. Among the activation methods, photorelease has shown immense potential due to its increased bioorthogonality and ease of control. Our previous efforts to prodrug podophyllotoxin centered around a 2-nitrobenzyl functionality as a photocage, which as reported in previous literature will be released upon UV photoirradiation via a Norrish type II mechanism. We first report two-step pathways in synthesizing two novel o-nitrobenzyl photoreleasable prodrugs, allowing the small molecules to be photoreleased and activated at will. However, due to the clinical limitations of UV light, we additionally present an infrared cleavable prodrug of podophyllotoxin–a more practical and medically effective compound as IR light is skin permeable–through a two-step photocage reaction with coumarin. Furthermore, we pursue the synthesis of a more efficient podophyllotoxin carbonate by attaching carbonyldiimidazole to podophyllotoxin. Through these two new directions, we aim to optimize the production of prodrug podophyllotoxin.


Monastrol and 2,4-dihydropyrimidines for anticancer therapy

Benchtop nuclear magnetic resonance (NMR) spectroscopy has enabled the monitoring and optimization of chemical transformations while simultaneously providing kinetic, mechanistic, and structural insight into reaction pathways with quantitative precision. Moreover, benchtop NMR proton lock capabilities further allow for rapid and convenient monitoring of various organic reactions in real-time, as the use of deuterated solvents is not required. The complementary role of 19F NMR-based kinetic monitoring in the fluorination of bioactive compounds serves many benefits in the drug discovery process, since fluorinated motifs additionally improve drug pharmacology. In this study, 19F NMR spectroscopy was utilized to monitor the synthesis of novel trifluorinated analogs of monastrol, a small molecule kinesin Eg5 inhibitor, and to probe the mechanism of the Biginelli cyclocondensation, the multicomponent reaction used to synthesize dihydropyrimidine scaffolds. After isolating a trifluorinated hexahydropyrimidine product that did not dehydrate through the Biginelli cyclocondensation, we underwent this final step to obtain 6-trifluoromonastrol. This workflow was also applied to the synthesis of a trifluorinated analog of LaSOM 63, a compound previously reported to induce apoptotic cell death through the inhibition of ecto-5’nucleotidase activity. To further our studies, we used computational approaches to model the energetic pathways for the final dehydration in the formation of monastrol, LaSOM 63, and their respective trifluorinated analogs. Here, we present discoveries regarding the application of benchtop 19F NMR spectroscopy to provide high resolution reaction kinetics and mechanistic insight into the Biginelli reaction. See our latest paper in ACS Omega!

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Pharmacophore mapping and discovery of phenylisoxazole-based piperazyl acrylate covalent inhibitors of G12C K-RAS

K-RAS is a GTPase involved in several cellular pathways related to cell survival and persistence, including the RAS/MAPK pathway, and is a known oncogene, whose mutations are implicated in a broad variety of cancers, including breast, ovarian, lung, and blood cancers. Specifically, the G12C mutation in the Switch II domain has been recently targeted by a number of groups for development of covalent small molecule inhibitors, first pioneered by the Shokat lab at UCSF and later by industry groups at Mirati, Janssen, Amgen, and others. More recently, AMG-510 (Sotorasib) has received FDA authorization as the first KRAS inhibitor approved for clinical use as a chemotherapeutic agent; MRTX849 (Adagrasib) is in advanced clinical trials. To this end, we have used computer modeling tools to map a pharmacophore hypothesis for the northern hemisphere aryl fragment, whose binding engagement to G12C KRAS is poorly understood; and with these tools we have in parallel devised a scalable and rapidly diversifiable three step synthesis of isoxazole-based KRAS inhibitors. In vitro evaluation of the efficacy of our compounds is currently underway.


Small molecules in chemical neuroscience: analogs of rivastigmine and vinpocetine

Many derivatives of alkaloid compounds, which are naturally occurring in plants, are used to treat neurodegenerative diseases such as schizophrenia and dementia. These include physostigmine and its synthetic alternatives, one of which is rivastigmine. Our study attempts to synthesize rivastigmine and a series of novel analogs in order to understand the effects such compounds have on neuroactivity in schizophrenic C. elegans through computational molecular docking and in-vitro screens. See our latest paper in the Journal of Emerging Investigators! / Editor's Choice!


Semisynthesis of bioactive andrographolide analogs as novel Nf-KB modulators

Andrographolide is a natural product extracted from the plant Andrographis paniculata, and has been shown to be incredibly versatile in biological activity. Andrographolide demonstrates anticancer, antiviral, antioxidant, and more properties, while also being relatively nontoxic. The compound has an ɑ, β unsaturated lactone, which serves as a Michael acceptor, irreversibly alkylating its protein targets. Numerous studies have been reported attempting to create novel analogs of andrographolide in order to increase efficacy, but the complexity of the compound proves to be an issue in development. We aim to build on current approaches to improving andrographolide as a drug, as well as experimenting with chemoselective modification of both the A/B trans-decalin core, which we postulate is important for target binding, and the C-ring butenolide warhead. See our latest paper in the Journal of Emerging Investigators!


Photochemical and photocatalytic C-H fluorination strategies

Fluorination of organic compounds has emerged as a significant topic in medicinal chemistry due to the multiple benefits a drug obtains with the presence of a fluorine group. Here, we fluorinate eugenol through excitation and radical formation via a photocatalyst, followed by capture and fluorination of the position with a fluorinating agent. Our efforts involve computational modeling as well as methodology studies with various photocatalysts and fluorinating agents, in addition to radical initiators, in order to control site selectivity of eugenol's fluorination.

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Berberine analogs as DNA-binding photosensitizers

Berberine, a natural product alkaloid, has been shown to exert biological activity via in situ production of singlet oxygen, a highly reactive oxygen species, when photo irradiated. Berberine utilizes singlet oxygen in its putative mechanism of action, wherein it forms an activated complex with DNA and photosensitizes triplet oxygen to singlet oxygen to specifically oxidize guanine residues, halting cell replication, leading to cell death. This has potential application in photodynamic therapy, alongside other such compounds which also act as photosensitizers and produce singlet oxygen in situ. The quantification of singlet oxygen in various photosensitizers, including berberine, is essential for determining their photosensitizer efficiencies.  Here, we present the usage of time course 1H nuclear magnetic resonance (NMR) spectroscopy to trap singlet oxygen via a 4+2 cycloaddition with terpinene to monitor Berberine & Berberine derivative's photosensitizing ability.


Doramectin and antiparasitic avermectin natural products

Doramectin, an antiparasitic drug used in veterinary medicine, is part of a class of versatile avermectins extracted from the fermentation broth of Streptomyces avermitilis, a soil bacterium species. These 16-membered macrocyclic lactones have displayed insecticidal and anthelmintic activity, and most recently, antiviral and anticancer activity, making them biologically potent molecules of interest. Here, we compare the effects of three avermectins, doramectin, ivermectin, and abamectin, on vinegar eels and C. elegans through computational modeling and in vivo assays. Doramectin consists of disaccharide, benzofuran, and spiroketal moieties, and removal of the disaccharide yields an aglycone scaffold with two allylic alcohols. In an additional methodology work, we attempt the selective oxidation of allylic alcohols at C5 and C13, comparing their relative nucleophilicity. Moreover, the disaccharide is especially crucial due to its hydrophilicity and hydrogen bond donor capabilities - this hydrophilic head draws doramectin to the hydrophobic residues of glutamate-gated chloride channels in parasites, increasing cytotoxicity. Replacing this disaccharide with a more hydrophilic moiety will likely amplify bioavailability and bioactivity.


Photocaged 2-nitrobenzyl prodrugs and development of photolabile antibody-drug conjugates

The toxicity of many pharmaceutical drugs, specifically cancer drugs, is known to have many harmful side effects on patients. One method towards reducing toxicity while maximizing efficacy of a drug is the development of prodrugs, specifically through the use of photo-cleavable o-nitrobenzyl linkers. Using aromatic and benzylic substitutions we aim to test the photo-release kinetics of various linker analogs as well as synthesis of antibody-drug conjugates for increased specificity in clinical applications. ADC technology bridges the development of small molecule cancer therapeutics to the clinic. Applying our investigation of photo release kinetics of nitrobenzyl alcohols, we aim to  amalgamate the best of small molecule research with biological macromolecules, such as antibodies, to be at the forefront of next gen cancer therapeutic research.


19F NMR enabled synthesis of carmofur analogs as covalent inhibitors of SARS-CoV-2 Mpro

The COVID-19 pandemic caused by the SARS-CoV-2 virus is one of the greatest challenges to public health that modern medicine has faced, as over 2.7 million people have died of COVID-19 and the number of cases continue to grow. It is crucial for researchers to develop new drugs and evaluate the efficacy of repurposed drugs to treat COVID-19. Our group utilizes 19F NMR to optimize the synthesis of carmofur, an antineoplastic agent and a potential inhibitor of the SARS-CoV-2 main protease (Mpro), as a potential treatment for COVID-19. We also conduct mutational analysis studies involving homology modeling and molecular dynamics simulations to evaluate the efficacy of carmofur analogs against mutations in Mpro. See our latest paper in the Canadian Journal of Chemistry!


2,4-Diarylpyrimidines for anti-HIV therapeutics (non-nucleoside reverse transcriptase inhibitors)

As part of the class of retroviruses, HIV, the human immunodeficiency virus, relies on inserting their own genetic material into their host’s genome. The enzyme reverse transcriptase (RT) enables the reverse transcription of viral RNA to DNA, thus enabling the viral insertion into the host. One treatment for HIV, and the subsequent disease of AIDs, are NNRTIs or non-nucleoside reverse transcriptase inhibitors. These allosteric inhibitors bind to the RT enzyme and disable it which block the enzyme’s activity and viral reproduction. Previous NNRTIs included etravirine and doravirine amongst others. Here, the structure of rilpivirine, a second generation NNRTI, was used to design a library of analogs that were then screened in a high throughput virtual screening and synthesized for enzymology studies with RT-qPCR.


Towards the Total Synthesis of Psychrophilin F

The field of natural product chemistry, specifically surrounding cyclic peptides, has seen a surge in popularity as scientists continue to study their benefits as therapeutics. Known for their structural stability and ability to target specific receptors without hydrolyzing, cyclic peptide natural products may be at the forefront of the next major medical breakthroughs. Our research focuses specifically on the cyclic tripeptide Psychrophilin E. Its natural counterpart is extracted from the marine-derived fungus Aspergillus versicolor ZLN-60. Having a very inefficient isolation method—requiring 100L of fungus to produce 30mgs of product— it has both ecological and economic repercussions. We hope to synthesize Psychrophilin E and further analogs to overcome these obstacles. Such analogs include the glycine analog, which can have a greater binding affinity to its biological target than Psychrophilin E itself by decreasing steric hindrance, leading to a more effective molecule. As such, our research presents the possibility of a new antiproliferative compound, with possible benefits in anticancer therapeutics. Its potential lies in the treatment of disorders such as rheumatoid arthritis and cancer. Further studies can help to gain a greater understanding of its usage in medical and pharmaceutical settings.


High Resolution Mass Spectrometry based methods on Direct Measurement of Biomarkers for Neurodegenerative Disease

Parkinson’s disease (PD), the second-most prominent neurodegenerative disease, caused by the progressive degeneration of dopaminergic neurons in the substantia nigra, thus production of the neurotransmitter, dopamine, will diminish following its onset. PD patients suffer from muscle tremors and stiffness, leading to overall impaired movement and coordination from dopamine imbalances in the basal ganglia that normally controls appropriate motor function. Dopamine, in the mammalian brain, was found to be metabolized into homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). The ability to quantitatively measure dopamine and its metabolites will establish a highly sensitive biomarker basis for evaluating the progress and state of diseased brain tissues. We envision these methods will provide basises for diagnostic applications and testing efficacies of future therapeutic options. Efficient and rapid liquid chromatography mass spectrometry methods on various instruments has been developed for high throughput metabolite screening taken directly from in vivo tissue samples.

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