A5021203577- Biochemical and Molecular Research
- Folate and B Vitamins Research
- HIV/AIDS drug development and treatment
- Spectroscopy Techniques in Biomedical and Chemical Research
- Adenosine and Purinergic Signaling
- Click Chemistry and Applications
- Cancer-related Molecular Pathways
- Chemical Synthesis and Analysis
- Synthesis and Characterization of Heterocyclic Compounds
- Multicomponent Synthesis of Heterocycles
- Asymmetric Hydrogenation and Catalysis
- Synthesis and biological activity
- Photoacoustic and Ultrasonic Imaging
- Epigenetics and DNA Methylation
- AI in cancer detection
- Calcium signaling and nucleotide metabolism
- Metabolism, Diabetes, and Cancer
- Advanced Breast Cancer Therapies
- Microwave-Assisted Synthesis and Applications
- Immune Cell Function and Interaction
- Gold and Silver Nanoparticles Synthesis and Applications
- Molecular Biology Techniques and Applications
Edinburgh College
2023
Duquesne University
2012-2023
University of Edinburgh
2021-2023
Mylan (United States)
2014
Abstract Isonitriles are delicately poised chemical entities capable of being coaxed to react as nucleophiles or electrophiles. Directing this tunable reactivity with metal and non‐metal catalysts provides rapid access a large array complex nitrogenous structures ideally functionalized for medicinal applications. Isonitrile insertion into transition complexes has featured in numerous synthetic mechanistic studies, leading deployment isonitriles catalytic processes, including multicomponent...
We synthesized 5-substituted pyrrolo[2,3-d]pyrimidine antifolates (compounds 5–10) with one-to-six bridge carbons and a benozyl ring in the side chain as antitumor agents. Compound 8 4-carbon was most active analogue potently inhibited proliferation of folate receptor (FR) α-expressing Chinese hamster ovary KB human tumor cells. Growth inhibition reversed completely or part by excess folic acid, indicating that FRα is involved cellular uptake, resulted S-phase accumulation apoptosis....
Novel fluorinated 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine analogues 7–12 were synthesized and tested for selective cellular uptake by folate receptors (FRs) α β or the proton-coupled transporter (PCFT) antitumor efficacy. Compounds 8, 9, 11, 12 showed increased in vitro antiproliferative activities (∼11-fold) over nonfluorinated 2, 3, 5, 6 toward engineered Chinese hamster ovary HeLa cells expressing FRs PCFT. also inhibited proliferation of IGROV1 A2780 epithelial ovarian...
Abstract Novel therapies are urgently needed for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy. In addition, that target unique vulnerabilities in tumor microenvironment (TME) of EOC have largely been unrealized. One strategy to achieve selective drug delivery therapy involves use targeted antifolates via their uptake by folate receptor (FR) proteins, resulting inhibition essential one-carbon (C1) metabolic pathways. FRα is highly expressed EOCs, along with...
Abstract Small heteroaryl‐diyne ( Het‐DY ) tags with distinct vibrational frequencies, and physiologically relevant cLog P were designed for multiplexed bioorthogonal Raman imaging. Pd−Cu catalyzed coupling, combined the use of Lei ligand, was shown to improve overall yields desired heterocoupled tags, minimizing production homocoupled side‐products. Spectral data in agreement trends predicted by DFT calculations systematic introduction electron‐ rich/poor rings stretched frequency limit...
Tumor-targeted specificities of 6-substituted pyrrolo[2,3-d]pyrimidine analogues 1, where the phenyl side-chain is replaced by 3′,6′ (5, 8), 2′,5′ (6, 9), and 2′,6′ (7, 10) pyridyls, were analyzed. Proliferation inhibition isogenic Chinese hamster ovary (CHO) cells expressing folate receptors (FRs) α β in rank order, 6 > 9 5 7 8, with 10 showing no activity, being inactive, respectively. Antiproliferative effects toward FRα- FRβ-expressing reflected competitive binding [3H]folic acid. Only...
Pemetrexed and related 5-substituted pyrrolo[2,3-d]pyrimidine antifolates are substrates for the ubiquitously expressed reduced folate carrier (RFC), proton-coupled transporter (PCFT) receptors (FRs) which more tumor-selective. A long-standing goal has been to discover tumor-targeted therapeutics that draw from one-carbon metabolic vulnerabilities of cancer cells selective transport by FRs PCFT over RFC. We discovered a methyl group at 6-position pyrrole ring in bicyclic scaffold...
Fast-acquisition Raman methodologies such as stimulated scattering (SRS) and coherent anti-Stokes (CARS) microscopy, which generate image contrast using the active vibrational frequency of a given chemical, provide information on biochemical composition tissues. This has enabled detailed imaging interaction between tumor cells surrounding microenvironment (e.g. vasculature, stromal cells) without need for additional labelling. In addition, we have developed novel, highly spectroscopically...
Abstract Folates are important single carbon transferring cofactors required for the biosynthesis of purine and pyrimidine nitrogen bases DNA. Antifolates inhibit synthesis these nitrogenous function as antineopastic agents. The use currently marketed antifolates such methotrexate (MTX pemetrexed (PMX) is limited by dose-limiting toxicity due to non-selective transport ubiquitously expressed reduced folate carrier (RFC). We previously reported a series 6-substituted pyrrolo[2,3-d]pyrimidine...
Abstract Review: [180 refs.
Abstract Two major hurdles in cancer therapy are the inability of chemotherapeutic agents to selectively target tumor cells over normal tissues, and development cell resistance. The multi-enzyme-targeted anticancer drug pemetrexed (PMX) suffers from dose-limiting toxicity, part due its membrane transport by reduced folate carrier (RFC) which is ubiquitously expressed cells. We recently described a novel series 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates. A highly active...
Abstract Three specialized systems exist for membrane transport of folates and antifolates across biological membranes. The reduced folate carrier (RFC) is ubiquitously expressed in tumors normal tissues. Folate receptors (FR) α β, the proton-coupled receptor (PCFT) exhibit narrow patterns tissue expression serve physiologic roles. FRs are a number cancer cells (e.g., FRα ovarian non-small cell lung cancer; FRβ acute myelogenous leukemia), whereas PCFT large human solid but not leukemias....