Nucleosides for anticancer and antiviral therapies
Nucleoside antimetabolites such as gemcitabine, fludarabine, clofarabine, acyclovir, ganciclovir, and zidovudine are bioprecursor prodrugs that are widely used as anticancer- or antiviral agents and their importance continues to increase. These antimetabolites utilize nucleoside salvage pathways for their transformation into active nucleoside triphosphates. Irrespective of the final intracellular targets of the triphosphates, which primarily are human or viral DNA and their respective polymerases or reverse transcriptases, the rate-limiting key activation step of the prodrugs is usually the initial conversion of the nucleoside to the corresponding monophosphate by phosphorylating enzymes, often deoxynucleoside kinases. Thymidine kinase (TK) is one of these deoxynucleoside kinases. Most eukaryotes and prokaryotes and many DNA viruses code for proteins with thymidine kinase activity. However, among all approved nucleoside antimetabolites only the HIV prodrugs zidovudine and stavudine are activated by human thymidine kinase 1 (hTK1). This is probably due to the fact that TKs have very stringent substrate specificities. Dr. Tjarks’ research activities focus on the in silico design, synthesis, and biological evaluation of inhibitors and substrates of hTK1 and TKs from viruses, such as the Epstein-Barr virus, for anticancer and antiviral therapies.
A second research focus of Dr. Tjarks’ group is the synthesis of boron cluster radiohalogenated therapeutics and imaging agents. Most radiopharmaceutical biomolecules (e.g. antibodies, carbohydrates, growth factors) that contain radiohalogenated boron clusters are less susceptible to dehalogenation under physiological conditions than their counterparts containing conventional radiohalogen-carbon bonds. There is an unexplored potential for such boron cluster radiohalogenated biomolecules to be used in the radiotherapy and imaging of cancer.
A third research focus of Dr. Tjarks' group is the design and synthesis of nanoparticle prodrugs of anticancer agents, such as Bortezomib, to increase tumor selectivity and reduce unwanted side effects.
- Hasabelnaby, S; Goudah, A; Agarwal, HK; Abd, Alla, MS; Tjarks, W. Synthesis, chemical and enzymatic hydrolysis, and aqueous solubility of amino acid ester prodrugs of 3-carboranyl thymidine analogs for boron neutron capture therapy of brain tumors. European journal of medicinal chemistry. 2012 Sep;55:325-34
- Tiwari, R; Toppino, A; Agarwal, HK; Huo, T; Byun, Y; Gallucci, J; Hasabelnaby, S; Khalil, A; Goudah, A; Baiocchi, RA; Darby, MV; Barth, RF; Tjarks, W. Synthesis, biological evaluation, and radioiodination of halogenated closo-carboranylthymidine analogues. Inorganic chemistry. 2012 Jan 2;51(1):629-39
- Agarwal, HK; Buszek, B; Ricks, KG; Tjarks, W. Synthesis of Closo-1,7-Carboranyl Alkyl Amines. Tetrahedron letters. 2011 Oct 26;52(43):5664-5667
- Yang, W; Barth, RF; Wu, G; Huo, T; Tjarks, W; Ciesielski, M; Fenstermaker, RA; Ross, BD; Wikstrand, CJ; Riley, KJ; Binns, PJ. Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors. Journal of neuro-oncology. 2009 Dec;95(3):355-65
- Yang, W; Barth, RF; Wu, G; Tjarks, W; Binns, P; Riley, K. Boron neutron capture therapy of EGFR or EGFRvIII positive gliomas using either boronated monoclonal antibodies or epidermal growth factor as molecular targeting agents. Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine. 2009 Jul;67(7-8 Suppl):S328-31
- Tiwari, R; Mahasenan, K; Pavlovicz, R; Li, C; Tjarks, W. Carborane clusters in computational drug design: a comparative docking evaluation using AutoDock, FlexX, Glide, and Surflex. Journal of chemical information and modeling. 2009 Jun;49(6):1581-9
- Barth, RF; Yang, W; Wu, G; Swindall, M; Byun, Y; Narayanasamy, S; Tjarks, W; Tordoff, K; Moeschberger, ML; Eriksson, S; Binns, PJ; Riley, KJ. Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors. Proceedings of the National Academy of Sciences of the United States of America. 2008 Nov 11;105(45):17493-7
- Yang, W; Wu, G; Barth, RF; Swindall, MR; Bandyopadhyaya, AK; Tjarks, W; Tordoff, K; Moeschberger, M; Sferra, TJ; Binns, PJ; Riley, KJ; Ciesielski, MJ; Fenstermaker, RA; Wikstrand, CJ. Molecular targeting and treatment of composite EGFR and EGFRvIII-positive gliomas using boronated monoclonal antibodies. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008 Feb 1;14(3):883-91
- Tjarks, W; Tiwari, R; Byun, Y; Narayanasamy, S; Barth, RF. Carboranyl thymidine analogues for neutron capture therapy. Chemical communications (Cambridge, England). 2007 Dec 21;(47):4978-91
- Wu, G; Yang, W; Barth, RF; Kawabata, S; Swindall, M; Bandyopadhyaya, AK; Tjarks, W; Khorsandi, B; Blue, TE; Ferketich, AK; Yang, M; Christoforidis, GA; Sferra, TJ; Binns, PJ; Riley, KJ; Ciesielski, MJ; Fenstermaker, RA. Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007 Feb 15;13(4):1260-8
- Recipient of the 2009 Miriam R. Balshone Memorial Award For Distinguished Teaching in the Pharm.D. Program of The Ohio State University
- Dr. rer. nat., 1989, University of Bremen, Germany
- M.S., 1986, University of Bremen