Regina ZHUK

Professor Regina ZHUK Department Director, Rimonyx Pharmaceuticals, Ltd. Kiryat Weizmann Science Park Ness-Ziona 70400 P.O.Box 4056 Israel Home: Hatayasim 14/11 Nes Ziona 74062 Israel Phone: +972-89389505 E-mail: [email protected]

Born: December 6, 1936, Moscow, Russia

• Synthesis of Nucleoside Analogues
• Anticancer, Antiviral and Immunomodulating Drug Design
• Drug Development

Brief Description of Main Research:

Two original drugs designed - anticancer Ftorafur ( Tegafur ) and antiviral Furavir. Technologies for Ftorafur, Acyclovir and Furavir large scale production elaborated.  A series of 7(9)-substituted guanines is synthesized and evaluated as immunomodulating agents. A new trend of   research is connected with the investigation of  butyric acid derivatives as anti-cancer drugs and thieno[2,3-c]pyridines as anti-inflammatory agents.

    - 125 scientific papers and abstracts published;
    - 45 author's certificates and patents granted
    -  6 PhD students and 20 Master's degree students supervised

Languages: Russian, Latvian, English

• Riga Technical University (Faculty of Chemistry), Latvia, 1959
• Dr.chem. (Candidate of Sciences in former USSR, PhD in Western countries), Institute of Organic Synthesis, Latvian Academy of Sciences, Riga, 1969
• Dr.habil.chem. (Doctor of Sciences in former USSR), Institute of Organic Synthesis, Latvian Academy of Sciences, Riga, 1977

Thesis:"Analogues of pyrimidine nucleosides and nucleotides"

Latvian Institute of Organic Synthesis:

• Research Associate, Laboratory of the Chemistry of Heterocyclic Compounds, 1965-1969
• Head of Research Group, Laboratory of Nucleic Acids Components, 1969-1994
• Professor of Medicinal Chemistry, 1994 -1999

Bar Ilan University (Israel):

• Professor, 2000 -
• Director Medicinal Chemistry Rimonyx Pharmaceuticals, Ltd., 2003 -

• Foreign Member, Latvian Academy of Sciences, 2000
• Award plague, Taiho Pharmaceutical Company, Tokyo, Japan, 2005
• The D.H.Grindel Medal and Prize (Pharmaceutical Company "Grindex", Latvia), 1995
• Medal and Diploma, Tsurumi University, Yokohama, Japan,1994
• Medal and Diploma, Latvian Institute of Organic Synthesis, 1982

• President of the Latvian Association for Medicinal Chemistry
• Member of the Management Committee of the European Federation for Medicinal Chemistry
• Member of the International Society of Nucleic Acids Chemistry
• Member of the Editorial Board for The Chinese Pharmaceutical Journal
• Member of the Israel Chemical Society and the Israel Association for Medicinal Chemistry.

• The lecturer at the 9th International Round Table Nucleosides, Nucleotides and their Biological Applications, Uppsala, Sweden, 1990, at the XI International Symposium on Medicinal Chemistry, Jerusalem, Israel, 1990, and

at the 2lst Symposium on Nucleic Acids Chemistry, Matsujama, Japan, 1994.

• Lecture on Drug Design in Nucleoside Analogues. - Institute of Biochemistry, Martin-Luther University, Halle-Wittenberg, Germany, 1993.
• Lectures on Synthesis of Nucleoside Analogues and Drug Design based on these compounds. - The National Defense Medical Center, Taipei, Taiwan, Republic of China and National Sun Yat-Sen University, Kaohsiung, Taiwan, Republic of China, 1994
• Lectures on the Development of the Anticancer Drug Ftorafur. - The Development Center for Biotechnology, Teipei, Taiwan, Republic of China, 1994; the School of Chemistry, Kaohsiung Medical College, Kaohsiung, Republic of China, 1994; Tsurumi University, Yokohama, Okayama University, Okayama, and Taiho Pharmaceutical Co. LTD, Hanno Research Center, Japan, 1994.
• Lectures on Drug Design in Nucleoside Analogues - Department of Chemistry, Bar ilan University , Ramat Gan, Israel, 2000; and Department of chemistry, University of Calgary, Canada, 2001
• Lecture on the History of Ftorafur.-Taiho Pharmaceutical Co. Hanno Research Center, Japan, 2005

• Institute of Biochemistry and Biophysics, PAN, Warsaw, Poland (prof. D.Sugar).
• Martin-Luther University Halle-Wittenburg, Halle, Germany (prof. S.Hoffmann).
• Laboratory of Organic Chemistry, University of Amsterdam, Amsterdam, the Netherlands (prof. J.G.Koomen).

1. S.A.Hiller, R.A.Zhuk, M.Yu.Lidak. Pyrimidine nucleoside analogues. I. N₁-(a-furanidyl)derivatives of natural pyrimidine bases and their antimetabolites. - Dokl. Akad. Nauk SSSR, 1976, N 2, pp.332-335 (1967) (in Russian).
2. S.A.Hiller, R.A.Zhuk, L.A.Sherinya, D.E.Zarin. 1-(a,w-Dihydroxyalkyl)uracils and their phosphates. - Nucleic Acids Res., Spec., 1975,. Publ. N 1, pp.169-171.
3. S.A.Hiller, D.E.Zarin, R.A.Zhuk, Pyrimidine nucleoside analogues X. 5-Substituted 1-(1,3-Dihydroxypropyl-2)uracils. - Nucleic Acids Res., 1976,. 3(3), pp. 721-727.
4. R.A.Zhuk, A.E.Berzin, V.N.Silin, E.E.Liepinsh, 2-(5-Substituted uracil-1-yl) tetrahydrofuran-5-carboxylic acids as pyrimidine ucleotide analogues. - Nucleic Acids Res., Spec., 1978, Publ. N 3, pp. 19-22.
5. Ftorafur. An Antitumor Drug.(Ed. by R.A.Zhuk), 1979, Riga: Zinatne.
6. R.A.Zhuk, L.T.Kaulinya, A.S.Ludzisha, E.E.Liepinsh, M.Yu.Lidak. Tetrahydrofuryl- and alkopxyalkyl analogues of pyrimidine nucleosides. - Nucleic Acids Res., Symp. Ser., 1981, N 9, pp.123-125.
7. A.S.Ludzisha, Je.G.Shpaer, R.A.Zhuk, M.P.Eninsh, N.J.Ghuyeva, Ja.A.Eiduss. Nucleic Acids Res., Symp. Ser., 1984, N 14, pp. 227-229.
8. R.Zhuk, M.Y.Lidak, A.A.Zidermane, A.Gilev. Correlation between structure and activity in substituted 5-fluorouracils, in Ftorafur, Proceedings of the International Symposium, Ed. by R.A.Zhuk, 1985, Riga: Zinatne, pp. 16-26.
9. M.A.Madre, R.A.Zhuk, M.Y.Lidak. Purine nucleoside analogues. 4. 7-Alkylated 9-(2-hydroxymethyl)guanine. - Chem. Heterocycl. Comp., 1989, vol. 25, N 5, pp. 535-540.
10. A.A.Golbraikh, J.Betins, J.Balodis, R.A.Zhuk, G.V.Nikiforovich. Conformational aspects of antiviral activity of deoxyguanosine acyclic analogues. - Nucleic Acids Res., 1989, vol. 17, pp. 7965-7977.
11. M.Madre, R.Zhuk, M.Lidak. New Prodrugs of Acyclovir with antiviral activity. -Nucleosides & Nucleotides, 1991, vol.10, pp. 279-282.
12. M.A.Madre, R.A.Zhuk, M.Y.Lidak. Purine nucleoside analogues. 5. Acycloguanosine derivatives, containing O-alkoxyalkyl substituent in the acyclic moiety.- Bioorg. Khim., 1991, vol. 17, N 11, pp. 1516-1520 (in Russian).
13. R.A.Zhuk, M.A.Madre, A.V.Ananiev, L.G.Pogosyan, Zh.J.Akopyan. Antiviral and immunomodulating activity of acyclic guanosine analogues. - Abstr. of Papers XIIth Intern. Symp. of Medicinal Chemistry, Basel, Switzerland, Sept. l3-17, 1992, p.333.
14. M.A.Madre, R.A.Zhuk, M.Y.Lidak. Purine nucleoside analogues. 6. Chlorination of acycloguanosine and its derivatives with thionyl chloride. - Chem. Heterocycl. Comp. 1992, vol. 28, N 5, pp. 567-569.
15. R.A.Zhuk, M.A.Madre. Synthesis of 7,8-disubstituted guanines as potential PNP inhibitors. - Abstr. of Papers 4th Intern. Symp. on Molecular Aspects of Chemotherapy , 23-25 June 1993, Gdansk-Poland, p.56 (1993).
16. R.A.Zhuk, M.A.Madre. Synthesis of 7-(2-hydroxymethyl)guanine and related compounds as immunomodulators. - Nucleic Acids, Symp. Ser.., 1994, N 31, pp. 5-6.
17. M.A.Madre, L.Geita, R.A.Zhuk, G.-J.Koomen. Purine Nucleoside Analogues. 7*. 9-[2-(Alkylthio)ethoxymethyl]Derivatives of Adenine, Hypoxanthine and Guanine. - The Chinese Pharmaceutical Journal, 1995, vol. 47, pp. 469-481.
18. M.A.Madre, R.A.Zhuk, N.Panchenko, J.A.J.Geenevasen, A.M. van den Burg, G.-J.Koomen. Some peculiarities of N2-acetyl-8-bromoguanine alkylation. - Coll. Czech. Chem. Commun., 1996, vol. 61, sp. issue, pp. 20-22.
19. M.A.Madre, R.A.Zhuk, G.-J.Koomen. Addition of 2,3-dihydrofuran to N2-acetyl-8-bromoguanine. – Nucleosides&Nucleotides., 1997, vol. 6, N 7-9, pp.1107-1110.
20. R.A.Zhuk, M.A.Madre, M.Khan, L.Poluektova. Immunosuppressive effects of 8-bromoguanine derivatives. - 6th Intern. Symp. on Molecular Aspects of Chemotherapy, Gdansk, Poland, 9-12 July 1997: Abstr. book, 1997, p. 135.
21. R.A.Zhuk. Structure-activity relationship in ftorafur (tegafur) and related 5-FU prodrugs, Adv. in experimental medicine and biology. - 1998 - Vol. 431: Purine and pyrimidine metabolism in man IX, (Ed. A. Griesmacher, P. Chiba, M.M. Muller). - New York: Plenum Press, 1998, pp. 677-680.
22. M.A.Madre, R.A.Zhuk, B.Golankiewicz. Purine nucleoside analogues. 8. N²-Acety-lation of guanine derivatives. - Polish J. Chem., 1998, vol. 72, N 10, pp. 2242-2246.
23. M.A. Madre, R.A. Zhuk, N. Panchenko, J. Geenevasen, A.M. van den Burg, G.-J. Koomen. Purine nucleoside analogues. 10. A new synthetic route to 8-substituted-7(9)-alkoxyalkylguanines. - Heterocyclic Communications, 1998, vol. 4, N 6, pp.581-588.
24. A.Rephaeli, R.Zhuk, A.Nudelman. Prodrugs of butyric acid from bench to bedside: synthetic design, mechanisms of action, and clinical applications. - Drug Dev. Res., 2000, vol. 50, pp. 379-391.
25. Y.Zimra, A.Nudelman, R.Zhuk, E.Rabizadeh, M.Shaklai, A.Aviram, A.Rephaeli. - J.Cancer Res. Clin. Oncol., 2000, vol. 126, pp. 693-698.
26. A.Nudelman, E.Gnizi, Y.Katz, R.Azulai, M.Cohen-Ohana, R.Zhuk, S.R.Sampson, L.Langzam, E.Fibach, E.Prus, V.Pugach, A.Rephaeli. Prodrugs of butyric acid. Novel derivatives possesssing increased aqueous solubility and potential for treating cancer and blood diseases. - Eur. J. Med., 2001, vol. 36, pp. 63-74.

Patents granted:

1. Brit. Pat. 1,168,391 (1969).
2. US Pat. 3,635,946 (1972).
3. US Pat. 3,912,734 (1975).
4. US Pat. 3,947,444 (1976).
5. US Pat. 3,954,760 (1976).
6. US Pat. 4,916,225 (1990).

• R.Zhuk (Head of Project). The Development of Antiviral Drugs Acycloguanosine and Furavir as well as their Delivery Systems. Latvian Council of Science (1994-1996).
• R.Zhuk (Head of Project). Design of Specific Supramolecular Receptors Based on Long-alkyl-chain Nucleobase Derivatives. Latvian Council of Science (1997-2000).
• R.Zhuk (Principal Investigator). Synthesis and Biological Properties of Nucleoside Analogues. NATO International Scientific Exchange Programmes Linkage Grant (HTECH.LG 940571) (1994)

Last update 05.02 .2008