Education

• Ph.D., The Ohio State University, 1988
• B.S., University of Wyoming, 1983

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Areas of Interest

Design, Synthesis and Studies of Steroid Sulfatase Inhibitors

The research area of Dr. Li focuses in the design, synthesis and biochemical testing of steroidal and non-steroidal steroid sulfatase inhibitors as potential agents for the treatment of hormone-dependent cancers. Estrogen levels in breast tumors of post-menopausal women are as much as 10 times higher than estrogen levels in plasma, presumably due to in situ formation of estrogen. The major source of estrogen in breast cancer cells may be conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. One of our goals is to develop potent estrone sulfatase inhibitors as potential agents for the treatment of estrogen-dependent breast cancer. We have synthesized both the steroidal and non-steroidal estrone sulfatase inhibitors.

Our second approach is to design and synthesize inhibitors with dual actions: inhibiting estrone sulfatase and serve as antiestrogen. (E) and (Z)-4-hydroxytamoxifen sulfamates have been synthesized and (E)-4-hydroxytamoxifen sulfamate was shown to inhibit estrone sulfatase. The development of several series of dual inhibitors are currently in progress.

Another project is to develop melatonin receptor ligands as tools to be used in the melatonin receptor field. The first objective is to develop charged melatonin receptor ligands to study melatonin receptor regulation. The second objective is to develop MT2-selective melatonin receptor ligand to study the molecular structure of the MT2 melatonin receptor. The third objective is to develop MT2 selective reversible melatonin receptor antagonists as poential agents to study the functions of MT2 receptor in vivo. A charged ligand (TMEPI) and an irreversible melatonin receptor ligand (BMNEP) have been developed in our laboratory.

Our third project involves the development of tubulin targeting agents with dual action. Tubulin targeting agents (Taxol and Vinka alkaloids) have been used for the treatment of cancers for many years. We have developed 2 small molecules (CT-100 and OSU 149) with anti-tubulin activities. CT-100 is a thalidomide derivative with a Taxol like mode of action. OSU149 is a colchicine binder with potent cytotoxic activity in NCI 60 cell lines in low to subnanomolar IC50 values. Both compounds also exhibit potent anti-angiogenic activity. Research is ongoing to investigate the mechanism of anti-angiogenic activity as well as their actions on other molecular targets.

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Publications

1. Thomas MJ,; Mameli M,; Carta M,; Valenzuela CF,; Li PK,; Partridge LD. Neurosteroid
paradoxical enhancement of paired-pulse inhibition through paired-pulse facilitation of
inhibitory circuits in dentate granule cells. Neuropharmacology 2005 Mar;48(4):584-96.

2. Brueggemeier RW,; Diaz-Cruz ES,; Li PK,; Sugimoto Y,; Lin YC, Shapiro CL. Translational studies on aromatase, cyclooxygenases, and enzyme inhibitors in breast cancer. J Steroid Biochem Mol Biol. 2005 May;95(1-5):129-36.

3. El-Sherif Y,; Witt-Enderby P,; Li PK,; Tesoriero J,; Hogan MV,; Wieraszko A. The actions of a charged melatonin receptor ligand, TMEPI, and an irreversible MT2 receptor agonist, BMNEP, on mouse hippocampal evoked potentials in vitro. Life Sci. 2004 Nov
12;75(26):3147-56.

4. Nahar, L.; Sarker, S. D.; Li, P. K.; Turner, A. B. Synthesis of New Estrone Derivatives Using Excess Oxalyl Chloride. Chemistry of Natural Compounds (Translation of Khimiya
Prirodnykh Soedinenii) 40(1):50-53, 2004.

5. Caldeira, Jerri C.; Wu, Yan; Mameli, Manuel; Purdy, Robert H.; Li, Pui-Kai; Akwa, Yvette; Savage, Daniel D.; Engen, John R.; Valenzuela, C. Fernando. Fetal alcohol exposure alters neurosteroid levels in the developing rat brain. Journal of Neurochemistry 90(6), 1530-1539, 2004.

6. Shi J, Xiao Z, Ihnat MA, Kamat C, Pandit B, Hu Z, Li PK. Structure-activity-relationships studies of the anti-angiogenic activities of linomide. Bioorg Med Chem Lett, 13(6):1187-1189, 2003.

7. Chu GH, Witt-Enderby PA, Jones M, Li PK. Synthesis and pharmacological analysis of high affinity melatonin receptor ligands. Chem Pharm Bull, 50(2):272-275, 2002.

8. Marks MG, Shi J, Fry MO, Xiao Z, Trzyna M, Pokala V, Ihnat MA, Li PK. Effects of putative hydroxylated thalidomide metabolites on blood vessel density in the chorioallantoic membrane (CAM) assay and on tumor and endothelial cell proliferation. Biol Pharm Bull, 25(5):597-604, 2002.

9. Xiao Z, Schaefer K, Firestine S, Li PK. Solid-phase synthesis of thalidomide and its analogues. J Comb Chem, 4:149-153, 2002.

10. Xiao Z, Waters NC, Woodard CL, Li Z, Li PK. Design and synthesis of Pfmrk inhibitors as potential antimalarial agents. Bioorg & Med Chem Lett, 11:2875-2878, 2001.

11. Chu GH, PK Li. Synthesis of naphthalenic melatonin receptor ligands. Synthetic Commun, 31(4):621-9, 2001.

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Professional Experience

1984-1986 Graduate Teaching Assistant, The Ohio State University, Columbus, OH

1986-1988 Graduate Research Assistant, The Ohio State University, Columbus, OH

1988-1989 Postdoctoral Researcher, Department of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH

1989-1990 Postdoctoral Researcher, Department of Veterinary Physiology and Pharmacology, The Ohio State University, Columbus, OH

1990-1995 Assistant Professor, School of Pharmacy, Department of Pharmaceutical Chemistry and Pharmaceutics, Duquesne University, Pittsburgh, PA

1995-1999 Associate Professor, School of Pharmacy, Department of Pharmaceutical Chemistry and Pharmaceutics, Duquesne University, Pittsburgh, PA

1999-present Associate Professor, College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, OH

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