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PRINCIPAL INVESTIGATOR Henry Lee, Ph.D. College of Pharmacy and Pharmaceutical Sciences 1515 South Martin Luther King Jr. Blvd. Frederick S. Humphries Science Research Center, Suite 308-J Florida A&M University Tallahassee, FL 32307 Telephone: 850-599-3308 E-mail: [email protected] Project Title: Synthesis and Evaluation of New Local Anti-inflammatory Steroids - (Regular Score Project) The use of corticosteroids in the treatment of inflammatory conditions has been limited primarily due to their systemic suppressive effects on the adrenal function and the immune system. To overcome this limitation, a focused effort has been made to synthesize locally active anti-inflammatory steroids without systemic adverse effects based on the antedrug concept. In this approach, anted rugs are designed to exert their actions at the application site, but to undergo predictable biotransformations to form inactive and readily excretable metabolites upon entry into the systemic circulation. Thus, the true anted rug acts locally and is devoid of systemic adverse effects. It is proposed to synthesize a new group of steroidal antedrugs and evaluate them comprehensively with respect to their local and systemic anti-inflammatory activities and systemic adverse effects. To further delineate the mode of action of the new steroids, new compounds are to be studied for their ability to bind to glucocorticoid receptors, to induce tyrosine aminotransferase activity and to inhibit nitrogen oxide (NO) generation. In molecular biology accessment, transcriptional effects of steroids on nuclear factor ĸB(NF-ĸB) interleukin 10(lL-10) will be studied by Western blot. Results of these studies will yield valuable insight into the structural characteristics for the maximum separation of local anti-inflammatory activity from systemic adverse effects, and mode of action of these non-systemic anti-inflammatory steroids with the promise of providing a solid rational basis for development of new potent anti-inflammatory steroids devoid of systemic side effects. PATENTS U.S. Patent, Application No. 11/015,743 "Anti-tumor Activity of Steroidal Nucleosides", 2005. Korean Patent No. 324631 "Estrogen Derivatives and Their Salts as Hair Growth Promotor," 2002. Korean Patent No. 368103, "Estrogen Derivatives and Their Salts as Ingredients of Hair Growth Preparations, " 2002. U.S. Patent No. 5,200,518, "Anti-inflammatory Carboxycyclic Derivatives", 1993. Canadian Patent No.1,274,502, "Anti-inflammatory Carboxy Pregnane Derivative", 1990. U.S. Patent No. 4,840,624, "Female Condom Device," 1989. U.S. Patent No. 4,762,919, "Anti-inflammatory Carboxy Pregnan Derivatives," 1988. U.S. Patent No. 4,588,530, "Anti-inflammatory Prednisolone Steroids," 1986. PUBLISHED PUBLICATIONS - 1972-2006 Park, K.K., Ko, D.H., You, Z., Heiman, A.S. and Lee, H.J. Synthesis and pharmacological evaluations of new steroidal anti-inflammatory antedrugs: 9alpha-Fluoro-1beta, 17alpha,21trihydroxy-3,20-dioxopregna-,4-diene-16alpha-carboxylate (FP16CM) and its derivatives. Steroids. 71 (1):83-89, 2006. You, Z., A. Moshin Mian and Henry J. Lee*. New AZT Conjugates as Potent Anti-HIV Agents. Nucleosides, Nucleotides & Nucleic Acid, 25(1), 37-54, 2006. Zhengqing You and Henry Joung Lee (2006). New AZT Conjugates as Potent Anti-HIV Agents, Nucleosides. Nucleotides and Nucleic Acids, 25(1 ). 37-54. Kwan-K. Park, Dong-H. Ko, Z. You, Omar F. Khan and Henry J. Lee (2006). In vitro Antiinflammatory Activities of New Steroidal Antedrugs: [16α17α-d] Isoxazoline and [16α,17α-d]-3'-Hydroxy-Iminoformyl Isoxazoline Derivatives of Prednisolone and 9α -Fluoroprednisolone, Steroids, 71,(3), 183-188. M. Omar F. Khan, Kwan K. Park and Henry J. Lee (2005). Antedrugs: An Approach to Safer Drugs, Current Med. Chem., 12, 2227-2239. Park, K-K, D.H. Ko, Z. You, J. S. Cooperwood, J. Park ad H. J. Lee (2004). Chirality Effect of C-20 on Metabolism of Methyl 11β, 17α,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate Derivatives, Steroids, 69(2), 8791. Park, K.K., D.H. Ko, Z. You and H. J. Lee (2003). Metabolism of steroidal anti-inflammatory antedrugs in vitro: Methyl 3,20-dioxo-11β, 17α,21-trihydroxy-1,4-pregnadiene-16α-carboxylate; its 9α-fluorinated, and their 21-0-acyl derivatives Steroids, 48(4),315-319. You, Z., A. M. Mian, R. P. Agrawal, and H. J. Lee (2003). Synthesis, Anti-HIV and Anti-tumor Activity of New AZT Conjugates of Steroid Acids, Nucleosides and Nucleotides, 22(11), 2049-2060. Edwards, J., G. Tanaka, A. Anderson, C. Eybl, H. Lee and Z. You (2003), Molecular Modeling of SteroidNucleoside Conjugates, Structural Chemistry, 14(5),467-478. Ko, D.H., A. S. Heiman, C. E. Hudson and H. J. Lee (2002). New Steroidal Anti-inflammatory Antedrugs: Methyl 3,20-dioxy-9α-fluoro-11β, 17α-trihydroxy-1,4-pregnadiene-16α-carboxylate and its 21-0-acyl Derivatives, Steroids, _67, 211-219. Lee, H. J., J. S. Cooperwood, Z. You and D.H. Ko (2002). Prodrug and Antedrug; Two Diametrical Approaches in Designing Safer Drugs, Arch. Pharmacal Res., 25(2), 111-136. McLean, H. M. and H. J. Lee (2002). Binding of Conjugates of Prednisolone and Non-Steroidal Antiinflammatory Drugs to Glucocorticoid Receptors and their Acute Pharmacological Activities in Rats, Med. Chem. Res., 11(4), 238-247. McLean, H. M., A. S. Heiman and H. J. Lee (2002). Synthesis and Pharmacological Evaluations of Novel Conjugates of Steroidal-Antedrugs and Non-Steroidal Anti-inflammatory Drugs, Med. Chem. _Res., 11(5), 255-277. You, Z., A. S. Heiman, M. Chen and H. J. Lee (2000). Novel Steroid Spiro Enones: Condensation of Prednisolone Derivatives and Diethyl Oxalate, Steroids, 65, 109-115. Ko, D.H., A. S. Heiman, M. Chen and H. J. Lee (2000). New Steroidal Anti-inflammatory Antedrugs:Methyl 21-desoxy-21-chloro-11β, 17α-dihydroxy-3,20-dioxo-1,4-pregnadiene-16α-carboxylate, Methyl 21-desoxy21-chloro-11β -hydroxy-3,20- dioxo-1,4-pregnadiene-16- pregnadiene-16α-carboxylate, and their9α-fluoro11β,17α, 21-trihydroxy-1,4-pregnadiene-16α Carboxylate and their 9α-Fluoro Derivatives, Steroids, 65, 210218. Lee, H. J. and D.H. Ko, (1999). A Novel Approach to the Discovery of Non-systemic Anti-inflammatory Antedrug, Arch. Pharm. Res., 22(3), 279-287. Lee, H. J., Z. You, D.H. Ko and K. J. Yoon (1998). New Steroidal Anti-inflammatory Agents: Prednisolone Derivatives with an isoxazoline Fusion at the 16-17-Carbons and an Alkyl Carboxylate at the 16α -position. Drugs Explt. Clin. Res., 24(2), 57-66. Heiman, A. S., F. Hickman, D.H. Ko and H. J. Lee (1998). New Steroidal Anti-inflammatory Antedrugs Bind to Macrophage Glucocorticoid Receptors and Inhibit Nitric Oxide Generation. Steroids, 63, 644649. Lee, H. J., D.H. Ko, Z. You and H. McLean (1998). Recent Advances in Prodrugs and Antedrugs. Cur. Opinion in Drugs Dis. Devel., 1(2), 235-244. Lee, H. J. and D.H. Ko, (1997). Antedrugs: A novel approach to the development of safer antiinflammatory steroids Soc. Biomed. Res. Symposium, 1, 33-40. Lee, H. J., A. S. Heiman and D.H. Ko (1997). A novel approach to the development of safer antiinflammatory steroids. In Trends in Biopharmaceutical and Toxicological Sciences (eds. S.K. Lee and Y. Surh) Seoul National University Press, Seoul, 128-130. Valente, E., J. Zubkowki, H. Lee and K. Lee et al. (1997). Structure of 9-Fluoro-11, 17, 21-trihydroxy1,4-prenadiene-3,20-dione-21 acetate (9-fluoroprednisolone-21-acetate), J.Chem.Cryst.. 27(4), 219222. Heiman, A. S., D.H. Ko, M. Chen and H. J. Lee (1997). New Steroidal Anti-inflammatory Antedrugs, Steroids. 62, 491-498. Ko, D.H., M. F. Maponya, M. A. Khalil, E.T. Oriaku, Z. You and H. J. Lee (1997). New Anti-inflammatory Steroids: [16α,17α-d]-3'-Hydrocy-lminoformyl lsoxazoline Derivatives of Prednisolone and 9αFluoroprednisolone. Med. Chem. Res., 7(5), 313-324. You, Z. and H. J. Lee (1996). One step conversion of highly dipolarophilic olefins to a-Hydroxy- βCyanoadducts with Metal Fulminate, Tetrahedron Letters, 37(8), 1165-1168. Balagopala, M. I., A. P. Ollapally and H. J. Lee (1996). An improved synthesis of azidothymidine. Nucleotides and Nucleosides, 15(4), 899-906. Khalil, M. A., M. F. Maponya, D.H. Ko, Z. You, E. T. Oriaku and H. J. Lee (1996). New Antiinflammatory steroids: [16α, 17α -d]isoxazoline derivatives of prednisolone. Med. Chem. Res., 6.,52-60. Kwon, T., A. S. Heiman, E. T. Oriaku, K. Yoon and H. J. Lee (1995). New Steroidal Ant-inflammatory Antedrugs: Steroidal [16α, 17α -d]-3'-Carbethosyisoxazolines, J. Med. Chem., 38, 1048-1051. Yoon, K., T. Kwon, S. Choi and H. J. Lee (1995). Steroidal anti-inflammatory antedrugs: Synthesis and pharmacological evaluation of 16α -alkoxycarbonyl-17 -deoxyprednisolone derivatives. Steroids, 60(7), 445-451. Balagopala, M. I., A P. Ollapally and H. J. Lee (1995). Synthesis and Anti-HIV activity of steroidal prodrugs of AZT. Cell Mol. BioI., 41(S-1), 1-7. You, Z., M. Khalil, D. Hong and H. J. Lee (1995). Suppression of the Mattox Rearrangement of 16αCyanoprednisolones in Acid: Synthesis of Methyl 16α-prednisolone carboxylates. Tetrahedron Letters, 36(19), 3303-3306. Hong, D., A. S. Heiman, T. Kwon and H. J. Lee (1994). Synthesis of 6-methoxycarbonylprednisolone and its derivatives as new anti-inflammatory steroidal antedrugs, .J. Pharmaceut. Sci 83:(3), 357-361. McLean, H. M., M. Khalil, A S. Heiman and H. J. Lee (1994). Novel fluorinated anti-inflammatory steroid with reduced side effects: Derivatives of steroid-16-carboxy ester, J. Pharmaceut. Sci. 83:(4), 476-480. Heiman, A.S., D. Hong and H. J. Lee (1994). Receptor binding affinity and antiproliferative activity of new anti-inflammatory antedrug: 6-methoxycarbonyl prednisolone and its derivatives. Steroids, 59, 324329. Balagopala, M. I., A. P. Ollapally and H. J. Lee (1994). Synthesis and Anti-HIV activity of Alkyl Steroidal 3'-azido-3'-deoxythymidine-5'-yl phosphotriesters as Prodrugs of AZT, Nucleosides and Nucleotides, 13(9), 1843-1853. Khalil, M. A, T. Kwon and H. J. Lee (1993). A novel approach to the development of safer antiinflammatory steroids: Antedrugs, Current Topics in Med. Chem.1, 173-202. Sharma, A. P., A. P. Ollapally and H. J. Lee (1993). Synthesis and Anti-HIV Activity of Prodrugs of Azidothymidine. Antiviral Chem. Chemotherapy, 4(2), 93-96. Choi, S. J., A. S. Heiman and H. J. Lee, (1992). Enzyme Induction and Receptor Binding Affinity of Steroidal 20-Carboxamides in Rat HTC Cells. Steroids, 57,313-318. Lee, H. J., H. M. McLean, A. S. Heiman and H. P. Kim (1992). New Anti-inflammatory Antedrugs: Steroids Acid Esters and Amides. Drugs Exptl. Clin. Res. 18(7), 261-273. Sin, K. S., H. J. Lee and H. P. Kim (1991). Synthesis and Pharmacological Evaluation of New Topical Anti-inflammatory Steroids. Drugs. Exptl. Clin. Res. 17(8), 375-380. AI-Habet, S. M., I. B. Taraporewala and H. J. Lee (1990). Pharmacokinetics of Prednisolone and its novel local anti-inflammatory steroid-21-oate ester derivatives. Drug Metab. Dispo. 18(1), 617-621. AI-Habet, S. M. H. and H. J. Lee (1990). In Vitro Hydrolysis of Steroid Acid Ester Derivatives of Prednisolone in the Plasma of Different Species. J. Pharmace. Sci., 79(10), 916-918. Heiman, A. S., I. B. Taraporewala, H. M. McLean and H. J. Lee (1990). New Potent Topical Antiinflammatory Steroids with Reduced Side Effects-Derivatives of Steroid-16-Carboxy Esters. J. Pharmace. Sci., 79(7), 617-621. Lee, H. J., A. S. Heiman and I. B. Taraporewala (1989). New Steroidal Anti-inflammatory Drugs in New Developments in Anti-Rheumatic Therapy (eds. K. D. Rainsford and G. P. Velo), Klumer Academic Publisher, Lancaster, England. pp. 153-186. AI-Habet, S. M. H., K. K. Redda and H. J. Lee (1989). Use and Abuses of Anabolic Steroids by At Athletes in Cocaine, Mariiuana, Designer Drugs: Chemistry, Pharmacology and Behavior. (eds. K. K. Redda, C.A.Walker and G. Barnett), CRC Press, Boca Raton, FL. USA pp. 211-231. Lee, H. J., I. B. Taraporewala and A. S. Heiman (1989). Anti-inflammatory Steroids: Research Trends and New Compounds Drugs of Today. 25(9), 577-588. Lee, H. J. (1989). Drug of Future: P16CM. Drug of Future, 14(10), pp. 960-962. AI-Habet, S. M. and H. J. Lee (1989). High Performance Liquid Chromatographic Determination of Prednisolone and Its Steroid-21-0ate Ester Derivatives in Plasma: Pharmacokinetic Application. J. Pharmace. Sci., 78(2), 105-108. Taraporewala, I. B., H. P. Kim, A. S. Heiman and H. J. Lee (1989). A novel class of local anti-inflammatory steroid: I. Analogs of Methyl 11,17,21-trihydroxy-3,20-dioxo-1,4-pregradiene-16-carboxylate. Arzneim. Forsch./Drug Res., 39(1), 21-25. Heiman, A. S., H. P. Kim, I. B. Taraporewala and H. J. Lee (1989). A novel class of anti-inflammatory steroids: II. Pharma-cological studies of methyl 11β, 17α,21-trihydroxy-3,20-dioxopregna-1,4-diene-16αcarboxylate and methyl 11α,21-dihydroxy-3,20-dioxo pregra-1,4-diene-16-carboxylate. Arzneim. Forsch./Drug Res., 39(1 ), 262-266. Heiman, A. S., I. B. Taraporewala and H. J. Lee (1989). Local anti-inflammatory activity of steroid-21-oate esters in the Carrageenan Pleurisy Model of Acute Inflammatory. Drug Devel. Res., 17(2), 153-160. Kim, H. P., K. J. Yeon, S. M. Byun and H. J. Lee (1989). Synthesis and local anti-inflammatory activity of esters of 20R- and 20S- Dihydropredinisolonic Acid. Arch. Pharm. Res., 12(2), 63-67. Yeon, K. J., S. M. Byun, H. J. Lee and H. P. Kim (1989). Hydrolysis of esters and amides of 20R and 20SDichoprednisolonic Acid in Rat Serum and Liver Homogenate. Arch. Pharm. Res., 12(2), 68-72. McLean, H. M. and H. J. Lee (1989). Synthesis and Pharmacological Evaluation of Conjugates of Prednisolone and Non-steroidal anti-inflammatory agents. Steroids. 54(4), 421-439. Sah, H. K., H. J. Kim, H. P. Kim, H. J. Lee and S. M. Byun (1988). Liposomes with Anti-inflammatory Steroid Prednisolone Palmitate. Drug Devel. Indus. Pharm., 14(6),765-777. Kim, H. P., J. Bird, A. S. Heiman, G. F. Hudson, I. B. Taraporewala and H. J. Lee (1987). Synthesis of New Anti-inflammatory Steroidal 20-Carboxamides: (20 R, S) 21-(N-substituted) amino-11, 17,20trihydroxy-3,21dioxo-1,4-pregnadien. J. Med. Chem., 30, 2239-2244. Lee, H. J., A. S. Heiman and I. B. Taraporewala (1987). Anti-inflammatory Steroids: Research and Applications in the 1980's Res. Bulletin-FAMU. 29 (1), 37-39. Kim, H. P., J. W. Lee, H. J. Kim, S. M. Byun and H. J. Lee (1987), Development and Structure Activity Relationship of New Local Anti-inflammatory Steroids. Arch. Pharm. Res., 10(3), 184-187. Bird, J., J. C. Lay and H. J. Lee (1986). The effect of new local Anti-inflammatory Steroids on Leukocyte Migration and Prostanoid Liberation in Rats. J. Pharmacy Pharmacol., 38,589-594. Bird, J., H. P. Kim and H. J. Lee (1986). Topical Anti-inflammatory Activity of Esters of Steroid-21-oic acids. Steroids, 47(1), 35-40. Khalil, M. A, J. C. Lay and H. J. Lee (1985). Synthesis of a New Anti-inflammatory Steroidal Acid Ester: Methyl 11-hydroxy-3, 20-dioxo-1,4-predgnadien-21-oate. J. Pharm. Sci., 74(2),180-183. Lee, J. W. and H. J. Lee (1985). Binding of ester and amide epimers of 20-didydroprednisolonic Acid to Cytosol Receptors and their Acute Pharmacological Activities in Rats, J. Steroid Biochem., 23(6A), 943948. Kumari, D. and H. J. Lee (1985). Hydrolysis of Methyl Steroid-21-0ates and Acetyl Steroid-21-ols by Rat Liver Microsomes. Druq Meta. Dispo., 13(5),627-629. DiPetrillo, T., H. J. Lee and K. R. Cutroneo (1984). Anti-inflammatory Adrenal Steroids That Neither Inhibit Skin Collagen Synthesis Nor Cause Dermal Atrophy. Arch. Dermatol., 120, 878-883. Lee, H. J., M. A. Khalil and J. W. Lee (1984). Antedrug: A Conceptual Basis for Safer Antiinflammatory Steroids, Druq Exp. Clin. Res., 10(12), 835-844. Lee, J. W., H. P. Kim and H. J. Lee (1984). Anti-inflammatory Activities of the Epimers of N-propyl 20dihydropredni-solinamide, Steroid, 44(6), 511. Olejniczak, E. and H. J. Lee (1984). Effect of Chronically Administered Methyl Prednisolonate and Methyl 17-, Deoxprednisolonate. Steroids, 43(6), 657-662. Lee, H. J. and A. M. Nathoo (1983). Systemic Activities of New Anti-inflammatory Steroids: Methyl 20dihydroprednisolonate, Steroids, 41(5), 609-615. Lee, H. J. (1982). Proqress in Research and Clinical Application of Corticosteroids (eds. H. J. Lee and T. Fitzgerald). Heyden & Son, Inc., Philadelphia. Soliman, M. R. I., A. M. Nathoo, A. S. Heiman, E. Cook and H. J. Lee (1982). Anti-inflammatory Activity of Prednisolone Derivatives. In Proqress in Research and Clinical Application of Corticosteroids (eds. H. J. Lee and T. Fitzgerald). Heyden & Son, Inc., Philadelphia, pp. 253-267. Lee, H. J. (1982). Preface in Proqress in Research and Clinical Application of Corticosteroids (eds. H. J. Lee and T. Fitzgerald). Heyden & Son, Inc., Philadelphia, P. vii. Clark, J. E. and H. J. Lee (1982). Local Injection of Cortico- steroids. Cur. Therap. Res., 2(4), 766-781. Heiman, A. S., Z. M. Nathoo and H. J. Lee (1982). Effects of New Anti-inflammatory Steroids Derived from Prednisolone on P-A Axis and Lysosomal Stabilization. Drug Dev. Res., 2(4), 377-382. Lee, H. J. and M. R. I. Soliman (1982). Anti-inflammatory Steroids without Pituitary-Adrenal Suppression. Science, 215, 989-991. Soliman, M. R. I. and H. J. Lee (1981). Anti-inflammatory Activity of Acid Ester Derivatives of Prednisolone. Res. Comm. Chem. Path. Pharm., 33(2), 357-360. Heiman, A. S. and H. J. Lee (1981). Stabilization of Rat Liver Lysosomes by. New Anti-inflammatory Steroids in vivo. Steroids, 38(4), 365-37. Lee, H. J., H. L. Bradlow, M. C. Moran and M. R. Sherman (1981). Binding of Glucocorticoid 21-oic Acids and Esters to Molybdate Stabilized Hepatic Receptors, J. Steroid Biochem., 14, 1325-1335. Lee, H. J. and R. W. Trottier (1980). Anti-inflammatory Activity of Two Novel Derivatives of Prednisolone. Res. Comm. Chem. Path. Pharm., 27, 611-614. Lee, H. J. (1977). Acidic Metabolites of Prednisolone. Experientia. 33, 253. Lee, H. J. and C. Monder (1977). Oxidation of Corticosteroids to Steroidal Carboxylic Acids by an Enzyme from Hamster Liver. Biochem., 16(17), 3810-3814. Martin, K. L., S-W Oh, H. J. Lee and C. Monder (1977). Studies on 21-H-Labeled Corticosteroids: Evidence of Isomerization of the KetoI Side-Chain of 11-deoxycosterone by a Hamster Liver Enzyme. Biochem., 16(17),3803-3809. Lee, H. J., C. Monder and J. Roboz (1976). Identification of Acidic Metabolites of Corticosteroids by Mass Spectrometer. Conf. Mass Spec., 24,578-580. Bradlow, H., L. Zumoff, C. Monder, H. J. Lee and L. Hellman (1973). Isolation and Identification of Four New Carboxylic Acid Metabolites of Cortisol in Man. J. Clin. Endocrino!. Metab., 37,124-131. Lee, H. J. and G. R. Waller (1972). Ricine Metabolism and Translocation of Alkaloids in Ricinus communis. Phytochem. 11, 965-973. Lee, H. J. and G. R. Waller (1972). Biosynthesis of the Pyridine Alkaloids from Triptervgium wilfordii Hook. Phytochem., 11. 2233-2240.