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Faculty
| Gary Posner, PhD |
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"One of our most exciting discoveries is that some of our rationally designed trioxane dimers have both strong antimalarial activity and strong anticancer activity."
The research groups led by Gary Posner and Theresa Shapiro continued their collaborative work to develop effective new antimalarial drugs. Two novel compounds, each a bridged dimer of artemisinin, were synthesized from naturally occurring artemisinin in just four chemical steps. The syntheses were scaled up to obtain multigram quantities in overall yields of 32 percent to 44 percent. Both compounds exhibit potent antimalarial activity in vitro. In rodent models of malaria, both compounds are active when given orally or intravenously, and both are more active and safer than clinically used sodium artesunate. Furthermore, both compounds showed activity in a transgenic adenocarcinoma of mouse prostate model. Compared with non-tumorigenic cell lines, activity was greatest in the aggressive, tumorigenic and metastatic prostate cancer cell lines.
CONTACT DR. POSNER
Johns Hopkins University
School of Arts & Sciences
Remsen Hall 216
3400 North Charles Street
Baltimore, MD 21218
email: ghp@jhu.edu
phone: 410-516-4670
fax: 410-516-8420
LINKS
SELECTED PUBLICATIONS
Paik IH, Xie S, Shapiro TA, Labonte T, Narducci Sarjeant AA, Baege AC, Posner GH. Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity.J Med Chem. 2006 May 4;49(9):2731-4.
Malaria-Infected Mice Are Cured by a Single Dose of Novel Artemisinin Derivatives, T.A. Shapiro,, I-K. Paik, W. Chang, K. Borstnik, S. Sinishtaj, A.S. Rosenthal, L. E. Woodard, L. C. Hess, A. R. Usera, W. A. Maio, and G.H. Posner J. Amer. Med. Assoc.
Guyton KZ, Kensler TW, Posner GH. Chemopreventive efficacy of natural vitamin D and synthetic analogs. Humana Press, Cancer Chemoprevention, Volume 1, Chap. 17, 2004.
Jeyadevan JP, Bray PG, Chadwick J, Mercer AE, Byrne A, Ward SA, Park BK, Williams DP, Cosstick R, Davies J, Higson AP, Irving E, Posner GH, O'Neill PM. Antimalarial and antitumor evaluation of novel C-10 non-acetal dimers of 10beta-(2-hydroxyethyl)deoxoartemisinin. J Med Chem 47:1290-1298, 2004. Abstract
O'Neill PM, Posner GH. A medicinal chemistry perspective on artemisinin and related endoperoxides. J Med Chem 47:2945-2964, 2004. Abstract
Posner GH, Crawford KR, Yang HW, Kahraman M, Jeon HB, Li H, Lee JK, Suh BC, Hatcher MA, Labonte T, Usera A, Dolan PM, Kensler TW, Peleg S, Jones G, Zhang A, Korczak B, Saha U, Chuang SS. Potent, low-calcemic, selective inhibitors of CYP24 hydroxylase: 24-sulfone analogs of the hormone 1alpha, 25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol 89-90:5-12, 2004. Abstract
Posner GH, Jeon HB, Sarjeant A, Riccio ES, Doppalapudi RS, Kapetanovic IM, Saha U, Dolan P, Kensler TW. Low-calcemic, efficacious, 1alpha, 25-dihydroxyvitamin D3 analog QW-1624F2-2: calcemic dose-response determination, preclinical genotoxicity testing, and revision of A-ring stereochemistry. Steroids 69:757-762, 2004. Abstract
Posner GH, McRiner AJ, Paik I-H, Sur S, Borstnik K, Xie S, Shapiro TA, Alagbala A, Foster B. Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents. J Med Chem 47:1299-1301, 2004. Abstract
Posner GH, O'Neill PM. Knowledge of the proposed chemical mechanism of action and cytochrome p450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides. Acc Chem Res 37:397-404, 2004. Abstract
Bachi MD, Korshin EE, Hoos R, Szpilman AM, Ploypradith P, Xie S, Shapiro TA, Posner GH. A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic beta-sulfonyl-endoperoxides. J Med Chem 46:2516-2533, 2003. Abstract
Posner GH, Paik IH, Sur S, McRiner AJ, Borstnik K, Xie S, Shapiro TA. Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy. J Med Chem 46:1060-1065, 2003. Abstract
Borstnik K, Paik I-H, Posner GH. Malaria: New chemotherapeutic peroxide drugs. Mini-Reviews in Med Chem 2:573-583, 2002.
Borstnik K, Paik IH, Shapiro TA, Posner GH. Antimalarial chemotherapeutic peroxides: artemisinin, yingzhaosu A and related compounds. Int J Parasitol 32:1661-1667, 2002. Abstract
Korshin EE, Hoos R, Szpilman AM, Konstantinovski L, Posner GH, Bachi MD. An efficient synthesis of bridged bicyclic peroxides structurally related to antimalarial Yingzhaosu A based on radical co-oxygenation of Thiols and Monoterpenes. Tetrahedron, 58:2449-2469, 2002.
Posner GH, Jeon HB, Ploypradith P, Paik IP, Borstnik, K, Xie S, Shapiro TA. Orally active, water soluble, antimalarial 3-Aryltrioxanes: short synthesis and preclinical efficacy testing in rodents. J Med Chem 45:3824-3828, 2002.
Posner GH, Northrop J, Pail I-K, Bortsnik K, Dolan P, Kensler TW, Xie S, Shapiro TA. New chemical and biological aspects of artemisinin-derived trioxane dimers. Bioorganic and Med Chem 10:227-232, 2002. Abstract
O'Neill PM, Miller A, Bishop LPD, Hindley S, Maggs JL, Ward SA, Roberts SM, Scheinman F, Hoos R, Posner GH, Park BK. Synthesis, antimalarial activity, Biomimetic Iron(II) Chemistry, and the in vitro metabolism of novel, potent C-10-Phenoxy derivatives of dihydroartemisinin. J Med Chem 44:58-68, 2001. Abstract
Posner GH, Jeon HB, Parker MH, Krasavin M, Paik I-K, Shapiro TA. Antimalarial simplified 3-aryltrioxanes: synthesis and preclinical efficacy/toxicity testing in rodents. J of Med Chem 44:3054-3058, 2001. Abstract
Posner GH, Krasavin M, McCutchen M, Ploypradith P, Maxwell JP, Elias JS, Parker MH. New antimalarial trioxanes and endoperoxides, Antimalarial Chemotherapy, P. Rosenthal, Ed. John Wiley, 255-263, 2001.
Szpilman AM, Korshin EE, Hoos R, Posner GH, Bachi MD. Iron(II)-induced cleavage of antimalarial beta-sulfonyl endoperoxides. Evidence for the generation of potentially cytotoxic carbocations. J Organic Chem 66:6531-6540, 2001. Abstract
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