QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.064600v1 309/3/1051    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bai, A. Articles by Zhou, D. Search for Related Content PubMed PubMed Citation Articles by Bai, A. Articles by Zhou, D.

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Prodrug Modification Increases Potassium Tricyclo[5.2.1.0^2,6]-decan-8-yl Dithiocarbonate (D609) Chemical Stability and Cytotoxicity against U937 Leukemia Cells

Departments of Pathology and Laboratory Medicine (A.B., Y.W., D.Z.) and Biochemistry and Molecular Biology (C.L., Y.A.H.), Medical University of South Carolina, Charleston, South Carolina; and Department of Chemistry, Washington State University, Pullman, Washington (G.P.M.)

Potassium tricyclo[5.2.1.0^2,6]-decan-8-yl dithiocarbonate (D609) is a selective antitumor agent, potent antioxidant, and cytoprotectant. It has the potential to be developed as a unique chemotherapeutic agent that may provide dual therapeutic benefits against cancer, e.g., enhancing tumor cell death while protecting normal tissues from damage. However, D609 contains a dithiocarbonate (xanthate) group [O-C(=S)S^-/O-C(=S)SH], which is chemically unstable, being readily oxidized to form a disulfide bond with subsequent loss of all biological activities. Therefore, we developed the synthesis of a series of S-(alkoxyacyl) D609 prodrugs by connecting the xanthate group of D609 to an ester via a self-immolative methyleneoxyl group. These S-(alkoxylacyl)-D609 prodrugs are designed to release D609 in two steps: esterase-catalyzed hydrolysis of the acyl ester bond followed by conversion of the resulting hydroxymethyl D609 to formaldehyde and D609. Three S-(alkoxyacyl) D609 prodrugs were synthesized by varying the steric bulkiness of the acyl group. These prodrugs are stable to ambient conditions, but readily hydrolyzed by esterases to liberate D609 in a controlled manner. More importantly, the lead prodrug methyleneoxybutyryl D609 is biologically more effective than D609 in inhibiting sphingomyelin synthase, thereby increasing the level of ceramide and inducing apoptosis in U937 leukemia cells. The prodrug has a significantly lower LD₅₀ value than that of D609 (56.6 versus 117 µM) against U937 cells. These findings demonstrate that prodrug modification of the xanthate moiety with an alkoxyacyl group can improve D609 oxidative stability and enhance its antitumor activity.

Address correspondence to: Dr. Daohong Zhou, Department of Pathology, Medical University of South Carolina, 165 Ashley Ave., Suite 309, P.O. Box 250908, Charleston, SC 29425. E-mail: zhoud{at}musc.edu