Prodrug modification increases potassium tricyclo[5.2.1.0 2,6]-decan-8-yl dithiocarbonate (D609) chemical stability and cytotoxicity against U937 leukemia cells

Aiping Bai, G. Patrick Meier, Yong Wang, Chiara Luberto, Yusuf A. Hannun, Daohong Zhou

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Potassium tricyclo[5.2.1.02,6]-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.

Original languageEnglish (US)
Pages (from-to)1051-1059
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume309
Issue number3
DOIs
StatePublished - Jun 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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