Investigational New Drugs

, Volume 24, Issue 5, pp 383–392 | Cite as

The selectivty and anti-metastatic activity of oral bioavailable butyric acid prodrugs

  • Ada Rephaeli
  • Michal Entin-Meer
  • Dikla Angel
  • Nataly Tarasenko
  • Tal Gruss-Fischer
  • Irena Bruachman
  • Don R. Phillips
  • Suzanne M. Cutts
  • Daphne Haas-Kogan
  • Abraham Nudelman
Preclinical Studies


Acyloxyalkyl ester prodrugs of histone deacetylase inhibitors, a family of anti-cancer agents, are metabolized intracellularly to acids and aldehyde(s). The purpose of this study was to assess the in vitro and in vivo anticancer activity, selectivity and oral bioavailability of these prodrugs. The prodrugs exhibited a hierarchal potency of AN-193 ≥ AN-7 > AN-1 and AN-9 ≫ AN-10 against murine lung carcinoma (3LLD122) and human breast carcinoma (MCF-7) cell lines. AN-9, and to even greater extent AN-7, displayed preferential cytotoxicity against leukemic and glioblastoma cells compared to their normal cellular counterparts-normal mononuclear and astrocytes cells, respectively. In vivo, anti-metastatic activity was evaluated in a metastatic model of lung cancer in which Lewis lung carcinoma (3LLD122) cells are injected intravenously into C57/BL mice and produce lung nodules. The prodrugs administered orally demonstrated a significant inhibition of lung-lesion formation and their hierarchal potency concurred with that observed in vitro, with the exception of AN-193 that was the least active compound. Escalating doses of AN-7 (5–100 mg/kg), administered by oral or intraperitoneal routes and displayed equivalent anti-metastatic activities, confirmed the good oral bioavailability of AN-7. Consistent with these findings, a time course study of histone acetylation in subcutaneously implanted 3LL122 tumors showed 2–4 fold increases in histone acetylation within 0.5 h of intravenous, intraperitoneal, or oral administration of AN-7 (100 mg/kg). Relative contributions of the prodrug metabolites to the anti-neoplastic activity and the best candidate for clinical studies are discussed.


AN-1 AN-7 AN-9 Histone acetylation Formaldehyde Lewis lung carcinoma 

Abbreviations used


butyric acid


malignant glioma




dimethyl sulfoxide


histone deacetylase


histone deacetylase inhibitors




structure activity relationships


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Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Ada Rephaeli
    • 1
  • Michal Entin-Meer
    • 2
  • Dikla Angel
    • 1
    • 4
  • Nataly Tarasenko
    • 1
  • Tal Gruss-Fischer
    • 1
  • Irena Bruachman
    • 1
  • Don R. Phillips
    • 3
  • Suzanne M. Cutts
    • 3
  • Daphne Haas-Kogan
    • 2
  • Abraham Nudelman
    • 4
  1. 1.Felsenstein Medical Research Center, Sackler School of MedicineTel Aviv UniversityPetach TikvaIsrael
  2. 2.Department of Radiation Oncology and Comprehensive Cancer CenterUniversity of California, San FranciscoSan FranciscoUSA
  3. 3.Department of BiochemistryLa Trobe UniversityVictoriaAustralia
  4. 4.Chemistry DepartmentBar-Ilan UniversityRamat GanIsrael

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