Investigational New Drugs

, Volume 26, Issue 1, pp 25–34 | Cite as

Pharmacological evaluation of C-3 modified Betulinic acid derivatives with potent anticancer activity

  • Praveen Rajendran
  • Manu JaggiEmail author
  • Manoj K. Singh
  • Rama Mukherjee
  • Anand C. Burman
Preclinical Studies


In vitro and in vivo pharmacological screening of Betulinic acid (BA) and five dihydro-BA derivatives modified at C-3 position [4-nitrobenzyl-oximino (1), 2-4-difluoro-benzoyloxy (2), 2-4-difluoro-benzylidene-amino (3), benzoyl-hydrazono (4), and 4-fluorophenyl-hydrazono (5)], having potent in vitro anti-cancer activity was carried out using ADME, animal PK and tumor studies. We found that BA and the derivatives had poor aqueous solubility (<0.1 μg/ml), low to moderate permeability (log Pe < −5.0) and high plasma protein binding (>70%). Although BA and 5 were metabolized by human liver microsomes, derivatives 1, 2, 3 and 4 possessed good in vitro metabolic stability. Except 3 which inhibited CYP1A2 isoform by more than 50% none of the other compounds inhibited key cytochrome P450 enzyme isoforms (CYP1A2, CYP2C9, CYP2D6 and CYP3A4) at 10 μM. Based on in vitro results one derivative 1 was tested in rodent PK and tumor studies. We found that 1 exhibited favorable pharmacokinetic characteristics of a systemically administered drug and showed better in vivo anti-tumor efficacy as compared to BA in a human colon cancer xenograft model. Our results show that BA derivatives are potential anti-cancer compounds which need to be explored in detail.


Betulinic acid Derivatives Cancer ADME In vitro In vivo 



betulinic acid


parallel artificial membrane permeability assay


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Praveen Rajendran
    • 1
  • Manu Jaggi
    • 1
    Email author
  • Manoj K. Singh
    • 1
  • Rama Mukherjee
    • 1
  • Anand C. Burman
    • 1
  1. 1.Experimental Oncology LabDabur Research FoundationGhaziabadIndia

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