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

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Summary

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.

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Abbreviations

BA:

betulinic acid

PAMPA:

parallel artificial membrane permeability assay

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Authors and Affiliations

  1. Experimental Oncology Lab, Dabur Research Foundation, 22, Site-IV, Sahibabad, Ghaziabad, Uttar Pradesh, 201010, India

    Praveen Rajendran, Manu Jaggi, Manoj K. Singh, Rama Mukherjee & Anand C. Burman

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  1. Praveen Rajendran
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  2. Manu Jaggi
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  3. Manoj K. Singh
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  4. Rama Mukherjee
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  5. Anand C. Burman
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Correspondence to Manu Jaggi.

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Rajendran, P., Jaggi, M., Singh, M.K. et al. Pharmacological evaluation of C-3 modified Betulinic acid derivatives with potent anticancer activity. Invest New Drugs 26, 25–34 (2008). https://doi.org/10.1007/s10637-007-9081-4

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