title: Pharmacological evaluation of C-3 modified Betulinic acid derivatives with potent anticancer activity.
abstract: 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 microg/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 microM. 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.
authors.affiliation: Experimental Oncology Lab, Dabur Research Foundation, 22, Site-IV, Sahibabad, Ghaziabad, Uttar Pradesh, 201010, India.
authors.forename: Praveen
authors.initials: P
authors.lastname: Rajendran
authors.forename: Manu
authors.initials: M
authors.lastname: Jaggi
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Singh
authors.forename: Rama
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Anand C
authors.initials: AC
authors.lastname: Burman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053978:Pentacyclic Triterpenes; D011485:Protein Binding; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013426:Sulfaphenazole / Q000494:pharmacology; D014315:Triterpenes / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D000094062:Betulinic Acid
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D013426:Sulfaphenazole; D003577:Cytochrome P-450 Enzyme System; C507848:CYP2C9 protein, rat; D011802:Quinidine; D007654:Ketoconazole; D000094062:Betulinic Acid