Abstract
A series of 3-substituted derivatives of betulin and betulinic aldehyde were synthesized as promising anticancer agents. The newly triterpenes were tested against five human cancer cell lines like biphenotypic B myelomonocytic leukaemia (MV-4-11), adenocarcinoma (A549), prostate (Du-145), melanoma (Hs294T), breast adenocarcinoma (MCF-7) and normal human mammary gland (MCF-10A). The compound 9 showed towards Du-145, MCF-7 and Hs294T cells significant antiproliferative activity with IC50 ranging from 7.3 to 10.6 μM. The evaluation of ADME properties of all compounds also includes their pharmacokinetic profile. The calculated TPSA values for synthetized derivatives are in the range between 43.38 Å2 and 55.77 Å2 suggesting high oral bioavailability. The molecular docking calculations showed that triterpene 9 fits the active site of the serine/threonine protein kinase Akt.
Highlights
More than 120 drugs of plant origin are used for the treatment or amelioration of various diseases
The outer bark layer of the birch tree contain as major compound betulin 1 (Figure 1) (12–30% of dry weight) and trace amounts of other triterpenes such as allobetulin, betulinic acid, betulinic aldehyde and lupeol [2]
The introduction of the 2-butynoyl group at the C-3 position in compound 9 resulted in an increase of antiproliferative activity in Du-145, Hs294T and MCF-7 cell lines when compared with betulin 1
Summary
More than 120 drugs of plant origin are used for the treatment or amelioration of various diseases. In the case of derivatives of betulinic aldehyde, only compound 16 exhibited significant activity against MV-4-11 cells, 6-fold more potent than the 3-acetylbetulinic aldehyde 3. The compounds 6, 9, 13–14, 16, betulin 1 and cisplatin were evaluated in vitro for antiproliferative activity against human cell lines like adenocarcinoma (A549), prostate (Du-145), melanoma (Hs294T), breast adenocarcinoma (MCF-7) and normal mammary gland (MCF-10A). The introduction of the 2-butynoyl group at the C-3 position in compound 9 resulted in an increase of antiproliferative activity in Du-145, Hs294T and MCF-7 cell lines when compared with betulin 1. The results obtained for compound 9 from the PASS program confirmed the studies of antiproliferative activity against Hs294T and MCF-7 cells.
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