bc9b00565_si_001.pdf (2.9 MB)
2‑Deoxyglycoside Conjugates of Lupane Triterpenoids with High Cytotoxic ActivitySynthesis, Activity, and Pharmacokinetic Profile
journal contribution
posted on 2019-10-08, 17:36 authored by Pavla Perlikova, Miroslav Kvasnica, Milan Urban, Marian Hajduch, Jan SarekA set
of 41 glycosidic conjugates of pentacyclic triterpenes was
synthesized in order to improve the solubility of highly cytotoxic
parent compounds. Their in vitro cytotoxic activity
was evaluated in 25 cancer cell lines and 2 noncancer fibroblasts.
Fifteen compounds had high cytotoxicity on the T-lymphoblastic leukemia
cell line CCRF-CEM and 6 of them were active in multiple cell lines
of various histogenic origin and not toxic in fibroblasts. Compound 11a had IC50 of 0.64 μM in CCRF-CEM cells,
0.60 μM in K-562 cells, and 0.37 μM in PC-3 cells; compound 12a had IC50 of 0.64 μM in CCRF-CEM cells
and 0.71 μM in SW620 cells; compound 17b had IC50 of 0.86 μM in HCT116 cells and 0.92 μM in PC-3
cells. Compounds 11b and 12b were slightly
less active than the previously mentioned derivatives; however, their
solubility was significantly better, and therefore they were selected
for the in vivo evaluation of the pharmacokinetic
profile in mice. In both compounds, the maximum concentration in plasma
was achieved very rapidlythe highest level in plasma was found
1 h after administration (22.2, respectively, 6.4 μM). For compound 12b, the resorption was followed with fast elimination, and
12 h after administration, the compound was not detected in plasma.
In contrast, compound 11b was eliminated more slowly;
it was still present in plasma after 12 h, but its concentration dropped
below the detection limit after 24 h. The elimination half-time determined
for compound 11b was 2.4 h and for compound 12b just about 1.4 h. These values are reasonable for further drug development.
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0.86 μ Mcompound 12 bplasma0.64 μ Mcytotoxic parent compounds6.4 μ Mcompound 11 b2 noncancer fibroblasts25 cancer cell lines41 glycosidic conjugates0.71 μ MSW 620 cellsPC -3 cells0.60 μ MCompounds 11 bHCT 116 cells0.92 μ M0.37 μ Mcompound 17 bIC 50T-lymphoblastic leukemia cell line CCRF-CEM12 hK -562 cellsCCRF-CEM cells
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