2-Deoxyglycoside Conjugates of Lupane Triterpenoids with High Cytotoxic Activity—Synthesis, Activity, and Pharmacokinetic Profile

0511505 - ÚOCHB 2020 RIV US eng J - Journal Article
Perlíková, Pavla - Kvasnica, Miroslav - Urban, M. - Hajdúch, M. - Šarek, J.
2-Deoxyglycoside Conjugates of Lupane Triterpenoids with High Cytotoxic Activity—Synthesis, Activity, and Pharmacokinetic Profile.
Bioconjugate Chemistry. Roč. 30, č. 11 (2019), s. 2844-2858. ISSN 1043-1802. E-ISSN 1520-4812
R&D Projects: GA MPO(CZ) FV10599; GA ČR(CZ) GA19-01383S; GA MŠMT(CZ) EF16_019/0000827
Institutional support: RVO:61388963 ; RVO:61389030
Keywords : betulinic acid * stereoselective synthesis * antiviral activity
OECD category: Organic chemistry
Impact factor: 4.031, year: 2019
Method of publishing: Limited access
https://pubs.acs.org/doi/abs/10.1021/acs.bioconjchem.9b00565

A 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 rapidly—the 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.
Permanent Link: http://hdl.handle.net/11104/0301752