# Synthesis, Structure, and In Vitro Biological Evaluation of Semi-Synthetic Derivatives of Betulin
## 3 Results and Discussion
### Computational Studies
#### 3.3.3 Antiproliferative Activity  
Designing hybrid molecules based on the combination of two biologically active compounds of natural origin seems to be justified due to the possibility of their simultaneous delivery to target organs. Moreover, hybrid molecules provide better dosage compliance and reduction in drug-drug interactions. An example of a hybrid molecule is the combination of \(\alpha\)-lipoic acid and tacrine. The obtained hybrid compound has a synergistic effect on three target pathways (cholinergic hypothesis, the amyloid pathway, and oxidative stress), which may allow it to be used in the treatment of [PERSON]'s disease [44]. Naturally occurring \(\alpha\)-lipoic acid and its ester derivatives are also the subject of extensive research regarding anticancer activity [25; 45; 46]. [PERSON] et al. described the synthesis and studies of the anticancer activity of conjugates of pentacyclic triterpenes of the oleanane type with \(\alpha\)-lipoic acid. The synthesized compounds were tested against a human liver cancer cell line (BEL-7402), chronic myeloid leukemia cell line (K562), and normal human liver cell line (L-O2). Lipoate derivatives were characterized by moderate cytotoxic activity against chronic myeloid leukemia cells (K562) with IC\({}_{50}\) values ranging from 64.3 \(\mu\)M to \(>\)200 \(\mu\)M. Unfortunately, none of the tested compounds turned out to be active against human liver cancer cells (BEL-7402). It is worth noting, however, that all tested \(\alpha\)-lipoate esters showed no toxic effect on normal liver cell lines (L-O2) [47]. The new triterpenes **6-10**, betulin, and \(\alpha\)-lipoic acid were tested for antiproliferative activity in vitro against seven human cancer cell lines like biphenotypic B myelomonocytic leukemia (MV4-11), lung carcinoma (A549), breast cancer (MCF-7), prostate adenocarcinoma (PC-3), colon cancer (HCT116), pancreas cancer (MiaPaca-2), and melanoma (Hs294T). The results of inhibiting the proliferation of cancer cells and normal breast epithelial MCF-10A cells with the tested compounds are presented in Table 5.  
Biphenylopic B myelomonocytic leukemia cells are the most sensitive to the action of \(\alpha\)-lipoate derivatives **8-10**. The IC\({}_{50}\) values of compounds **8-10** against MV4-11 cells are in the range of 37.9-76.5 \(\mu\)M. The compound with activity against prostate adenocarcinoma (PC-3) and colon cancer (HCT116) cell lines is derivative **10** with (1,2-dithiolan-3-yl)pentanoyl moiety at the C3 position. The presence of a (1,2-dithiolan-3-yl)pentanoyl group at the C28 position (compounds **6** and **7**) leads to a decrease in activity against MV4-11 cells. All synthesized compounds do not have cytotoxic effects on human normal epithelial cells from mammary gland (MCF-10A). SI selectivity indices are determined by dividing the IC\({}_{50}\) value for the normal line (MCF-10A) using the IC\({}_{50}\) value for the specific tumor line being tested. A favorable SI (\(>\)1.0) indicates that the substance has greater effectiveness against cancer cells than toxicity against normal cells.