Polyamine derivatives of betulinic acid and β-sitosterol: A comparative investigation

Abstract

β-Sitosterol and betulinic acid were used in designing their conjugates with selected polyamines bearing either an amide bond, or an ester and an amide bond simultaneously in the target molecule. The synthesized compounds were subjected to basic cytotoxic and antimicrobial tests. The synthetic protocol is described separately for each of the three series of the target amides, because each series of compounds required a different synthetic approach. The cytotoxicity was tested on cells derived from human T-lymphoblastic leukemia, breast adenocarcinoma and cervical cancer, and compared with the tests on normal human fibroblasts. Most of the target compounds (5a–5c, 11a–11c and 16a–16c) showed medium to high cytotoxicity (0.7–7.8μM), however, in some cases the compounds showed high cytotoxicity even toward normal human fibroblasts (11a–11c). Two compounds of this series (11c and 16c) also displayed antimicrobial activity with high and selective microbe specificity. The compound 11c was potent against Escherichia coli (minimal inhibition concentration (MIC) 6.25μgmL−1, i.e. 9.75nMmL−1) and Staphylococcus aureus (MIC 12.5μgmL−1, i.e. 19.5nMmL−1), and showed medium activity against Pseudomonas aeruginosa. The compound 16c was highly active against Enterococcus faecalis and S. aureus (both, MIC 3.125μgmL−1, i.e. 4.22nMmL−1), both Gram-positive bacteria, however showed only weak activity against E. coli and no activity against P. aeruginosa, both Gram-negative bacteria, which indicates possible microbe specificity of 16c. Comparing β-sitosterol-based series (5a–5c) and betulinic acid series (11a–11c and 16a–16c) of the target compounds, the latter one gave more promising structures. The compounds 11c and 16c showed effects which may be described as multifarious activity (pleiotropic effects).