RESUMO
Triterpene acids, namely, 20,29-dihydrobetulinic acid (BA), ursolic acid (UA) and oleanolic acid (OA) were converted into C-28-amino-functionalized triterpenoids 4â»7, 8a, 15, 18 and 20. These compounds served as precursors for the synthesis of novel guanidine-functionalized triterpene acid derivatives 9bâ»12b, 15c, 18c and 20c. The influence of the guanidine group on the antitumor properties of triterpenoids was investigated. The cytotoxicity was tested on five human tumor cell lines (Jurkat, K562, U937, HEK, and Hela), and compared with the tests on normal human fibroblasts. The antitumor activities of the most tested guanidine derivatives was lower, than that of corresponding amines, but triterpenoids with the guanidine group were less toxic towards human fibroblasts. The introduction of the tris(hydroxymethyl)aminomethane moiety into the molecules of triterpene acids markedly enhanced the cytotoxic activity of the resulting conjugates 15, 15c, 18b,c and 20b,c irrespective of the triterpene skeleton type. The dihydrobetulinic acid amine 15, its guanidinium derivative 15c and guanidinium derivatives of ursolic and oleanolic acids 18c and 20c were selected for extended biological investigations in Jurkat cells, which demonstrated that the antitumor activity of these compounds is mediated by induction of cell cycle arrest at the S-phase and apoptosis.
Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Guanidinas/química , Neoplasias/patologia , Triterpenos/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade , Triterpenos/farmacologiaRESUMO
We studied the antischistosomal activity of betulin, betulinic acid and its 9 triphenylphosphonium derivatives characterized by a covalently linkage of the hydrophobic fragment of triterpenoid at C(2)- or C(30)-position with the triphenylphosphonium moiety via a hydrocarbon bridge. The triphenylphosphonium salts showed in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms of Schistosoma mansoni at low micromolar concentrations. In contrast betulin and betulinic acid were inactive against NTS and adult S. mansoni. Of the 9 triphenylphosphonium derivatives tested, the allyl salts 10 (IC50 of 0.76 µg/mL) and 11 (IC50 of 0.64 µg/mL) demonstrated the highest antischistosomal activity against adult S. mansoni. Low worm burden reductions of 22% were observed in vivo for these two compounds. In conclusion, triphenylphosphonium derivatives were obtained from available natural betulin by simple transformations, rendering it practical and useful for large scale application. However, further structural modifications are necessary to translate the promising antischistosomal in vitro activities into in vivo.
Assuntos
Anti-Helmínticos/química , Anti-Helmínticos/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Triterpenos/química , Triterpenos/uso terapêutico , Animais , Anti-Helmínticos/síntese química , Anti-Helmínticos/farmacologia , Feminino , Humanos , Camundongos , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Compostos Organofosforados/uso terapêutico , Triterpenos Pentacíclicos , Esquistossomose mansoni/parasitologia , Triterpenos/síntese química , Triterpenos/farmacologia , Ácido BetulínicoRESUMO
The cytotoxic profile and antiproliferative and mitochondrial effects of triterpene acid conjugates with mitochondriotropic lipophilic triphenylphosphonium (TPP+) and F16 cations were evaluated. Maslinic and corosolic acids chosen as the investigation objects were synthesized from commercially available oleanolic and ursolic acids. Study of the cytotoxic activity of TPP+ and F16 triterpenoid derivatives against six tumor cell lines demonstrated a comparable synergistic effect in the anticancer activity, which was most pronounced in the case of MCF-7 mammary adenocarcinoma cells and Jurkat and THP-1 leukemia cells. The corosolic and maslinic acid hybrid derivatives caused changes in the progression of tumor cell cycle phases when present in much lower doses than their natural triterpene acid precursors. The treatment of tumor cell lines with the conjugates resulted in the cell cycle arrest in the G1 phase and increase in the cell population in the subG1 phase. The cationic derivatives of the acids were markedly superior to their precursors as inducers of hyperproduction of reactive oxygen species and more effectively decreased the mitochondrial potential in isolated rat liver mitochondria. We concluded that the observed cytotoxic effect of TPP+ and F16 triterpenoid conjugates is attributable to the ability of these compounds to initiate mitochondrial dysfunctions. Their cytotoxicity, antiproliferative action, and mitochondrial effects depend little on the type of cationic groups used.
Assuntos
Antineoplásicos , Compostos Organofosforados , Triterpenos , Triterpenos/química , Triterpenos/farmacologia , Triterpenos/síntese química , Humanos , Animais , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Compostos Organofosforados/síntese química , Ratos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácido Oleanólico/análogos & derivadosRESUMO
A series of 34 new amine- and guanidine-functionalized derivatives of betulinic, ursolic, and oleanolic acids were synthesized and tested for their antimicrobial activity against the growth of four bacterial strains (Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus (MRSA)) and two fungal strains (Candida albicans and Cryptococcus neoformans). The obtained compounds were also tested for the cytotoxic effect against HEK293 human embryonic kidney cell line and hemolytic activity against human red blood cells. Most of the prepared amino and guanidinium derivatives of betulinic, ursolic, and oleanolic acids showed a considerably higher bacteriostatic activity against methicillin-resistant S. aureus than the parent compounds. The most active compounds (MICsâ¯≤â¯0.25⯵g/ml or 0.4-0.5⯵M) were superior over the clinically used antibiotic vancomycin in the antibacterial effect (MIC of 1⯵g/ml or 0.7⯵M). Apart from antibacterial activity, new triterpene acid derivatives exhibited excellent antifungal activity against Cryptococcus neoformans, with MICs values being as low as 0.25⯵g/ml (0.4⯵M), and were approximately 65 times as active as fluconazole, a known antifungal agent. Four most promising compounds we identified (7, 13, 24, and 33) showed not only high bacteriostatic effect, but also low cytotoxicity against mammalian HEK293 cells and high hemolytic selectivity.