Anticancer Potential of Betulonic Acid Derivatives

Clinical trials have evidenced that several natural compounds, belonging to the phytochemical classes of alkaloids, terpenes, phenols and flavonoids, are effective for the management of various types of cancer. Latest research has proven that natural products and their semisynthetic variants may serve as a starting point for new drug candidates with a diversity of biological and pharmacological activities, designed to improve bioavailability, overcome cellular resistance, and enhance therapeutic efficacy. This review was designed to bring an update regarding the anticancer potential of betulonic acid and its semisynthetic derivatives. Chemical derivative structures of betulonic acid including amide, thiol, and piperidine groups, exert an amplification of the in vitro anticancer potential of betulonic acid. With the need for more mechanistic and in vivo data, some derivatives of betulonic acids may represent promising anticancer agents.

Modification at A-Ring and Cytotoxic Activity of Betulonic Acid and its N-Methylpyperazinyl Amide

Since cancer remains one of the most prevalent diseases today, there is an urgent need for the development of new agents. Triterpenoids may act in multiple pathways displaying antiproliferative, antiangiogenic, anti-inflammatory, and pro-apoptotic activities that place them as promising multifunctional agents in treating cancer. In this paper a series of betulonic acid and its N-methylpyperazinyl amide derivatives, especially holding C2-nicotinoylidene/furfurylidene/fluorobenzylidene fragments, have been synthesized and evaluated for their cytotoxic activity against the NCI-60 cancer cell line panel. N-Methylpiperazinyl amides of betulinic acid 11 and 4-pyridinoylidene-betulinic acid 9 as well as betulonic acid C2-4-pyridinoylidene- 14 or furfurylidene 16 derivatives were found to be the leading compounds with GI50 values of 0.49 μM for leukemia CCRF-CEM, 1.60 μM and 1.36 μM for colon cancer HCT-116 and 1.66 μM for melanoma LOX IMVI cell lines, respectively. The activity displayed for these compounds was higher than for the standard drug doxorubicin against colon cancer HCT-15 and ovarian cancer NCI/ADR-RES cell lines. Cell cycle analysis indicates that compound 11 promotes cytotoxic activity through the apoptosis induction both in conditionally normal (HEK293) and in cancer (A549, MCF-7) cells, whereas compound 14 exhibits both cytostatic and cytotoxic activity, dependently on cell line evaluated. In particular, in HEK293 cells the compound 14 induces mainly apoptotic cell death, while in A549 and MCF-7 cells cytostatic effect is dependent on cell cycle arrest in G2/M phase.Our results suggest that betulinic acid N-methylpyperazinyl amide 11 is the promising compound for the future drug development antitumor studies.

Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

ABSTRACTThe lack of medication to suppress coronavirus infections is a main reason for the dramatic course of the COVID-19 pandemic. There is an urgent need to identify suitable coronavirus drug targets and corresponding lead molecules. Here we describe the discovery of a class of coronavirus inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. SAR exploration of these 1,2,3-triazolo fused betulonic acid derivatives yielded lead molecule 5h as a strong inhibitor (antiviral EC50: 0.6 μM) of human coronavirus 229E replication. An nsp15 endoribonuclease active site mutant virus was markedly less sensitive to 5h, and selected resistance to the compound mapped to mutations in the N-terminal part of nsp15, at an interface between two nsp15 monomers. The biological findings were substantiated by the nsp15 binding mode for 5h, predicted by docking. Hence, besides delivering a distinct class of inhibitors, our study revealed a druggable pocket in the nsp15 hexamer with relevance for anti-coronavirus drug development.

Evaluation of Cytotoxicity and α-Glucosidase Inhibitory Activity of Amide and Polyamino-Derivatives of Lupane Triterpenoids

A series of two new and twenty earlier synthesized branched extra-amino-triterpenoids obtained by the direct coupling of betulinic/betulonic acids with polymethylenpolyamines, or by the cyanoethylation of lupane type alcohols, oximes, amines, and amides with the following reduction were evaluated for cytotoxicity toward the NCI-60 cancer cell line panel, α-glucosidase inhibitory, and antimicrobial activities. Lupane carboxamides, conjugates with diaminopropane, triethylenetetramine, and branched C3-cyanoethylated polyamine methyl betulonate showed high cytotoxic activity against most of the tested cancer cell lines with GI50 that ranged from 1.09 to 54.40 µM. Betulonic acid C28-conjugate with triethylenetetramine and C3,C28-bis-aminopropoxy-betulin were found to be potent micromolar inhibitors of yeast α-glucosidase and to simultaneously inhibit the endosomal reticulum α-glucosidase, rendering them as potentially capable to suppress tumor invasiveness and neovascularization, in addition to the direct cytotoxicity. Plausible mechanisms of cytotoxic action and underlying disrupted molecular pathways were elucidated with CellMinner pattern analysis and Gene Ontology enrichment analysis, according to which the lead compounds exert multi-target antiproliferative activity associated with oxidative stress induction and chromatin structure alteration. The betulonic acid diethylentriamine conjugate showed partial activity against methicillin-resistant S. aureus and the fungi C. neoformans. These results show that triterpenic polyamines, being analogs of steroidal squalamine and trodusquemine, are important substances for the search of new drugs with anticancer, antidiabetic, and antimicrobial activities.