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

Oxana B Kazakova,Denis A Babkov,Gul'Nara V Giniyatullina,Alexander A Spasov,Elena V Sokolova,Akhat G Mustafin

doi:10.3390/molecules25204833

Oxana B Kazakova, Denis A Babkov + Show 4 more

Open Access

https://doi.org/10.3390/molecules25204833

Copy DOI

Abstract

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.

Highlights

Pentacyclic triterpenoids are natural products which are widespread in the plant kingdom and are useful substrates for the synthesis of various compounds with important bioactivities [1,2,3].The introduction of nitrogen-containing substituents into a triterpenoid scaffold resulted in a series of anticancer, antimicrobial, and antiviral agents [4,5,6,7,8,9,10,11]
We focused on the evaluation of their cytotoxicity toward the NCI-60 cancer cell line panel, α-glucosidase inhibitory, and antimicrobial activities, as well as synthesis of two new lupane carboxamides
The target derivatives were purified by column chromatography in good yields and their structure was confirmed by the NMR spectra, in which the signals of amide bond were found at δ 4.00 and 5.55 ppm in 1 НNMR spectra, and δ 174.51 and 177.56 ppm in 13 C NMR spectra, respectively

Summary

Introduction

Pentacyclic triterpenoids are natural products which are widespread in the plant kingdom and are useful substrates for the synthesis of various compounds with important bioactivities [1,2,3].The introduction of nitrogen-containing substituents into a triterpenoid scaffold resulted in a series of anticancer, antimicrobial, and antiviral agents [4,5,6,7,8,9,10,11]. Conjugates of steroids and polyamines have been actively investigated in recent years as potential new cationic steroidal antibiotics [12]. Molecules 2020, 25, 4833 known compound is squalamine, which has been shown to inhibit mitogen-induced proliferation and the migration of endothelial cells in vitro and caused significant in vivo inhibition of angiogenesis [13]. This steroidal broad-spectrum antibiotic exhibits activity against Gram-positive and Gram-negative bacteria, fungi, and viruses [14]. Some triterpene–spermine conjugates form dynamic supramolecular networks in solutions which influence their cytotoxicity [22]

Methods

Results

Conclusion