The combination of the “correct” triterpenoid, the “correct” spacer and rhodamine B (RhoB) seems to be decisive for the ability of the conjugate to accumulate in mitochondria. So far, several triterpenoid rhodamine B conjugates have been prepared and screened for their cytotoxic activity. To obtain cytotoxic compounds with EC50 values in a low nano-molar range combined with good tumor/non-tumor selectivity, the Rho B unit has to be attached via an amine spacer to the terpenoid skeleton. To avoid spirolactamization, secondary amines have to be used. First results indicate that a homopiperazinyl spacer is superior to a piperazinyl spacer. Hybrids derived from maslinic acid or tormentic acid are superior to those from oleanolic, ursolic, glycyrrhetinic or euscaphic acid. Thus, a tormentic acid-derived RhoB conjugate 32, holding a homopiperazinyl spacer can be regarded, at present, as the most promising candidate for further biological studies.
Isonucleosides are rather stable regioisomeric analogs of nucleosides with broad therapeutic potential. We have previously demonstrated the ability of 5′ and 6′-isonucleosides to inhibit the activity of acetylcholinesterase, a major target for Alzheimer’s disease therapy. Continuing with our research on this topic, we report herein on the synthesis and biological evaluation of a variety of novel terminal isonucleosides and theobromine isonucleotide analogs. Xylofuranose-based purine or uracil 5′-isonucleosides and xylofuranos-5′-yl or glucos-6′-yl theobromine derivatives were accessed via Mitsunobu coupling between partially protected xylofuranose or glucofuranose derivatives with a nucleobase using conventional or microwave-assisted heating conditions. Theobromine-containing N-isonucleosidyl sulfonamide and phosphoramidate derivatives were synthesized from isonucleosidyl acetate precursors. The most active compounds in the cholinesterase inhibition assays were a glucopyranose-based theobromine isonucleosidyl acetate, acting as a dual inhibitor of acetylcholinesterase (AChE, Ki = 3.1 µM) and butyrylcholinesterase (BChE, Ki = 5.4 µM), and a 2-O,4-O-bis-xylofuranos-5′-yl uracil derivative, which displayed moderate inhibition of AChE (Ki = 17.5 µM). Docking studies revealed that the active molecules are positioned at the gorge entrance and at the active site of AChE. None of the compounds revealed cytoxic activity to cancer cells as well as to non-malignant mouse fibroblasts.
The coupling of acetylated piperazinylamide spacered triterpenoic oleanolic acid and ursolic acid with meta or para substituted carboxylated malachite green analogs gave conjugates 10, 11, 15, and 16 that were cytotoxic for several human tumor cell lines. Especially, an oleanolic acid-derived compound 10 was cytotoxic for MCF-7 human breast carcinoma cells (EC 50 = 0.7 μM). These derivatives represent first examples of triterpenoic acid derivatives holding a cationic scaffold derived from malachite green.
Graphical Abstract
A set of overall 40 carboxamides was prepared from five different natural occurring triterpenoids including oleanolic, ursolic, maslinic, betulinic, and platanic acid. All of which were derived from ethylene diamine holding an additional substituent connected to the ethylene diamine group. These derivatives were evaluated regarding their inhibitory activity of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) employing Ellman’s assay. We further determined the type of inhibition and inhibition constants. Carboxamides derived from platanic acid have been shown to be potent and selective BChE inhibitors. Especially the mixed-type inhibitor (3β)-N-(2-pyrrolidin-1-ylethyl)-3-acetyloxy-20-oxo-30-norlupan-28-amide (35) showed a remarkably low Ki of 0.07 ± 0.01 µM (Ki′ = 2.38 ± 0.48 µM) for the inhibition of BChE.
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