Mitocanic Di- and Triterpenoid Rhodamine B Conjugates

Miamisburg 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.

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Sarigerme
Mitochondrial membranes of malignant cells hold an increased membrane potential compared to non–malignant cells. This effect fosters the accumulation of cationic molecules, hence inducing high selectivity for mitocans holding a (more or less) lipophilic cation such as a rhodamine scaffold. The same effect applies for triphenylphosphonium cations and to a small extent for quaternary ammonium ions, zwitterionic N-oxides and triterpenes substituted with BODIPYs or a safirinium moiety [67].
To date, hybrid molecules have been prepared from oleanolic acid (OA, Figure 2), ursolic acid (UA), glycyrrhetinic acid (GA), betulinic acid (BA), maslinic acid (MA), augustic acid (AU), 11-keto-β-boswellic acid (KBA), asiatic acid (AA), tormentic acid (TA) and euscaphic acid (EA).
OA-derived RhoB conjugates appear to be superior to analog UA-derived compounds in the majority of cases with respect to their cytotoxicity. Although AKBA-derived derivatives have good cytotoxicity properties, they were found to be less cytotoxic compared to other triterpene carboxylic acid derivatives, but they often showed better tumor cell/non-tumor cell selectivity. So far, the best cytotoxicity properties have been found for MA-, EA- and TA-derived derivatives. These allowed the transition to compounds of nano-molar activity, while many other triterpene carboxylic acid derivatives were cytotoxic only on a micro-molar concentration range. MA- derived derivatives seem to be approximately equivalent to EA-derived compounds. They are currently only surpassed in many tumor cell lines only by the analogous derivatives from TA. From results available so far, it can be concluded that compounds holding a homopiperazinyl spacer are superior to those with a piperazinyl spacer. This underlines the importance of the spacer for obtaining good cytotoxicity properties. (Molecules. 2020 Nov; 25(22): 5443.)

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