Mitocanic Di- and Triterpenoid Rhodamine B Conjugates

Abstract

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.

The Presence of a Cyclohexyldiamine Moiety Confers Cytotoxicity to Pentacyclic Triterpenoids

“…All compounds show only low selectivity. This finding distinguishes these compounds from substituted benzylamides (such as EM2) [ 21 ] but also from derivatives with an additional rhodamine B [ 24 , 25 ] moiety being present.…”

“…While unsubstituted triterpene carboxylic acids, e.g., oleanolic acid ( OA ) [ 13 , 14 , 15 ], ursolic acid ( UA ) [ 6 ], betulinic acid ( BA ) [ 16 ], and platanic acid [ 17 , 18 , 19 , 20 ] ( PA ) ( Figure 1 ) have a relatively low cytotoxicity, the 3- O -acetylated amides of these compounds have especially become the focus of scientific interest in recent years. For example, triterpenoic benzyl amides (such as EM2) [ 21 , 22 ] and (homo)-piperazinyl-amides [ 23 , 24 ], as well as the rhodamine B conjugates [ 24 ] of the latter, have cytotoxic effects on numerous human tumor cell lines even in nanomolar concentrations [ 25 ]. However, some of these mitocanic compounds are quite cytotoxic to nonmalignant cells, and selective cytotoxicity can only be achieved by a several well-defined conjugates [ 25 ].…”

“…For example, triterpenoic benzyl amides (such as EM2) [ 21 , 22 ] and (homo)-piperazinyl-amides [ 23 , 24 ], as well as the rhodamine B conjugates [ 24 ] of the latter, have cytotoxic effects on numerous human tumor cell lines even in nanomolar concentrations [ 25 ]. However, some of these mitocanic compounds are quite cytotoxic to nonmalignant cells, and selective cytotoxicity can only be achieved by a several well-defined conjugates [ 25 ].…”

“…Triterpenoic amides holding both a piperazinyl or homopiperazinyl moiety and an extra rhodamine B moiety were moderately to highly cytotoxic to a variety of human tumor cell lines [ 25 ]. A somewhat differentiated picture, however, was found for compounds holding an ethylenediamine moiety instead [ 24 ].…”

Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids

“…Thus, the presence of an amino substituent in ring A leads to cytotoxic but unselective compounds [ 10 ]. Simple carboxylic acid amides are often cytotoxic in micro polar concentrations and highly selective [ 11 , 12 , 13 , 14 ], whereas rhodamine B conjugates can reach EC 50 values in the nano-molar concentration range but hold the risk of being highly cytotoxic for all types of cells [ 15 , 16 ].…”