Ester and amide derivatives of rhodamine B exert cytotoxic effects on different human tumor cell lines

<jats:title>Abstract</jats:title><jats:p>Three esters of rhodamine B (<jats:bold>1</jats:bold>–<jats:bold>3</jats:bold>) differing in their alkyl chain lengths as well as several rhodamine B amides (<jats:bold>4</jats:bold>–<jats:bold>9</jats:bold>) were synthesized in good yields and tested for their cytotoxicity in SRB assays employing several human tumor cell lines. The rhodamine B esters were unselective but showed cytotoxicity of as low as EC<jats:sub>50</jats:sub> = 0.15 ± 0.02 µM. The rhodamine B amides were slightly less cytotoxic but showed good selectivity against MCF-7 and A2780 tumor cell lines. Especially a morpholinyl derivative <jats:bold>4</jats:bold> was ~20 time more cytotoxic for MCF-7 than for nonmalignant NIH 3T3 cells.</jats:p&gt

Mitocanic Di- and Triterpenoid Rhodamine B Conjugates

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

Madecassic Acid—A New Scaffold for Highly Cytotoxic Agents

Due to their manifold biological activities, natural products such as triterpenoids have advanced to represent excellent leading structures for the development of new drugs. For this reason, we focused on the syntheses and cytotoxic evaluation of derivatives obtained from gypsogenin, hederagenin, and madecassic acid, cytotoxicity increased—by and large—from the parent compounds to their acetates. Another increase in cytotoxicity was observed for the acetylated amides (phenyl, benzyl, piperazinyl, and homopiperazinyl), but a superior cytotoxicity was observed for the corresponding rhodamine B conjugates derived from the (homo)-piperazinyl amides. In particular, a madecassic acid homopiperazinyl rhodamine B conjugate 24 held excellent cytotoxicity and selectivity for several human tumor cell lines. Thus, this compound was more than 10,000 times more cytotoxic than parent madecassic acid for A2780 ovarian cancer cells. We assume that the presence of an additional hydroxyl group at position C–6 in derivatives of madecassic, as well as the (2α, 3β) configuration of the acetates in ring A, had a beneficial effect onto the cytotoxicity of the conjugates, as well as onto tumor/non-tumor cell selectivity

Synthesis and cytotoxic evaluation of malachite green derived oleanolic and ursolic acid piperazineamides

<jats:title>Abstract</jats:title><jats:p>The coupling of acetylated piperazinylamide spacered triterpenoic oleanolic acid and ursolic acid with<jats:italic>meta</jats:italic>or<jats:italic>para</jats:italic>substituted carboxylated malachite green analogs gave conjugates<jats:bold>10</jats:bold>,<jats:bold>11</jats:bold>,<jats:bold>15</jats:bold>, and<jats:bold>16</jats:bold>that were cytotoxic for several human tumor cell lines. Especially, an oleanolic acid-derived compound<jats:bold>10</jats:bold>was cytotoxic for MCF-7 human breast carcinoma cells (EC<jats:sub>50</jats:sub> = 0.7 μM). These derivatives represent first examples of triterpenoic acid derivatives holding a cationic scaffold derived from malachite green.</jats:p&gt

Synthesis and cytotoxicity of diastereomeric benzylamides derived from maslinic acid, augustic acid and bredemolic acid

36 substituted benzylamides were prepared starting from maslinic acid, bredemolic acid, and augustic acid and evaluated for their cytotoxicity in SRB assays employing several human tumor cell lines as well as non-malignant fibroblasts. Thereby, the benzylamides of maslinic acid, however, were found to be more cytotoxic than those obtained from augustic acid or bredemolic acid. The best compound (18, derived from maslinic acid) showed an EC50 value of 1.3 μM against A375 melanoma cells. Additional staining experiments revealed that this compound acted rather by apoptosis than by necrosis

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

Semi-synthetic triterpenoids, holding an amino substituted seven-membered A-ring (azepano-ring), which could be synthesized from triterpenic oximes through a Beckmann type rearrangement followed by a reduction of lactame fragment, are considered to be novel promising agents exhibiting anti-microbial, alpha-glucosidase, and butyrylcholinesterase inhibitory activities. In this study, in an attempt to develop new antitumor candidates, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives of betulin, oleanolic, ursolic, and glycyrrhetinic acids were evaluated for their cytotoxic activity against five human cancer cell lines and non-malignant mouse fibroblasts by means of a colorimetric sulforhodamine assay. Azepanoallobetulinic acid amide derivative 11 was the most cytotoxic compound of this series but showed little selectivity between the different human tumor cell lines. Flow cytometry experiments showed compound 11 to act mainly by apoptosis (44.3%) and late apoptosis (21.4%). The compounds were further screened at the National Cancer Institute towards a panel of 60 cancer cell lines. It was found that compounds 3, 4, 7, 8, 9, 11, 15, 16, 19, and 20 showed growth inhibitory (GI50) against the most sensitive cell lines at submicromolar concentrations (0.20–0.94 μM), and their cytotoxic activity (LC50) was also high (1–6 μM). Derivatives 3, 8, 11, 15, and 16 demonstrated a certain selectivity profile at GI50 level from 5.16 to 9.56 towards K-562, CCRF-CEM, HL-60(TB), and RPMI-8226 (Leukemia), HT29 (Colon cancer), and OVCAR-4 (Ovarian cancer) cell lines. Selectivity indexes of azepanoerythrodiol 3 at TGI level ranged from 5.93 (CNS cancer cell lines SF-539, SNB-19 and SNB-75) to 14.89 for HCT-116 (colon cancer) with SI 9.56 at GI50 level for the leukemia cell line K-562. The present study highlighted the importance of A-azepano-ring in the triterpenic core for the development of novel antitumor agents, and a future aim to increase the selectivity profile will thus lie in the area of modifications of azepano-triterpenic acids at their carboxyl group