Improved Synthesis of N-Benzylaminoferrocene-Based Prodrugs and Evaluation of Their Toxicity and Antileukemic Activity

Abstract

We report on an improved method of synthesis of N-benzylaminoferrocene-based prodrugs and demonstrate its applicability by preparing nine new aminoferrocenes. Their effect on the viability of selected cancer cells having different p53 status was studied. The obtained data are in agreement with the hypothesis that the toxicity of aminoferrocenes is not dependent upon p53 status. Subsequently the toxicity of a selected prodrug (4) was investigated ex vivo using rat precision cut liver slices and in vivo on hybrid male mice BDF1. In both experiments no toxicity was observed: ex vivo, up to 10 μM; in vivo, up to 6 mg/kg. Finally, prodrug 4 was shown to extend the survival of BDF1 mice carrying L1210 leukemia from 13.7 ± 0.6 days to 17.5 ± 0.7 days when injected daily 6 times at a dose of 26 μg/kg starting from the second day after injection of L1210 cells.

Activity of aminoferrocene-based prodrugs against prostate cancer

“…12 Moreover, we have demonstrated that prodrug 1 exhibits practically no toxicity up to 10 µM in precision cut liver slices (ex vivo) and up to 6 mg/kg in hybrid male mice BDF1 (DBA/2,♀ x C57Bl/6, ♂) (in vivo). 15 Furthermore, we have observed that, when administered in 6 daily doses of 26 µg/kg, prodrug 1 extends the survival of hybrid male mice BDF1 (DBA/2,♀ x C57Bl/6, ♂), which carry L1210 leukemia, from 13.7 + 0.6 days to 17.5 + 0.7 days. The prolonged survival correlates with enhanced oxidative stress and membrane damage in cancer cells isolated from treated animals.…”

“…12 We have reported on aminoferrocene-based prodrugs, which are activated by the cleavage of a C-B bond in the presence of cancer-specific H 2 O 2 concentrations with formation of ROS-generating, ironcontaining catalysts and quinone methides (antioxidant system inhibitors). [13][14][15] These products act synergistically by increasing the ROS concentration in cells that finally leads to their death. We have demonstrated that the best prodrug of this type, prodrug 1 (N-ferrocenyl-N-benzylaminocarbonyloxymethyl-phenylboronic acid pinacol ester, Figure 1) exhibits significant toxicity towards cancer cell lines (HL-60, HeLa, SK-OV-3, U-373) and primary cancer cells (CLL).…”

“…The prolonged survival correlates with enhanced oxidative stress and membrane damage in cancer cells isolated from treated animals. 15 Effects of these ROS-activated prodrugs on prostate cancer have not been studied yet. Other prodrugs activated by cleavage of the B-C bond in the presence of H 2 O 2 include DNA-alkylating agents 16,17 and a recently reported cinnamaldehyde-releasing prodrug.…”

“…These prodrugs are activated by related mechanisms outlined in Figure 1 except that in the former case a relatively stable N-benzylaminoferrocene (4) is formed as a ROS-generating catalyst, whereas in the latter case iron ions are generated from initially produced, unstable aminoferrocene. [13][14][15] Moreover, we report our preliminary data on the antitumor activity of prodrug 1 on CBA mice bearing subrenal capsule xenografts of human prostate adenocarcinoma. [19][20][21] Prodrugs 1 and 2 were prepared as described previously.…”

Gold(I) NHC-based homo- and heterobimetallic complexes: synthesis, characterization and evaluation as potential anticancer agents

“…The technique is an FDAapproved model for studies of drug toxicity and metabolism. It was previously used for the assessment of toxicity of metal-based compounds like cisplatin (kidney), [52] experimental gold compounds (liver, kidney and colon) [53] and aminoferrocene-containing pro-drugs (liver) [54]. In the present study, we investigated the effects of 2, 3, 4 Au(I) homobimetallic compounds, mononuclear 6 Cu(II) and 7 Ru(II) complexes, and Au(I) mononuclear 5 and heterobimetallic 8 compounds, on the activity of the isolated TrxR seleno-enzyme, and on the homologous enzyme glutathione reductase.…”