Synthesis and Selective Anticancer Activity of Organochalcogen Based Redox Catalysts

Abstract

Many tumor cells exhibit a disturbed intracellular redox state resulting in higher levels of reactive oxygen species (ROS). As these contribute to tumor initiation and sustenance, catalytic redox agents combining significant activity with substrate specificity promise high activity and selectivity against oxidatively stressed malignant cells. We describe here the design and synthesis of novel organochalcogen based redox sensor/effector catalysts. Their selective anticancer activity at submicromolar and low micromolar concentrations was established here in a range of tumor entities in various biological systems including cell lines, primary tumor cell cultures, and animal models. In the B-cell derived chronic lymphocytic leukemia (CLL), for instance, such compounds preferentially induce apoptosis in the cancer cells while peripheral blood mononuclear cells (PBMC) from healthy donors and the subset of normal B-cells remain largely unaffected. In support of the concept of sensor/effector based ROS amplification, we are able to demonstrate that underlying this selective activity against CLL cells are pre-existing elevated ROS levels in the leukemic cells compared to their nonmalignant counterparts. Furthermore, the catalysts act in concert with certain chemotherapeutic drugs in several carcinoma cell lines to decrease cell proliferation while showing no such interactions in normal cells. Overall, the high efficacy and selectivity of (redox) catalytic sensor/effector compounds warrant further, extensive testing toward transfer into the clinical arena.

Activity of aminoferrocene-based prodrugs against prostate cancer

“…14 In contrast, catalytic organochalcogene-based prodrugs exhibit in the similar assay a cancer-cell specificity (CLL/MNC) not exceeding the factor of 4. 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.…”

“…Furthermore, Jacob, Herling and co-workers have shown that organochalcogenes are activated in the presence of ROS with formation of GSH peroxidize mimics, whose activity depletes the intracellular GSH concentration, thereby enhancing the oxidative stress. 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.…”

Targeting the disturbed redox equilibrium in chronic lymphocytic leukemia by novel reactive oxygen species-catalytic ‘sensor/effector’ compounds

“…We designed and synthesized a range of novel organochalcogen-based catalysts [9] and employed them in this proof-of-principle study to exploit the observed elevated ROS levels in CLL and their diminished glutathione content. By turning existing OS into a lethal cocktail of ROS and by catalyzing the oxidation of key cysteine proteins and enzymes, they should be capable of elevating ROS levels preferentially in those cells that already carry an abnormally high redox burden.…”

“…By exploiting pre-existing differences in ROS between normal and CLL cells, one could achieve relevant catalyst specificity. We previously described the chemistry of our novel catalytic compounds and their efficacy in a broad range of tumor models and expand here on their encouraging in vitro activity in CLL [9]. Based on established concepts of intraclonal heterogeneity with respect to proliferative activity and environmental dependence [10], we analyzed ROS levels within CLL samples along a gradient of CD5 expression, which can serve as a surrogate for such 'age' associated features.…”

Oxidatively Activated DNA‐Modifying Agents for Selective Cytotoxicity

“…[18,19] Several new chemotherapy strategies are being examined to take advantage of increased reactive oxygen levels within cancerous cells relative to healthy cells. [20][21][22] Thus, DNA-modifying agents that are activated by ROS can be more specific than the current agents if an appropriate activation strategy can be designed ( Figure 1). …”