Tumor inhibition modification

Modification of the Cyclopentadienyl Ligands, The results described so far suggest that the MX2 moiety within the metallocene dihalides represents the active center of the molecules. However, modification of the cyclopentadienyl rings in (C5H5)2TiCl2 as the model system also has a significant influence on the tumor-inhibiting potency of titanocene dichloride. 

Nucleic acids in the DNA contain a high number of nucleophilic sites that can be attacked by electrophilic intermediates (metabolites) of chemical compounds. DNA adducts formed may cause alterations in the expression of a critical gene in the cell and thus lead to cell death. For example, modification of p53 tumor suppressor gene may inactivate the functions of the p53 protein and render cells sensitive to malignant transformation. Also, formation of RNA adducts may inhibit key cellular events because RNA is essential for protein synthesis. 

Further modifications of the CAAX tetrapeptide structure led to inhibitor 3 which blocked H-Ras farnesylation with an IC50 of 11 nmol/1 [23]. Tumor cell lines expressing mutant H- and N-Ras were most sensitive against this compound that inhibits tumor growth of EJ-1 human bladder carcinomas by about... 

Many clinically relevant NSAIDs exert off-target effects unrelated to their ability to inhibit COX enzymes. For example, INDO and SS induce apoptosis of tumor cells and modulate y-secretase activity (15, 16). INDO also activates the nuclear transcription factor PPARy (17). The complexity of in vivo pharmacologic effects makes it a challenge to separate the contribution of COX inhibition from other effects in a given pharmacologic response. Thus, the removal of COX inhibitory activity by a minor modification, such as the removal of a methyl group, provides an opportunity to dissect COX-dependent and COX-independent effects of certain NSAIDs. In fact, DM-INDO and DM-SS activate PPARy in HCA-7 cells with dose responses similar to those of the parent drugs (14). Likewise, the rfei -methyl compounds exhibit potency similar to the parent compounds in their ability to induce apoptosis in RKO cells, a human colon cancer cell line, and to activate PPARy in cellular reporter assays. 

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