pifithrin-beta and pifithrin

Since activation of p53 in response to cytotoxic stress may have proapoptotic or protective effects depending on the nature of the injury, inhibitors of p53 may have therapeutic interest as modulators of chemotherapy toxicity or efficacy. In an attempt to identify novel p53 inhibitors, a quality collection of compounds structurally related to pifithrin-β were designed and synthesized as potential inhibitors of p53. The biochemical and biological evaluations supported that compounds of the tetrahydrobenzothiazole series were inhibitors of the p53 transcriptional activity and were effective in enhancing paclitaxel-induced apoptosis. In contrast, in spite of the increased cytotoxic potency, selected compounds of the benzothiazole series were not able to modulate the transcriptional activity of p53, as indicated by lack of change of p21 expression. The therapeutic interest of the compounds of the former series in combination with taxanes was confirmed in a human tumor xenograft model.

Topics: Animals; Antineoplastic Agents; Benzothiazoles; Cell Line, Tumor; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Inhibitory Concentration 50; Ovarian Neoplasms; Toluene; Transplantation, Heterologous; Tumor Suppressor Protein p53

Pifithrin α (PFTα), an inhibitor of the p53 protein, is regarded as a lead compound for cancer and neurodegenerative disease therapy. There is some evidence that this compound activates the aryl hydrocarbon receptor (AhR) in a complete independent way of the p53 inhibition and that it is easily converted to its condensation product pifithrin β (PFTβ). The aim of this study was to explore the ability of PFTα and of PFTβ to induce a variety of AhR mediated processes.. Computational analysis using quantum chemical calculations and chemical analysis have been used to study the conformation of the compounds as well as the cyclization reaction. The AhR mediated processes of these compounds have been studied in a rainbow trout cell line (RTG-2) and in a rat hepatoma cell line (H4IIE).. PFTα molecule could not take a planar conformation required for AhR activation whereas PFTβ showed a conformation similar to those of the prototypical AhR ligand β-naphthoflavone. In both cell lines, PFTα and PFTβ provoked different responses related with AhR activation. However, when cyclization of PFTα to PFTβ was hampered by acetylation of the exocyclic nitrogen, all these responses were not observed. These results lead to the conclusion that the activation of the AhR is probably caused by PFTβ instead of PFTα.. Since PFTα is a promising compound for the development of new pharmaceuticals inhibiting p53, the chemical instability of this compound as well as the capacity of its transformation product should be taken into account.

Topics: Animals; Benzothiazoles; Cell Line; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Fibroblasts; Heterocyclic Compounds, 4 or More Rings; Oncorhynchus mykiss; Polymerase Chain Reaction; Rats; Receptors, Aryl Hydrocarbon; Toluene; Tumor Suppressor Protein p53

Several neurological disorders manifest symptoms that result from the degeneration and death of specific neurons. p53 is an important modulator of cell death, and its inhibition could be a therapeutic approach to several neuropathologies. Here, we report the design, synthesis, and biological evaluation of novel p53 inhibitors based on the imino-tetrahydrobenzothiazole scaffold. By performing studies on their mechanism of action, we find that cyclic analogue 4b and its open precursor 2b are more potent than pifithrin-alpha (PFT-alpha), which is known to block p53 pro-apoptotic activity in vitro and in vivo without acting on other pro-apoptotic pathways. Using spectroscopic methods, we also demonstrate that open form 2b is more stable than 4b in biological media. Compound 2b is converted into its corresponding active cyclic form through an intramolecular dehydration process and was found two log values more active in vivo than PFT-alpha. Thus, 2b can be considered as a new prodrug prototype that prevents in vivo p53-triggered cell death in several neuropathologies and possibly reduces cancer therapy side effects.

Topics: Administration, Topical; Animals; Antineoplastic Agents; Apoptosis; Axotomy; Benzothiazoles; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; Drug Design; Drug Stability; Etoposide; Imines; Male; Mice; Neocortex; Neuroprotective Agents; Optic Nerve; Phosphorylation; Prodrugs; Rats; Rats, Wistar; Retinal Ganglion Cells; Thiazoles; Toluene; Tumor Suppressor Protein p53; Vitreous Body

The chemoprotection of cells from apoptosis induced by toxins or ionizing radiation could be important for biodefense and in the treatment of acute injuries. We describe a series of small heterocycles, including fused benzothiazoles, benzimidazoles, and related compounds, that abrogate thymocyte apoptosis induced by dexamethasone and gamma-irradiation. To optimize the protective activity of the previously reported pifithrin-alpha (PFT-alpha, 1), various derivatives and analogues of this and the corresponding ring-closed imidazobenzothiazole (IBT, 39) were synthesized. The aromatic analogues of 39 were more protective than 39, while the aromatic analogues of 1 were not active. Compound 19 containing a pyrrolidinyl substituent on the phenyl ring provided potent antiapoptotic activity (EC50 of 1.31 microM compared to 4.16 microM for 1). Modification of aromatic 39 with a pyrrolidinyl para substituent (compound 60) enhanced the activity, lowering the EC50 to 0.35 microM. Also, 60 provided significant protection against gamma-irradiation-induced apoptosis, as expected. Compounds 19 and 60 may be promising for potential clinical development.

Topics: Animals; Apoptosis; Benzimidazoles; Benzothiazoles; Dexamethasone; Gamma Rays; Imidazoles; In Vitro Techniques; Lymphocytes; Mice; Mice, Inbred C57BL; Pyrrolidines; Structure-Activity Relationship; Thiazoles; Thymus Gland; Toluene; Tumor Suppressor Protein p53