Identification of the Spiro(oxindole-3,3′-thiazolidine)-Based Derivatives as Potential p53 Activity Modulators

Abstract

Here, we report the design of new analogues of spirooxoindolepyrrolidine nucleus as modulators of p53 activity. Compounds (3R,7aR)-6-(4-chlorobenzyl)-1H-spiro[imidazo[1,5-c]thiazole-3,3'-indoline]-2',5,7(6H,7aH)-trione (9c) and (3R,7aR)-5'-methyl-6-(3,4,5-trimethoxybenzyl)-1H-spiro[imidazo[1,5-c]thiazole-3,3'-indoline]-2',5,7(6H,7aH)-trione (10d) are the most potent compounds of this series, inhibiting cell growth of different human tumor cells at submicromolar and micromolar concentrations, respectively. Compound 9c induces apoptotic cell death in human melanoma cell line M14 at 24 h, while in the same condition, treatment with 10d showes a clear arrest at G2/M phase inducing delay of cell cycle progression. Possibly, these activities may be due to inhibition of p53-MDM2 interaction and subsequent p53 release and activation.

The NADPH Oxidase Inhibitor Imipramine-Blue in the Treatment of Burkitt Lymphoma

“…Imipramine-blue possesses a high therapeutic potency in vitro, comparable to that of doxorubicin, for the cell lines SH-SY5Y, MDA-MB231, HeLa, and HEK-293WT (24)(25)(26)(27). The most sensitive cell lines toward imipramine-blue treatment were BL30B95, BL2, BL2B95, and the neuroblastoma cell line KELLY with IC 50 (24 hours) values lower than 0.8 mmol/L (0.79, 0.49, 0.16, and 0.78 mmol/L).…”

New aspects of the formation of 2-substituted thiazolidine-4-carboxylic acids and their thiohydantoin derivatives

“…46,47 Annulation of hydantoin ring to thiazolidine derivatives showed anticancer activity (modulator of P53 activity) 11 and assumed to treat Alzheimer via interaction with amyloid β peptide (Aβ 25-35). 48 It seemed to us that annulation of thiohydantoin moiety to thiazolidines might have biological applications.…”

“…However, the same product was formed in 95% yield by using our simple and convenient procedure. Thus, stirring an equimolar mixture of thiazolidine-4-carboxylic acid (7b) and phenyl isothiocyanate (11) in acidified methanol at room temperature gave 12b (Scheme 5). The stereochemistry of 12b was assigned according to its spectral data and by comparison with the previously reported data.…”

“…1 The thiazolidine-4-carboxylic acid core used in biology as a pseudo-/thio-proline or bioisostere of proline to improve the desired biological or physical properties of a compound without making significant changes in the chemical structure. [2][3][4][5][6][7] TCDs exhibit a broad spectrum of anticancer activities [8][9][10][11][12] against, e.g. liver, 13,14 breast, [13][14][15] colon, 13,16 prostate, 17 endometrial 13 and melanoma 17 cell lines.…”

p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis

“…This effect could be caused by either inhibi tion of p53 entry into the nucleus or, more likely, an inhibi tory effect on stability of p53 through induction of ubiquitin ligases, e.g., MDM2, which is often overexpressed in mela noma and recognized as one of the main causes of p53 inac tivity in melanoma cells (Polsky et al, 2002;Muthusamy et al, 2006;Ji et al, 2012). Reactivating p53 to restore its tumor suppressive capacity has received great attention, with emphasis on reduction of mdm2 to achieve this (Smalley et al, 2007;GomezMonterrey et al, 2010;Michaelis et al, 2011;Verhaegen et al, 2012). Recently, elevated expression of MDM4 was demonstrated to be a key determinant of impaired p53 func tion in melanoma (Gembarska et al, 2012).…”