Identification of the spiro(oxindole-3,3'-thiazolidine)-based derivatives as potential p53 activity modulators.
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.
Department of Pharmaceutical and Toxicological Chemistry, University of Naples "Federico II", Italy.
Isabel
I
Gomez-Monterrey
Alessia
A
Bertamino
Amalia
A
Porta
Alfonso
A
Carotenuto
Simona
S
Musella
Claudio
C
Aquino
Ilaria
I
Granata
Marina
M
Sala
Diego
D
Brancaccio
Delia
D
Picone
Carmine
C
Ercole
Paola
P
Stiuso
Pietro
P
Campiglia
Paolo
P
Grieco
Pio
P
Ianelli
Bruno
B
Maresca
Ettore
E
Novellino
D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000378:metabolism
C000594641:6-(4-chlorobenzyl)-1H-spiro(imidazo(1,5-c)thiazole-3,3'-indoline)-2',5,7(6H,7aH)-trione; D007211:Indoles; D013141:Spiro Compounds; D053778:Thiazolidines; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2