2-Acetylpyridine thiosemicarbazones: cytotoxic activity in nanomolar doses against malignant gliomas.
2-acetylpyridine N(4)-phenyl thiosemicarbazone (H2Ac4Ph), and its N(4)-ortho-tolyl (H2Ac4oT), N(4)-meta-tolyl (H2Ac4mT), N(4)-para-tolyl (H2Ac4pT), N(4)-ortho-chlorophenyl (H2Ac4oClPh), N(4)-meta-chlorophenyl (H2Ac4mClPh) and N(4)-para-chlorophenyl (H2Ac4pClPh) derivatives were assayed for their cytotoxicity against RT2 (expressing p53 protein) and against T98 (expressing mutant p53 protein) glioma cells. The compounds were highly cytotoxic against RT2 (IC50=24-1.4 nM) and T98 cells (IC50=50-1.0 nM). IC50 for cisplatin=5 (RT2) and 17 μM (T98). The thiosemicarbazones presented haemolytic activity with IC50>10(-3)M, indicating a very good therapeutic index. SAR studies suggested that stereo properties are critical to define the potential activity of the studied compounds against the RT2 cell line, while electronic properties seem to be important for interaction with the biological target in T98 cells.
Lessa
Josane A
JA
Departamento de Química, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
Mendes
Isolda C
IC
da Silva
Paulo R O
PR
Soares
Marcella A
MA
dos Santos
Raquel G
RG
Speziali
Nivaldo L
NL
Romeiro
Nelilma C
NC
Barreiro
Eliezer J
EJ
Beraldo
Heloisa
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D013882:Thiosemicarbazones; C033836:2-acetylpyridine thiosemicarbazone