20S proteasome as novel biological target for organochalcogenanes.
A series of hypervalent selenium- and tellurium-containing compounds (organoselenuranes and organotelluranes) was evaluated aiming novel inhibitors of a threonine protease, namely the 20S proteasome (20S PT). In vitro assays demonstrated high inhibitory potency and specificity of these compounds toward the β2 catalytic site of the 20S PT. Organotelluranes were identified as more potent inhibitors than organoselenuranes since their IC50 ranged from 3.5 to 16 μM while for organoselenuranes the IC50 ranged from 16 to 35 μM indicating great potential to be explored in 20S proteasome inhibition. Cellular assays with those compounds were employed to verify the cytotoxicity and ability to inhibit 20S proteasome in cell. These assays demonstrated that organoselenuranes are capable of maintaining their selectivity in cell while the organotelluranes became inactive under cellular conditions. Stability studies of the organochalcogenanes were performed by (77)Se and (125)Te NMR analysis. It was observed that organotelluranes are stable under enzymatic assay conditions and, organoselenuranes, the structures responsible for inhibitory activity are cyclized organoselenuranes.
Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, 05508-900, São Paulo, Brazil.
Leandro
L
Piovan
Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, 05508-900, São Paulo, Brazil.
Priscila
P
Milani
Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, 05508-900, São Paulo, Brazil.
Marcio S
MS
Silva
Instituto Butantan, Laboratório de Bioquímica e Biofísica, Av. Vital Brasil 1500, 05503-900, São Paulo, Brazil.
Patrícia G
PG
Moraes
Instituto Butantan, Laboratório de Bioquímica e Biofísica, Av. Vital Brasil 1500, 05503-900, São Paulo, Brazil. Electronic address: marimasi@butantan.gov.br.
Marilene
M
Demasi
Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, 05508-900, São Paulo, Brazil. Electronic address: leandroh@iq.usp.br.
Leandro H
LH
Andrade
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013691:Tellurium / Q000737:chemistry*
D009942:Organometallic Compounds; D016566:Organoselenium Compounds; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; D013691:Tellurium
20S proteasome; Inhibitors; Selenium; Tellurium