New thioderivatives of gossypol and gossypolone, as prodrugs of cytotoxic agents.
New dithiane or dithiolane derivatives of gossypol and gossypolone were synthesized with dithiolethane or dithiolpropane in the presence of BF(3)/Et(2)O. These thioderivatives exhibited low toxicity on KB cells (human epidermoid carcinoma cells of the mouth). They react easily with electrophiles in aprotic solvents to regenerate gossypolone or to form dehydrogossypoldithianes and dehydrogossypoldithiolanes, which display higher toxicity on KB cells. In addition, the low toxicity of gossypol thioderivatives was reversed by nitric oxide donors in physiological media. These experiments suggest that gossypol and gossypolone dithianes and dithiolanes can be used as prodrugs that target tumor cells surrounded by high concentrations of nitric oxide.
Dao
Vi-Thuy
VT
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif sur Yvette, France.
Dowd
Michael K
MK
Gaspard
Christiane
C
Martin
Marie-Thérèse
MT
Hémez
Julie
J
Laprévote
Olivier
O
Mayer
Michel
M
Michelot
Robert J
RJ
D045744:Cell Line, Tumor; D006072:Gossypol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D011355:Prodrugs / Q000737:chemistry / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000633:toxicity*
D011355:Prodrugs; D013438:Sulfhydryl Compounds; C043259:gossypolone; D006072:Gossypol