Synthesis and evaluation of water-soluble etoposide esters of malic acid as prodrugs.
Thirty etopside esters of malic acid were synthesized and have been shown to exhibit improved aqueous solubility and stability in neutral solution except for compounds 7Ia-c and 9Ia-c. Compounds 6Ia-c, 6IIb-c, 8Ia-b and 10Ib have been shown to function as prodrugs, whereas the other synthesized derivatives were too stable to reveal parent drugs in vivo. Among synthesized compounds, 8Ib, 4'-O-demethyl 4'-L-malyl epipodophyllotoxins showed the most potent anticancer activity and favorable stability in vitro.
Department of Pharmacy, Zhejiang Medical College, 481 Binwen Road, Hangzhou 310053, China.
Jing
J
Chen
Wenting
W
Du
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004952:Esters / Q000737:chemistry* / Q000494:pharmacology; D005047:Etoposide / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020014:K562 Cells; D008293:Malates / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D004952:Esters; D008293:Malates; D011355:Prodrugs; D014867:Water; D005047:Etoposide; C030298:malic acid