Preparation and antitumor activity of 2''-O-, 3''-O- and 2'',3''-di-O-substituted derivatives of etoposide.
The 2''-O-, 3''-O- and 2'',3''-di-O-substituted derivatives (4a--p) of etoposide were prepared by nucleophilic substitution of 4'-O-benzyloxycarbonyletoposide (2) followed by deprotection. Controlled reaction (a limited amount of reagents and low temperature) was required for preparing the mono-O-substituted derivatives. In terms of ED125 values, doses which show 125% of T/C against P388 leukemia in mice, both the 2''-O-acetate (4a, ED125 = 0.18 mg/kg) and 3''-O-acetate (4b, 0.23 mg/kg) were nearly as active as etoposide (1, 0.19 mg/kg), while the 2'',3''-di-O-acetate (4c, 1.9 mg/kg) was somewhat less potent. In the replacement with other substituents, antitumor activity of the 2''-O-substituted derivatives was affected much more by the difference of the substituents as compared with that of the corresponding 3''-O-substituted derivatives. In the 2'',3''-di-O-substituted derivatives, the activity was decreased additively on the substituents.
Ohnuma
T
T
Bristol-Myers Squibb Research Institute, Ltd., Tokyo Research Center, Japan.
Obata
R
R
Nishiyama
Y
Y
Yamasaki
T
T
Kamei
H
H
Naito
T
T
Oki
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D005047:Etoposide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains
D000970:Antineoplastic Agents; D005047:Etoposide