Synthesis and antitumor properties of N1-acyloxymethyl derivatives of bis(2,6-dioxopiperazines).
Many N1-acyloxymethyl derivatives VI of bis(2,6-dioxopiperazine) I, ICRF-154, were prepared and tested for antitumor activity. The treatment of I with formaldehyde gave a crystalline bis(N1-hydroxymethyl) derivative VII, which was acylated under various conditions to give bis(N1-acyloxymethyl) derivatives VI. Antitumor activity of VI against P388 leukemia in mice was studied. Several bis(N1-acyloxymethyl) compounds such as phenylacetyloxymethyl VI-6, methoxycarbonyloxymethyl VI-41, isobutoxycarbonyloxymethyl VI-44, and furancarboxymethyl VI-38 compounds were found to have potent antitumor activities. On the other hand, water-soluble esters having an amine or a carboxylic acid function in their acyl groups showed rather reduced activity. These bis(N1-acyloxymethyl) derivatives VI were presumably hydrolyzed into the parent bis(2,6-dioxopiperazine) I by nonspecific esterase in the body to exhibit their antitumor activity.
Cai
J C
JC
Shu
H L
HL
Tang
C F
CF
Komatsu
T
T
Matsuno
T
T
Narita
T
T
Yaguchi
S
S
Koide
Y
Y
Takase
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010879:Piperazines; D011929:Razoxane / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D000970:Antineoplastic Agents; D010879:Piperazines; D011929:Razoxane