Cyclopentenone prostaglandins (PGs) such as
prostaglandin A1 (
PGA1) and
prostaglandin J2 (
PGJ2) significantly increased the life span of
Ehrlich ascites tumor-bearing mice. In order to obtain PG derivatives which have more potent antitumor activity than
PGA1 and
PGJ2, we synthesized a number of alkylidenecyclopentenone PGs and studied the antitumor activity of these compounds in vitro and in vivo.
delta 7-PGA1, 12-epi-delta 7-PGA1, and delta 12,14-PGJ2 showed 50% inhibitory concentrations of 0.3 microgram/ml against the growth of L1210 culture cells. These compounds are several times more cytotoxic than parent compounds. From a structure-activity relationship analysis, we concluded that, as for
PGA derivatives: (a) a double bond in C7-8 potentiates the cytotoxicity; (b) a 15-hydroxy group is not essential for cytotoxicity; (c) the stereochemistry of R2 chain is not essential, while 12-epi derivatives also have full activity; (d) a double bond in C12-13 seems to be essential for full activity, and for PGJ derivatives a double bond in C12-13 and C14-15 potentiates the cytotoxicity. These compounds showed marked antitumor activity against
Ehrlich ascites tumor in vivo. At doses of 20-30 mg/kg/day three or five consecutive i.p. treatments with these compounds resulted in a 66 to 111% increase in life span with long-term survivors. A single i.p. injection with 12-epi-delta 7-PGA1 (100 mg/kg) resulted in 73% increase in life span with 33% of long-term survivors, indicating an activity comparable to that of
cyclophosphamide (200 mg/kg). However,
delta 7-PGA1 and 12-epi-delta 7-PGA1 were marginally effective against
P388 leukemia. Treatment with
delta 7-PGA1 (10 mg/kg/day i.p.) and 12-epi-delta 7-PGA1 (20 mg/kg/day i.p.) on Days 1-9 resulted in 25.8 and 29.6% increases in life span, respectively.
delta 7-PGA1 and delta 12-PGJ2 derivatives may be a potential new class of
antitumor agents.