Mycophenolic acid, a novel antibiotic of low toxicity containing no nitrogen atoms in its structure, induces tumor regression in several murine solid tumor assays. It has been reported in extensive structure-activity studies that chemical modifications on the antibiotic itself reduce or eliminate antitumor activity. With the objective of antitumor activity enhancement, nitrogencontaining analogs of mycophenolic acid were synthesized according to a program directed toward the ultimate synthesis of close bioisosteres of the antibiotic. Initial efforts reported here describe the terpenoid side-chain degradation of Ngeranyl-2(1H)-pyridones and Ngeranylglutarimides, where the terminal isopropylidene is replaced with a carboxyl group as it occurs in mycophenolic acid. The resulting nitrogen-containing analogs of the antitumor antibiotic were inactive in the L-1210 and Walker 256 tumor systems.
Keyphrases 0 Mycophenolic acid-synthesis and antitumor evaluation of nitrogen analogs Antitumor agents-synthesis and antitumor evaluation of nitrogen analogs of mycophenolic acid Mycophenolic acid (I) was first isolated more than 75 years ago (1) from Penicillium culture filtrates and was subsequently shown to possess weak antifungal and antibacterial properties (2-4). Renewed interest in the metabolite was created by communications from three laboratories (5-7) describing its antiviral and antitumor properties.
Virus-induced Rous sarcoma and Friend leukemia were found to be inhibited by I. Although I does not inhibit the growth of L-1210, P-388, and other murine leukemias, it does cause tumor regression in the Walker 256, Sarcoma 180, Lewis lung, and Mecca