Thomas Michael Wilson

Asymmetric synthesis of dideazafolate antitumor agents via amidomethylation of nonracemic oxazolidinone imidates. Synthesis of LY309887, a cytotoxic dideazafolate analog related to lometrexol

Abstract The asymmetric synthesis of LY309887, a cytotoxic dideazatetrahydrofolate analog related to lometrexol, has been accomplished via an application of diastereoselective amidomethylation of a chiral titanium (IV) acyloxazolidinone enolate.

Asymmetric synthesis and absolute configuration of 5,10-dideaza-5,6,7,8-tetrahydropteroic acid and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF)

Abstract Lipase-catalyzed enantioselective esterification of 2-substituted 1,3-diols has been utilized in the asymmetric synthesis and consequent configurational assignments of the title compounds.

Synthesis of LY288601, a 5.6-Dihydropyprrolo[2,3-d]pytrimidine Based Antifolate Compunds Related to LY231514

An expeditious synthesis of LY288601 (2), the 5,6-dihydro analog of the pyrrolo[2,3-d]pyrimidine-based antifolate compound LY231514 (1a), is described. The synthesis proceeds in eight steps from tert-butyl 4-iodobenzoate and involves the elaboration of a 2-amino-4-hydroxypyrmidine ring onto an activated 3-carboalkoxy-2-pyrrolidinone via reaction with guanidine as a key step

Synthesis and Antitumor Activity of LY288601, the 5,6-Dihydro Analog of LY231514

The series of deaza analogs of folic acid has been a rich source of compounds of interest as potential antitumor drugs.1 The mode of action of these compounds is, however, related to structure in ways not yet fully understood. For example, DDATHF2 is a specific inhibitor of glycinamide ribonucleotide formyl transferase (GARFT)3 while the related pyrrolo[2,3-d]pyrimidine-based analog, LY231514, has been found to inhibit thymidylate synthase (TS) 4 Both (6R)-DDATHF (lometrexol)5 and LY2315146 have shown promising in vivo antitumor activity against a variety of murine and human tumor cell lines and are currently undergoing clinical evaluation. LY288601 may be viewed as a hybrid structure which possesses both the ring saturation of DDATHF and the 6,5-heterocyclic ring system of the pyrrolo[2,3-d]pyrimidine-based LY231514. LY288601 was first described by Akimoto and coworkers7 (as Takeda T-41440) but only limited cytotoxicity data has been reported.8 We report here a convenient alternate synthesis of LY288601, the results of cell culture cytotoxicity and reversal experiments, and in vivo antitumor evaluation of this compound in comparison with DDATHF and LY231514.