The Synthesis and Thymidylate Synthase Inhibitory Activity of L-.gamma.-L-Linked Dipeptide and L-.gamma.-Amide Analogs of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)

Abstract

Sixteen gamma-linked dipeptide and four L-Glu-gamma-amide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) have been synthesized and evaluated as inhibitors of thymidylate synthase (TS). Z-blocked L-Glu-gamma-L-linked dipeptides and L-Glu-gamma-amides were prepared by condensing alpha-tert-butyl-N-(benzyloxycarbonyl)-L-glutamic acid with the appropriate tert-butyl-protected L-amino acid or amine. The Z group was removed by catalytic hydrogenolysis, and the resulting dipeptides or L-Glu-gamma-amides were condensed with the appropriate pteroic acid analogue trifluoroacetate salt using diethyl cyanophosphoridate as coupling reagent. Deprotection with trifluoroacetic acid in the final step gave the desired quinazoline gamma-linked dipeptides and L-Glu-gamma-amides as their trifluoroacetate salts. Nearly all the dipeptide analogues were potent inhibitors of TS, the best being ICI 198583-gamma-L-2-aminoadipate (IC50 = 2 nM). Several of these dipeptides were found to be susceptible to enzymatic hydrolysis in mice. The quinazoline monocarboxylate L-Glu-gamma-amides, lacking an alpha'-carboxyl group, are less active against TS and L1210 cell growth but are also not susceptible to enzymatic hydrolysis in mice.

Folate receptor β as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients

“…To investigate whether the folate antagonists tested in the current study would convey potential growth‐inhibitory effects against macrophage‐like cells, this parameter was investigated in human monocytic macrophage THP‐1 cells (Table 1). Consistent with the RFC as the dominant transport route in THP‐1 cells, potent growth‐inhibitory effects were observed for all folate antagonists, except CB300635 and BCG 945, both of which have a poor affinity for the RFC (25, 27).…”

“…Pemetrexed (Altima; Eli Lilly, Indianapolis, IN) (20) was obtained via the VU University Medical Center pharmacy department. The following folate antagonist drugs were also obtained: raltitrexed (Tomudex/ZD1694; AstraZeneca, London, UK) (21), PT523 and PT644 (Dr. A. Rosowsky, Harvard Medical School, Boston, MA) (22, 23), GW1843 (Glaxo Wellcome, Research Triangle Park, NC) (24), CB300635 (Institute of Cancer Research, Sutton, UK) (25), plevitrexed (BGC 9331; BTG International, London, UK) (26), BGC 945 (both the 6 R , S and 6 S forms; BTG International) (27), 5,10‐dideazatetrahydrofolate (DDATHF; Eli Lilly) (28), and AG2034 (Agouron/Pfizer Pharmaceuticals, San Diego, CA) (29). (Illustrations of the chemical structures of these folate antagonists are available online at http://jwvanderheijden.blogspot.com/.) Preclinical and clinical background information on these antifolates has previously been published (6, 18).…”

Design, Synthesis, and Biological Evaluation of Classical and Nonclassical 2-Amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors

“…Although polyglutamylation of certain antifolates is necessary for their cytotoxic activity, it has also been implicated in toxicity to host cells because of cellular retention of the polyanionic poly-γ-glutamate metabolites which also do not efflux from normal cells. 20 Additionally, tumor cells develop resistance to antifolates that depend on polyglutamylation for their antitumor effects by producing low or defective FPGS and thereby limiting their utility. Another problem associated with classical antifolates is their dependence on the carrier systems for their uptake into tumor cells.…”

2‐Amino‐4‐oxo‐6‐substituted‐pyrrolo[2,3‐d]pyrimidines as Potential Inhibitors of Thymidylate Synthase.

“…A major drawback of these classical antifolates is that they enter cells via the reduced folate uptake system, which when impaired can lead to drug resistance [13][14][15][16]. These toxicities arise because of their polyionic nature which allows retention in normal cells [19]. Although polyglutamylation is necessary for the cytotoxicity to tumor cells, it has also been implicated as a possible cause of detrimental side effects, such as renal and hepatic toxicities in the host.…”