An efficient synthetic route to l-γ-methyleneglutamine and its amide derivatives, and their selective anticancer activity

Abstract

l-γ-Methyleneglutamic acid amides selectively inhibit the growth of MCF-7 (ER+/PR+/HER2−), SK-BR-3 (ER−/PR−/HER2+), and triple negative MDA-MB-231 cancer cell lines.

Synthesis and Biological Evaluation of tert-Butyl Ester and Ethyl Ester Prodrugs of L-γ-Methyleneglutamic Acid Amides for Cancer

“…The syntheses of tert-butyl ester prodrugs of the Lγ-methyleneglutamic acid amides (11 and 13-20, Figure 4A), starting from the commercially available L-pyroglutamic acid 41 (Scheme 1), were performed by following our previously published report. 11 An esterification of 41 with tert-butyl acetate in the presence of perchloric acid 13 produced 42 in 70% yield. A Boc-protecting reaction of the amide 11,14 of 42 gave 43 in 87% yield.…”

“…Scheme 1. Syntheses of tert-butyl ester prodrugs of the L-γ-methyleneglutamic acid amides (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Reagents and conditions: a) AcO t Bu, HClO4, 23 °C, 18h, 70%; b) (Boc)2O, DMAP, Et3N, CH2Cl2, 23 °C, 18 h, 87%; c) i. LiHMDS, CF3CO2CH2CF3, THF, -78 °C, 4 h, ii.…”

“…An esterification of 41 with ethanol in the presence of sulfuric acid 18 produced 45 in 60% yield. A Bocprotecting reaction of the amide 11,14,[19][20][21] of 45 gave 46 in 91% yield. Introduction of the methylene group at C4 of compound 46 using a modified αmethylenation method 11,15 produced 35 in 55% yield.…”

“…Our lab recently reported an efficient synthetic route to L-γ-methyleneglutamine (1, Figure 1) and its amide derivatives (3-10, Figure 1). 11 Many of these L-γ-methyleneglutamic acid amides, such as 5, 6, and 9, were as efficacious as tamoxifen or olaparib in inhibiting the cell growth of MCF-7 (ER + /PR + /HER2 − ) and SK-BR-3 (ER − /PR − /HER2 + ) breast cancer cells after 24 or 72 h of treatment (Figures 2A-D). Compounds 5 and 6 also exerted similar efficacy to olaparib in inhibiting the cell growth of the triple-negative MDA-MB-231 breast cancer cells after 24 h of treatment (Figure 2E).…”

“…Structures L-γ-methyleneglutamine (1) and L-γ-methyleneglutamic acid amides 3-10. The numbering 2 was used for L-γ-methyleneglutamic acid in our previous report 11 and is intentionally skipped in this report. As part of our ongoing effort to modify these glutamine-based compounds to develop more selective and efficacious anticancer agents, we synthesized and evaluated two series of tert-butyl ester and ethyl ester prodrugs of these L-γmethyleneglutamic acid amides and the cyclic metabolite and its tert-butyl ester and ethyl ester prodrugs (Figures 4A-C) on the three breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 and the non-malignant MCF-10A breast cell line.…”