Nonhydrolyzable phosphotyrosyl (pTyr) mimetics serve as important components of many competitive Grb2 SH2 domain inhibitors. To date, the most potent of these inhibitors have relied on phosphonate-based structures to replace the 4-phosphoryl group of the parent pTyr residue. Reported herein is the design and evaluation of a new pTyr mimetic, p-malonylphenylalanine (Pmf), which does not contain phosphorus yet, in Grb2 SH2 domain binding systems, approaches the potency of phosphonate-based pTyr mimetics. When incorporated into high affinity Grb2 SH2 domain-directed platforms, Pmf is 15-20 times more potent than the closely related previously reported pTyr mimetic, O-malonyltyrosine (OMT). Pmf-containing inhibitors show inhibition constants as low as 8 nM in extracellular Grb2 binding assays and in whole cell systems, effective blockade of both endogenous Grb2 binding to cognate erbB-2, and downstream MAP kinase activation. Evidence is provided that use of an N(alpha)()-oxalyl auxiliary enhances effectiveness of Pmf and other inhibitors in both extracellular and intracellular contexts. As one of the most potent Grb2 SH2 domain-directed pTyr mimetics yet disclosed, Pmf may potentially have utility in the design of new chemotherapeutics for the treatment of various proliferative diseases, including breast cancer.

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Synthesis of 3-(3,4-dimethoxyphenyl)propyl-3-(3,4-dimethoxyphenyl) propanoate (18), a cytotoxic natural ester, was carried out by a convenient synthetic path with a total yield of 49%. Sixteen of its analogues (19-34) were also prepared. Seventeen unsaturated derivatives of 18, compounds 1-17, were also synthesized to examine the structure-activity relationship of this type of ester. All of the synthetic compounds were passed through the cytotoxicity screenings on human tumor cell lines, such as PC-3, Hela, A549, BEL7404, CNE, and KB. Some of the esters exhibited moderate inhibitory effects on these tumor cell lines. The phenolic derivatives exhibited the highest cytotoxicity among these derivatives, while the unsaturated esters were more cytotoxic than the saturated analogues. Some of the compounds also exhibited inhibition on alpha-glucosidase.