Synthesis of halo alkyl and alkenyl ortho-carboxy aryls and bromo nitro lactones as inhibitors of protein tyrosine phosphatases and cancer cell growth

Changes to a cell's DNA can result in cancer, which is permanently sustained cellular proliferation. When malfunctioning genes, oncogenes, were verified to be of human origin in the 1970s, drugs were designed to target their encoded, abnormal enzymes. Tyrosine kinases have been established as an oft-modified oncogene enzyme family, but the protein tyrosine phosphatases (PTPs) were not investigated as thoroughly. PTPs have gradually been established as relevant enzymes that work in tandem with tyrosine kinases in cell signaling and are not just "house-keeping" enzymes. Some PTPs are thought to initiate tumorigenesis, and others may play a complementary role after the onset of cancer by extending the duration of cellular signals. Reversible inhibition of these enzymes by an oxalylamino group substituted on an ortho-carboxy aryl have been described in the literature. Modification of the oxalylamino group to favor irreversible inhibition of these cysteine-dependent enzymes may prevent inhibitor efflux by cells and subsequent mutation to gain resistance. Replacement of the oxalylamino group with halogenated propanoate and propenoate esters minimally inhibited cancer cell growth but did not inhibit activity of PTPs. Of the ortho-carboxy aryl structures, a methyl dichloropropanoate (compound 24) and a lactone alkene (compound 29) inhibited cell growth by 50% (GI-50) at micromolar concentrations. The GI-50s for compounds 24 and 29 were 19.9 (DU-145, prostate carcinoma) and 9.4 micromolar (A549, lung cancer), respectively. In contrast, brominated nitro lactones were able to inhibit both cancer cell growth and the activity of PTPs. In a sulforhodamine B assay, these compounds were able to achieve GI-50s as low 5.3 micromolar (compound 33 against BXPC-3, pancreatic adenocarcinoma), and some killed 50% of cancer cells (LC-50) at micromolar concentrations. Compound 33 displayed LC-50 of 23.3 micromolar (BXPC-3), and compound 35 had LC-50s of 32.9 and 32.7 micromolar against BXPC-3 and colon adenocarcinoma (KM20L2), respectively. A single concentration (100 micromolar) inhibition assay of inhibitor PTPs resulted in no enzyme activity for 4 out of 5 PTPs tested with compound 33. Similar results were obtained for compounds 35 and 37. Future analysis will determine if these bromo nitro lactones are irreversibly inhibiting PTPs.