Small molecule HAT inhibitors are useful tools to unravel the role of histone acetyltransferases (HATs) in the cell and have relevance for oncology. We synthesized a series of N-acylanthranilic acids (11-16) and of N-acyl-5-hydroxyanthranilic acids (17-22) bearing C6, C8, C10, C12, C14, along with C16 acyl chain at the 2-amino position of anthranilic acid or 5-hydroxyanthranilic acid. Enzyme inhibition of these compounds was investigated, using in vitro PCAF HAT assays. All synthesized compounds (65-76%) showed similar inhibitory activity to anacardic acid (68%) at 100 μM. The cytotoxicity, against one normal cell line (HSF) and eight cancer cell lines (HT-29, HCT-116, MDA-231, A-549, Hep3B, Caski, HeLa and Caki), were evaluated by the SRB method.

Small molecule HAT inhibitors are useful tools to unravel the role of histone acetyltransferases (HATs) in the cell and they also have relevance in oncology. We synthesized a series of 2-acylamino-1-(3- or 4-carboxyphenyl)benzamides 8–19 bearing C6, C8, C10, C12, C14, and C16 acyl chains at the 2-amino position of 2-aminobenzoic acid. Enzyme inhibition of these compounds was investigated using in vitro PCAF HAT assays. The inhibitory activities of compounds 8–10, 16, and 19 were similar to that of anacardic acid, and 17 was found to be more active than anacardic acid at 100 μM. Compounds 11–15 showed the low inhibitory activity on PCAF HAT. The cytotoxicity of the synthesized compounds was evaluated by SRB (sulforhodamine B) assay against seven human cancer cell lines: HT-29 (colon), HCT-116 (colon), MDA-231 (breast), A549 (lung), Hep3B (hepatoma), HeLa (cervical) and Caki (kidney) and one normal cell line (HSF). Compound 17 was more active than anacardic acid against human colon cancer (HCT 116, IC50: 29.17 μM), human lung cancer (A549, IC50: 32.09 μM) cell lines. 18 was more active than anacardic acid against human colon cancer (HT-29, IC50: 35.49 μM and HCT 116, IC50: 27.56 μM), human lung cancer (A549, IC50: 30.69 μM), and human cervical cancer (HeLa, IC50: 34.41 μM) cell lines. The apparent permeability coefficient (Papp, cm/s) values of two compounds (16 and 17) were evaluated as 68.21 and 71.48 × 10−6 cm/s by Caco-2 cell permeability assay.