Retinoic Acid Metabolizing Enzyme Blocking Agents (RAMBAs) are being developed in attempts to overcome retinoid resistance by our laboratory and others. Our RAMBAs are considered 'atypical RAMBAs' because they are endowed with multiple anticancer activities along with high binding affinity towards CYP26A1. We have discovered two lead candidates VN/14-1 and VN/66-1 for breast and prostate cancer therapy. Here we describe systematic optimization of leads by substituting different privileged moieties in hydrophobic, alkene spacer and carboxylic acid regions. We prepared VN/14-1 by convergent synthesis starting from a- ionone. Synthesis of oxadiazole derivative was accomplished by coupling of amidoxime with VN/14-1. Different retinamides were prepared using aromatic and heterocyclic amines. Aromatic RAMBAs were synthesized by aldol condensation ionone intermediate with aromatic aldehydes. These compounds were evaluated for their abilities to inhibit growth of drug-resistant MDA-MB 231 and MDA-MB-468 triple negative breast cancer cells lines. Exciting results for promising compounds will be presented.

Development of second generation atypical RAMBAs for triple negative breast cancer therapy

244th National Meeting (2012)

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