| The benzopyranone ring system is the core structure found in a number of natural products such as the flavonoids and isoflavonoids. Substituted 4H-1-benzopyran-4-ones have shown activity as protein tyrosine kinase inhibitors, estrogen receptor agonists or antagonists, or inhibitors of steroidogenic enzymes. Initial synthetic chemistry produced a novel synthetic route utilizing readily available salicylic acids and terminal alkynes as starting materials to construct the benzopyranone nucleus. This approach is characterized by mild and high yielding reactions with good functional group tolerance, and is ideal for developing combinatorial libraries centered around the benzopyranone ring system. The hypothesis of this research is that the design, synthesis, and screening of substituted benzopyranone libraries would allow us to utilize the biological potential of these molecules and develop more selective therapeutic agents for molecular targets in breast cancer.; The novel solution-phase chemistry developed to synthesize the benzopyranones can be accomplished in several steps. Retrosynthetically, it was envisioned that the benzopyranones could arise from the cyclization of alkynones. Substituted bis-TBDMS salicylic acids underwent a one-pot acid chlorination-Sonogashira coupling resulting in the synthesis of the critical intermediate, alkynone, in excellent yields. The one-pot acid chlorination-Sonogashira coupling, key for introducing diversity, displays a wide substituent tolerance in both of the coupling partners.; Michael addition of a secondary amine to the alkynone, followed by a 6-endo-trig cyclization results in the formation of the six membered benzopyranone with yields from 70–96%. By using a secondary amine addition to the alkynone, the synthetic strategy prevents the cyclization of the competing five-membered benzofuranone and thus resolves the regioselectivity problem encountered by previous efforts. Synthetic approaches for diversifying the benzopyranone skeleton have also been pursued; substituents at the 3-position on the ring system would dramatically increase the diversity of our library. Evaluation of a library with more than forty synthetic benzopyranones in initial bioassays (cell proliferation, estrogen receptor binding, and aromatase) using human breast cancer cell lines has resulted in agents exhibiting enhanced and differential activities on breast cancer cell growth and on aromatase inhibition. Continued synthetic efforts will concentrate on development of more selective agents for molecular targets in breast cancer based upon the benzopyranone nucleus. |
