The design and synthesis of simplified viridin analogs as PI3K inhibitors
Date of Completion
Chemistry, Organic|Chemistry, Pharmaceutical
Phosphoinositide-3-kinase (PI3K) plays an integral role in a cellular signaling transduction pathway which is ultimately responsible for cellular growth, differentiation, and apoptosis. This pathway is often overactivated in many types of cancers and extensive efforts in the development of PI3K inhibitors for anticancer therapy are of interest. The natural product furanosteroids, viridin and wortmannin, are potent, irreversible PI3K inhibitors with IC 50 values of 4-5 nM. The inhibitory potency is attributed to the covalent binding by Lys833 in the ATP active site which opens up the electrophilic furan ring. ^ We have developed an efficient synthetic route to analogs of viridin. Our Type I and Type II analogs were pursued to decrease the overall electrophilicity of the furan ring and improve its stability in comparison to the natural product furanosteroids. Our Type I analog contains a vinylogous amide to decrease the reactivity of the furan ring. The key building block involved the conversion of 3,4-dibromofuran to the fused tricyclic vinylogous amide core. Further conversion to the A-B-C-E furanosteroid core is discussed and will be presented herein. Our progress towards seco-B Type II analogs to relieve the furan ring strain was achieved through amide couplings and is also discussed. ^
Sundstrom, Teather Jo, "The design and synthesis of simplified viridin analogs as PI3K inhibitors" (2009). Doctoral Dissertations. AAI3393026.