427-78-1Relevant articles and documents
Gibberellin JRA-003: A Selective Inhibitor of Nuclear Translocation of IKKα
Annand, James R.,Henderson, Andrew R.,Cole, Kyle S.,Maurais, Aaron J.,Becerra, Jorge,Liu, Yejun,Weerapana, Eranthie,Koehler, Angela N.,Mapp, Anna K.,Schindler, Corinna S.
, p. 1913 - 1918 (2020)
The small molecule gibberellin JRA-003 was identified as an inhibitor of the NF-kB (nuclear kappa-light-chain-enhancer of activated B cells) pathway. Here we find that JRA-003 binds to and significantly inhibits the nuclear translocation of pathway-activating kinases IKKα (IκB kinase alpha) and IKKβ (IκB kinase beta). Analogs of JRA-003 were synthesized and NF-κB-inhibiting gibberellins were found to be cytotoxic in cancer-derived cell lines (HS 578T, HCC 1599, RC-K8, Sud-HL4, CA 46, and NCIH 4466). Not only was JRA-003 identified as the most potent synthetic gibberellin against cancer-derived cell lines, it displayed no cytotoxicity in cells derived from noncancerous sources (HEK 293T, HS 578BST, HS 888Lu, HS 895Sk, HUVEC). This selectivity suggests a promising approach for the development of new therapeutics.
A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products
Huigens III, Robert W.,Morrison, Karen C.,Hicklin, Robert W.,Flood J.r., Timothy A.,Richter, Michelle F.,Hergenrother, Paul J.
, p. 195 - 202 (2013/05/09)
High-throughput screening is the dominant method used to identify lead compounds in drug discovery. As such, the makeup of screening libraries largely dictates the biological targets that can be modulated and the therapeutics that can be developed. Unfortunately, most compound-screening collections consist principally of planar molecules with little structural or stereochemical complexity, compounds that do not offer the arrangement of chemical functionality necessary for the modulation of many drug targets. Here we describe a novel, general and facile strategy for the creation of diverse compounds with high structural and stereochemical complexity using readily available natural products as synthetic starting points. We show through the evaluation of chemical properties (which include fraction of sp 3 carbons, ClogP and the number of stereogenic centres) that these compounds are significantly more complex and diverse than those in standard screening collections, and we give guidelines for the application of this strategy to any suitable natural product.
