427-78-1Relevant academic research and scientific papers
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.
Synthesis and antitumor activity of novel gibberellin derivatives with tetracyclic diterpenoid skeletons
Zhu, Shi-ying,Luo, Fa-zeng,Sun, Ping-Hua
, p. 1341 - 1354 (2020/05/11)
Gibberellic acid (GA3) is a tetracyclic diterpene compound which displays interesting bioactivities. Recently, its potential use for preparing antitumor drug leads has been highlighted, and various modification methods of GA3 have been reported. Aiming at investigating GA3 derivatives with potential antitumor activities, ring distortion of GA3 under different conditions was carried out, and this was followed with amidation or substitution, yielding four series of derivatives. The chemical structure of these compounds were analyzed by 1H-NMR, 13C-NMR, HRMS, FTIR and polarimetry, and SXRD was employed to further confirm the spatial configurations of derivatives 3c and 7d. The antitumor activities of three series of derivatives were evaluated by using MTT assay and ELISA. Results shows that, among amide derivatives, compounds with a saturated linear amide showed better activity than those with an aromatic amide. Among ester derivatives, compounds with a meta-substituted benzyl group showed better activities than those with a para-substituted benzyl group. The antitumor activity of ester derivatives might possibly be linked with the inhibition of FGFR1 activation and KDR activation. Overall, this study discussed how the antitumor activity of GA3 was formed, thereby assisting the future design of more effective active GA3 derivatives. [Figure not available: see fulltext.]
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.
1β-Hydroxygibberellin A5. Preparation and Comparison with Gibberellin A3
Kirkwood, Paul S.,MacMillan, Jake,Hutchison, Michael
, p. 707 - 712 (2007/10/02)
The preparation of 1β-hydroxygibberellin A5 from gibberellin A3 is described.Unlike its naturally occurring allylic isomer gibberellin A3, 1β-hydroxygibberellin A5 is stable to aqueous alkali and acid-catalysed aromatisation of ring A does not occur.Reasons for these differences, and for the hitherto unreported 3-epimerisation of gibberellin A3 by base, are discussed in terms of O-alkyl fission of the lactone bridge.
