Andrographolide, a labdane diterpenoid lactone natural product extracted from Andrographis paniculata, has demonstrated potent biological activity and therapeutic potential against cancer, Alzheimer's disease, diabetes, and multiple sclerosis. Andrographolide is also reported to significantly inhibit the Nf-κB signalling pathway, which is active in immune system function and regulation of inflammatory cells. However, andrographolide is not optimized for human systems. In order to improve upon these aspects, we present the design and semisynthesis of a library of andrographolide analogues with either modified electronics of the 12,13 unsaturated lactone to increase cytotoxicity via the addition of electron withdrawing groups or attached hydrophobic residues along the 3,19 diol region, thereby improving the bioavailability of the compound. Reactivity of the top piece butenolide warhead was quantified via a time-resolved colorimetric <i>ex vivo</i> Michael addition assay using Elleman’s Method, wherein reduced-glutathione was the electron donor. The antiproliferative effects of these hydrophobic residues were assayed via MTT using clinically relevant Jurkat and HCT-116 cell lines, and the direct pathway of NF-kB inhibition was studied via novel RT-qPCR analysis, using 27 genes involved in both the NF-kB protein complex and the mitogen-activated protein kinase (MAPK) pathway.

Rational design, semisynthesis, and quantitative biological mechanistic studies of andrographolide derivatives in efforts to optimize its structure for clinical use

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.