Reactivity informed Pharmacophore Editing. Biological Evaluation of Andrographolide A-ring Synthesis скачать в хорошем качестве

Reactivity informed Pharmacophore Editing. Biological Evaluation of Andrographolide A-ring Synthesis

250610 Department of Chemistry, Biochemistry & Physics Reactivity-informed Pharmacophore Editing and Biological Evaluation of Andrographolide and Synthesis of A-ring Analogs: Closing the Loop on the Oxetane Natural products and their analogs have long served as inspiration for the exploration and development of small molecules with therapeutic significance. One such compound is andrographolide, a labdane diterpenoid extracted from the plant Andrographis paniculata, which has been extensively studied as an anticancer therapeutic. It is known to function putatively through covalent inhibition of NF-kB, a transcription factor at the crossroad of a myriad of cell signaling pathways that modulate tumor survival and metastasis. Functionalization of the C-19 hydroxyl might alter the primary mode of action from inhibition of NF-kB to the modulation of the Wnt/𝜷-catenin signaling pathway. To interrogate the structure-activity relationship of this position, we synthesized a library of andrographolide analogs by protecting the C-19 hydroxyl with large, hydrophobic silyl and trityl ethers. Inspired by the observed biological trends amongst the library, we sought to further interrogate more complex A-ring oxy-functionalization. Among several targets for A-ring functionalization, we were intrigued by early isolation of an A-ring oxetane analog that is a biosynthetic byproduct isolated from A. paniculata (Jantan et al., Phytochemistry 1994), whose synthetic preparation and biological properties are not well described. After investigation of several synthetic route candidates, we identified an efficient route to access the A-ring oxetane with three chromatographic purifications. En route, we describe mechanistic insight into A-ring reactivity of andrographolide and its analogs. With the oxetane in hand, we then shifted our attention to further diversification of the A ring diol system, synthesizing analogs involving deoxygenation at various positions, and exploration of various oxidation patterns as viable intermediates to probe the reactivity of andrographolide. RESEARCHERS: Rushika, Irvington High School ‘26; Galen Liu, San Mateo High School ‘26; Andrew Chyu, Dublin High School ‘26 ADVISOR: Njoo Lab Synthesis | Physical Organic Chemistry | Catalysis | Chemical Biology | Spectroscopy | Medicinal Chemistry KEYWORDS: Andrographolide | Natural Product | Oxetane