{"id":190,"date":"2024-04-28T21:10:45","date_gmt":"2024-04-28T21:10:45","guid":{"rendered":"https:\/\/src.cikeys.com\/2024\/?page_id=190"},"modified":"2024-04-28T22:37:01","modified_gmt":"2024-04-28T22:37:01","slug":"reactivity-informed-pharmacophore-editing-and-biological-evaluation-of-andrographolide-and-its-analogs","status":"publish","type":"page","link":"https:\/\/src.cikeys.com\/2024\/conference-schedule\/oral-presentations\/reactivity-informed-pharmacophore-editing-and-biological-evaluation-of-andrographolide-and-its-analogs\/","title":{"rendered":"Reactivity-informed Pharmacophore Editing and Biological Evaluation of Andrographolide and its Analogs"},"content":{"rendered":"\n<h2 class=\"wp-block-heading\">Carina Zhou, Sanghyuk Ko, Tiffany Gu, &amp; Dr. Edward Njoo<\/h2>\n\n\n\n<div class=\"wp-block-columns is-layout-flex wp-container-core-columns-is-layout-8f761849 wp-block-columns-is-layout-flex\">\n<div class=\"wp-block-column is-layout-flow wp-block-column-is-layout-flow\" style=\"flex-basis:66.66%\">\n<p class=\"wp-block-paragraph\">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 anti-cancer therapeutic. It is known to function putatively through covalent inhibition of Nf-kB, a transcription factor that modulates tumor survival and metastasis. Remarkably, functionalization of the C-19 hydroxyl and C-17 alkene putatively alters the primary mode of action from inhibition of Nf-kB to the modulation of the Wnt\/\ud835\udf37-catenin signaling pathway. To interrogate the structure-activity relationship of these two positions, we synthesized a library of andrographolide analogs by protecting the C-19 hydroxyl with large, hydrophobic silyl and trityl ethers and epoxidizing C-17. We also optimized the facio-selective installation of the epoxide on the C-8\/17 exo-olefin. MTT assays revealed that all of our C-19 analogs in HCT-116 colorectal cancer cells showed greater anti-proliferation compared to that of andrographolide but had relatively similar IC50 values in MDA-MB-231 metastatic breast cancer cells. Additionally, previous studies show that the installation of a TBDPS protecting group at C-19 and epoxidation of C-17 led to modulation of the Wnt\/\ud835\udf37-catenin signaling pathway through GSK3\ud835\udf37 inhibition. To further investigate the mechanism of action of these analogs, we performed western blots to assess the relative levels of active \ud835\udf37-catenin compared to phosphorylated \ud835\udf37-catenin. Finally, we describe progress towards the first chemical synthesis of an andrographolide A-ring oxetane analog, which is a co-isolated naturally-occurring metabolite of Andrographis paniculata, whose biological activity and synthetic preparation have not been previously described.<\/p>\n<\/div>\n\n\n\n<div class=\"wp-block-column is-layout-flow wp-block-column-is-layout-flow\" style=\"flex-basis:33.33%\">\n<p class=\"wp-block-paragraph\"><strong><a href=\"https:\/\/src.cikeys.com\/2024\/conference-schedule\/oral-presentations\/\">Oral Presentation<\/a><\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">10:45am <strong>\u2013<\/strong> 12:15pm<br>Del Norte 2550<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Chemistry<\/strong><\/p>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Carina Zhou, Sanghyuk Ko, Tiffany Gu, &amp; Dr. Edward Njoo 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 anti-cancer therapeutic. It [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":49,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"categories":[27,4],"tags":[29],"class_list":["post-190","page","type-page","status-publish","hentry","category-del-norte-2550","category-oral-presentations","tag-chemistry","post"],"_links":{"self":[{"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/pages\/190","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/comments?post=190"}],"version-history":[{"count":3,"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/pages\/190\/revisions"}],"predecessor-version":[{"id":366,"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/pages\/190\/revisions\/366"}],"up":[{"embeddable":true,"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/pages\/49"}],"wp:attachment":[{"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/media?parent=190"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/categories?post=190"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/src.cikeys.com\/2024\/wp-json\/wp\/v2\/tags?post=190"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}