Overcoming Synthetic Challenges of Oridonin A‑Ring Structural Diversification: Regio- and Stereoselective Installation of Azides and 1,2,3-Triazoles at the C‑1, C‑2, or C‑3 Position

Efficient and concise synthetic approaches have been developed for the rapid and diverse installation of azide functionalities at the C-1, C-2, or C-3 positions of oridonin (<b>1</b>) with highly controlled regio- and stereoselectivity, while keeping key reactive pharmacophores intact by utilizing unique preactivation strategies based on the common synthon <b>4</b>. Further functionalization of these azides through click chemistry yielding triazole derivatives successfully provides access to an expanded natural scaffold-based compound library for potential anticancer agents

Overcoming Synthetic Challenges of Oridonin A‑Ring Structural Diversification: Regio- and Stereoselective Installation of Azides and 1,2,3-Triazoles at the C‑1, C‑2, or C‑3 Position

Efficient and concise synthetic approaches have been developed for the rapid and diverse installation of azide functionalities at the C-1, C-2, or C-3 positions of oridonin (<b>1</b>) with highly controlled regio- and stereoselectivity, while keeping key reactive pharmacophores intact by utilizing unique preactivation strategies based on the common synthon <b>4</b>. Further functionalization of these azides through click chemistry yielding triazole derivatives successfully provides access to an expanded natural scaffold-based compound library for potential anticancer agents

Overcoming Synthetic Challenges of Oridonin A‑Ring Structural Diversification: Regio- and Stereoselective Installation of Azides and 1,2,3-Triazoles at the C‑1, C‑2, or C‑3 Position

Efficient and concise synthetic approaches have been developed for the rapid and diverse installation of azide functionalities at the C-1, C-2, or C-3 positions of oridonin (<b>1</b>) with highly controlled regio- and stereoselectivity, while keeping key reactive pharmacophores intact by utilizing unique preactivation strategies based on the common synthon <b>4</b>. Further functionalization of these azides through click chemistry yielding triazole derivatives successfully provides access to an expanded natural scaffold-based compound library for potential anticancer agents

Novel Nitrogen-Enriched Oridonin Analogues with Thiazole-Fused A‑Ring: Protecting Group-Free Synthesis, Enhanced Anticancer Profile, and Improved Aqueous Solubility

Oridonin (<b>1</b>), a complex <i>ent</i>-kaurane diterpenoid isolated from the traditional Chinese herb Isodon rubescens, has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile. Nevertheless, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility, and poor bioavailability. Herein, we report the concise synthesis of a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring through an efficient protecting group-free synthetic strategy. Most of them, including compounds <b>7</b>–<b>11</b>, <b>13</b>, and <b>14</b>, exhibited potent antiproliferative effects against breast, pancreatic, and prostate cancer cells with low micromolar to submicromolar IC₅₀ values as well as markedly enhanced aqueous solubility. These new analogues obtained by rationally modifying the natural product have been demonstrated not only to significantly induce the apoptosis and suppress growth of triple-negative MDA-MB-231 breast cancer both in vitro and in vivo but also effective against drug-resistant ER-positive MCF-7 clones