Modular ketal-linked prodrugs and biomaterials enabled by organocatalytic transisopropenylation of alcohols

Abstract

Isopropenyl ethers are critical intermediates for accessing medicinally valuable ketal-based prodrugs and biomaterials, but traditional approaches for the synthesis of isopropenyl ethers suffer from poor functional group compatibility and harsh reaction conditions. Here, we develop an organocatalytic transisopropenylation approach to solve these challenges, enabling the synthesis of isopropenyl ethers from various hydroxyl-group-containing small-molecule drugs, polymers, and functional building blocks. The method provides a straightforward and versatile synthesis of isopropenyl ethers, features excellent tolerance of diverse functional groups, applies to a wide range of substrates, and allows scalable synthesis. The development of this organocatalytic transisopropenylation approach enables access to modular preparation of various acid-sensitive ketal-linked prodrugs and functionalized ketalated biomaterials. We expect our syntheses and transformations of isopropenyl ethers will find utility in several diverse fields, including medicinal chemistry, drug delivery, and biomaterials.

Local delivery of tumor‐targeting nano‐micelles harboring GSH‐responsive drug release to improve antitumor efficiency

“…Then, the released PPR‐NP were prone to be taken up by tumor cells due to the targeting capability, which potentially avoid to affect other cell around tumor cells. Delivery systems responsive to intracellular environment of tumor cells has been reported to improve to therapeutics efficacy 39,40 . Herein, PPR‐NP, once taken up by tumor cells could rapidly release PTX in responsible to the high concentration of GSH in tumor cell, thus inducing tumor cell death.…”

“…Delivery systems responsive to intracellular environment of tumor cells has been reported to improve to therapeutics efficacy. 39,40 Herein, PPR-NP, once taken up by tumor cells could rap-…”

pH-Sensitive nanocarrier assisted delivery of adenosine to treat osteoporotic bone loss

“…[47][48][49] Paper Biomaterials Science Several pH-responsive chemical functional groups such as esters, carbonates, ketals, hydrazones, and imines have been utilized to deliver therapeutics. [50][51][52][53] In this study, we leveraged the acidic microenvironment of the osteoporotic bone tissue as a trigger to release adenosine from a nanocarrier.…”

“…47–49 Several pH-responsive chemical functional groups such as esters, carbonates, ketals, hydrazones, and imines have been utilized to deliver therapeutics. 50–53 In this study, we leveraged the acidic microenvironment of the osteoporotic bone tissue as a trigger to release adenosine from a nanocarrier. Adenosine is an osteoanabolic molecule that promotes osteoblastogenesis and decreases osteoclastogenesis.…”

Click Nanogels from pH-Labile Dextran Prodrugs for Robust Solid Tumor Chemotherapy

“…Alternatively, covalent conjugation of chemotherapeutic drugs with nanocarriers may provide well-defined prodrugs with high DLCs. As such, a lot of nanomicelles from poly­(ethyl glycol)-linked prodrugs were reported with high DLCs (5–15%) for various cancer chemotherapies. − Besides, pH-labile linkers such as hydrazone, ketal, and cis -aconityl groups are broadly applied to covalently connect chemotherapeutic drugs with nanocarriers for responsive drug release in acidified tumor and/or endosomes and thereby enhanced antitumor activity. − These important research studies present a great translational potential of prodrug-based nanomedicines for cancer chemotherapy.…”