Function-Oriented and Modular (+/-)-cis-Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF-κB Inhibitors.

Described herein is a function-oriented synthesis route and biological evaluation of pseudoguaianolide analogues. The 10-step synthetic route developed retains the topological complexity of the natural product, installs functional handles for late-stage diversification, and forges the key bioactive Michael acceptors early in the synthesis. The analogues were found to be low-micromolar Nrf2 activators and micromolar NF-κB inhibitors and dependent on the local environment of the Michael acceptor moieties.

Diastereoselective Synthesis of 2,3,4-Trisubstituted Tetrahydrofurans via Thermally Reactive 1,5-Diene-tert-butyl Carbonates.

We report that 3,3-dicyano-1,5-dienes bearing tert-butyl carbonates can be thermally converted to 2,3,4-trisubstituted tetrahydrofurans. The transformation relies on two thermally reactive functional groups, a 1,5-diene and a tert-butyl carbonate, that react cooperatively to yield the furan scaffolds by thermal Cope rearrangement, Boc deprotection, and oxy-Michael addition. Described herein is background related to the discovery, optimization, and scope of the key transformation and representative functional group interconversion chemistry for the tetrahydrofuran scaffolds.

Assembly of Terpenoid Cores by a Simple, Tunable Strategy.

Oxygenated, polycyclic terpenoid natural products have important biological activities. Although total synthesis of such terpenes is widely studied, synthetic strategies that allow for controlled placement of oxygen atoms and other functionality remains a challenge. Herein, we present a simple, scalable, and tunable synthetic strategy to assemble terpenoid-like polycycloalkanes from cycloalkanones, malononitrile, and allylic electrophiles, abundantly available reagent classes.

Building Blocks for the Construction of Bioorthogonally Reactive Peptides via Solid-Phase Peptide Synthesis.

The need for post-synthetic modifications and reactive prosthetic groups has long been a limiting factor in the synthesis and study of peptidic and peptidomimetic imaging agents. In this regard, the application of biologically and chemically orthogonal reactions to the design and development of novel radiotracers has the potential to have far-reaching implications in both the laboratory and the clinic. Herein, we report the synthesis and development of a series of modular and versatile building blocks for inverse electron-demand Diels-Alder copper-free click chemistry: tetrazine-functionalized artificial amino acids. Following the development of a novel peptide coupling protocol for peptide synthesis in the presence of tetrazines, we successfully demonstrated its effectiveness and applicability. This versatile methodology has the potential to have a transformational impact, opening the door for the rapid, facile, and modular synthesis of bioorthogonally reactive peptide probes.

(18)F-labeled-bioorthogonal liposomes for in vivo targeting.

Liposomes are attractive vehicles for the controlled release of drugs and cytotoxins and have a long-standing history in medical research and clinical practice. In addition to established therapeutic indications, liposomes have several favorable properties for molecular imaging, including high stability and the ability to be labeled with radioisotopes, as well as paramagnetic and fluorescent contrast agents. However, long circulation times and difficulties in creating targeted liposomes have proven challenges for imaging. In this study, we have addressed these limitations using a recently developed strategy for bioorthogonal conjugation, the reaction between tetrazines and trans-cyclooctenes. By coating radiolabeled liposomes with trans-cyclooctene and pretargeting with a tetrazine coupled to a targeted peptide, we were able to selectively enhance the retention of liposomes and bind them to tumor tissue in live animals. The rapid reaction between tetrazines and trans-cyclooctenes allowed imaging to be performed with the short-lived PET tracer (18)F, yielding signal-to-background activity ratios of 7:1. The covalent, bioorthogonally driven tumor-targeting of liposomes by in vivo click chemistry is promising and should be explored for more selective and rapid delivery of radiodiagnostics and radiotherapeutics, two classes of drugs which particularly benefit from fast clearance, low nonspecific binding, and the associated reduced toxicity to kidneys and bone marrow.