Jeremy Just

New Method for the Rapid Extraction of Natural Products: Efficient Isolation of Shikimic Acid from Star Anise

A new, practical, rapid, and high-yielding process for the pressurized hot water extraction (PHWE) of multigram quantities of shikimic acid from star anise (Illicium verum) using an unmodified household espresso machine has been developed. This operationally simple and inexpensive method enables the efficient and straightforward isolation of shikimic acid and the facile preparation of a range of its synthetic derivatives.

Controlled oxidation of pyrroles: synthesis of highly functionalized γ-lactams

The oxidation of pyrroles usually leads to uncontrolled polymerization and decomposition. To overcome this problem, the controlled oxidation of substituted pyrroles with Dess-Martin periodinane is reported. This strategy yields a range of 5-aroyloxypyrrolinones.

Chemoselective reduction of 2-acyl-N-sulfonylpyrroles: synthesis of 3-pyrrolines and 2-alkylpyrroles.

The partial reduction of pyrroles is not a common practice even though it offers a potential route to pyrroline building blocks, commonly used for synthesis. We have investigated the reduction of 2-acyl-N-sulfonylpyrroles and by varying the hydride source and solvent, achieved a chemoselective reduction, leading to 3-pyrrolines and alkyl pyrroles in high yield.

Seven-membered rings

New synthetic methods continue to be developed to construct seven-membered heterocyclic compounds containing one, two, or three of the heteroatoms N, O, or S. The focus of much of the literature has been on aromatic systems containing at least 1 N atom and has often been driven by a desire to prepare these heterocycles in a stereocontrolled fashion, the search for new bioactives, and the synthesis of natural products. Prominent synthetic methods include transition metal-catalyzed, cycloaddition/annulation, cascade-type, and CeH functionalization processes. Review articles on the synthesis of seven-membered nitrogen heterocycles through the Ugi multicomponent reaction (17CHE382), synthetic approaches, and biological activities of benzodiazepines (17MOC453), the isolation, structure determination, medicinal properties, and total synthesis of marine natural products containing an oxepanyl ring (17MAD361), the synthesis and medicinal importance of benzoxepines (17LDD1086), methods for the synthesis of 1,2,3-, 1,2,4-, 1,2,5-, and 1,3,5-triazepines (17JCCS1023), and the isolation, biosynthesis, and biological activity of natural products that contain a sevenmembered ring with three or more heteroatoms (17JNP3060), as well as indole-fused azepines and analogs as anticancer lead molecules (17EJM244) have been published.

Chapter 6 – Seven-Membered Rings

The review covers work published in the calendar year 2012. Novel reaction chemistry and new ring synthetic methods for azepines, benzoazepines, oxepines, thiepines, diazepines, benzodiazepines, dioxepines, and dithiepines are reviewed.

Novel polygodial analogs P3 and P27: Efficacious therapeutic agents disrupting mitochondrial function in oral squamous cell carcinoma

Polygodial, a drimane sesquiterpenoid dialdehyde isolated as a pungent component of the water pepper Persicaria hydropiper, exhibits antifeedant, antimicrobial, anti-inflammatory and anticancer effects. Polygodial also activates transient receptor potential vanilloid subtype 1 (TRPV1) channels. Previously, we described the synthesis of a C12-Wittig derivative of polygodial, termed P3, with significant antiproliferative effects against multiple cancer types including oral squamous cell carcinoma (OSCC). In the present study, a more potent derivative, P27, with superior anti-proliferative effects in vitro and antitumor effects in Cal-27 derived xenografts is described. Polygodial, P3, and P27 all significantly decreased OSCC tumor growth, with P27 being equipotent with polygodial and P3 being the least efficacious. However, neither analog elicited the adverse effect observed with polygodial: Profound transient inflammation. Although P3 and P27 pharmacophores are based on polygodial, novel effects on OSCC cell cycle distribution were identified and shared anticancer effects that are independent of TRPV1 activity were observed. Polygodial elicits an S-phase block, whereas P3 and P27 lead to G2/M phase arrest. Pretreatment of OSCC cells with the TRPV1 antagonist capsazepine does not affect the antiproliferative activity of P3 or P27, indicating that TRPV1 interactions do not regulate OSCC cell proliferation. Indeed, calcium imaging studies identified that the analogs neither activate nor antagonize TRPV1. Behavioral studies using a rat model for orofacial pain confirmed that these analogs fail to induce nocifensive responses, indicating that they are non-noxious in vivo. All compounds induced a significant concentration-dependent decrease in the mitochondrial transmembrane potential and corresponding apoptosis. Considering that P27 is equipotent to polygodial with no TRPV1-associated adverse effects, P27 may serve as an efficacious novel therapy for OSCC.