1. Synthesis of the Alkylsulfonate Metabolites Cysteinolic Acid, 3-Amino-2-hydroxypropanesulfonate, and 2,3-Dihydroxypropanesulfonate
Laura Burchill, Luca Zudich, Phillip L van der Peet, Jonathan M White, Spencer J Williams J Org Chem. 2022 Mar 18;87(6):4333-4342. doi: 10.1021/acs.joc.2c00036. Epub 2022 Feb 24.
Chiral hydroxy- and aminohydroxysulfonic acids are widespread in the marine and terrestrial environment. Here we report simple methods for the synthesis of d- and l-cysteinolic acid (from (Boc-d-Cys-OH)2 and (Boc-l-Cys-OH)2, respectively), R- and S-3-amino-2-hydroxypropanesulfonate (from S- and R-epichlorohydrin, respectively), and R- and S-2,3-dihydroxypropanesulfonate (from S- and R-epichlorohydrin, respectively). d-Cysteinolate bile salts were generated by coupling with cholic and chenodeoxycholic acids. A series of single-crystal 3D X-ray structures confirmed the absolute configurations of the aminosulfonates. By comparison of optical rotation, we assign naturally occurring 3-amino-2-hydroxypropanesulfonate from Gateloupia livida as possessing the R-configuration. This simple synthetic approach will support future studies of the occurrence, chemotaxonomic distribution, and metabolism of these alkylsulfonates.
2. Imaging biomarker roadmap for cancer studies
James P B O'Connor, et al. Nat Rev Clin Oncol. 2017 Mar;14(3):169-186. doi: 10.1038/nrclinonc.2016.162. Epub 2016 Oct 11.
Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.
3. Phosphonate-phosphinate rearrangement
Renzhe Qian, Alexander Roller, Friedrich Hammerschmidt J Org Chem. 2015 Jan 16;80(2):1082-91. doi: 10.1021/jo502567j.
LiTMP metalated dimethyl N-Boc-phosphoramidates derived from 1-phenylethylamine and 1,2,3,4-tetrahydronaphthalen-1-ylamine highly selectively at the CH3O group to generate short-lived oxymethyllithiums. These isomerized to diastereomeric hydroxymethylphosphonamidates (phosphate-phosphonate rearrangement). However, s-BuLi converted the dimethyl N-Boc-phosphoramidate derived from 1-phenylethylamine to the N-Boc α-aminophosphonate preferentially. Only s-BuLi deprotonated dimethyl hydroxymethylphosphonamidates at the benzylic position and dimethyl N-Boc α-aminophosphonates at the CH3O group to induce phosphonate-phosphinate rearrangements. In the former case, the migration of the phosphorus substituent from the nitrogen to the carbon atom followed a retentive course with some racemization because of the involvement of a benzyllithium as an intermediate.
