Divergent syntheses of all stereoisomers of phytosphingosine and their use in the construction of a ceramide library Jeong-Ju Park a , Ji Hyung Lee a , Qian Li b , Kristine Diaz b , Young-Tae Chang b,c, * , Sung-Kee Chung a, * a Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea b Department of Chemistry, New York University, New York, NY 10003, USA c National University of Singapore, Singapore 117543, Singapore Received 28 September 2007 Available online 14 February 2008 Dedicated to the memory of the late Professor A. Ian Scott, a mentor, colleague, and friend. Abstract Sphingolipids such as ceramide and sphingosine-1-phosphate have recently attracted intense research interests because of their func- tional roles as signaling molecules in many important physiological processes, such as growth arrest, apoptosis, and inflammatory responses, and cell proliferation, vascular maturation and trafficking of lymphocytes. The well-defined modular structures of ceramides and related glycosylceramides are ideally amenable to library formation for medicinal chemistry investigation. We have developed diver- gent synthetic routes to all eight phytosphingosine stereoisomers and then proceeded to prepare phytosphingosine-based ceramide library composed of more than 500 compounds. Ó 2008 Elsevier Inc. All rights reserved. Keywords: Phytosphingosine; Ceramide; Library; Solid phase acylating reagent; Apoptosis; Inflammatory response 1. Introduction Sphingolipids have long been recognized as essential structural components of all eukaryotic cell membranes together with glycerolipids and sterols. More recently, however, their functional roles in cellular signaling and physiology, particularly those of ceramides and sphingo- sine-1-phosphates (S1Ps) as signaling molecules have been appreciated [1]. Ceramides have for many years been known to be involved in the inflammatory responses. Now it is clear that they act as second messengers in the signal transduction pathway triggered by several agents of stress, including oxidative stress, ionizing radiation, and extracellular stimuli such as proinflammatory cyto- kines and lipopolysaccharide. There are three metabolic pathways available for the production of ceramides: (1) de novo synthesis primarily in the endoplasmic reticulum and mitochondria, (2) hydrolysis of sphingomyelin through the action of sphingomyelinase, which is secreted by cells such as endothelial cells and alveolar macrophages in response to inflammatory stimuli, and (3) acylation of sphingosine [2]. In general, the increase of cellular ceramide level activates NF-jB and activator protein-1, leading to the expression of multiple inflammatory proteins that amplify the inflammatory responses. An increased cera- mide level also results in the stimulation of apoptotic sig- naling pathways, apparently activating caspases and inducing clustering of death receptors in the cell mem- branes. It is interesting to note that ceramides are pro- apoptotic, whereas the other major sphingolipid, S1P is suppressing apoptosis. The relative level of ceramide and S1P has been proposed to function as an evolutionary con- served rheostat that determines cell fate [1d]. Thus, cera- mides play important functional roles in the regulation of 0045-2068/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.bioorg.2007.12.004 * Corresponding authors. Fax: +82 54 279 3399. E-mail addresses: chmcyt@nus.edu.sg (Y.-T. Chang), skchung@ postech.ac.kr (S.-K. Chung). www.elsevier.com/locate/bioorg Available online at www.sciencedirect.com Bioorganic Chemistry 36 (2008) 220–228