QC Queens College

Selected Research Publications

We make synthetic sphingolipid analogs available for collaborations with NHLBI-funded investigators and other professional researchers in the scientific community whose studies are pertinent to cardiovascular and lung biology and sphingolipid-mediated signaling events. Requests for compounds should be submitted to robert.bittman@qc.cuny.edu

Synthesis and properties of sphingosine-based inhibitors of sphingosine kinase 1 and/or 2

F. Tonelli, K. G. Lim, C. Loveridge, J. Long, S. M. Pitson, G. Tigyi, R. Bittman, S. Pyne, and N. J. Pyne, “FTY720 and (S)-FTY720 Vinylphosphonate Inhibit Sphingosine Kinase 1 and Promote Its Proteasomal Degradation in Human Pulmonary Artery Smooth Muscle, Breast Cancer, and Androgen-independent Prostate Cancer Cells,” Cell. Signal. 22, 1536-1542 (2010).
S. Pyne, R. Bittman, and N. J. Pyne, “Sphingosine Kinase Inhibitors and Cancer: Seeking the Golden Sword of Hercules,” Cancer Res. 71, 6576-6582 (2011).
K. G. Lim, F. Tonelli, Z. Li, X. Lu, R. Bittman, S. Pyne, and N. J. Pyne, “FTY720 Analogues as Sphingosine Kinase 1 Inhibitors: Enzyme Inhibition Kinetics, Allosterism, Proteasomal Degradation, and Actin Rearrangement in MCF-7 Breast Cancer Cells,” J. Biol. Chem. 286, 18633-18640 (2011).
K. G. Lim, C. Sun, R. Bittman, N. J. Pyne, and S. Pyne, “(R)-FTY720 Methyl Ether Is a Specific Sphingosine Kinase 2 Inhibitor: Effect on Sphingosine Kinase 2 Expression in HEK293 Cells and Actin Rearrangement and Survival of MCF-7 Breast Cancer Cells,” Cell. Signal. 23, 1590-1595 (2011).
K. G. Lim, F. Tonelli, E. Berdyshev, I. Gorshkova, T. Leclercq, S. M. Pitson, R. Bittman, S. Pyne, and N. J. Pyne, “Inhibition Kinetics and Regulation of Sphingosine Kinase 1 Expression in Prostate Cancer Cells: Functional Differences between Sphingosine Kinase 1a and 1b,” Int. J. Biochem. Cell Biol. 44, 1457-1464 (2012).
F. Tonelli, M. Alossaimi, L. Williamson, R. J. Tate, D. G. Watson, E. Chan, R. Bittman, N. J. Pyne, and S. Pyne, “The Sphingosine Kinase Inhibitor 2-(p-Hydroxyanilino)-4-(p-chlorophenyl)thiazole Reduces Androgen Receptor Expression via an Oxidative Stress Dependent Mechanism,”,Br. J. Pharmacol. 168, 1497-1505 (2013).
D. J. Baek, N. MacRitchie, S. Pyne, N. J. Pyne, and R. Bittman, “Synthesis of Selective Inhibitors of Sphingosine Kinase 1,” Chem. Commun. 49, 2136-2138 (2013).
D. G. Watson, F. Tonelli, M. Alossaimi, L. Williamson, E. Chan, I. Gorshkova, E. Berdyshev, R. Bittman, N. J. Pyne, and S. Pyne, “The Roles of Sphingosine Kinase 1 and 2 in Regulating the Warburg Effect in Prostate Cancer Cells,” Cell. Signal. 25, 1011-1017 (2013).
Z. Liu, N. MacRitchie, S. Pyne, N. J. Pyne, and R. Bittman, “Synthesis of (S)-FTY720 Vinylphosphonate Analogues and Evaluation of Their Potential as Sphingosine Kinase 1 Inhibitors and Activators,” Bioorg. Med. Chem. 21, 2503-2510 (2013).

Synthesis and properties of caged sphingolipids

R. S. Lankalapalli, A. Ouro, L. Arana, A. Gómez Muñoz, and R. Bittman, “Caged Ceramide 1-Phosphate Analogues: Synthesis and Properties,” J. Org. Chem. 74, 8844-8847 (2009).
Y. A. Kim, D. M. Carter Ramirez, W. J. Costain, L. J. Johnston, and R. Bittman, “A New Tool to Assess Ceramide Bioactivity: 6-Bromo-7-hydroxycoumarinyl-Caged Ceramide,” Chem. Commun. 47, 9236-9238 (2011).
L. Arana, P. Gangoiti, A. Ouro, I. G. Rivera, M. Ordoñez, M. Trueba, R. S. Lankalapalli, R. Bittman, and A. Gomez-Muñoz, “Generation of Reactive Oxygen Species (ROS) Is a Key Factor for Stimulation of Macrophage Proliferation by Ceramide 1-Phosphate,” Exp. Cell Res. 318, 350-360 (2012).
A.Ouro, L. Arana, P. Gangoiti, I. G. Rivera, M. Ordoñez, M. Trueba, R. S. Lankalapalli, R. Bittman, and A. Gomez-Muñoz, “Ceramide 1-Phosphate Stimulates Glucose Uptake in Macrophages,” Cell. Signal. 25, 786-795 (2013).
D. M. Carter Ramirez, S. P. Pitre, Y. A. Kim, R. Bittman, and L. Johnston, “Photouncaging of Ceramides Promotes Reorganization of Liquid-Ordered Domains in Supported Lipid Bilayers,” Langmuir 29, 338-347 (2013).
D. M. Carter Ramirez, Y. A. Kim, R. Bittman, and L. Johnston, “Lipid Phase Separation and Protein-Ganglioside Clustering in Supported Bilayers Are Induced by Photorelease of Ceramide,” Soft Matter 9, 4890-4899 (2013)

Use of BODIPY-labeled lipids for live cell imaging or enzyme assays

R. D. Singh, Y. Liu, C. L. Wheatley, E. L. Holicky, A. Makino, D. L. Marks, T. Kobayashi, G. Subramaniam, R. Bittman, and R. E. Pagano, “Caveolar Endocytosis and Microdomain Association of a Glycosphingolipid Analog Is Dependent On Its Sphingosine Stereochemistry,” J. Biol. Chem. 281, 30660-30668 (2006).
R. D. Singh, E. L. Holicky, Z-J. Cheng, S. Y. Kim, C. L. Wheatley, D. L. Marks, R. Bittman, and R. E. Pagano, “Inhibition of Caveolar Uptake, SV40 Infection, and β1-Integrin Signaling by a Nonnatural Glycosphingolipid Stereoisomer,” J. Cell Biol. 176, 895-901 (2007).
D. L. Marks, R. Bittman, and R. E. Pagano, “Use of Bodipy-labeled Sphingolipid and Cholesterol Analogs to Examine Membrane Microdomains in Cells,” in special issue on Focus on Molecular Imaging, Histochem. Cell Biol. 130, 819-832 (2008).
P. Bandhuvula, Z. Li, R. Bittman, and J. D. Saba, “Sphingosine 1-Phosphate Lyase Enzyme Assay using a BODIPY-labeled Substrate,” Biochem. Biophys. Res. Commun. 380, 366-370 (2009).
M. Jansen, Y. Ohsaki, L. R. Rega, R. Bittman, V. M. Olkkonen, and E. Ikonen, “Role of ORPs in Sterol Transport from Plasma Membrane to ER and Lipid Droplets in Mammalian Cells,” Traffic 12, 218-231 (2011).
D. Wüstner, L. Solanko, F. W. Lund, O. Garvik, Z. Li, R. Bittman, T. Korte, and A. Herrmann, “Quantitative Assessment of Sterol Traffic in Living Cells by Dual Labeling with Dehydroergosterol and BODIPY-Cholesterol,” Chem. Phys. Lipids 164, 221-235 (2011).
M. Bidet, O. Joubert, B. Lacombe, M. Ciantar, R. Nehmé, P. Mollat, L. Bretillon, H. Faure, R. Bittman, M. Ruat, and I. Mus-Veteau, “Patched Regulates the Hedgehog Pathway via Cholesterol Efflux,” PLoS One 6(9):e23834 (2011).
S. Sankaranarayanan, G. Kellner-Weibel, M. de la Llera-Moya, M. C. Phillips, B. F. Asztalos, R. Bittman, and G. H. Rothblat, “A Sensitive Assay for ABCA1-Mediated Cholesterol Efflux Using Bodipy-Cholesterol, J. Lipid Res. 52, 2332-2340 (2011).
C. Röhrl, C. Meisslitzer-Ruppitsch, R. Bittman, Z. Li, G. Pabst, R. Prassl, W. Strobl, J. Neumüller, A. Ellinger, M. Pavelka, and H. Stangl, “Combined Light and Electron Microscopy using Diaminobenzidine Photooxidation to Monitor Trafficking of Lipids Derived from Lipoprotein Particles,” Curr. Pharm. Biotechnol. 13, 331-340 (2012). [Special issue: New methodology and approaches in lipid transport in atherosclerosis and cardiovascular disease; PMID: 21470121.]
T. Blom, Z. Li, R. Bittman, P. Somerharju, and E. Ikonen, “Tracking Sphingosine Metabolism and Transport in Sphingolipidoses: NPC1 Deficiency as a Test Case,” Traffic 13, 1234-1243 (2012).
J. W. Walters, J. L. Anderson, R. Bittman, M. Pack, and S. A. Farber, “Visualization of Lipid Metabolism in the Zebrafish Intestine Reveals a Relationship between NPC1L1-Mediated Cholesterol Uptake and Dietary Fatty Acid,” Chem. Biol. 19, 913-925 (2012).
F. W. Lund, M. A. Lomholt, L. M .Solanko, R. Bittman, and Daniel Wüstner, “Two-Photon Time-Lapse Microscopy of BODIPY-Cholesterol Reveals Anomalous Sterol Diffusion in Chinese Hamster Ovary Cells,” BMC Biophysics 5, 20 doi:10.1186/2046-1682-5-20 (2012).
C. Martel, W. Li, B. Fulp, A. M. Platt, E. L. Gautier, M. Westerterp, R. Bittman, A. R. Tall, S.-H. Chen, M. J. Thomas, D. Kreisel, M. A. Swartz, M. G. Sorci-Thomas, and G. J. Randolph, “Lymphatic Vasculature Mediates Macrophage Reverse Cholesterol Transport in Mice,” J. Clin. Invest. 123, 1571-1579 (2013).
S. Milles, T. Meyer, H. A. Scheidt, R. Schwarzer, L. Thomas, M. Marek, L. Szente, R. Bittman, A. Herrmann, T. G. Pomorski, D. Huster, and P. Mueller, “Organization of Fluorescent Cholesterol Analogues in Lipid Bilayers – Lessons from Cyclodextrin Extraction,” Biochim. Biophys. Acta, e-pub (April 2013).

Syntheses and applications of novel analogs of cholesterol, glycerolipids, and sphingolipids to provide insights about biological or biophysical problems

Analogs of FTY720, an immunosuppressive lipid that is phosphorylated in vivo:

X. Lu and R. Bittman, “Enantioselective Synthesis of the Phosphate Esters of the Immunosuppressive Lipid FTY720,” Tetrahedron Lett. 47, 825-827 (2006).
C. Sun and R. Bittman, “A Photoreactive Analogue of the Immunosuppressant FTY720,” J. Org. Chem. 71, 2200-2202 (2006).
K. R. Watterson, K. M. Berg, S. G. Payne, A. S. Miner, R. Bittman, S. Milstien, P. H. Ratz, and S. Spiegel, “Sphingosine 1-Phosphate and the Immunosuppresant FTY720-Phosphate Regulate Detrusor Muscle Tone,” FASEB J. 21, 2818-2828 (2007).
R. P. Coelho, S. G. Payne, R. Bittman, S. Spiegel, and C. Sato-Bigbee, “The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors,” J. Pharmacol. Exp. Ther. 323, 626-635 (2007).
X. Lu, C. Sun, W. J. Valentine, S. E, J. Liu, G. Tigyi, and R. Bittman, “Chiral Vinylphosphonates and Phosphonates Analogues of the Immunosuppressive Agent FTY720,” J. Org. Chem. 74, 3192-3195 (2009).
S. M. Camp, R. Bittman, E. T. Chiang, L. Moreno-Vinasco, T. Mirzapoiazova, S. Sammani, X. Lu, C. Sun, M. Harbeck, M. Roe, V. Natarajan, J. G. Garcia, and S. M. Dudek, “Synthetic Analogs of FTY720 [2-Amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] Differentially Regulate Pulmonary Vascular Permeability in vivo and in vitro,” J. Pharmacol. Exp. Ther. 331, 54-64 (2009).
E. V. Berdyshev, I. Gorshkova, A. Skobeleva, R. Bittman, X. Lu, S. M. Dudek, T. Mirzapoiazova, J. G. N. Garcia, and V. Natarajan, “FTY720 Inhibits Ceramide Synthases and Upregulates Dihydrosphingosine 1-Phosphate Formation in Human Lung Endothelial Cells,” J. Biol. Chem. 284, 5467-5477 (2009).
S. Lahiri, H. Park, E. L. Laviad, X. Lu, R. Bittman, and A. H. Futerman, “Ceramide Synthesis Is Modulated by the Sphingosine Analog FTY720 via a Mixture of Uncompetitive and Noncompetitive Inhibition in an Acyl-CoA Chain-length Dependent Manner,” J. Biol. Chem. 284, 16090-16098 (2009).
T. Blom, N. Bäck, A. L. Mutka, R. Bittman, Z. Li, A. de Lera, P. T. Kovanen, U. Diczfalusy, and E. Ikonen, “FTY720 Stimulates 27-Hydroxycholesterol Production and Confers Atheroprotective Effects in Human Primary Macrophages,” Circ. Res. 106, 720-729 (2010).
F. Tonelli, K. G. Lim, C. Loveridge, J. Long, S. M. Pitson, G. Tigyi, R. Bittman, S. Pyne, and N. J. Pyne, “FTY720 and (S)-FTY720 Vinylphosphonate Inhibit Sphingosine Kinase 1 and Promote Its Proteasomal Degradation in Human Pulmonary Artery Smooth Muscle, Breast Cancer, and Androgen-independent Prostate Cancer Cells,” Cell. Signal. 22, 1536-1542 (2010).
W. J. Valentine, G. N. Kiss, J. Liu, S. E, M. Gotoh, K. Murokami-Murofushi, T. C. Pham, D. L. Baker, A. L. Parrill, X. Lu, C. Sun, R. Bittman, N. J. Pyne, and G. Tigyi, “(S)-FTY720-Vinylphosphonate, an Analogue of the Immunosuppressive Agent FTY720, Is a Pan-antagonist of Sphingosine 1-Phosphate GPCR Signaling and Inhibits Autotaxin Activity,” Cell. Signal. 22, 1543-1553 (2010).
K. G. Lim, F. Tonelli, Z. Li, X. Lu, R. Bittman, S. Pyne, and N. J. Pyne, “FTY720 Analogues as Sphingosine Kinase 1 Inhibitors: Enzyme Inhibition Kinetics, Allosterism, Proteasomal Degradation, and Actin Rearrangement in MCF-7 Breast Cancer Cells,” J. Biol. Chem. 286, 18633-18640 (2011).
K. G. Lim, C. Sun, R. Bittman, N. J. Pyne, and S. Pyne, “(R)-FTY720 Methyl Ether Is a Specific Sphingosine Kinase 2 Inhibitor: Effect on Sphingosine Kinase 2 Expression in HEK293 Cells and Actin Rearrangement and Survival of MCF-7 Breast Cancer Cells,” Cell. Signal. 23, 1590-1595 (2011).
B. Mathew, J. R. Jacobson, E. Berdyshev, Y. Huang, X. Sun, Y. Zhao, L. M. Gerhold, J. Siegler, C. Evenoski, T. Wang, T. Zhou, R. Zaidi, L. Moreno-Vinasco, R. Bittman, C. T. Chen, P. J. LaRiviere, S. Sammani, Y. A. Lussier, S. M. Dudek, V. Natarajan, R. R. Weichselbaum, and J. G. N. Garcia, “Role of Sphingolipids in Murine Radiation-Induced Lung Injury: Protection by Sphingosine 1-Phosphate Analogues,” FASEB J. 25, 3388-3400 (2011).
W. J. Valentine, V. I. Godwin, D. Osborne, J. Liu, Y. Fujiwara, J. Van Brocklyn, R. Bittman, A. L. Parrill, and G. Tigyi, “FTY720 (Gilenya) Phosphate Selectivity of Sphingosine 1-Phosphate Receptor Subtype 1 (S1P1) G Protein-coupled Receptor Requires Motifs in Intracellular Loop 1 and Transmembrane Domain 2,” J. Biol. Chem. 286, 30513-30525 (2011).
V. Natarajan, S. M. Dudek, J. R. Jacobson, L. Moreno-Vinasco, L. S. Huang, T. Abassi, B. Mathew, Y. Zhao, L.Wang, R. Bittman, R. Weichselbaum, E. Berdyshev, and J. G. N. Garcia, “Sphingosine-1-Phosphate, FTY720, and Sphingosine-1-Phosphate Receptors in the Pathobiology of Acute Lung Injury,” Am. J. Respir. Cell Mol. Biol., e-pub March 14 (2013).

C-Glycoside analogs of the immunostimulatory glycosphingolipid a-GalCer:

X. Lu, L. Song, L. S. Metelitsa, and R. Bittman, “Synthesis and Evaluation of an a-C-Galactosylceramide Analogue that Induces Th1-biased Responses in Human Natural Killer T Cells,” ChemBioChem 7, 1750-1756 (2006).
Z. Liu, H.-S. Byun, and R. Bittman, “Synthesis of Immunostimulatory a-C-Galactosylceramide Glycolipids via Sonogashira Coupling, Asymmetric Epoxidation, and Trichloroacetimidate-Mediated Epoxide Opening,” Org. Lett. 12, 2974-2977 (2010).
O. Patel, G. Cameron, D. G. Pellicci, Z. Liu, H.-S. Byun, T. Beddoe, J. McCluskey, R. W. Franck, A. R. Castaño, Y. Harrak, A. Llebaria, R. Bittman, S. A. Porcelli, D. Godfrey, and J. Rossjohn, “Natural Killer T-Cell Receptor Recognition of CD1d-C-GalactosylCeramide,” J. Immunol. 187, 4705-4713 (2011).
Z. Liu, H.-S. Byun, and R. Bittman, “Total Synthesis of a-1C-GalactosylCeramide, an Immunostimulatory C-Glycosphingolipid, and Confirmation of the Stereochemistry in the First Generation Synthesis,” J. Org. Chem. 76, 8588-8598 (2011) (Featured Article).
P. P. Chang, P. Barral, J. Fitch, A. Pratama, C. S. Ma, A. Kallies, J. J. Hogan, V. Cerundolo, S. G. Tangye, R. Bittman, S. L. Nutt, R. Brink, D. I. Godfrey, F. D. Batista, and C. G. Vinuesa, “Identification of Bcl-6-dependent Follicular Helper NKT Cells That Provide Cognate Help for B Cell Responses,” Nat. Immunol. 13, 35-43 (2011).
Z. Liu and R. Bittman, “Synthesis of C-Glycoside Analogues of a-Galactosylceramide via Linear Allylic C─H Oxidation and Allyl Cyanate to Isocyanate Rearrangement,” Org. Lett. 14, 620-623 (2012).
Z. Liu, A. N. Courtney, L. S. Metelitsa, and R. Bittman, “C-Glycosphingolipids with an exo-Methylene Substituent: Stereocontrolled Synthesis and Immunostimulation of Mouse and Human Natural Killer T Lymphocytes,” ChemBioChem 13, 1733-1737 (2012).

Analogs of cholesterol:

N. Zhong, H.-S. Byun, and R. Bittman, "Hydrophilic Cholesterol-binding Molecular Imprinted Polymers," Tetrahedron Lett. 42, 1839-1841 (2001).
N. Zhong, H. Ohvo-Rekilä, B. Ramstedt, J. P. Slotte, and R. Bittman, "Removal of Cholesterol and Palmitic Acid from Langmuir Monolayers by Complexation with New Water-soluble Cyclodextrin Derivatives," Langmuir 17, 5319-5323 (2001).
X. Xu, R. Bittman, C. Vilchèze, G. Duportail, and E. London, "Effect of the Structure of Natural Sterols and Sphingolipids on the Formation of Ordered Sphingolipid/Sterol Domains (Rafts): Comparison of Cholesterol to Plant, Fungal, and Disease-Associated Sterols, and Comparison of Sphingomyelin, Cerebrosides, and Ceramide," J. Biol. Chem. 276, 33540-33546 (2001).
J. R. Harris, S. Bhakdi, U. Meissner, D. Scheffler, R. Bittman, G. Li, A. Zitzer,and M. Palmer, "Interaction of the Vibrio cholerae Cytolysin (VCC) with Cholesterol, Some Cholesterol Esters, and Cholesterol Derivatives: A TEM Study," J. Struct. Biol. 139, 122-135 (2002).
M. Merris, W. G. Wadsworth, U. Khamrai, R. Bittman, D. J. Chitwood, and J. Lenard, "Sterol Effects and Sites of Sterol Accumulation in Caenorhabditis elegans: Developmental Requirement for 4a-Methylsterol," J. Lipid Res. 44, 172-181 (2003).
Z. Li, E. Mintzer, and R. Bittman, “First Synthesis of Free Cholesterol-BODIPY Conjugates,” J. Org. Chem. 71, 1718-1721 (2006).
J. E. Shaw, R. F. Epand, R. M. Epand, Z. Li, R. Bittman, and C. M. Yip, “Correlated Fluorescence-AFM Microscopy of Membrane Domains: Structure of Fluorescence Probes Determines Lipid Localization,” Biophys. J. 90, 2170-2178 (2006).
Z. Li and R. Bittman, “Synthesis and Spectral Properties of Cholesterol- and FTY720-Containing Boron Dipyrromethene Dyes,” J. Org. Chem. 72, 8376-8382 (2007).
M. Hölttä-Vuori, R. L. Uronen, J. Repakova, E. Salonen, I. Vattulainen, P. Panula, Z. Li, R. Bittman, and E. Ikonen, “BODIPY-Cholesterol: A New Tool to Visualize Sterol Trafficking in Living Cells and Organisms,” Traffic 9, 1839-1849 (2008).
F. S. Ariola, Z. Li, C. Cornejo, R. Bittman, and A. A. Heikal, “Membrane Fluidity and Lipid Order in Ternary Giant Unilamellar Vesicles using a New Bodipy-Cholesterol Derivative,” Biophys. J. 96, 2696-2708 (2009).
S. Scolari, K. Müller, R. Bittman, A. Herrmann, and P. Müller,Interaction of Mammalian Seminal Plasma Protein PDC-109 with Cholesterol – Implications for a Putative CRAC Domain,” Biochemistry 49, 9027-9031 (2010).

Analogs of sphingomyelin:

B.-L. Waarts, R. Bittman, and J. Wilschut, "Sphingolipid- and Cholesterol-Dependence of Alphavirus Membrane Fusion. Lack of Correlation with Lipid Raft Formation in Target Liposomes," J. Biol. Chem. 277, 38141-38147 (2002).
T. Mehnert, R. Bittman, R. Jacob, and K. Beyer, “Structure and Lipid Interaction of N-Palmitoylsphingomyelin in Bilayer Membranes as Revealed by 2H NMR Spectroscopy,” Biophys. J. 90, 939-946 (2006).
T. Bartels, R. S. Lankalapalli, R. Bittman, M. F. Brown, and K. Beyer, “Raftlike Mixtures of Sphingomyelin and Cholesterol Investigated by Solid-State ²H NMR Spectroscopy,” J. Am. Chem. Soc. 130, 14521-14532 (2008).
S. Soni, D. S. LoCascio, Y. Liu, J. A. Williams, R. Bittman, W. Stillwell, and S. R. Wassall, “Docosahexaenoic Acid Enhances Segregation of Lipids between Raft and Non-Raft Domains: ²H NMR Study,” Biophys. J. 95, 203-214 (2008).
P. V. Subbaiah, D. Sircar, R. S. Lankalapalli, and R. Bittman, “Effect of Double Bond Geometry in Sphingomyelin on Its Antioxidant Properties,” Arch. Biochem. Biophys. 481, 72-79 (2009).

Analogs of glycerolipids:

R. Bittman, D. Qin, D.-A. Wang, G. Tigyi, P. Samadder, and G. Arthur, "Synthesis and Anti-tumor Properties of a Plasmalogen Methyl Ether Analogue," Tetrahedron 57, 4277-4282 (2001).
G. Li, P. Samadder, G. Arthur, and R. Bittman, "Synthesis and Antiproliferative Properties of a Photoactivatable Analogue of ET-18-OCH₃," Tetrahedron 57, 8925-8932 (2001).
K. Yokoyama, D. L. Baker, T. Virag, K. Liliom, H.-S. Byun, G. Tigyi, G., and R. Bittman,^"Stereochemical Properties of Lysophosphatidic Acid Receptor Activation and Metabolism," Biochim. Biophys. Acta 1582, 295-308 (2002).
C. Zhang,D. L. Baker, S. Yasuda, N. Makarova, L. Johnson, L. Balazs, G. Marathe, T. M. McIntyre, Y. Xu, G. D. Prestwich, H.-S. Byun, R. Bittman, and G. Tigyi, "Lysophosphatidic Acid Induces Neointima Formation Through PPAR Activation," J. Exp. Med. 199, 763-774 (2004).
T. Tsukahara,R. Tsukahara, S. Yasuda, N. Makarova, W. J. Valentine, P. Allison, H. Yuan, D. L. Baker, Z. Li, R. Bittman, A. Parrill, and G. Tigyi, “Different Residues Mediate Recognition of 1-O-Oleyl-lysophosphatidic Acid and Rosiglitazone in the Ligand-Binding Domain of Peroxisone Proliferator-activated Receptor g,” J. Biol. Chem. 281, 3398-3407 (2006).
D. L. Baker, Y. Fujiwara, K. R. Pigg, R. Tsukahara, S. Kobayashi, H. Murofushi, A. Uchiyama, K. Murakami-Murofushi, E. Koh, R. W. Bandle, H.-S. Byun, R. Bittman, D. Fan, M. Murph, G. B. Mills, and G. Tigyi, “Carba Analogs of Cyclic Phosphatidic Acid Are Selective Inhibitors of Autotaxin and Cancer Cell Invasion and Metastasis,” J. Biol. Chem. 281, 22786-22793 (2006).
R. S. Lankalapalli, J. T. Eckelkamp, D. Sircar, D. A. Ford, P. V. Subbaiah, and R. Bittman, “Synthesis and Antioxidant Properties of an Unnatural Plasmalogen Analogue Bearing a trans O-Vinyl Ether Linkage,” Org. Lett. 11, 2784-2789 (2009).
K. M. W. Keough, M. R. Morrow, and R. Bittman, “Phospholipid-Cholesterol Bilayers,” Encyclopedia of NMR 6, 3372-3379 (2012).
R. Bittman, “Glycerolipids: Chemistry,” in Springer Encyclopedia of Biophysics, Section on Lipids, G. C. K. Roberts, Ed. (2013)

Analogs of sphingosines and ceramides:

A. Zitzer, R. Bittman, C. A. Verbicky, R. K. Erukulla, S. Bhakdi, S. Weis, A. Valeva, and M. Palmer, "Coupling of Cholesterol and Cone-shaped Lipids in Bilayers Augments Membrane Permeabilization by the Cholesterol-specific Toxins Streptolysin O and Vibrio cholerae Cytolysin," J. Biol. Chem. 276, 14628-14633 (2001).
H. L. Brockman, M. M. Momsen, R. E. Brown, L. He, J. Chun, H.-S. Byun, and R. Bittman, "The 4,5-Double Bond of Ceramide Regulates Its Dipole Potential, Elastic Properties, and Packing Behavior," Biophys. J. 87, 1722-1731 (2004).
Megha, P. Sawatzki, T. Kolter, R. Bittman, and E. London, “Effect of Ceramide N-Acyl Chain and Polar Headgroup Structure on the Properties of Ordered Lipid Domains (Lipid Rafts),” Biochim. Biophys. Acta 1768, 2205-2212 (2007).
S. Chiantia, J. Ries, G. Chwastek, D. Carrer, Z. Li, R. Bittman, and P. Schwille, “Role of Ceramide in Membrane Protein Organization Investigated by Combined AFM and FCS,” Biochim. Biophys. Acta Biomembranes 1778, 1356-1364 (2008).
H. Fyrst, X. Zhang, D. R. Herr, H.-S. Byun, R. Bittman, R, V. H. Phan, G. L. Harris, and J. D. Saba, “Identification and Characterization by Electrospray Mass Spectrometry of Endogenous Drosophila Sphingadienes,” J. Lipid Res. 49, 597-606 (2008).
H. Fyrst, B. Oskouian, P. Bandhuvula, Y. Gong, H. S. Byun, R. Bittman, A. R. Lee, and J. D. Saba, “Natural Sphingadienes Inhibit Akt-Dependent Signaling and Prevent Intestinal Tumorigenesis,” Cancer Res. 69, 9457-9464 (2009).
R. S. Lankalapalli, A. Ouro, L. Arana, A. Gómez Muñoz, and R. Bittman, “Caged Ceramide 1-Phosphate Analogues: Synthesis and Properties,” J. Org. Chem. 74, 8844-8847 (2009).
Y. A. Kim, D. M. Carter Ramirez, W. J. Costain, L. J. Johnston, and R. Bittman, “A New Tool to Assess Ceramide Bioactivity: 6-Bromo-7-hydroxycoumarinyl-Caged Ceramide,” Chem. Commun. 47, 9236-9238 (2011).
C. Habrukowich, D. K. Han, A. Le, K. Raizul, W. Pan, M. Ghosh, Z. Li, K. Dodge-Kafka, X. Jiang, R. Bittman, and T. Hla, “Sphingosine Interaction with Acidic Leucine-rich Nuclear Phosphoprotein-32A (ANP32A) Regulates Cyclooxygenase (COX)-2 Expression in Human Endothelial Cells,” J. Biol. Chem. 285, 26825-26831 (2010).
R. Bucki, A. Kułakowska, F. J. Byfield, M. Żendzian-Piotrowska, M. Baranowski, M. Marzec, J. P. Winer, N. J. Ciccarelli, J. Górski, W. Drozdowski, R. Bittman, and P. A. Janmey, "Plasma Gelsolin Modulates Cellular Response to Sphingosine 1-Phosphate," Am. J. Physiol. Cell Physiol. 299, C1516-C1523 (2010).
M. N. Perera, V. Ganesan, L. Siskind, Z. M. Szulc, J. Bielawaski, A. Bielawska, R. Bittman, and M. Colombini, “Ceramide Channels: Influence of Molecular Structure on Channel Formation in Membranes,” Biochim. Biophys. Acta – Biomembranes 1818, 1291-1301 (2012).
M. N. Perera, S. H. Lin, Y. K. Peterson, A. Bielawska, Z. M. Szulc, R. Bittman, and M. Colombini, “Bax and Bcl-XL Exert Their Regulation on Different Sites of the Ceramide Channel,” Biochem. J. 445, 81-91 (2012).

Phytosphingosines:

Z. Liu, H.-S. Byun, and R. Bittman, “Asymmetric Synthesis of D-ribo-Phytosphingosine from 1-Tetradecyne and (4-Methoxyphenoxy)acetaldehyde,” Featured Article in J. Org. Chem. 75, 4356-4364 (2010).

Analogs of other lipids:

E. V. Berdyshev, J. Goya, I. Gorshkova, G. D. Prestwich, H.-S. Byun, R. Bittman, and V. Natarajan, “Characterization of Sphingosine 1-Phosphate Lyase Activity by Electrospray Ionization-Liquid Chromatography/Tandem Mass Spectrometry Quantitation of (2E)-Hexadecenal,” Anal. Biochem. 408, 12-18 (2011).
A. Kumar, H.-S. Byun, R. Bittman, and J. D. Saba, “The Sphingolipid Degradation Product trans-2-Hexadecenal Induces Cytoskeletal Reorganization and Apoptosis in a JNK-Dependent Manner,” Cell. Signal. 23, 1144-1152 (2011).
A Mahendran, A. Vuong, D. Aebisher, Y. Gong, R. Bittman, G. Arthur, A. Kawamura, and A. Greer, “Synthesis, Characterization, Mechanism of Decomposition, and Antiproliferative Activity of a Class of PEGylated Benzopolysulfanes Structurally Similar to the Natural Product Varacin,” J. Org. Chem. 75, 5549-5557 (2010).
P. Upadhyaya, A. Kumar, H.-S. Byun, R. Bittman, J. D. Saba, and S. S. Hecht, “The Sphingolipid Degradation Product trans-2-Hexadecenal Forms Adducts with DNA,” Biochem. Biophys. Res. Commun. 424, 18-21 (2012).

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New methodology for the preparation of natural and unnatural sphingolipids

L. He, H.-S. Byun, and R. Bittman, "A Stereocontrolled, Efficient Synthetic Route to Bioactive Sphingolipids: Synthesis of Phytosphingosine and Phytoceramides from Unsaturated Ester Precursors via Cyclic Sulfate Intermediates," J. Org. Chem. 65, 7618-7626 (2000).
L. He, H.-S. Byun, and R. Bittman, "Stereoselective Preparation of Ceramide and Its Skeleton Backbone Modified Analogues via Cyclic Thionocarbonate Intermediates Derived by Catalytic Asymmetric Dihydroxylation of a,b-Unsaturated Ester Precursors," J. Org. Chem. 65, 7627-7633 (2000).
J. Chun, L. He, H.-S. Byun, and R. Bittman, "Synthesis of Ceramide Analogues Having the C(4)-C(5) Bond of the Long-chain Base as Part of an Aromatic or Heteroaromatic System, J. Org. Chem. 65, 7634-7640 (2000).
R. Bittman and C. A. Verbicky, "Methanolysis of Sphingomyelin: Toward an Epimerization-free Methodology for the Preparation of D-erythro-sphingosylphosphoryl-choline," J. Lipid Res. 41, 2089-2093 (2000).
J. Chun, G. Li, H.-S. Byun, and R. Bittman, "A Concise Route to D-erythro-Sphingosine from N-Boc-L-serine Derivatives via Sulfoxide or Sulfone Intermediates," Tetrahedron Lett. 43, 375-377 (2002).
J. Chun, G. Li, H.-S. Byun, and R. Bittman, "Synthesis of New Trans Double Bond Sphingolipid Analogues: D^4,6 and D⁶ Ceramides," J. Org. Chem. 67, 2600-2605 (2002).
J. Chun, H.-S. Byun, and R. Bittman, "First Asymmetric Synthesis of 6-Hydroxy-4-Sphingenine-containing Ceramides. Use of Chiral Propargylic Alcohols to Prepare a Lipid Found in Human Skin," J. Org. Chem. 68, 348-354 (2003).
X. Lu, H.-S. Byun, and R. Bittman, "Synthesis of L-lyxo-Phytosphingosine and Its 1-Phosphonate Analogue Using a Threitol Acetal Synthon," J. Org. Chem. 69, 5433-5438 (2004).
C. Sun and R. Bittman, "An Efficient Preparation of Isosteric Phosphonate Analogues of Sphingolipids by Opening of Oxirane and Cyclic Sulfamidate Intermediates with a-Lithiated Alkylphosphonic Esters," J. Org. Chem. 69, 7694-7699 (2004).
X. Lu and R. Bittman, "Efficient and Versatile Synthesis of (2S,3R)-Sphingosine and Its 2-Azido-3-O-benzoyl Analogue," Tetrahedron Lett. 46, 1873-1875 (2005).
X. Lu and R. Bittman, “Enantioselective Synthesis of the Phosphate Esters of the Immunosuppressive Lipid FTY720,” Tetrahedron Lett. 47, 825-827 (2006).
H.-S. Byun, X. Lu, and R. Bittman, “Stereoselective Total Synthesis of Serine Palmitoyl-CoA Transferase Inhibitors,” Synthesis 2447-2474 (2006).
M. Nylund, M. A. Kjellberg, J. G. Molotkovsky, H.-S. Byun, R. Bittman, and P. Mattjus, “Molecular Features that Affect Glycolipid Transfer Protein Mediated Galactosylceramide Transfer between Vesicles,” Biochim. Biophys. Acta 1758, 807-812 (2006).
H.-S. Byun and R. Bittman, “Selective Deuterium Labeling of the Sphingoid Backbone: Facile Syntheses of 3,4,5-Trideuterio-D-erythro-sphingosine and 3-Deuterio-D-erythro-sphingomyelin,” Chem. Phys. Lipids 163, 809-813 (2010).
H.-S. Byun and R. Bittman, “Practical Multigram-scale Synthesis of 4,6- and 4,8-Sphingadienes, Chemopreventive Sphingoid Bases,” Chem. Phys. Lipids 165, 794-801 (2012).
A. Kumar, A. K. Pandurangan, F. Lu, H. Fyrst, M. Zhang, H. S. Byun, R. Bittman, and J. D. Saba, “Chemopreventive Sphingadienes Downregulate Wnt Signaling via a PP2A/Akt/GSK3ß Pathway in Colon Cancer,” Carcinogenesis 33, 1726-1735 (2012).

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Photoreactive lipids

G. Li and R. Bittman, "Synthesis of Novel Phenoxy-linked Diazirine Glycero- and Sphingolipid Probes via Trialkylaryltin Intermediates," Tetrahedron Lett. 41, 6737-6741 (2000).
G. Li, P. Samadder, G. Arthur, and R. Bittman, "Synthesis and Antiproliferative Properties of a Photoactivatable Analogue of ET-18-OCH₃," Tetrahedron 57, 8925-8932 (2001).
E. A. Mintzer, B.-L. Waarts, J. Wilschut, and R. Bittman, "Behavior of a Photoactivatable Analog of Cholesterol, 6-Photocholesterol, in Model Membranes," FEBS Lett. 501, 181-184 (2002).
X. Lu, S. Cseh, H.-S. Byun, G. Tigyi, and R. Bittman, "Total Synthesis of Two Photoactivatable Analogues of the Growth Factor-like Mediator Sphingosine 1-Phosphate: Differential Interaction with Protein Targets," J. Org. Chem. 68, 7046-7050 (2003).
X. Lu and R. Bittman, “Synthesis of a Photoactivatable (2S,3R)-Sphingosylphosphorylcholine Analogue,” J. Org. Chem. 70, 4746-4750 (2005).
Z. Li, D. L. Baker, G. Tigyi, and R. Bittman, “Synthesis of Photoactivatable Analogues of Lysophosphatidic Acid and Covalent Labeling of Plasma Proteins,” J. Org. Chem. 71, 629-635 (2006).
C. Sun and R. Bittman, “A Photoreactive Analogue of the Immunosuppressant FTY720,” J. Org. Chem. 71, 2200-2202 (2006).
R. S. Lankalapalli, A. Baksa, K. Liliom, and R. Bittman, “Synthesis and Properties of a Photoactivatable Analogue of Psychosine (b-Galactosylsphingosine),” ChemMedChem 5, 682-686 (2010).

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The synthesis and properties of unnatural ceramides with anticancer activity in vitro

J. Chun, H.-S. Byun, G. Arthur, and R. Bittman, "Synthesis and Growth Inhibitory Activity of Chiral 5-Hydroxy-2-N-acyl-3E-sphingenines: Ceramides with an Unusual Sphingoid Backbone," J. Org. Chem. 68, 355-359 (2003).
K. W. Crawford, R. Bittman, J. Chun, H.-S. Byun, and W. D. Bowen, “Novel Ceramide Analogues Display Selective Cytotoxicity in Drug-resistant Breast Tumor Cell Lines Compared to Normal Breast Epithelial Cells,” Cell. Mol. Biol. 49, 1017-1023 (2003).
A. P. Struckhoff, R. Bittman, M. E. Burow, S. Clejan, S. Eliot, T. Hammond, A. B. Scandurro, Y. Tang, and B. S. Beckman, "Novel Ceramide Analogs as Potential Chemotherapeutic Agents in Breast Cancer," J. Pharmacol. Exp. Ther. 309, 523-532 (2004).
X. Lu, G. Arthur, and R. Bittman, “Synthesis of a Novel Ceramide Analogue via Tebbe Methylenation and Evaluation of Its Antiproliferative Activity,” Org. Lett. 7, 1645-1648 (2005).
R. Bittman, Z. Li, P. Samadder, and G. Arthur, “Anticancer Activity of a Ceramide Analog Containing a Disulfide Linkage,” Cancer Lett. 251, 53-58 (2007).
L. Jahreiss, M. Renna, R. Bittman, G. Arthur, and D. C. Rubinsztein, “1-O-Hexadecyl-2-O-methyl-3-O-(2'-acetamido-2'-deoxy-b-D-glucopyranosyl)-sn-glycerol (Gln) Induces Cell Death with More Autophagosomes Which Is Autophagy-Independent,” Autophagy 5, 835-846 (2009).
H.-S. Byun, R. Bittman, P. Samadder, and G. Arthur, “Synthesis and Antitumor Activity of Ether Glycerophospholipids Bearing a Carbamate Moiety at the sn-2 Position: Selective Sensitivity Against Prostate Cancer Cell Lines,” ChemMedChem 5, 1045-1052 (2010).

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Labeled cerebrosides: synthesis and applications in membrane research

P. Mattjus, B. Malewicz, J. T. Valiyaveettil, W. J. Baumann, R. Bittman, and R. E. Brown, "Sphingomyelin Modulates the Transbilayer Distribution of Galactosylceramide in Phospholipid Membranes," J. Biol. Chem. 277, 19476-19481 (2002).
R. D. Singh, V. Puri, J. T. Valiyaveettil, D. L. Marks, R. Bittman, and R. E. Pagano, " Selective Caveolin-1-dependent Endocytosis of Glycosphingolipids," Mol. Biol. Cell 14, 3254-3265 (2003).
B. Malewicz, J. T. Valiyaveettil, K. Jacob, H.-S. Byun, P. Mattjus, W. J. Baumann, R. Bittman, and R. E. Brown, "The 3-Hydroxy Group and 4,5-trans Double Bond of Sphingomyelin Are Essential for Modulation of Galactosylceramide Transmembrane Asymmetry," Biophys. J. 88, 2670-2680 (2005).
Y. Liu and R. Bittman, “Synthesis of Fluorescent Lactosylceramide Stereoisomers,” Chem. Phys. Lipids 142, 58-69 (2006).

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Ether-linked glycerolipids with anticancer activity in vitro

G. Yang, R. W. Franck, R. Bittman, P. Samadder, and G. Arthur, "Synthesis and Growth-Inhibitory Properties of Glucosamine-derived Glycerolipids," Org. Letters 3, 197-200 (2001).
R. Bittman, W. R. Perkins, and C. E. Swenson, "TLC ELL-12: Liposomal ET-18-OCH₃," Drugs Fut. 26, 1052-1058 (2001).
P. Samadder, C. Richards, R. Bittman, , R. P. Bhullar, and G. Arthur, “The Antitumor Ether Lipid 1-O-Octadecyl-2-O-methyl-rac-glycerophosphocholine (ET-18-OCH₃) Inhibits the Association between Ras and Raf-1,” Anticancer Res. 23, 2291-2296 (2003).
P. Samadder, R. Bittman, H.-S. Byun, R. Bhullar, and G. Arthur, "The Differential Modulation of Signaling Pathways and Epithelial Cancer Cell Proliferation by the S and R Enantiomers of 2’-(Trimethylammonio)ethyl 4-(Hexadecyloxy)-3-methoxy-1-butene-phosphonate, Novel Phospholipid Antitumor Agents," J. Med. Chem. 47, 2710-2713 (2004).
G. Arthur, P. Samadder, and R. Bittman, "ET-18-OCH₃ Inhibits the Phosphorylation and Activation of p70 S6 Kinase in MCF-7 Cells," Anticancer Res. 24, 95-100 (2005).
P. Samadder, R. Bittman, H.-S. Byun, and G. Arthur, “A Glycosylated Antitumor Ether Lipid Kills Cells via Paraptosis-like Cell Death,” Biochem. Cell Biol. 87, 401-414 (2009).
P. Samadder, H.-S. Byun, R. Bittman, and G. Arthur, “An Active Endocytosis Pathway Is Required for the Cytotoxic Effects of Glycosylated Antitumor Ether Lipids (GAELs),” Anticancer Res. 31, 3809-3818 (2011).
P. Samadder, H.-S. Byun, R. Bittman, and G. Arthur, “A Fluorescent Alkyllysophospholipid Analog Exhibits Selective Cytotoxicity Against the Hormone-insensitive Prostate Cancer Cell Lline PC3,” in Anti-Cancer Agents in Medicinal Chemistry (Special Issue on Antitumor Alkyl-lysophospholipid Analogs and Cancer Therapy), in press (2013).
G. Arthur and R. Bittman, “Glycosylated Antitumor Ether Lipids: Activity and Mechanism of Aaction,”in Anti-Cancer Agents in Medicinal Chemistry (Special Issue on Antitumor Alkyl-lysophospholipid Analogs and Cancer Therapy), in press (2013).

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Calorimetric studies of phospholipids

Z. Li, E. Mintzer, and R. Bittman, "The Critical Micelle Concentrations of Lyso-phosphatidic Acid and Sphingosylphosphorylcholine," Chem. Phys. Lipids 130, 197-201 (2004).
E. Mintzer, H. Sargsyan, and R. Bittman, “Lysophosphatidic Acid and Lipopolysaccharide Bind to the PIP₂-Binding Domain of Gelsolin,” Biochim. Biophys. Acta 1758, 85-89 (2006).

Last updated May 1, 2013.