Laboratory of Joseph M. Ready
Department of Biochemistry
University of Texas Southwestern Medical Center
Dallas, Texas

The Ready group is engaged in the discovery and synthesis of biologically active small molecules. We focus equally on natural products and synthetic compounds emerging from high-throughput screening efforts. Synthetic studies on natural products are guided by an interest in novel approaches to polycyclic skeletons. Target selection is influenced by both issues of molecular complexity and biological activity. Additionally, we collaborate with biologists at UT Southwestern and elsewhere to discover small molecules with promising biological activity using high-throughput screening strategies. We are involved in efforts to identify small molecules with relevance to neurodegenerative diseases, cancer and infectious disease. In these efforts we work with clinicians, pharmacologists and biologists to develop drug-like compounds through proof-of-concept stages in animal models of disease. Both classes of chemicals - natural products and synthetic compounds - are often discovered using unbiased phenotypic screening. Accordingly, our synthetic efforts are directed at providing tools to facilitate mode-of-action studies such as photo-crosslinking probes and reagents for affinity chromatography. In the course of target-directed synthetic projects, we often exploit the opportunity to develop novel reagents or transformation. Current research is directed toward the discovery of novel cycloadditions and catalytic C-C cross-coupling reaction. We anticipate that the combination of these efforts will greatly expand the power of organic chemistry and enable the rapid and efficient synthesis of valuable complex molecules.

Examples of research projects from the group are given below.

Publications

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Zhang, W.; Ready, J. M. “The Ketene-Surrogate Coupling: Catalytic Conversion of Aryl Iodides into Aryl Ketenes through Ynol Ethers.” Angew. Chem. Int. Ed. 2014, 52, 8980-8984.

pdf Wang, G.; Han, T,; Nijhawan, D.; Theodoropoulos, P.; Naidoo, J.; Yadavalli, S.; Mirzaei, H.; Pieper, A.; Ready, J. M.; McKnight, S. L. “The P7C3 Class of Neuroprotective Chemicals Function by Activating the Rate-limiting Enzyme in NAD Salvage.” Cell 2014, 158, 1324-1334.
pdf Yin, T.C.; Britt, J.K.; De Jesus-Cortes, H.; Lu, Y.; Genova, R.M.; Khan, M.Z.; Voorhees, J.R; Shao, J.; Katzman, A.C.; Huntington, P.J.; Wassink, C.; McDaniel, L.; Newell, E.A.; Dutca, L.M.; Naidoo, J.; Cui, H.; Bassuk, A.G.; Harper, M.M.; McKnight, S.L.; Ready, J.M.; Pieper, A.A. P7C3 Neuroprotective Chemicals Block Axonal Degeneration and Preserve Function after Traumatic Brain Injury. Cell Reports 2014, 8, 1731-1740.
pdf Naidoo, J.; De Jesus-Cortes, H.; Huntington, P.; Estill, S; Morlock, L. K.; Starwalt, R.; Mangano, T. J.; Williams, N. S.; Pieper, A. A.; Ready, J. M. “Discovery or a Neuroprotective Chemical, (S)-N-(3-(3,6-Dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridine-2-amine [(-)-P7C3-S243], with Improved Druglike Properties.
pdf Pieper, A. A.; McKnight, S. L.; Ready, J. M. “P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases.” Chem. Soc. Rev. 2014, 43, 6716-6726.
pdf Walker, A. K.; Rivera, P. D.; Wang, Q.; Chuang, J.-C.; Tran, S.; Osborne-Lawrence, S.; Estill, S. J.; Starwalt, R.; Huntington, P.; Morlock, L.; Naidoo, J.; Williams, N.; Ready, J. M.; Eisch, A. J.; Piper, A. A.; Zigman, J. M. “The P7C3-class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis.” Mol. Psychiatry 2014, in press.
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Brown, C.S.; Lee, M.S.; Leung, D.W.; Wang, T.; Xu, W.; Luthra, P.; Anantpadma, M.; Shabman, R.S.; Melito, L.M.; MacMillan, K.S.; Borek, D.M.; Otwinowski, Z.; Ramanan, P.; Stubbs, A.J.; Peterson, D.S.; Binning, J.M.; Tonelli, M.; Olson, M.A.; Davey, R.; Ready, J.M.; Basler, C.F.; Amarasinghe, G.K. “In silico derived small molecules bind the filovirus VP35 protein and inhibit its polymerase cofactor activity,” J. Mol. Biol. 2014, 2045.

pdf Wang, Y.; Wang, C.; Butler, J. R.; Ready, J. M. “Dehydrogenative Coupling to Enable the Enantioselective Total Synthesis of (-)-Simaomicin a.” Angew. Chem. Int. Ed. 2013, 52, 8980.
pdf Naidoo, J.; Bemben, C. J.; Allwein, S. R.; Liang, J.; Pieper, A. A.; Ready, J. M. “Development of a Scalable Synthesis of P7C3-A20, a Potent Neuroprotective Agent.” Tetrahedron Lett. 2013, 54, 4429.
pdf Kilgore, J. A.; Du, X.; Melito, L.; Wei, S.; Wang, C.; Chin, H. G.; Posner, B.; Pradhan, S.; Ready, J. M.; Williams, N. S.* “Identification of DNMT1 Selective Antagonists Using a Novel Scintillation Proximity Assay.” J. Biol. Chem. 2013, 288, 19673.
pdf Antczak, M.; Ready, J.M. “Two-, Three-, and Four-Component Coupling to form Isoquinolones Based on Directed Metalation.” Chem. Sci. 2012, 3, 1450-1454.
pdf De Jesús-Cortés, H.; Xu, P.; Drawbridge, J.; Estill, S. J.; Huntington, P.; Tran, S.; Britt, J.; Tesla, R.; Morlock, L.; Naidoo, J.; Melito, L. M.; Williams, N. S.; Ready, J. M.; McKnight, S. L.; Pieper, A. A. “Neuroprotective Efficacy of Aminopropyl Carbazoles in a Mouse Model of Parkinson’s Disease.” Proc. Natl. Acad. Sci. USA, 2012, doi: 10.1073/pnas.1213956109.
pdf Tesla, R.; Wolf, H. P.; Xu, P.; Drawbridge, J.; Estill, S. J.; Huntington, P.; McDaniel, L.; Knobbe, W.; Morlock, L.; Naidoo, J.; Williams, N. S.; Ready, J. M.; McKnight, S. L.; Pieper, A. A. “Neuroprotective Efficacy of Aminopropyl Carbazoles in a Mouse Model of Amyotrophic Lateral Sclerosis.” Proc. Natl. Acad. Sci. USA, 2012, doi: 10.1073/pnas.1213960109.
pdf Wang, Y.; Ready, J.M. "Cyclocondensation of Amino-propargyl Silanes" Org. Lett. 2012, 14, 2308-2311.
pdf Cai, F.; Pu, X.; Qi, X.; Lynch, V.; Radha, A.; Ready, J.M. "Chiral Allene-Containing Phosphines in Asymmetric Catalysis" J. Am. Chem. Soc. 2011, 133, 18066-18069.
pdf Butler, J.R.; Wang, C.; Bian, J.; Ready, J.M. "Enantioselective Total Synthesis of (-)-Kibdelone C" J. Am. Chem. Soc. 2011, 133, 9956-9959.
pdf Lee, K.S.; Ready, J.M. “Oxidative Arylation of Homoallylic Alcohols” Angew. Chem. Int. Ed. 2011, 50, 2111-2114.
pdf MacMillan, K.S.; Naidoo, J.; Liang, J.; Melito, L.; Williams, N.S.; Morlock, L.; Huntington, P.J.; Estill, S.J.; Longgood, J.;. McKnight, S.L.; Pieper, A.A.; De Brabander, J.K, Ready, J.M. "Development of Proneurogenic, Neuroprotective Small Molecules" J. Am. Chem. Soc. 2011, 133, 1428-1437
pdf Antczak, M. I.; Cai, F.; Ready, J. M. "Asymmetric Synthesis of Tertiary Benzylic Alcohols" Org. Letters, 2011, 13, 184-187.
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Pieper, A.A.; Xie, S.; Capota, E.; Estill, S.J.; Zhong, J.; Long, J.M.; Becker, G.L.; Huntington.; Goldman, S.E.; Shen, C.H.; Capota, M.; Britt, J.K.; Kotti, T.; Brat, D. J.; Williams, N.S.; MacMillan, K.S.; Naidoo, J.; Melito, L.; Hsieh, J.; De Brabander, J.; Ready, J.M.; McKnight, S.L. “Discovery of a pro-neurogenic, neuroprotective chemical” Cell 2010, 142, 39-51.

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Pu, X.; Qi, X.; Ready, J. M. “Allenes in Asymmetric Catalysis: Asymmetric Ring Opening of meso-Epoxides Catalyzed by Allene-Containing Phosphine Oxides” J. Am. Chem. Soc. 2009, 131, 10364-10365.

pdf Espindola, A.P.D.M.; Crouch, R.; DeBergh, J.R.; Ready, J.M.; MacMillan, J.M. "Deconvolution of Complex NMR Spectra in Small Molecules by Multi-Frequency Homonuclear Decoupling (MDEC)" J. Am. Chem. Soc. 2009, 131, 15994-15995.
pdf Qi, X.; Ready, J. M. “Synthesis of Cyclopentenones from Cyclopropanes and Silyl Ynol Ethers” Angew. Chem. Int. Ed. 2008, 47, 7068-7070. 
pdf Pu, X; Ready, J. M. “Direct and Stereospecific Synthesis of Allenes via Reduction of Propargylic Alcohols with Cp2Zr(H)Cl” J. Am. Chem. Soc. 2008, 130, 10874-10875.
pdf DeBergh, J. R.; Spivey, K. M.; Ready, J. M. “Preparation of Substituted Enol Derivatives from Terminal Alkynes and Their Synthetic Utility” J. Am. Chem. Soc. 2008, 130, 7828-7829.
pdf Liu, X.; Ready, J. M. “Directed Hydrozirconation of Homopropargylic Alcohols” Tetrahedron, 2008, 64, 6955-6960.
pdf Zhang, D. H.; Ready, J. M. "Directed Hydrozirconation of Propargylic Alcohols" J. Am. Chem. Soc. 2007, 129, 10288-10289
pdf Germanas, J. P.; Wang, S.; Miner, A.; Hao, W.; Ready, J. M. "Discovery of Small-Molecule Inhibitors of Tyrosinase" Bioorg. Med. Chem. Lett. 2007, 6871-6875.
pdf Lynch, K. W.; Ready, J. M. "Sceince at the Interface of Chemistry and Biology at UT Southwestern" ACS Chem. Biol. 2007, 512-514.
pdf Qi, X.; Ready, J. M. "Copper-Promoted Cycloaddition of Diazocarbonyl Compounds with Copper Acetylides" Angew. Chem. Int. Ed. 2007, 46, 3242-3244.
pdf Zhang, D. H.; Ready, J. M. "Iron-Catalyzed Carbometalation of Propargylic and Homopropargylic Alcohols" J. Am. Chem. Soc. 2006, 128, 15050-15051.
pdf Bian, J.; Wingerden, M. V.; Ready, J. M. “Enantioselective Total Synthesis of (+)- and (-)-Nigellamine A2” J. Am. Chem. Soc. 2006, 128, 7428-7429.
pdf Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood, J. L. “Total Synthesis of Welwitindolinone A Isonitrile” J. Am. Chem. Soc. 2006, 128, 1448-1449.
pdf Zhang, D. H.; Ready, J. M. “Tandem Carbocupration/Oxygenation of Terminal Alkynes” Org. Lett. 2005, 7, 5681-5683.
pdf Malosh, C. F.; Ready. J. M. “Catalytic Cross-Coupling of Alkylzinc Halides with α-Chloroketones” J. Am. Chem. Soc. 2004, 126, 10240-10241.
pdf Ready, J. M.; Reisman, S. E.; Hirata, M.; Weiss, M. M.; Tamaki, K.; Ovaska, T.; Wood, J. L. “A Mild and Efficient Synthesis of Oxindoles: Application to the Synthesis of Welwitindolinone A Isonitrile.” Angew. Chem. Int. Ed., 2004, 43, 1270-1272.
pdf Ready, J. M.; Jacobsen, E. N. “A Practical Oligomeric [(salen)Co] Catalyst for Asymmetric Epoxide Ring-Opening Reactions.” Angew. Chem. Int. Ed., 2002, 41, 1374-1377.
pdf Ready, J. M.; Jacobsen, E. N.  “Highly Active Oligomeric (salen)Co Catalysts for Asymmetric Epoxide Ring Opening Reactions.”  J. Am. Chem. Soc. 2001, 123, 2687-2688.
pdf Ready, J. M.; Jacobsen, E. N. "Asymmetric Catalytic Synthesis of a-Aryloxy Alcohols:  Kinetic Resolution of Terminal Epoxides via Highly Enantioselective Ring Opening with Phenols" J. Am. Chem. Soc. 1999, 121, 6086-6087.

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Page maintained by Joseph Ready
Last updated Sept, 2013