Positions

Overview

  • I received a BS in Chemistry from the University of Virginia in 1977 and a PhD from Duke University in 1985. While a student at Duke University under Dr. Barbara Shaw in Chemistry and Dr. David Sedwick in the Department of Medicine, I obtained a diverse education in experimental design and basic research covering topics from cell culture, protein isolation and gel electrophoresis to organic synthesis and drug design.

    After a brief postdoctoral fellowship at NIEHS in the Research Triangle Park with Dr. Robert London in the area of deuterated probe development for in vivo NMR metabolism, I began a 25-year career in drug design and synthesis at Southern Research Institute in Birmingham, Alabama, advancing to the position of Director of Drug Discovery Technology. Although involved in numerous diverse programs from chemical education and outreach, optimization of Bath and Body Works bubble baths, chemical and biological diversity acquisition, and high throughput drug discovery technology, my major areas of emphasis were medicninal chemistry and new target and drug discovery against cancer and infectious diseases, particularly tuberculosis.

    In 2012, I joined the University of Alabama at Birmingham to pursue a long time dream of supporting advanced education while also focusing on independent research in drug design against cancer and infectious diseases.

    • Selected Publications

    Academic Article

    Year Title Altmetric
    2019 Synthesis of Aza-acyclic Nucleoside Libraries of Purine, Pyrimidine, and 1,2,4-Triazole 2019
    2019 Parallel Solution Phase Synthesis and Preliminary Biological Activity of a 5′-Substituted Cytidine Analog Library 2019
    2018 Comparing and Validating Machine Learning Models for Mycobacterium tuberculosis Drug Discovery 2018
    2018 A small diversity library of α-methyl amide analogs of sulindac for probing anticancer structure-activity relationships 2018
    2018 Oxazole and thiazole analogs of sulindac for cancer prevention 2018
    2018 Amine containing analogs of sulindac for cancer prevention 2018
    2017 Synthesis and preliminary assessment of the anticancer and Wnt/β-catenin inhibitory activity of small amide libraries of fenamates and profens 2017
    2017 Diverse amide analogs of sulindac for cancer treatment and prevention 2017
    2016 Screening and development of new inhibitors of FtsZ from M. tuberculosis 2016
    2016 Machine Learning Model Analysis and Data Visualization with Small Molecules Tested in a Mouse Model of Mycobacterium tuberculosis Infection (2014-2015) 2016
    2015 Autocrine fibroblast growth factor 18 signaling mediates Wnt-dependent stimulation of CD44-positive human colorectal adenoma cells 2015
    2015 Open Source Bayesian Models. 1. Application to ADME/Tox and Drug Discovery Datasets 2015
    2014 Biochemical and structural characterization of mycobacterial aspartyl-tRNA synthetase AspS, a promising TB drug target 2014
    2014 Synthesis and General Biological Activity of a Small Adenosine-5′-(Carboxamide and Sulfanilamide) Library 2014
    2014 Solution-phase parallel synthesis of acyclic nucleoside libraries of purine, pyrimidine, and triazole acetamides 2014
    2014 Are bigger data sets better for machine learning? Fusing single-point and dual-event dose response data for mycobacterium tuberculosis 2014
    2014 Parallel solution-phase synthesis and general biological activity of a uridine antibiotic analog library 2014
    2014 Identification of shikimate kinase inhibitors among anti-Mycobacterium tuberculosis compounds by LC-MS 2014
    2014 Combining computational methods for hit to lead optimization in mycobacterium tuberculosis drug discovery 2014
    2014 Synthesis of novel Peptidyl adenosine antibiotic analogs 2014
    2014 Global human-kinase screening identifies therapeutic host targets against influenza 2014
    2014 Looking back to the future: Predicting in vivo efficacy of small molecules versus Mycobacterium tuberculosis 2014
    2013 Fusing dual-event data sets for mycobacterium tuberculosis machine learning models and their evaluation 2013
    2013 A novel quinoline derivative that inhibits mycobacterial FtsZ 2013
    2013 A chemical proteomics approach to profiling the ATP-binding proteome of Mycobacterium tuberculosis 2013
    2013 Enhancing Hit Identification in Mycobacterium tuberculosis Drug Discovery Using Validated Dual-Event Bayesian Models 2013
    2013 6-Oxo and 6-thio purine analogs as antimycobacterial agents 2013
    2013 Bayesian models leveraging bioactivity and cytotoxicity information for drug discovery 2013
    2013 Parallel solution-phase synthesis of an adenosine antibiotic analog library 2013
    2012 Design, synthesis and activity of thio-linked arabinofuranosyl disaccharides against mycobacterial tuberculosis (MTB) and Mycobacterium avium complex (MAC) 2012
    2012 Silibinin inhibits Wnt/β-catenin signaling by suppressing Wnt co-receptor LRP6 expression in human prostate and breast cancer cells 2012
    2012 Synthesis and SAR of geminal substitutions at the C5′ carbosugar position of pyrimidine-derived HCV inhibitors 2012
    2012 Synthesis and SAR of pyridothiazole substituted pyrimidine derived HCV replication inhibitors 2012
    2012 Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors 2012
    2012 5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors 2012
    2012 Identification of novel Mt-Guab2 inhibitor series active against M. tuberculosis 2012
    2012 Novel substituted pyrimidines as HCV replication (replicase) inhibitors 2012
    2012 High throughput screening of a library based on kinase inhibitor scaffolds against Mycobacterium tuberculosis H37Rv 2012
    2011 Novel pyridopyrazine and pyrimidothiazine derivatives as FtsZ inhibitors 2011
    2011 Identification of novel diphenyl urea inhibitors of Mt-GuaB2 active against Mycobacterium tuberculosis 2011
    2010 NSAIDs: Old drugs reveal new anticancer targets 2010
    2010 A novel sulindac derivative lacking cyclooxygenase-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model 2010
    2009 Sulindac sulfide selectively inhibits growth and induces apoptosis of human breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP, and activation of protein kinase G 2009
    2009 Antituberculosis activity of the molecular libraries screening center network library 2009
    2009 High-throughput screening for inhibitors of Mycobacterium tuberculosis H37Rv 2009
    2009 A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity 2009
    2009 Mycolic acid methyltransferase, MmaA4, is necessary for thiacetazone susceptibility in Mycobacterium tuberculosis 2009
    2009 Synthesis of deoxygenated α(1 → 5)-linked arabinofuranose disaccharides as substrates and inhibitors of arabinosyltransferases of Mycobacterium tuberculosis 2009
    2008 Synthesis of 4-deoxy-4-thioarabinofuranosyl disaccharides, analogs of Mycobacterial arabinogalactan 2008
    2008 Expression, purification and characterisation of soluble GlfT and the identification of a novel galactofuranosyltransferase Rv3782 involved in priming GlfT-mediated galactan polymerisation in Mycobacterium tuberculosis 2008
    2008 EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR 2008
    2008 Binding mode analysis of 2, 4-diamino-5-methyl-5-deaza-6-substituted pteridines with mycobacterium tuberculosis and human dihydrofolate reductases 2008
    2007 Thiacetazone, an antitubercular drug that inhibits cyclopropanation of cell wall mycolic acids in mycobacteria 2007
    2007 Disaccharide analogs as probes for glycosyltransferases in Mycobacterium tuberculosis 2007
    2007 Synthesis of symmetrical C- and pseudo-symmetrical O-linked disaccharide analogs for arabinosyltransferase inhibitory activity in Mycobacterium tuberculosis 2007
    2007 Novel boron-containing, nonclassical antifolates: Synthesis and preliminary biological and structural evaluation 2007
    2007 Programs to facilitate tuberculosis drug discovery: The tuberculosis antimicrobial acquisition and coordinating facility 2007
    2007 EthA, a common activator of thiocarbamide-containing drugs acting on different mycobacterial targets 2007
    2006 Symmetrical and unsymmetrical analogues of isoxyl; active agents against Mycobacterium tuberculosis 2006
    2006 New antifolate inhibitors for Mycobacterium avium 2006
    2006 Novel conjugate of moxifloxacin and carboxymethylated glucan with enhanced activity against Mycobacterium tuberculosis 2006
    2006 Mycobacterium tuberculosis cells growing in macrophages are filamentous and deficient in FtsZ rings 2006
    2005 New Mycobactenum avium antifolate shows synergistic effect when used in combination with dihydropteroate synthase inhibitors 2005
    2005 Erratum: Degradation of Quillaja saponaria Molina saponins: Loss of the protective effects of a herpes simplex virus 1 subunit vaccine (International Immunopharmacology (2002) 2:12 (1703-1711) DOI: 10.1016/S1567-5769(02)00192-3) 2005
    2005 Synthesis of novel 5-aryl-2-thio-1,3,4-oxadiazoles and the study of their structure-anti-mycobacterial activities 2005
    2005 Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models 2005
    2004 Synthesis and preliminary in vitro evaluation of antimycobacterial activity of new pyrrolo[1,2-a] quinoxaline-carboxylic acid hydrazide derivatives 2004
    2004 Structure of Mycobacterium tuberculosis FtsZ reveals unexpected, G protein-like conformational switches 2004
    2004 SRI-286, a thiosemicarbazole, in combination with mefloquine and moxifloxacin for treatment of murine Mycobacterium avium complex disease 2004
    2004 The use of microarray analysis to determine the gene expression profiles of Mycobacterium tuberculosis in response to anti-bacterial compounds 2004
    2004 A new 2-carbamoyl pteridine that inhibits mycobacterial FtsZ 2004
    2004 Synthesis of mannopyranose disaccharides as photoaffinity probes for mannosyltransferases in Mycobacterium tuberculosis 2004
    2004 Antimycobacterial Agents. 1. Thio Analogues of Purine 2004
    2003 Arabinofuranose disaccharide analogs as inhibitors of Mycobacterium tuberculosis 2003
    2003 Thiosemicarbazole (thiacetazone-like) compound with activity against Mycobacterium avium in mice 2003
    2003 Fractionation, structural studies, and immunological characterization of the semi-synthetic Quillaja saponins derivative GPI-0100 2003
    2002 Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives 2002
    2002 Synthesis of an arabinofuranosyl disaccharide photoaffinity probe for arabinosyltransferase activity in Mycobacterium tuberculosis 2002
    2002 2-Alkoxycarbonylaminopyridines: Inhibitors of Mycobacterium tuberculosis FtsZ 2002
    2002 Studies on n-octyl-5-(α-D-arabinofuranosyl)-β-D-galactofuranosides for mycobacterial glycosyltransferase activity 2002
    2002 Degradation of Quillaja saponaria Molina saponins: Loss of the protective effects of a herpes simplex virus 1 subunit vaccine 2002
    2002 Synthesis and biological evaluation of trehalose analogs as potential inhibitors of mycobacterial cell wall biosynthesis 2002
    2001 A facile method for deprotection of trityl ethers using column chromatography 2001
    2001 Synthesis and antifolate evaluation of the aminopterin analogue with a bicyclo[2.2.2]octane ring in place of the benzene ring 2001
    2001 Altered immunomodulating and toxicological properties of degraded Quillaja saponaria Molina saponins 2001
    2001 Synthesis of a fluorescent arabinofuranosyl disaccharide: A probe for arabinosyltransferase activity in Mycobacterium tuberculosis 2001
    2001 Studies on (β,1→5) and (β,1→6) linked octyl Galf disaccharides as substrates for mycobacterial galactosyltransferase activity 2001
    2001 Studies on α(1→5) linked octyl arabinofuranosyl disaccharides for mycobacterial arabinosyl transferase activity 2001
    2000 Synthesis of disaccharides related to the mycobacterial arabinogalactan 2000
    2000 Synthesis and evaluation of several new (2-chloroethyl)nitrosocarbamates as potential anticancer agents 2000
    2000 Development of semisynthetic triterpenoid saponin derivatives with immune stimulating activity 2000
    2000 Slow polymerization of Mycobacterium tuberculosis FtsZ 2000
    2000 Antimycobacterial activities of 2,4-diamino-5-deazapteridine derivatives and effects on mycobacterial dihydrofolate reductase 2000
    2000 Structure/function relationships of immunostimulating saponins 2000
    1999 Studies on β-D-Gal(f)-(1→4)-α-L-Rha(p) octyl analogues as substrates for mycobacterial galactosyl transferase activity 1999
    1999 Ethambutol-sugar hybrids as potential inhibitors of mycobacterial cell-wall biosynthesis 1999
    1998 In vitro activities of several diaminomethylpyridopyrimidines against Mycobacterium avium complex 1998
    1998 Susceptibilities of Mycobacterium tuberculosis and Mycobacterium avium complex to lipophilic deazapteridine derivatives, inhibitors of dihydrofolate reductase 1998
    1998 Tin(IV) chloride mediated glycosylation in arabinofuranose, galactofuranose and rhamnopyranose 1998
    1998 Homologated aza analogs of arabinose as antimycobacterial agents 1998
    1996 Structure-activity relationships of quinolone agents against Mycobacteria: Effect of structural modifications at the 8 position 1996
    1996 Development of drug targeting based on recombinant expression of the chicken avidin gene 1996
    1996 Glycosyltransferases as targets for inhibition of cell wall synthesis in M. tuberculosis and M. avium 1996
    1993 Conformational studies of thymidine dimers containing sulfonate and sulfonamide linkages by NMR spectroscopy 1993
    1992 5,5-Disubstituted Hydantoins: Syntheses and Anti-HIV Activity 1992
    1992 Nucleoside Sultones: Synthons for the Preparation of Novel Nucleotide Analogsues. 1. Synthesis and Ring-Opening Reactions 1992
    1992 Synthesis of Thymidine Dimers Containing Internucleoside Sulfonate and Sulfonamide Linkages 1992
    1991 2,4-Dichloro-5-(1-o-carboranylmethyl)-6-methylpyrimidine: A Potential Synthon for 5-(1-o-Carboranylmethyl)pyrimidines 1991
    1991 Progress toward the synthesis of nonionic oligonucleotide analogues with sulfonate and sulfonamide internucleotide linkages. 1991

    Research Overview

  • I have broad research interests from pure organic synthesis and the generation of novel, biologically relevant chemical diversity to medicinal chemistry and drug design targeting cancer and underserved diseases such as tuberculosis.

    Currently, my programs primarily involve drug design against single and essential targets in Mycobacterium tuberculosis including the asparyl-t-RNA synthetase (AspS), filamenting temperature sensitive protein Z (FtsZ), D-alanyl-D-alanine ligase (Ddl) and the highly related cell wall ligases MurC-F (crucial enzymes in cell wall biosynthesis), and shikimate kinase (MtSK).

    Many of these proteins are ATP dependent, highlighting my recent focus on analyzing and understanding the complete mycobacterial ATP binding proteome (ATPome) as an ideal and essential set of proteins for new drug development against tuberculosis. These proteins are essential for a variety of crucial cellular processes from environmental sensing and metabolic adaptation (the Pkn serine-threonine protein kinases) to energetic and catalytic pathways (topoisomerases, gyrases and cell wall attendant ligases such as Ddl and MurC-F). Furthermore, this area is timely with the rich datasets and protein structures available relating to the human kinome, allowing comparative inhibitor and crystal structure analyses in order to develop selective agents that target the bacterial proteins only.

    Finally, and relating to my early interests and roots in anticancer drug discovery, I have begun a collaboration with Dr. Zaneta Nikolovska-Coleska, the University of Michigan, investigating the epigenetic target Disruptor-of-Telomeric-Silencing-1-Like (DOT1L) protein. This early stage program has identified novel drug–like non-nucleosides that may represent significant potential for development of new drugs targeting this crucial histone methyltransferase in mixed lineage leukemias (MLL). Optimized small molecules may have advantages over the current, first-in-class clinical agent Pinometostat that demonstrates typical issues of nucleoside-based drugs (poor bioavailability and significant hepatic metabolism and clearance).

    Keywords - Organic and Medicinal Chemistry, Rational Drug Design, Infectious Diseases and Cancer

    • Full Name

  • Robert Reynolds