Timothy L. Macdonald
Bioorganic and Synthetic Organic Chemistry
The unifying theme of my research program is the application of organic chemical theory and technique to the investigation of problems in biology. Our longstanding interest has been in elucidating the molecular interactions and mechanisms of small molecule-protein interactions. Such interactions are fundamental to physiology, pharmacology, and toxicology and understanding these processes in molecular terms is essential for predicting modes of metabolism and developing new drugs. Our efforts are currently directed at several rather broad areas: elucidation of the molecular pharmacology of ligand-receptor interactions; identification of the molecular processes underlying idiosyncratic drug reactions; determination of the chemical mechanisms of the oxidative transformation of foreign and endogenous compounds by monooxygenase and dioxygenase enzymes; and characterization of the molecular mechanisms underlying the neurotoxicity of small molecules, metal ions, and reactive oxygen species.
Current studies of ligand-receptor interactions include the lysophospholipid signaling system, the colchicinoid site on tubulin, and the ternary drug-DNA-topoisomerase II complex responsible for the cytotoxicity of this class of anticancer agents. Lipid phosphoric acid mediators, such as lysophosphatidic acid and sphingosine-1-phosphate, have a range of biological properties mediated through at least eight G-protein coupled receptors of the EDG family. The cellular biology of these receptors and the physiological mechanisms controlling the processing of the lysophospholipids is beginning to emerge. We are undertaking a set of investigations directed at elucidating the molecular pharmacology of this receptor family and at utilizing this knowledge to target the modulation of lysophospholipid signaling to treat human disease. Specifically, our studies of the lysophospholipid autocoids have been directed at identifying the molecular determinants of the lipid mediator and the receptor that have been proposed to be critical to activity and at developing receptor selective agents for the EDG receptors.
We also have a long-standing interest in understanding ligand-receptor interactions which form ternary DNA-drug complexes with a DNA processing enzyme, and a small molecular ligand. Such complexes are a common theme for a diverse variety of “effectors” of cellular function, including hormone regulators of cellular transcription and translation, and of many antineoplastic agents. We have been examining the interaction of the representative antitumor agent, etoposide, which forms a ternary DNA-drug complexes with DNA topoisomerase I. Another area of research involves elucidation of the molecular mechanism through which colchicine interacts with its target, tubulin. These programs have fully integrated synthetic studies of rationally designed molecules and mechanistic studies of the processes through which these agents interact with their targets. Our studies will advance the knowledge of antitumor drug development for these classes of agents and culminate in the design and synthesis of fundamentally new structural classes of inhibitors of these critical anticancer targets.
An additional area of research is the molecular and cellular mechanisms by which idiosyncratic drug reactions occur. These reactions are the source of a range of toxic reactions to therapeutic agents and are thought to be mediated through the confluence of risk factors associated with drug bioactivation to reactive species, the formation of specific protein antigens and subsequent immune response. A knowledge of the chemical and immunological basis for idiosyncratic reactions would enable a protocol for prospectively identifying individual patient risk or susceptibility to particular agents or drug classes. We have previously investigated the mechanism of blepharoconjunctivitis and dermatitis associated with the use of the antiglaucoma drug, apraclonidine. Our current focus is on the mechanism underlying the aplastic anemia associated with the use of the anti-epileptic agent, felbamate.
Our research is additionally exploring the mechanistic and etiologic relationships between neurotoxicity and aberrant CNS processing of foreign and endogenous agents. The brain is the site of multiple, chronically progressive and clinically devastating diseases in which specific neuronal populations undergo neurodegeneration. An environmental contribution has been implicated in the etiology of many of these diseases, including Parkinson’s disease, motoneuron disease, and Alzheimer’s disease. In one avenue of study, we are examining the potential for the formation of endogenous or exogenous toxins by oxidative enzymes that have been localized to particular neuronal populations, such as the cytochromes P450 and their associated reductases. Through these studies, we hope to ascertain whether this enzyme class represents a primary basis for the etiology or treatment of these neurodegenerative diseases.
A model for the regulation of T-type Ca(2+) channels in proliferation: roles in stem cells and cancer. Gray LS, Schiff D, Macdonald TL. Expert Rev Anticancer Ther. 13:589-95 (2013).
Cost-effective and Large-scale synthesis of 16:0 Lysophosphatidic Acid. East JE, Macdonald TL. Synth Commun. 42:3614-3618 (2012).
Amixicile, a novel inhibitor of pyruvate: ferredoxin oxidoreductase, shows efficacy against Clostridium difficile in a mouse infection model. Warren CA, van Opstal E, Ballard TE, Kennedy A, Wang X, Riggins M, Olekhnovich I, Warthan M, Kolling GL, Guerrant RL, Macdonald TL, Hoffman PS. Antimicrob Agents Chemother. 56:4103-11 (2012).
Development of a phosphatase-resistant, L-tyrosine derived LPA1/LPA3 dual antagonist. East JE, Carter KM, Kennedy PC, Schulte NA, Toews ML, Lynch KR, Macdonald TL. Medchemcomm. 2:325-330 (2011).
Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate. Kharel Y, Mathews TP, Gellett AM, Tomsig JL, Kennedy PC, Moyer ML, Macdonald TL, Lynch KR. Biochem J. 440:345-53 (2011).