Date of Award

Spring 5-15-2017

Degree Type

Dissertation

Degree Name

PhD. Chemistry

Department

Chemistry and Biochemistry

Advisor

Cecilia H. Marzabadi, Ph.D

Committee Member

James E. Hanson, Ph.D

Committee Member

Gerald J. Buonopane, Ph.D

Keywords

charbohydrates, CNS disorders, SAR study, organic synthesis, carbohydrate drugs

Abstract

Central nervous system (CNS) disorders are becoming a major societal problem. Examples of well-known CNS disorders are: neurodegenerative disorders such as Parkinson's, Huntington's and Alzheimer’s diseases, epilepsy/seizures, addiction, bipolar disorder, catalepsy, meningitis, migraines, attention deficit/hyperactivity disorder (ADHD), and multiple sclerosis. CNS disorders can be caused by various factors and therefore can affect ages, genders and races of all.

The population of patients with CNS disorders is increasing and a significant percentage of patients have symptoms that are not controlled by existing treatments. In addition, since CNS disorders are chronic disorder, there is no cure and thus the patients have to live with the condition with possibility of medications that can well control the symptoms. In contrary, the development of CNS-drugs is not adequately fast enough mainly due to the complexity of pathologies and the low success rate in regard to new drug approval by federal institutions such as Food and Drug Administration (FDA) of the US. Designing CNS-drugs is very challenging and one of the biggest challenges is to overcome the blood-brain barrier (BBB). Due to the BBB, the physiochemical property criteria for CNS-drugs are narrower and more specific than general therapeutic compounds (i.e. Lipinski’s rule of five), and hence the development of CNS-drugs experiences a major delay and low success rate.

Carbohydrates can be useful because of their multi-functionalizable structures and high biocompatibility; properties suitable for CNS-drugs. As carbohydrates are most abundant natural compounds, they are often readily available at low cost. In addition, regio- and stereospecific modification can modify a molecule for the best fit to a target receptor. Moreover, carbohydrates can manipulate glucose transporters to pass through the BBB. However, not many carbohydrate drugs are available due to synthetic complexity and difficulties of regio- and/or stereospecific reactions. Therefore, we are interested in utilizing carbohydrate compounds for treatments of CNS disorders. Hence, we have developed a novel carbohydrate template for CNS-drugs and a series of analogs were prepared to study structure activity relationship (SAR) of our carbohydrate analogs on CNS receptors.

Despite the synthetic challenges, we have successfully prepared a library of novel carbohydrate analogs. The physicochemical properties of all the analogs were calculated to show that our analogs theoretically have high bioavailability for oral administration. In addition, the said analogs were tested against over 50 CNS receptors and the in vitro testing of the said compounds has revealed that structural modifications significantly change the biological activities as well as target receptors. Furthermore, our active compounds showed high selectivity to a specific receptor, implying that we can potentially reduce side effects that are associated with undesired binding activities. Ultimately, our novel carbohydrates have shown a great potential for treatments of various CNS disorders, and it can be further investigated for development of new drugs for the treatments of CNS disorders.

Download

Share

COinS