Graduation Year

2019

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

James W. Leahy, Ph.D.

Committee Member

Edward Turos, Ph.D.

Committee Member

Bill Baker, Ph.D.

Committee Member

Les Shaw, Ph.D.

Keywords

cannabinoids, natural products, skin PAMPA, Total synthesis, transdermal delivery, transdermal patch

Abstract

Small molecule drug discovery relies heavily on synthetic organic chemistry to develop novel chemical entities that elicit desirable therapeutic effects. The development of targeted chemical syntheses is of paramount importance to access molecules for biological evaluation and is usually considered the bottleneck in most drug discovery campaigns. Targets for chemical syntheses commonly draw inspiration from molecules of natural origin. Nature harbors a wealth of chemical diversity that has established itself over millions of years through chemical and biological evolution. Organisms have an inherent ability to protect themselves from predators and harmful environments. In doing so, many of them evolve to produce chemical defenses in order to survive in their environments. Unfortunately, most bioactive natural products are not present in large abundance and require chemical syntheses for evaluation of their therapeutic potential.

Antibiotic resistance has become a major health concern that is creating a health and financial burden on society. There is an unmet need to develop new antibiotics to combat the ever-evolving microbes. Drug-resistant bacteria capable of adopting biofilm morphology become increasingly resistant to antibiotic treatment, threatening the life of the patient. A series of marine natural products (MNPs) have recently been identified to exhibit promising activity against methicillin resistant Stahphylococcus aureus (MRSA) biofilms. One of the most potent compounds in the series was the MNP membranolide. The intriguing biological properties of membranolide have led us to develop an enantioselective synthesis of the natural product and related analogs for further evaluation against MRSA biofilms (outlined in chapter 2).

Microbial infections are not limited to bacteria. Parasitic and amoebic pathogens can cause infections as well, with the latter being underrepresented in drug discovery. The lack of research and development in the area of amoebic infections may be partly due to the rarity of occurrence. However, some amoebic infections have extremely high mortality rates, such as those caused by Naegleria fowleri, presenting a dire need for new therapeutics. Phytocannabinoid natural products have been found to exhibit anti-proliferation activity against N. fowleri and represent a class of compounds that may aid in the efforts in combatting its infections. A novel chemical synthesis is disclosed in chapter 3 that gives rise to tetrahydrocannabinol (THC) and cannabidiol (CBD) and related analogs to further evaluate and understand their biological activity. Furthermore, these compounds could be effective treatments against a myriad of other clinical indications including but not limited to pain, inflammation, anxiety and even Alzheimer’s disease.

The cannabinoids are well-known for their unique biological and physiochemical properties; however, they lack ideal pharmacokinetic profiles to become successful therapeutics. Their poor absorption through traditional delivery routes can be addressed either by analog development or different drug delivery methods. The low oral bioavailability and high lipophilicity of the cannabinoids has prompted the development of a transdermal route for their delivery. Throughout chapter 4, a novel transdermal delivery system for the cannabinoids is discussed including the first use of a skin PAMPA assay to assist in the transdermal patch development for the cannabinoids.

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