Over the last several decades, many highly promising drug candidates have failed to successfully navigate the complex human physiology during clinical trials. Drug candidates that do succeed in clinical trials have a higher proportion of chiral centers and sp3 carbons than those that don?t succeed. Unfortunately, the current limited selection of efficient synthetic chemistry tools fosters the generation of flat aromatic and sp2 carbon structures; a large proportion of drug candidates advanced into the clinic reflect that fact. Phenanthridinone and carbazole are two examples of flat aromatic structures that are commonly found in bioactive molecules and drug candidates. In fact, the phenanthridinone core is found in 3,200 bioactive compounds according to PubChem, while carbazole has been found in an astonishing 258,000. Clearly these structures interact with many biological macromolecules. It is likely that their structural profile contributes to their significant and indiscriminate bioactivity. However, their extensive bioactivity creates problems in complex human physiology where successful drug candidates are groomed for selective interactions to reduce side effects and toxicity. The current proposal presents a new synthetic chemistry tool that will allow the generation of phenanthridinone and carbazole analogs with chiral centers and sp3 carbons. Creating an efficient and enantioselective tool for this purpose will allow researchers to generate analogs that will hopefully retain the bioactivity of phenanthridinone and carbazole, but be more selective and potent in interactions with biological targets for therapeutic purposes. The new synthetic chemistry tool involves a short sequence of reactions to rapidly generate fused tricyclic ring systems with a chiral quaternary or tertiary center. The process involves desymmetrizing cyclohexadiene structures generated in the versatile Birch reduction-alkylation reaction. The use of palladium catalysts with chiral ligands in a desymmetrizing Mizoroki-Heck reaction will afford enantioselective control in the key step. The versatility of the Mizoroki-Heck reaction will allow the creation of a broad range of structures, including medium-size and heterocyclic rings. In the process, the substrate scope of the enantioselective intramolecular Mirzoroki-Heck reaction will be expanded. The phenanthridinone and carbazole analogs generated through this work will be screened with our biological collaborators at Lankenau Institute of Medical Research for anti-cancer activity. As an R15 proposal, one additional important benefit will be the science education experiences created for students at Bryn Mawr College. Both Bryn Mawr and the PI have a substantial record of accomplishment in training scientists and physicians. An award will allow these critical activities to continue.

Public Health Relevance

Vast amounts of chemical space are unexplored due to limitations in synthetic chemistry tools. The current chemical space for new drugs is heavily populated with flat aromatic structures that have a higher propensity for failure in clinical drug trials. The proposed project will create new synthetic tools to expeditiously construct complex structural motifs commonly found in successful therapeutic molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM123475-01A1
Application #
9516374
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Bond, Michelle Rueffer
Project Start
2018-05-01
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2021-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Bryn Mawr College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
067398420
City
Bryn Mawr
State
PA
Country
United States
Zip Code
19010