SYNTHESIS OF JUGLANALOIDS AND ANALOGUES USING PHASE-TRANSFER CATALYZED GREEN PROCESSES AND EVALUATION OF THEIR PHARMACOLOGICAL ACTIVITY

ALZHEIMER’S DISEASE (AD) IS STILL A MAJOR AND GROWING HEALTH ISSUE. THE ONSET OF THIS PATHOLOGY INVOLVES COMPLEX BIOLOGICAL PROCESSES. THE ACCUMULATION OF AMYLOID-Β (AΒ) PLAQUES IN THE BRAIN IS ONE OF THE KEY EVENTS OF AD PATHWAY, STIMULATING THE SEARCH FOR NEW SMALL MOLECULES TARGETING THESE PROTEINS EFFECTIVELY. TWO RECENTLY DISCOVERED ALKALOID ENANTIOMER PAIRS, JUGLANALOIDS A AND B, FROM THE BARK OF JUGLANS MANDSHURICA MAXIM, ARE OF PARTICULAR INTEREST DUE TO THEIR UNIQUE STRUCTURES AND POTENT INHIBITORY ACTIVITIES AGAINST AMYLOID-Β AGGREGATION. HOWEVER, THEIR LIMITED AVAILABILITY IN NATURE AND LACK OF STRUCTURE-ACTIVITY RELATIONSHIP (SAR) STUDIES HAVE SLOWED FURTHER PROGRESS. THIS DOCTORAL WORK FOCUSED ON ADDRESSING THOSE LIMITATIONS BY PROVIDING AN EFFICIENT SYNTHETIC ACCESS TO THESE COMPOUNDS USING A GREEN AND EFFECTIVE APPROACH AS WELL AS EXPLORING THEIR WIDE BIOLOGICAL POTENTIAL. A CONVERGENT ENANTIOSELECTIVE ROUTE TO JUGLANALOIDS A AND B WAS DEVELOPED IN WHICH ASYMMETRIC PHASE-TRANSFER CATALYSIS (APTC) PLAYED THE ROLE OF KEY STEREOCONTROLLING STEP. THIS METHODOLOGY WAS SELECTED DUE TO ITS MILD REACTION CONDITIONS, OPERATIONAL SIMPLICITY, AND EXCELLENT STEREOCONTROL. IT ENABLED THE SUCCESSFUL Γ-ALKYLATION OF PHTHALIDE ESTERS WITH SUBSTITUTED BROMOMETHYL BENZALDEHYDES BY UTILISING CHIRAL QUATERNARY AMMONIUM COMPOUNDS AS CATALYSTS (MAROUKA CATALYSTS). SUBSEQUENT CYCLIZATION AND REDUCTIVE AMINATION FURNISHED JUGLANALOIDS A AND B IN ENANTIOMERICALLY ENRICHED FORM AFTER A CONCISE EIGHT-STEP SEQUENCE. INSPIRED BY THEIR BIOLOGICAL POTENTIAL, COMPUTATIONAL STUDIES OF THE JUGLANALOIDS SCAFFOLDS WERE PERFORMED WITHIN THE GROUP OF PROF. GIUSEPPE BIFULCO IN DEPARTMENT OF PHARMACY AT UNIVERSITY OF SALERNO, ITALY. HENCE, GUIDED BY THE PREVIOUSLY REPORTED INHIBITION OF AΒ1-42 AGGREGATION, A VIRTUAL LIBRARY OF JUGLANALOID ANALOGUES WAS DEVELOPED. MOLECULAR DOCKING STUDIES HELPED TO PREDICT HOW THE MOLECULES INTERACT WITH AΒ AND GUIDED THE DESIGN OF MORE POTENT DERIVATIVES. A FURTHER INTERESTING FINDING WAS REVEALED BY PROF. BIFULCO’S GROUP UPON CONDUCTING BIOLOGICAL STUDIES ON JUGLANALOIDS, WHICH SHOWED THE INHIBITION OF 5-LIPOXYGENASE (5-LO), AN ENZYME INVOLVED IN INFLAMMATION AND ASSOCIATED TO ASTHMA, CANCER, AND NEURODEGENERATION DISEASES. THIS DUAL ACTION, TARGETING BOTH AMYLOID AGGREGATION AND INFLAMMATION, MAKES THESE MOLECULES ESPECIALLY VALUABLE. DUE TO THIS NEWLY ASCERTAINED POTENTIAL A SECOND VIRTUAL LIBRARY WAS DESIGNED FOR JUGLANALOID DERIVATIVES AS ANTI-5-LO AGENTS. SYNTHETIC EFFORTS FOR THESE DERIVATIVES WERE INITIATED AND DESCRIBED IN THE FINAL PART OF THIS THESIS. OVERALL, THIS WORK PROVIDES AN ASYMMETRIC, EFFICIENT AND NOVEL SYNTHETIC ROUTE TO JUGLANALOID A AND B. THE USE OF SYNTHETIC GREEN APPROACH AND COMPUTATIONAL MODELLING GAVE INSIGHTS INTO THE POTENTIAL OF JUGLANALOIDS IN THE TREATMENT OF ALZHEIMER’S DISEASE AS WELL AS IN INFLAMMATORY CONDITION, BUT IT ALSO PAVED THE WAY FOR THE CONSTRUCTION OF THE LIBRARIES OF DERIVATIVES SERVING AS MULTIFUNCTIONAL THERAPEUTIC LEAD IN THE FUTURE.