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DESIGN AND SYNTHESIS OF POTENT HIV-1 PROTEASE INHIBITORS AND ENANTIOSELECTIVE SYNTHESIS OF ANTIDIABETIC AGENT, CARAMBOLAFLAVONE

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posted on 2024-05-17, 12:22 authored by William L. RobinsonWilliam L. Robinson
HIV-1 protease inhibitor drugs are important components of current antiretroviral therapy (cART). The cART treatment regimens dramatically improved life expectancy and mortality of patients with HIV-1 infection and AIDS. However, new and improved protease inhibitor drugs are essential for future treatment options. To this end, syntheses of optically active (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-ol, (3aR,4R,7aS)-hexahydro-4H-furo[2,3-b]pyran-4-ol, and (3R,3aS,6aR)-hexahydrofuro[2,3-6]furan-3-ol have been accomplished. These stereochemically defined heterocyclic derivatives are important high-affinity P2 ligands for a variety of highly potent HIV-1 protease inhibitors. The key steps for the synthesis hexehydrofuropyranol involve an efficient Paternò-Büchi [2+2] photocycloaddition, catalytic hydrogenation, acid-catalyzed cyclization to form the racemic ligand alcohol, and enzymatic resolution with immobilized Amano Lipase PS-30. Optically active ligand alcohols were obtained with high enantiomeric purity. Enantiomer (-)-ligand alcohol has been converted to potent HIV-1 protease inhibitors.

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol(bis-tetrahydrofuran) is a key subunit of darunavir, an FDA approved HIV-1 protease inhibitor drug which is widely used for the treatment of HIV/AIDS patients. This stereochemically defined bicyclic heterocycle is also embedded in a variety of highly potent HIV-1 protease inhibitors. The synthesis of optically active bis-tetrahydrofuran was achieved in optically pure form utilizing commercially available and inexpensive 1,2-O-isopropylidene-α-D-xylofuranose or 1,2-O-isopropylidene-α-D-glucofuranose as the starting material. The key steps involve a highly stereoselective substrate-controlled hydrogenation of ethyl 2-(dihydrofuran-3(2H)-ylidene)acetate, a Lewis acid-catalyzed anomeric reduction of a 1,2-O-isopropylidene-protected glycofuranoside, and a Baeyer-Villiger oxidation of a tetrahydrofuranyl-2-aldehyde derivative. Optically active (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol ligand was converted to darunavir efficiently. Furthermore, both furopyranol and bis-tetrahydrofuran ligand alcohols have been converted into a variety of potent HIV-1 protease inhibitors including inhibitors containing P2'-boronic acid ligands.

Diabetes mellitus is a chronic, progressive metabolic disorder that seriously threatens human health worldwide, particularly in developing countries. The prevalence of diabetes has been increasing steadily, especially in developing countries. Carambolaflavone A is a natural flavonoid isolated from the leaves of starfruit tree, Averrhoacarambola, in 2005. Carambolaflavone A possesses a C-aryl glycosidic linkage. Carambolaflavone A exhibited significant antihyperglycemic properties. More detailed biological studies reveal that it can lower acute blood glucose. The biology and chemistry of carambolaflavone A attracted our interest in synthesis and further design of interesting structural variants. A convergent total synthesis of carambolaflavone A has been accomplished. The synthesis highlights a bismuth triflate-catalyzed stereoselective C-aryl glycosylation of flavan and an appropriately protected D-fucose derivative as the key step. The glycosylation partners were synthesized from commercially available (±)-naringenin and D-(+)-galactose, respectively. An oxidative bromination and elimination reaction sequence was utilized to construct the flavone. The natural product is obtained in 10 steps (longest linear sequence) from D-(+)-galactose.

Funding

National Institutes of Health

History

Degree Type

  • Doctor of Philosophy

Department

  • Chemistry

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Arun K. Ghosh

Additional Committee Member 2

Christopher Uyeda

Additional Committee Member 3

Elizabeth Parkinson

Additional Committee Member 4

Kavita Shah