Design, Synthesis, and Structure-Activity Relationship Investigation of 3’,4’-disubstituted Pyranochromone Derivatives With Diverse Biological Activities Public Deposited

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  • March 20, 2019
  • Zhou, Ting
    • Affiliation: Eshelman School of Pharmacy
  • The overall goals of this research are to design and synthesize novel 3',4'-disubstituted pyranochromone derivatives, to evaluate their anti-HIV activity and chemosensitizing potency, to elucidate structure-activity relationships (SAR), and to discover novel chemical entities. 3'R,4'R-Di-camphanoyl-khellactone analogs (DCKs) was first identified in our laboratory with high anti-HIV activity against wild-type HIV strain early in 1994. Using SAR-directed strategy, 3'R,4'R-di-camphanoyl-pyranochromone analogs (DCPs) were synthesized and evaluated in a continuing study, which showed high potency against both wild-type and multi-RT inhibitor-resistant strains. Mechanism study of DCK and its derivatives suggested that the compounds target HIV-RT in a unique way, by inhibiting its DNA-dependent DNA polymerase activity. A microwave-assisted one-pot reaction was first developed in our study and successfully applied in the preparation of 2',2'-dimethyl-chromone motifs which were key intermediates in DCK and DCP derivatives. The highly efficient microwave synthesis shrinked the reaction time over 12-fold with much higher yield than traditional heating system previously reported. Utilizing the optimized synthesis method, novel DCP analogs were designed and synthesized to further explore functionality requirements on the pyranochromone ring and to improve water solubility. SAR studies led us identified 5-alkyl-DCPs (98, 102) with increased efficacy against both wild-type and drug-resistant HIV strains. Simultaneously, novel DCPs (98, 115) also presented 5- and 10-time higher water-solubility than 2-EDCP (69). Furthermore, we explored the interaction between the planar ring and the binding pocket by constructing a tri-aryl-conjugated system, pyranoxanthones (DCXs). DCX and its analogs maintained and even increased the Π-Π stacking interaction with the residues inside the binding pocket. Several DCX analogs (131, 135, 144) increased anti-HIV potency against both virus strains and six analogs exhibited improved therapeutic index (TI) compared to the control 2-EDCP (69). Finally, we discovered that 3',4'-disubstituted pyranochomone (DSP) analogs showed strong potential to reverse multi-drug resistance (MDR) in cancer cell line. A SAR study were established and three DSP analogs (194, 197 and 204) fully resolved vincristine (VCR) resistance in KB-Vin cancer cells, which are over 2-fold more potent than verapamil, a prototype chemosensitizer. Preliminary mechanism study revealed that the chemosensitizing activity of DSP analogs results from the inhibition of cellular P-glycoprotein (P-gp) function.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Eshelman School of Pharmacy."
  • Lee, Kuo-Hsiung
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  • Chapel Hill, NC
  • Open access

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