DESIGN AND EVALUATION OF 5′-O-DICARBOXYLIC AND POLYARGININE FATTY ACYL DERIVATIVES OF ANTI-HIV NUCLEOSIDES

摘要: 2′,3′-Dideoxynucleoside (ddNs) analogs are the most widely used anti-HIV drugs in market. Even though these display very potent activities, they have a number of limitations when as therapeutic agents. The primary problem associated with ddNs is significant toxicity, such neuropathy and bone marrow suppression. Due to their hydrophilic nature, poor cellular uptake. Some nucleoside develop resistance over period time. Furthermore, themselves not pharmacologically active, undergo three-step phosphorylation order become active. Of steps, first step usually slow rate-limiting process. Herein, we report synthesis evaluation 2′,3′-dideoxynucleoside conjugates fatty acids varying chain length acyl poly-L-arginine derivatives. hypothesis this project was that conjugating nucleosides or derivatives will generate multifunctional agents enhanced activity uptake, less drug development compared parent alone. compounds also longer duration action through sustained intracellular release nucleosides. acid could higher uptake into cells because lipophilicity. This dissertation be revealed two manuscripts. In Manuscript, activities 5′-O-dicarboxylic monoester 3'-azido-3'-deoxythymidine (zidovudine, AZT), 2',3'-didehydro-2',3'-dideoxythymidine (stavudine, d4T), 3'-fluoro-3'deoxythymidine (alovudine, FLT) discussed. were synthesized improve lipophilicity potentially delivery polar 2′,3′dideoxynucleoside (ddN) analogs. Three different suberic (octanedioic acid), sebacic (decanedioic dodecanedioic for conjugation Among all compounds, 5′-O-suberate derivative AZT (1, EC50 = 0.10 nM) exhibited best profile other compound showed 80-fold than without any toxicity (TC50  500 nM). work published Tetrahedron Letters (2014, http://dx.doi.org/10.1016/j.tetlet.2014.02.001). second synthesis, activity, preformulation tests cell-penetrating peptides (CPPs) conjugated nucleosides, FLT, lamivudine (3TC) emtricitabine (FTC) All analogues. For example, poly-L-arginine-fatty 3fluoro-3-deoxythymidine, FLT-CO-(CH2)12-CO-(Arg)7, values 2.9 μM 3.1 against X4 R5 cell-free virus, respectively, while FLT had 0.2 0.1 μM, suggesting limited hydrolysis analogue. Further studies done on FLT-conjugate by determining lipid solubility (partition coefficient) solution state degradation. found stable acidic alkaline conditions. partition coefficient (Log P) conjugate -0.34. evaluated dissolution using four hydrogels thermogelling polymer. Gel formulations manufactured non-ionic (HPC-SL) anionic (Carbopol) polymers inclusion thermo-reversible gelling (Pluronic F-127) unstable shown HPLC profiles. has been submitted peer-reviewed journal. summary, provided more insights designing new generation poly-arginine CPPs. Overall, established strategy Manuscript I. data indicated addition positively-charged beneficial generating demonstrated II, possibly presence positively charged viral glycoprotein gp120. optimization CPP-fatty acid-nucleoside required improved optimized stability formulation performance.