Abstract
The Human Immunodeficiency Virus (HIV-1) has reached pandemic levels, with an estimated 36.9 million people infected worldwide. Over time, HIV infection progresses to AIDS, which compromises the immune system and ultimately results in death. While there is currently no cure for HIV, there are treatments that delay the onset of AIDS. One such treatment is highly active antiretroviral therapy (HAART), that uses a combination of inhibitors to delay the progression of HIV to AIDS. These drugs are effective, but their utility is diminished by toxic side effects and viral resistance. To overcome these problems, it is essential to develop new HIV inhibitors. Most of the drugs created are designed to attack the virus once the host cell has already been infected. A promising area of research has focused on developing potent anti-HIV drugs that can inhibit HIV entry before the host cell is compromised. Research has shown that polyanionic glycodendrimers, sugar-based polymers, are useful in applications as therapeutic agents. Glycodendrimers are being investigated for their potential as viral inhibitors, where interactions with a virus may inhibit viral adhesion to the host cell and prevent infection. The current study involved the determination of the most effective and optimum route to synthesize anti-viral glycodendrimers. To efficiently create glycodendrimers, it is important to construct them in high yielding, chemoselective reactions. An attractive methodology is through the covalent coupling of reducing carbohydrates with aminooxy nucleophiles to form oximes. Oxime linkages have been shown to be stable against hydrolysis. Moreover, oxime coupling can be performed with microwave-assistance in reduced reaction times and good yields. By these means, dendritic cores modified with aminooxy-terminated linkers can be conjugated with reducing sugars by microwave irradiation to create robust oxime-linked glycodendrimers in good yields. The first step for glycodendrimer synthesis involved creating aminooxy-functionalized dendrimers. The dendrimer core, poly(amidoamine) (PAMAM) generation 0, was amide coupled both traditionally and by microwave irradiation with short and long carboxy-terminated aminooxy linkers to create tetravalent branched cores. The coupling agents BOP, PyBOP, TBTU, EDCI/HOBt, and DCC/HOBt were used to compare yields and determine the best reagent for amide coupling. The best two-step yields using EDCI/HOBt were 94.0% and 71.0% for both the short and long tetravalent dendrimers, respectively. PAMAM generation 1 was next amide coupled by microwave irradiation using EDCI/HOBt with the short and long carboxy-terminated linkers to create octavalent branched cores in 65.3% and 77.9% two-step yields, respectively. Next, these modified dendritic cores were oxime coupled with the sugar maltotriose using microwave-assistance, creating novel glycodendrimers in a 98.4% and 70.9% yield for the short and long tetravalent dendrimers. Full substitution, however, was not achieved for the octavalent dendrimers. The short octavalent dendrimer was half-glycosylated in a 64.0% yield and the long octavalent dendrimer was hexa-glycosylated in an 83.5% yield. The study showed that glycodendrimers could be synthesized rapidly and in good yields. These oxime-linked glycodendrimers will ultimately be evaluated for their potential as viral inhibitors.