Abstract
The Human Immunodeficiency Virus (HIV) has caused a worldwide epidemic. Currently, an estimated 36.9 million people are infected with HIV. The current treatment for HIV is antiretroviral therapy (ART). Around 20.9 million people living with HIV have access to ART therapy. Right now, only 57% of the people infected are currently using ART. As of now, ART can only slow the progression of the virus but doesn’t cure the disease. Additionally, ART can have toxic side effects or become ineffective over time through viral resistance. This is why finding a way to prevent new HIV infections is very important. A promising new class of anti-HIV molecules are dendrimers. All dendrimers have common characteristics: A core, linkers that increase the number of ends, and terminal functional groups where the chemistry can occur. For glycodendrimers, the functional groups can include amino, carboxyl or aminooxy moieties. In our research, the dendrimers terminate in aminooxy groups, which can then react chemoselectively with sugars to yield oxime-linked glycodendrimers. As dendrimers and glycodendrimers have globular structures with multiple ends, they can exhibit the multivalent effect. Multivalency refers to the simultaneous interactions of multiple binding sites on one entity to multiple receptor sites on another. With this unique ability, sulfated glycodendrimers have been shown to bind to HIV virions and block fusion, and therefore the infection, of host cells. Our research is focused on the synthesis of multivalent glycodendrimers as HIV entry inhibitors. In the present study, three diverse pathways were used to synthesize three hexavalent and one octavalent core. After completing each of the pathways, cellobiose or the dimer of colominic acid was used to create the desired terminated glycodendrimers. The purpose of the first pathway was to create a flexible hexavalent core. This pathway began by synthesizing the linkers for the hexavalent core. The reaction involved the addition of an aminooxy group on one end of the diols, either diethylene glycol (DEG) or 1,3-propandiol. Next, a methanesulfonyl group was added to the remaining OH to complete the linker synthesis. The second step in the process was to create a trivalent core to accept the linkers. Unfortunately, the linker would not react with the core so none of the desired product was obtained. The next pathway explored increasing the valency of the core by using an octavalent dendrimer core. This second pathway began by synthesizing a new linker for the octavalent core. The first linker reaction involved the addition of an ether group to the linker. The second linker was synthesized to add the aminooxy group to the core. To make the tetravalent core, the mesylated linker was added to the core S under SN2 conditions. Next, a three-step process was used to obtain the desired amine-terminated octavalent core. Finally, the addition of the aminooxy linker was added under carbamate coupling. Unfortunately, it was not possible to achieve the desired octavalent aminooxy-terminated dendrimer core, so no glycodendrimers could be made by this route. This study entailed the determination of two failed and one effective route in synthesizing dendrimer cores. For the successful hexavalent dendrimer core, a longer linker was synthesized to add an ether group with a yield of 99.8%. Additionally, through the synthesis of this linker it was determined that purification methods of dialysis and FPLC were all that was needed to achieve the best yield and time for purification with 68.2%. Finally, for both the cellobiose and dimer of colominic acid glycodendrimers, the use of a smaller microwave cavity allowed for excellent yields of 77.8 and 79.2%, respectively. Further research needs to be conducted on this new core. The addition of more sugars, and further optimization of the yield of the hexavalent aminooxy terminated core is needed. Future research will be conducted to optimize the above steps, and finally to assess to the anti-HIV activity of the sulfated products.