Thesis

Synthesis of polar tertiary amine dendrimers terminated with glucosamine

This Thesis examines the synthesis of polar, tertiary amine dendrimers terminated with glucosamine. These glycodendrimers, once sulfated, could inhibit the binding of the HIV envelope glycoprotein, gp120, to host cells. Studies have shown that gp120 specifically binds to a variety of receptors, allowing HIV to infect a multitude of cell types. Upon further investigation, researchers have determined that gp120 uses sugar moieties on sphingolipids and sulfated polyanionic proteins as host cell receptors. Studies of analogs to these known gp120 receptors have shown that sulfated polyanionic sugars bind with a stronger affinity to gp120 than the host cell receptors themselves. Research has also shown that the infection process for HIV is multivalent in nature, which means multiple copies of gp120 bind to multiple copies of receptors simultaneously in order to gain access into the host cell. However, to mimic this process, multiple receptor analogs need to be clustered together on a scaffold. Dendrimers are hyper-branched, three dimensional, globular macromolecules. They are comprised of three parts: 1) a core, 2) repeating units attached in a radial manner to the core, and 3) terminal functional groups attached to the outer surface. These macromolecules are synthesized either from the core out to the terminal groups, known as divergent synthesis, or from the terminal groups inward toward the core, known as convergent synthesis. Due to the variability in synthesis, dendrimers can be any size and have any physical properties desired. Therefore, in this application, dendrimers allow gp120 receptor analogs to be positioned in a manner similar to what is found naturally on the surface of host cells. This work will show the successful synthesis of two core molecules [TEAm-(G1)3, TEAm-G1-(DAP)3], a glucosamine-terminated linker (G-AE-PA), as well as two glucosamine-terminated dendrimers [TEAm-G1-(GlcN)3, TEAm-G1-(G-AE-PA)3]. TEAm-(G1)3 was synthesized with a 99.6% yield, using a Michael-like addition and a trifluoroacetic acid (TFA) deprotection. TEAm-G1-(DAP)3 was synthesized in a similar manner, using two addition methods- methyl ester formation and amidation-resulting in a 29.3% yield of product. G-AE-PA was synthesized with a 14.2% yield, using benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexaflurophosphate (BOP)-mediated amide coupling followed by a TFA deprotection. Both dendrimers, TEAm-G1-(GlcN)3 and TEAm-G1-(G-AE-PA)3 were synthesized with a 32.8% and 61.4% yield, respectively. This was accomplished using a combination of three steps: Michael-like addition, TFA deprotection and BOP-mediated amide-coupling. The successful synthesis and future sulfation of these dendrimers could lead to the creation of viable drugs which have the ability to inhibit the binding of gp120 onto host cells, thereby inhibiting infection by HIV.

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