Synthesis of Sulfonamides Towards Down-Modulation of CD4, gp160, and TSHR

The macrocyclic polyamine, cyclotriazadisulfonamide (CADA), is a small molecule that is known to inhibit the entry of human immunodeficiency virus (HIV). The mechanism of action involves the binding of CADA to the signal peptide (SP) of human CD4 (hCD4) inside the membrane of the endoplasmic reticulum (ER), blocking the translocation of the protein into the ER lumen, and ultimately preventing the transport of the mature protein to the cell membrane. Through an alanine scan experiment, it was determined that the glutamine at position 15, lysins at positions 26 and 27, and a proline at position 20 of hCD4 were important for CADA’s potency. The most potent CADA analogue synthesized was CK147 which contains a para-N,N-dimethylbenzenesulfonyl side arm that is believed to interact with glutamine 15 of the hCD4 through dipole-dipole interactions. This study has created CADA analogues that retain the para-N,N-dimethylbenzenesulfonyl side arm, while modifying the tosyl side arm of CK147 to better understand the interaction of CADA with CD4. The goal of this study is to create disulfonamides that target signal peptides to down-modulate the expression of CD4, gp160, and TSHR. Of the compounds tested for CD4 down-modulation, TL020 and TL029 were found to be the most potent CADA analogues with IC50 values of 0.053 ± 0.001 μM. Several gold containing compounds were proposed to be synthesized to target gp160 due to the presence of methionines found in the hydrophobic region of gp160’s SP. Compounds containing hydrogen bond donor, hydrogen bond acceptor, and guanidino side arms were proposed for activity towards TSHR since the SP of TSHR contains charged amino acids