Design and Synthesis of Guanidinoglycosides Directed against the TAR RNA of HIV‐1

Abstract

Replication of human immunodeficiency virus type 1 (HIV-1) requires specific interactions of the Tat protein with the transactivation responsive region (TAR) RNA. Tat-TAR RNA Interaction is mediated by a short arginine-rich domain of the protein. Disruption of this interaction could, in theory, create a state of complete viral latency. Here, four novel 6-amino-6-deoxytrehalose guanidinoglycoside derivatives (10 and 13 ± 15) as target molecules have been designed to bind to TAR RNA for blocking the interaction of Tat-TAR RNA. They were obtained by coupling 6-amino-6-deoxy-a,a-trehalose (6) with the protected amino acids, deprotection by catalytic hydrogenation, followed by guanidinylated with S-methylisothiourea sulfate. Their abilities to inhibit Tat-TAR RNA interaction were determined by a Tat-dependent HIV-1 long terminal repeats (LTR)-driven chloramphenicol acetyltransferase (CAT) assays.

Design and Synthesis of Visible-Light-Responsive Azobenzene Building Blocks for Chemical Biology

“…Besides the charged groups, such as sulfonates in compound 8 , water solubility can also be introduced by functionalization with carbohydrates. ,− One such molecule is α,α-trehalose, a diglucose present in many organisms such as invertebrates, bacteria, and plants. − Having access to acetylated 6-azido-trehalose (Scheme ), we decided to ligate it to the fluorinated azobenzene core. In short, azobenzene 3 was subjected to palladium-catalyzed cross-coupling with lithium TMS-acetylide to afford the desired product 14 .…”

“…To a solution of compound 5 (100 mg, 0.36 mmol) in dry DCM (20 mL, degassed via two freeze–pump–thaw cycles) was added (OAc) 7 -azidotrehalose 15 (synthesized according to ref ( 70 )) (260 mg, 40 mmol, 1.1 equiv), followed by the addition of Cu(MeCN) 4 PF 6 (134 mg, 0.36 mmol, 1 equiv). The reaction mixture was stirred overnight at rt.…”

Discoveries of Tat-TAR Interaction Inhibitors for HIV-1

“…Based on the above findings, Wang et al [74,75] designed and synthesized a series of guanioglycosides directed against HIV-1 TAR RNA. These α,α-Trehalose derivatives bearing guanidine groups shown in TAR RNA important for Tat binding involves a set of nucleotides surrounding a characteristic UCU nucleotide bulge required for HIV-1 replication via the specific Tat-TAR complex formation.…”

Improved Synthesis of 6-Azido-6-deoxy- and 6,6′-Diazido-dideoxy-α,α-trehaloses

“…3,4 Trehalosamines have been isolated from microorganisms and been synthesized and found to have antimicrobial activity, 5,6 and several groups of investigators have recently reported the syntheses of 6-amino-and 6,6′-diamino-α,α-trehalose. [7][8][9] In the present study, we describe a convenient synthesis of 6-azido-and 6,6′-diazido-α,α-trehalose compounds in which we have used the triflate derivatives of the partially trimethylsilylated-α,α-trehaloses, displacing the trifluoromethanesulfonate group by azide in the presence of a crown ether in N,N-dimethylformamide at room temperature.…”