Design and Synthesis of Specific Inhibitors of the 3′-Processing Step of Hiv-1 Integrase

Abstract

The novel dinucleotide 5'-phosphate, [(L,D)-pIsodApdC], discovered in our laboratory, is a strong inhibitor of HIV-1 integrase for both the 3'-processing and the strand transfer steps. The rationale used in this molecular design was that residues immediately upstream of the dinucleotide cleavage site in the 3'-processing step might provide critical recognition/binding sites on integrase. The rationale for the second type of inhibitors was based on the elimination products (linear and cyclic dinucleotides) of 3'-processing. However, while the linear dinucleotide 5'-phosphate (pdGpdT) was active, its cyclic counterpart was inactive against both wild-type and mutant HIV integrase.

Exploring the Conformational and Biological Versatility of β‐Turn‐Modified Gramicidin S by Using Sugar Amino Acid Homologues that Vary in Ring Size

“…[20] Cyclic sulphate 19 was treated with sodium azide and subsequently with acid to give compound 20. [21] Intermediate 20 was hydrolyzed to provide carboxylic acid 21. Finally a benzyl group was introduced at the C-4 hydroxyl functionality to give 2,6-cis-pyranoid SAA 22 (20 % overall yield by starting from 16 b, Scheme 3).…”

“…NMR spectroscopy: 1 H and 13 C NMR spectra for all intermediates (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) were recorded on a Bruker AV-400 (400/100 MHz). The spectra of the peptides (GS4-6) were recorded on a Bruker DMX 600 equipped with a pulsed field gradient accessory and a cryo-probe.…”

(3′-5′)-Cyclic Dinucleotides: Synthetic Strategies and Biological Potential

“…1-(Mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT, 65 ) (6 equiv) is another efficient condensing agent. It was successfully used to prepare c-di-TMP ( 1 ) and c-pdGpT ( 103 ) from compounds 101 and 104 , respectively (Scheme ). , Simultaneous deprotection of the O 4 -position of thymine residues and phosphotriester groups of 102 was achieved using N 1 , N 1 , N 3 , N 3 -tetramethylguanidinium-2-nitrobenzaldoximate ( 74 ) (Scheme ) . Deprotection of 105 necessitated two reagents: aldoximate 45 to deprotect the phosphotriester groups and NH 4 OH for guanine deprotection (Scheme ) …”

“…C-pdGpT ( 103 ) is an elimination product of the 3′-end processing of HIV-1 integrase in vitro. , Therefore, it was evaluated as specific inhibitor of the 3′-processing step of both wild-type and mutant HIV-1 integrase. It was found inactive …”

“…Almost similarly, coupling 150 to 151 in the presence of MSNT ( 65 ) in pyridine afforded 152 that could be deprotected by successive use of Et 3 N in pyridine and then CHCl 2 COOH to provide 104 ( Scheme ) …”