Bis-cycloSal-d4T-monophosphates:  Drugs That Deliver Two Molecules of Bioactive Nucleotides

Abstract

Bis-cycloSal-d4T-monophosphates have been synthesized as potentially anti-HIV active "dimeric" prodrugs of 2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (d4TMP). These pronucleotides display a mask-drug ratio of 1:2, a novelty in the field of pronucleotides. Both bis-cycloSal-d4TMP 6 and bis-5-methyl-cycloSal-d4TMP 7 showed increased hydrolytic stability as compared to their "monomeric" counterparts and a completely selective hydrolytic release of d4TMP. The hydrolysis pathway was investigated via 31P NMR spectroscopy. Moreover, due to the steric bulkiness, compound 6 already displayed strongly reduced inhibitor potency toward human butyrylcholinesterase (BChE), while compound 7 turned out to be devoid of any inhibitory activity against BChE. Partial separation of the diastereomeric mixture of 6 revealed strong dependence of the pronucleotides' properties on the stereochemistry at the phosphorus centers. Both 6 and 7 showed good activity against HIV-1 and HIV-2 in wild-type CEM cells in vitro. These compounds were significantly more potent than the parent nucleoside d4T 1 in HIV-2-infected TK-deficient CEM cells, indicating an efficient TK-bypass.

Studies on Enzyme-Cleavable Dialkoxymethyl-cycloSaligenyl-2′,3′-dideoxy-2′,3′-didehydrothymidine Monophosphates

“…6-Bromo-4-tert-butylsalicyl alcohol (11b) was synthesized starting from 4-tert-butylphenol (12). Ortho-formylation of 12 was carried out almost as described in the literature.…”

L-Dopa Prodrugs: An Overview of Trends for Improving Parkinsons Disease Treatment

“…The synthesis of dimeric derivatives has become a common strategy for the production of prodrugs, in which two identical molecules are linked together through a spacer and after administration are metabolized into their two identical active components [52][53][54][55][56]. The first LD dimer was synthesized by Felix et al in order to enhance the LD BBB permeability.…”

Prodrug approaches to improving the oral absorption of antiviral nucleotide analogues

“…However, antiviral data was not reported for this compound and the fact that bulky substituents at that position increase the formation of the undesired diester (Figure 4B(26)) was not addressed. The best results (50-fold reduction in BChE inhibition) were observed when a bis- cyclo Sal moiety (Figure 4A(20)) was used [89]. …”

“…Recently, the development of bis- cyclo Sal pronucleotides was reported (Figure 4A(20)) [89]. These pronucleotides deliver two molecules of active drug for each biomolecule that is delivered.…”

“…Rather, the pronucleotides were hydrolyzed exclusively to the NMP [89]. These pronucleotides exhibited reduced BChE inhibition [88,89] and maintained antiviral activity comparable to that of the nucleoside in wild-type CEM cells while displaying significantly enhanced antiviral activity in kinase-deficient cells [89]. The pronucleotides displayed considerably higher cytotoxicity than the nucleoside.…”