Prodrugs of Nucleoside Triphosphates as a Sound and Challenging Approach: A Pioneering Work That Opens a New Era in the Direct Intracellular Delivery of Nucleoside Triphosphates

Abstract

Synthetic nucleosides, designed to mimic naturally occurring nucleosides, are important antiviral and anticancer chemotherapeutic agents. However, nucleosides are not active as such and need to be metabolized, step by step, to their corresponding active nucleoside triphosphates (NTPs). This is mediated by phosphorylating enzymes, mainly host cellular kinases with strong specificity for their substrates; in many cases, this specificity prevents efficient conversion into the NTPs. To circumvent this metabolic handicap, successful nucleo(s/t)ide prodrugs have been developed as a valuable concept in the design of effective drugs. The unique concept of the TriPPPro approach, developed by Chris Meier and colleagues, is a powerful tool for the intracellular delivery of active NTPs, bypassing all the phosphorylation steps required by nucleosides to yield the active NTP metabolites. This concept is illustrated herein with general examples.

Prodrugs of γ‐Alkyl‐Modified Nucleoside Triphosphates: Improved Inhibition of HIV Reverse Transcriptase

“…This is in accordance to our previous results for the DiPPro- [17,18] or the Tr i PPPro-compounds 5. [22,23] In all cases we observed the predominant formation of g-alkyl-d4TTPs 7 and d4TDP 2d in very low concentration (Figure 2B)b ut no NTP formation was detected, in contrast to the studies using the previously described Tr i PPPro compounds 5. [23,24] However,t he difference to the compounds bearing long lipophilic acyl groups was not very pronounced (2-to 3-fold).…”

“…In contrast to previous studies with Tr i PPPro-NTPs 5 containing as econd cleavable mask (first generation NTP prodrugs), [23][24][25] no d4TTP was detected in these studies using 6 or 7.Aside reaction occurred during the studies using compounds 7 that led to the formation of thymine by the cleavage of the glycosidic bond as reported before. [19,22] As shown in Figure SI1 in the Supporting information, this is the main reason for the decrease of 7z in PBS hydrolysis and the calculated half-life of 7z is about 1500 h.…”

“…[21] However, we recently reported the first chemical delivery system for NTPs through aprodrug technology (TriPPPro approach 5;S cheme 1). [22][23][24][25] We proved for d4T 1 and other nucleoside analogues that the corresponding Tr i PPPro compounds even retained pronounced anti-HIV activity in thymidine-kinase-deficient T-Scheme 1. Metabolism of nucleoside analoguessuch as d4T 1 and the corresponding nucleotide prodrugs thereof.…”

Prodrugs of γ‐Alkyl‐Modified Nucleoside Triphosphates: Improved Inhibition of HIV Reverse Transcriptase

“…Forschungsartikel compounds 7 that led to the formation of thymine by the cleavage of the glycosidic bond as reported before. [19,22] As shown in Figure SI1 in the Supporting information, this is the main reason for the decrease of 7z in PBS hydrolysis and the calculated half-life of 7z is about 1500 h.…”

“…[21] However,w er ecently reported the first chemical delivery system for NTPs through ap rodrug technology (TriPPPro approach 5;Scheme 1). [22][23][24][25] We proved for d4T 1 and other nucleoside analogues that the corresponding Tr i PPPro compounds even retained pronounced anti-HIV activity in thymidine-kinase-deficientT -cell cultures (CEM/ Scheme 1. Metabolism of nucleoside analoguessuch as d4T 1 and the corresponding nucleotide prodrugs thereof.…”