## 3 Anti-HIV Pronucleotides-Nucleotide Reverse-Transcriptase Inhibitors (NttTIs)  
The antiviral activity of anti-HIV pronucleotides is based on the presence in its structure of 2\({}^{\prime}\),3\({}^{\prime}\)-dideoxynucleosides (ddNs), which, due to the lack of the 3\({}^{\prime}\)-OH function in the dideoxynucleoside moiety, terminates the process of reverse transcription after the incorporation of a nucleotide analog into the growing viral DNA chain. This inhibits the synthesis of viral DNA and prevents virus replication (Scheme 16) [93]. Modified nucleosides are usually not biologically active as such, and must be phosphorylated in the cell to the appropriate 5\({}^{\prime}\)-triphosphate in order to exert a therapeutic effect [4].  
The efficacy of 2\({}^{\prime}\),3\({}^{\prime}\)-dideoxynucleosides in antiretroviral therapy is significantly hampered by their limited bioavailability and complex metabolic pathways [4]. In order to increase the therapeutic effect of ddNs, their administration in a phosphorylated form (i.e., as nucleotides) seemed to be a solution to bypass the first, often chimeric, phase of the phosphorylation cascade. Unfortunately, under physiological conditions nucleoside phosphates are ionized, which prevents their permeation through charged cell membranes. Moreover, biological membranes are rich in phosphatases, which rapidly hydrolyze the P-O-C ester linkages, leading to the reconstitution of the parent nucleosides. This would jeopardize the whole concept of improving the pharmacokinetics of a potential drug in this way [6; 94; 95; 96].  
Due to these limitations, the idea of pronucleotides was born, according to which antiviral nucleotides should be administered in a form able to cross the cell membranes. Once  
Figure 3: Homodinucleotides obtained by [PERSON] et al. via pyridinium phosphobetaine intermediates.  
inside the cell, the therapeutic nucleotide would be released through the use of chemical or enzymatic processes. Pronucleotides are thus prodrugs, which are not biologically active per se, but after chemical and/or enzymatic transformations, can generate a precursor of biologically active compound, the corresponding ddNMP (Scheme 1). Initially, the pronucleotide approach assumed the delivery of suitably masked 2\({}^{\prime}\),3\({}^{\prime}\)-dideoxynucleoside monophosphates, and over two decades, many monophosphate pronucleotide strategies were proposed and experimentally verified. In contrast, the concept of using protected nucleoside di- or triphosphates as possible prodrugs has long been of much less interest. This was mainly due to the fact that fully protected di- and triphosphates are unstable in the aqueous environment due to their high susceptibility to the hydrolysis of the uncharged P-O-P anhydride bond that basically excluded their use as therapeutic agents [97]. Only recently, it has emerged that partially protected pronucleotides are also apparently capable of entering the cell, as evidenced by their high antiviral activity. This opened a possibility of also exploring compounds with a di- or triphosphate skeleton as potential pronucleotides.  
The second part of this review will be focused on dedicated synthetic strategies that have been developed to prepare nucleoside di- and triphosphates useful in anti-HIV therapy as prodrugs (pronucleotide analogs of di- and triphosphates), along with the biological evaluation of the synthesized compounds.