Aryl nucleoside H-phosphonates. Part 16: synthesis and anti-HIV-1 activity of di-aryl nucleoside phosphotriesters.

Di-aryl nucleoside phosphotriesters have been explored as a new type of pronucleotides for the purpose of anti-HIV-1 therapy and efficient synthetic protocols, based on H-phosphonate chemistry, have been developed for the preparation of this class of compounds. It was found that anti-HIV-1 activity of the phosphotriesters bearing an antiviral nucleoside moiety (AZT, ddA) and also ddU was due, at least partially, to intracellular conversion into the corresponding nucleoside 5'-monophosphates, and their efficiency correlated well with the pK(a) values of the aryloxy groups present.

Synthesis and biological assay of new 2'-deoxyuridine dimers containing a 1,2,3-triazole linker. Part I.

We describe a simple method for the synthesis of modified dinucleosides containing pyrimidine nucleoside analogues (2'-deoxyuridine, thymidine and 5-fluoro-2'-deoxyuridine). Six different dimers with a 1,2,3-triazole linkage were obtained by azide-alkyne 1,3-dipolar cycloaddition (click reaction), starting from propargylated 2'-deoxyuridine and 5'-azido-nucleoside derivatives. Their cytotoxic activity was tested in five human cancer cell lines: cervical (HeLa), high grade gliomas (U-118 MG, U-87 MG, T98G), liver (HepG2), and normal human fibroblast cell line (MRC-5) using the sulforhodamine B (SRB) assay. The experiment showed that the obtained dimers with a 1,2,3-triazole moiety were very stable compounds, also in the physiological-like media, and had no anticancer activity.

New antiglioma zwitterionic pronucleotides with an FdUMP framework.

We have designed and synthesized new 5-fluoro-2'-deoxyuridine 5'-phosphate pronucleotides which can function as potential agents against the glioblastoma multiforme tumor. Their anti-malignant potency has been tested against T98G, U-118 MG, U-87 MG gliomas, HeLa, and Caco-2 cancer cell lines, using MRC-5 healthy cells as a reference. Five of the sixteen compounds (4c, 4f-i) exhibited significant anticancer potency and high selectivity indices (SI 12-66). It is likely that these zwitterionic pronucleotides may function in a similar manner to zwitterionic phospholipids, by inducing cell membrane charge disorder, making the cell permeable to bioactive agents. The most promising therapeutic pronucleotides 4c, 4f-h, have high intestinal-blood uptake potency (Caco-2 cell line), and may be considered as potential, orally administrated, anticancer drugs.

New 3'-O-aromatic acyl-5-fluoro-2'-deoxyuridine derivatives as potential anticancer agents.

New aromatic and aliphatic 3'-O-acyl-5-fluoro-2'-deoxyuridine derivatives were synthesized and evaluated as candidates for prodrugs against various cancer cell lines. As the most promising candidate for antimalignant therapeutics was found a dual-acting acyl derivative 7h, which apparently released not only the known anticancer nucleoside, 5-fluoro-2'-deoxyuridine (FdU), but also an additional active metabolite, acetylsalicylic acid, reinforcing thus therapeutic effect of FdU. Promising therapeutic indices showed also some aromatic dicarboxylic acids derivatives decorated with FdU esters (11 and 12).

Searching for anti-glioma activity. Ribonucleoside analogues with modifications in nucleobase and sugar moieties.

Several ribonucleoside analogues with modifications in the nucleobase and sugar moiety have been screened for anti-glioma activity in the T98G glioma cell line using cervical (HeLa) cell line as reference human malignant cells, and lung fibroblast (MCR-5) cell line as non-cancerous reference cells. Among the investigated compounds, ribonucleosides containing 6-chloropurine (3), 7-guanine (5) and a pyrrolopyrimidine (18) as nucleobases, show promising anti-glioma activity with good selectivity indices, and can be considered as lead structures for further anti-cancer studies.

Aryl H-phosphonates 17: (N-aryl)phosphoramidates of pyrimidine nucleoside analogues and their synthesis, selected properties, and anti-HIV activity.

New synthetic protocol for the preparation of nucleoside 5'-(N-aryl)phosphoramidate monoesters 4 was developed. It consisted of a condensation of the corresponding nucleoside 5'-H-phosphonates with aromatic- or heteroaromatic amines promoted by diphenyl phosphorochloridate, followed by oxidation of the produced H-phosphonamidates with iodine/water. 5'-(N-Aryl)phosphoramidate monoesters derived from 3'-azido-3'-deoxythymidine (AZT) or 2',3'-dideoxyuridine (ddU) nucleosides and various aromatic and heteroaromatic amines were evaluated as potential anti-HIV drugs. It was found that these compounds act most likely as pronucleotides and that some of them have therapeutic indices superior to those of the reference AZT.