Synthesis of Nucleoside Selenophosphoramidates via H-Phosphonate Intermediates.

Two synthetic routes for the preparation of nucleoside selenophosphoramidates have been developed by using H-phosphonate derivatives as key substrates. The first method is a one-pot synthesis, which involves the condensation of an amine with H-phosphonate monoesters, mediated by a coupling agent, followed by oxidation with elemental selenium (). The second approach makes use of the oxidative condensation reaction of H-phosphonoselenoate monoesters with amines promoted by iodine as an oxidizing agent ().

A new approach to phosphorylation of nucleosides using oxyonium phosphobetaines as intermediates.

Oxyonium phosphobetaines are recently discovered molecules with a unique O-P-O-N bond system, which makes them useful and versatile intermediates for the synthesis of phosphates and their derivatives. In this paper, the preliminary data on the application of these compounds in nucleoside phosphorylation were presented.

Azomethine Ylides-Versatile Synthons for Pyrrolidinyl-Heterocyclic Compounds.

Azomethine ylides are nitrogen-based three-atom components commonly used in [3+2]-cycloaddition reactions with various unsaturated 2π-electron components. These reactions are highly regio- and stereoselective and have attracted the attention of organic chemists with respect to the construction of diverse heterocycles potentially bearing four new contiguous stereogenic centers. This review article complies the most important [3+2]-cycloaddition reactions of azomethine ylides with various olefinic, unsaturated 2π-electron components (acyclic, alicyclic, heterocyclic, and exocyclic ones) reported over the past two decades.

H-Phosphonate Chemistry in the Synthesis of Electrically Neutral and Charged Antiviral and Anticancer Pronucleotides.

In this review a short account of our work on the synthesis and biological activity of electrically neutral and charged anti-HIV and anticancer pronucleotides, presented on the background of the contemporary research in this area, is given.

Reaction of Boranephosphonate Diesters with Pyridines or Tertiary Amines in the Presence of Iodine: Synthetic and Mechanistic Studies.

Boranephosphonate diesters react with heteroaromatic and certain tertiary amines in the presence of an oxidant (I) to afford the boron-modified phosphodiester analogues containing a P-B-N structural motif. Our multinuclear P and B NMR spectroscopy studies lend support for a two-step mechanism involving generation of a λ-boranephosphonate intermediate that immediately coordinates an amine in the solvent cage, leading to -pyridinium or -ammonium boranephosphonate betaine derivatives. We found that the type of the solvent used (e.

Aryl H-phosphonates. 19. New anti-HIV pronucleotide phosphoramidate diesters containing amino- and hydroxypyridine auxiliaries.

We have designed a new type of AZT and ddU phosphoramidate diesters containing various combinations of 2-, 3-, 4-aminopyridine and 2-, 3-, 4-hydroxypyridine moieties attached to the phosphorus center, as potential anti-HIV pronucleotides. Depending on the pK values of the aminopyridines and the hydroxypyridines used, alternative synthetic strategies based on H-phosphonate chemistry were developed for their preparation. Synthetic aspects of these transformations and the biological activity of the synthesized compounds are discussed.

Reaction of Boranephosphonate Diesters with Amines in the Presence of Iodine: The Case for the Intermediacy of H-Phosphonate Derivatives.

Mechanistic and stereochemical aspects of the reaction of boranephosphonate diesters with amines promoted by iodine were investigated. This is a complex, multistep reaction that ultimately produces the corresponding phosphoramidate diesters via a formal replacement of the borane group by an amine moiety. We found by a stereochemical correlation analysis that, contrary to a literature report, the whole transformation proceeded with total inversion of the configuration at the phosphorus center.

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).

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.

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).

Aryl H-Phosphonates 18. Synthesis, properties, and biological activity of 2',3'-dideoxynucleoside (N-heteroaryl)phosphoramidates of increased lipophilicity.

Recently, AZT (N-pyridyl)phosphoramidates were reported as a new type of potential anti-HIV therapeutics. In continuation of that work, here we present new (N-heteroaryl)phosphoramidate derivatives of antiviral 2',3'-dideoxynucleosides containing other types of N-heteroaryl moieties, particularly those with higher lipophilicity. The present studies comprise mechanistic investigations using (31)P NMR correlation analysis, which permitted improvements in the synthetic procedures.

Novel reactivity of Fhit proteins: catalysts for fluorolysis of nucleoside 5'-phosphoramidates and nucleoside 5'-phosphosulfates to generate nucleoside 5'-phosphorofluoridates.

Fragile histidine triad (HIT) proteins (Fhits) occur in all eukaryotes but their function is largely unknown. Human Fhit is presumed to function as a tumour suppressor. Previously, we demonstrated that Fhits catalyse hydrolysis of not only dinucleoside triphosphates but also natural adenosine 5'-phosphoramidate (NH2-pA) and adenosine 5'-phosphosulfate (SO4-pA) as well as synthetic adenosine 5'-phosphorofluoridate (F-pA).

The case of triethylammonium cation loss during purification of certain nucleotide analogues: a cautionary note.

Nucleotides, their analogues, and other phosphate esters and phosphoramidates often contain the triethylammonium cation as a counterion. We found that this may be lost during chromatographic purification or concentration of solutions, yielding products in acidic forms or containing sub-stoichiometric amounts of the counterion. This in turn may be detrimental, e.

Recent advances in H-phosphonate chemistry. Part 2. Synthesis of C-phosphonate derivatives.

This chapter provides an overview of recent advances in the development of new methods and protocols for the formation of the P-C bond using H-phosphonate diesters as starting materials. Various chemical and stereochemical aspects of the transition metal-catalyzed cross-coupling and organocatalyst-promoted reactions which are relevant to the synthesis of structurally diverse C-phosphonate derivatives are surveyed.

Recent advances in H-phosphonate chemistry. Part 1. H-phosphonate esters: synthesis and basic reactions.

This review covers recent progress in the preparation of H-phosphonate mono- and diesters, basic studies on mechanistic and stereochemical aspects of this class of phosphorus compounds, and their fundamental chemistry in terms of transformation of P-H bonds into P-heteroatom bonds. Selected recent applications of H-phosphonate derivatives in basic organic phosphorus chemistry and in the synthesis of biologically important phosphorus compounds are also discussed.

Design, synthesis and QSAR studies of dispiroindole derivatives as new antiproliferative agents.

A variety of 4'-aryl-3-(arylmethylidene)-1″-[(cyclic-amino)methylene]-1'-methyl-dispiro[cyclohexane-1,3'-pyrrolidine-2',3″-[3H]indole]-2,2″(1″H)-diones 4a-u were prepared via reaction of 2E,6E-bis(arylidene)-1-cyclohexanones 1a-i with azomethine ylides, generated in situ via a decarboxylative condensation of isatins 2a-c and sarcosine (3). Single crystal X-ray study of 4a, revealed structural and stereochemical features of these derivatives. While most of the synthesized compounds exhibit mild antitumor properties when tested against various human tumor cell lines (HEPG2 "liver", HELA "cervical" and PC3 "prostate" cancers), three of them, 4d and 4p (active against HEPG2), and compound 4g (active against HELA), demonstrated higher activities, that were close or even higher than that of the reference standard Doxorubicin.

Nucleoside 3',5'-cyclic H-phosphonates, new useful precursors for the synthesis of nucleoside 3',5'-cyclic phosphates and their analogues.

Nucleoside H-phosphonates activated with a condensing agent spontaneously formed nucleoside 3',5'-cyclic H-phosphonates. The cyclization was stereoselective and produced one of the P-diastereomers in preponderance (de ca. 80%).

Computational study of the mechanism and selectivity of palladium-catalyzed propargylic substitution with phosphorus nucleophiles.

The mechanism and sources of selectivity in the palladium-catalyzed propargylic substitution reaction that involves phosphorus nucleophiles, and which yields predominantly allenylphosphonates and related compounds, have been studied computationally by means of density functional theory. Full free-energy profiles are computed for both H-phosphonate and H-phosphonothioate substrates. The calculations show that the special behavior of H-phosphonates among other heteroatom nucleophiles is indeed reflected in higher energy barriers for the attack on the central carbon atom of the allenyl/propargyl ligand relative to the ligand-exchange pathway, which leads to the experimentally observed products.

Synthesis and QSAR study of novel cytotoxic spiro[3H-indole-3,2'(1'H)-pyrrolo[3,4-c]pyrrole]-2,3',5'(1H,2'aH,4'H)-triones.

1,3-Dipolar cycloaddition reaction of 1-aryl-1H-pyrrole-2,5-diones 1a-e with non-stabilized azomethine ylides, generated in situ via decarboxylative condensation of isatins 2a-c and sarcosine (3) in refluxing ethanol, afforded 4'-aryl-5'a,6'-dihydro-1'-methyl-spiro[3H-indole-3,2'(1'H)-pyrrolo[3,4-c]pyrrole]-2,3',5'(1H,2'aH,4'H)-triones 4a-o in good yields. Compound 4l exhibited high anti-tumor activity against HEPG2 (liver cancer) cell line (IC(50) = 12.16 μM) compared to that of Doxorubicin (IC(50) = 7.

31P NMR and computational studies on stereochemistry of conversion of phosphoramidate diesters into the corresponding phosphotriesters.

31P NMR spectroscopy was used to investigate a stereochemical course of a nitrite-promoted conversion of phosphoramidate diesters into the corresponding phosphotriesters. It was found that this reaction occurred with almost complete epimerization at the phosphorus center and at the C1 atom in the amine moiety. On the basis of the 31P NMR data, a plausible mechanism for the reaction was proposed.

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.

Palladium-catalyzed propargylic substitution with phosphorus nucleophiles: efficient, stereoselective synthesis of allenylphosphonates and related compounds.

A new, efficient method is developed, based on a palladium(0)-catalyzed reaction of propargylic derivatives with various phosphorus nucleophiles, to produce allenylphosphonates and their analogues with defined stereochemistry in the allenic and the phosphonate moiety.

Stereochemistry of internucleotide bond formation by the H-phosphonate method. 5. The role of Brønsted and H-bonding base catalysis in ribonucleoside H-phosphonate condensation-chemical and stereochemical consequences.

Efficiency and stereoselectivity of condensations of ribonucleoside 3'-H-phosphonates with ethanol promoted by pivaloyl chloride were investigated as a function of tertiary amines used. Side reactions leading to an increased demand for the condensing agent were identified as derived from an attack of the pivalate anion at carbonyl centers of reactive pivaloyl derivatives. The conditions that secured quantitative yields of H-phosphonate diester condensations were assessed.

O-Silylated C3-halohydrins as a novel class of protected building blocks for total, regio- and stereocontrolled synthesis of glycerolipid frameworks.

We propose O-silylated C3-halohydrins [1(3)-O-silyl-2-O-acyl-, 1,2(2,3)-O-bis(silyl)-, and 1(3)-O-acyl-2-O-silyl-3(1)-halo-sn-glycerides] as new chirons in the total synthesis of glycerolipid constructs. These are efficiently producible via opening of the oxirane ring of the corresponding glycidyl derivatives and permit (i) displacement of the iodine by a requisite carboxylate in the presence of O-triisopropylsilyl (O-TIPS), O-tert-butyldimethylsilyl (O-TBDMS), and O-acyl substituents; (ii) selective acylation across an appropriate silyloxy system [e.g.