Synthesis of phosphonate analogs of sphingomyelins and preparation of an affinity sorbent for sphingomyelinase purification

Phosphonate analogues of 2-N-stearoyl- (I) and 2-N-(undec-10-enoyl)-sphingomyelins (II) have been synthesised. Compound (II) was used as a starting product for preparation of a sorbent for sphingomyelinase affinity chromatography. The double bond of the unsaturated undec-10-enoyl moiety of the phosphonate analogue (II) was oxidized, and the modified (II) was coupled to amino-Toyopearl HW-65 to give a sorbent containing 4 mumoles of ligand per milliliter of the swollen resin.     

Synthesis and cytostatical evaluation of cytidine- and adenosine-5′-hexadecylphosphate and their phosphonate analogs

Four phospholipid conjugates containing the non-cytotoxic nucleosides cytidine and adenosine were prepared by condensation reactions, and their cytotoxic activity was tested in vitro against the human immortalized mammary epithelial cell H184 A₁N₄, the human mammary tumor cells MaTu and MCF7 and the B lymphoblast cell line Daudi. The synthesized compounds showed considerable activity towards H184 A₁N₄, MaTu and Daudi cells, but they were not effective against MCF7 cells. The phosphorus moiety—either monophosphate or monophosphonate—does not influence the effectiveness of the phospholipid derivatives in the case of the solid tumor cell lines and H184 A₁N₄. The leukemic Daudi cell line is strongly sensitive towards the different types of ester as well as to the type of the nucleoside component. Adenosine-5′-hexadecylphosphate proved to be the most potent compound among the substances prepared (IC₅₀: 9.0 μmol).     

alpha- and beta-substituted phosphonate analogs of LPA as autotaxin inhibitors

Autotaxin (ATX) is an attractive pharmacological target due to its lysophospholipase D activity which leads to the production of lysophosphatidic acid (LPA). Blockage of ATX produced LPA by small molecules could be a potential anticancer chemotherapy. In our previous study, we have identified the two beta-hydroxy phosphonate analogs of LPA (compounds f17 and f18) as ATX inhibitors. With this work, we investigated alpha- and beta-substituted phosphonate analogs of LPA and evaluated them for ATX inhibitory activity. The stereochemistry of beta-hydroxy phosphonates was also studied.     

Derivatives of phosphonate and vinyl phosphate analogs of D-ribose 5-phosphate

Propanal thiosemicarbazone (1a) showed activity in preventing anaphylactic shock in a mouse test-system; it also had some activity in stunting the growth of Botrytis allii. Hexanal thiosemicarbazone (1b) was active in the Botrytis allii test-system, and citral thiosemicarbazone (2) and citral guanylhydrazone nitrate (3) showed some activity in the same test-system. Heptanal guanylhydrazone nitrate (4) had some antibacterial activity against Staphylococcus aureus, and D-threo-pentosulose bis(thiosemicarbazone) (5) prevented anaphylactic shock in the mouse test-system. D-glycero-Tetrosulose bis(thiosemicarbazone) (6), D-lyxo-hexosulose bis-(guanylhydrazone) nitrate (7), D-galacto-heptosulose bis(thiosemicarbazone) (8), and D-galacto-heptosulose bis(guanylhydrazone) sulfate (9) showed some activity in stunting the growth of Botrytis allii. The copper chelate (10a) of D-arabino-hexosulose bis(thiosemicarbazone), and the copper (11a) and palladium (11b) chelates of 6-deoxy-L-arabino-hexosulose bis(thiosemicarbazone) showed antitumor activity in the KB cell-culture test-system. The palladium chelate 11b also showed some activity in the leukemia p-388 mouse test-system.     

Identification of novel nucleotide phosphonate analogs with potent anti-HCMV activity

We have recently described the discovery of new leads in the area of anti-HCMV research. Further structure - activity relationship studies have allowed us to identify potent and selective anti-HCMV nucleotide analogs. The synthesis as well as structure - activity relationship studies are described.     

Synthesis of lipid II phosphonate analogues

Simple analogues of lipid II were synthesized from 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-1-thio-β-d-glucopyranose using conjugate addition onto ethylidene bisphosphonate and subsequent Wadsworth–Horner–Emmons reaction with long chain aliphatic aldehydes.     

A new scheme for the synthesis of 5'-nucleotide phosphonate analogs

A convenient and general method is proposed for the synthesis of 5'-nucleotide phosphonate analogs starting from 5-deoxy-1,2-O-isopropylidene-alpha-D-xylo-hexofuranose.     

Phase transitions of alkyl ether analogs of phosphatidylcholine

The phase-transition temperatures of aqueous dispersions of diester, monoether and diether analogs of phosphatidylcholine were determinmed using transparinaric acid as a fluorescent probe. The diether analog of phosphatidylcholine has a higher phase-transition temperature, whilst the monoether analog has a lower phase-transition temperature than their diester counterpart.     

Synthesis and biological evaluation of phosphonate analogues of nevirapine

A series of nevirapine-based analogues containing the phosphonate functionality were prepared and evaluated in vitro against HIV RT. The effect of the phosphonate was evaluated against the wild type and Y181C HIV replication. An in vivo PK study was performed on a select analogue.     

Alkyl lysophosphatidic acid and fluoromethylene phosphonate analogs as metabolically-stabilized agonists for LPA receptors

We describe an efficient method for the synthesis of alkyl lysophosphatidic acid (LPA) analogs as well as alkyl LPA mono- and difluoromethylene phosphonate analogs. Each alkyl LPA analog was evaluated for subtype-specific LPA receptor agonist activity using a cell migration assay for LPA(1) activation in cancer cells and an intracellular calcium mobilization assay for LPA(2) and LPA(3) activation. Alkyl LPAs induced pronounced cell migration activity with equivalent or higher potency than sn-1-oleoyl LPA, while the alkyl LPA fluoromethylene phosphonates proved to be less potent agonists in this assay. However, each alkyl LPA analog activated Ca(2+) release by activation of LPA(2) and LPA(3) receptors. Interestingly, the absolute configuration of the sn-2 hydroxyl group of the alkyl LPA analogs was not recognized by any of the three LPA receptors. The use of alkyl LPA analogs further expands the scope of structure-activity studies, which will better define LPA-LPA receptor interactions.     

2-(Substituted phenyl)amino analogs of 1-methoxyspirobrassinol methyl ether: Synthesis and anticancer activity

New analogs of indole phytoalexin 1-methoxyspirobrassinol methyl ether have been designed by replacement of its 2-methoxy group with 2-(substituted phenyl)amino group. Synthesized by spirocyclization methodology, trans- and cis-diastereoisomers of target compounds were isolated and evaluated as potential anticancer and antimicrobial agents. Their molecular geometries were refined by ab initio minimizations. Pharmacophore modeling and QSAR studies were performed in order to correlate their molecular structure and biological activity.     

Synthesis and cytotoxicity of aurilide analogs

The artificial analogs of aurilide (1), a potent cytotoxic cyclodepsipeptide of marine origin, were synthesized, and the structure–activity relationships were investigated.     

Synthesis and properties of ApA analogues with shortened phosphonate internucleotide linkage

A complete series of the 2 '-5 ' and 3 '-5 ' regioisomeric types of r(ApA) and 2 '-d(ApA) analogues with the α-hydroxy-phosphonate C3 '-O-P-CH(OH)-C4 ″ internucleotide linkage, isopolar but non-isosteric with the phosphodiester one, were synthesized and their hybridization properties with polyU studied. Due to the chirality on the 5 '-carbon atom of the modified internucleotide linkage bearing phosphorus and hydroxy moieties, each regioisomeric type of ApA dimer is split into epimeric pairs. To examine the role of the 5 '-hydroxyl of the α-hydroxy-phosphonate moiety during hybridization, the appropriate r(ApA) analogues with 3 '(2 ')-O-P-CH(2)-C4 ″ linkage lacking the 5 '-hydroxyl were synthesized. Nuclear magnetic resonance (NMR) spectroscopy study on the conformation of the modified sugar-phosphate backbone, along with the hybridization measurements, revealed remarkable differences in the stability of complexes with polyU, depending on the 5 '-carbon atom configuration. Potential usefulness of the α-hydroxy-phosphonate linkage in modified oligoribonucleotides is discussed.     

Synthesis of allose-templated hydroxyornithine and hydroxyarginine analogs

Conformationally constrained amino acid analogs are widely used to probe the bioactive conformation of peptides. In this paper we report on the synthesis of hexafunctional allose-templated l- and d-hydroxyornithine and l- and d-hydroxyarginine analogs in which the allose-based polyol scaffold constrains the side chain of hydroxyornithine and hydroxyarginine in an extended conformation. The partially protected building blocks were selected for future use in solid-phase peptide synthesis using the Fmoc-strategy. The synthesis starts from a previously prepared C-glucosyl glycine analog. Multiple chemical protection-deprotection steps and an oxidation are used to prepare 3-keto-C-glucosyl analogs that serve as a precursor to install an amino function via reductive amination. Guanidinylation of the amino group provides access to allose-templated hydroxyarginine analogs. Both hexafunctional building blocks are further chemically modified to provide suitable protection for solid-phase peptide synthesis using the Fmoc-strategy.     

Synthesis and anti-angiogenic activity of cortistatin analogs

Analogs of cortistatins, a series of anti-angiogenic compounds isolated from the Indonesian marine sponge Cortisium simplex, were synthesized from estrone by using the Suzuki-Miyaura coupling reaction as the key step. The estrone-isoquinoline hybridized compound showed selective inhibitory activity against the proliferation and VEGF-induced migration of HUVEC.     

Synthesis and antitumor evaluation of benzoylphenylurea analogs

Novel series of benzoylphenylurea analogs 7-10 were prepared and evaluated for in vitro cytotoxic activity against a panel of eight different human cancer cell lines. A very interesting inhibition profile against BxPC3, Mia-Paca, and Hep2 cells with compound 10 has been observed. Compounds 8 and 9 showed the significant cytotoxicity in Hep2 cells. All cell lines were resistant to compound 7.     

Synthesis and bioevaluation of 22-hydroxyacuminatine analogs

A series of 22-hydroxyacuminatine analogs was prepared by using different Friedländer condensations. Several of the new compounds were tested for antiproliferative activity on cancer cell lines and for topoisomerase I inhibitory activity.     

Synthesis and antifungal activities of miltefosine analogs

Miltefosine is an alkylphosphocholine that shows broad-spectrum in vitro antifungal activities and limited in vivo efficacy in mouse models of cryptococcosis. To further explore the potential of this class of compounds for the treatment of systemic mycoses, nine analogs (3a?3i) were synthesized by modifying the choline structural moiety and the alkyl chain length of miltefosine. In vitro testing of these compounds against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans revealed that N-benzyl-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3a), N,N-dimethyl-N-(4-nitrobenzyl)-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3d), and N-(4-methoxybenzyl)-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3e) exhibited minimum inhibitory concentrations (MIC) of 2.5–5.0 μg/mL against all tested pathogens, when compared to miltefosine with MICs of 2.5–3.3 μg/mL. Compound 3a showed low in vitro cytotoxicity against three mammalian cell lines similar to miltefosine. In vivo testing of 3a and miltefosine against C. albicans in a mouse model of systemic infection did not demonstrate efficacy. The results of this study indicate that further investigation will be required to determine the potential usefulness of the alkylphosphocholines in the treatment of invasive fungal infections.