Kegg Pathway: Aminophosphonate metabolism

Bioorg Med Chem Lett. 2008 Apr 1; 18(7): 2320-3
Danila DC, Wang X, Hubble H, Antipin IS, Pinkhassik E

A series of Aminophosphonates was synthesized, and their ability to carry alanine, a model hydrophilic molecule, across phospholipid bilayer membranes was evaluated. Aminophosphonates facilitate the membrane transport at moderate rates, which make them a suitable platform for the design of carriers for continuous drug release devices.

J Chromatogr A. 2008 Mar 28; 1185(2): 233-40
Basset C, Dedieu A, Guérin P, Quéméneur E, Meyer D, Vidaud C

To improve general understanding of biochemical mechanisms in the field of uranium toxicology, the identification of protein targets needs to be intensified. Immobilized metal affinity chromatography (IMAC) has been widely developed as a powerful tool for capturing metal binding proteins from biological extracts. However uranyl cations (UO2(2+)) have particular physico-chemical characteristics which prevent them from being immobilized on classical metal chelating supports. We report here on the first development of an immobilized uranyl affinity chromatography method, based on the cation-exchange properties of Aminophosphonate groups for uranyl binding. The cation distribution coefficient and loading capacity on the support were determined. Then the stability of the uranyl-bonded phase under our chromatographic conditions was optimized to promote affinity mechanisms. The successful enrichment of uranyl binding proteins from human serum was then proven using proteomic and mass spectral analysis.

BMC Cancer. 2007; 7: 109
Chiu KP, Ariyaratne P, Xu H, Tan A, Ng P, Liu ET, Ruan Y, Wei CL, Sung WK

BACKGROUND: Melanoma is the major cause of skin cancer deaths and melanoma incidence doubles every 10 to 20 years. However, little is known about melanoma pathway aberrations. Here we applied the robust Gene Identification Signature Paired End diTag (GIS-PET) approach to investigate the melanoma transcriptome and characterize the global pathway aberrations. METHODS: GIS-PET technology directly links 5' mRNA signatures with their corresponding 3' signatures to generate, and then concatenate, PETs for efficient sequencing. We annotated PETs to pathways of KEGG database and compared the murine B16F1 melanoma transcriptome with three non-melanoma murine transcriptomes (Melan-a2 melanocytes, E14 embryonic stem cells, and E17.5 embryo). Gene expression levels as represented by PET counts were compared across melanoma and melanocyte libraries to identify the most significantly altered pathways and investigate the expression levels of crucial cancer genes. RESULTS: Melanin biosynthesis genes were solely expressed in the cells of melanocytic origin, indicating the feasibility of using the PET approach for transcriptome comparison. The most significantly altered pathways were metabolic pathways, including upregulated pathways: purine metabolism, Aminophosphonate metabolism, tyrosine metabolism, selenoamino acid metabolism, galactose utilization, nitrobenzene degradation, and bisphenol A degradation; and downregulated pathways: oxidative phosphorylation, ATPase synthesis, TCA cycle, pyruvate metabolism, and glutathione metabolism. The downregulated pathways concurrently indicated a slowdown of mitochondrial activities. Mitochondrial permeability was also significantly altered, as indicated by transcriptional activation of ATP/ADP, citrate/malate, Mg++, fatty acid and amino acid transporters, and transcriptional repression of zinc and metal ion transporters. Upregulation of cell cycle progression, MAPK, and PI3K/Akt pathways were more limited to certain region(s) of the pathway. Expression levels of c-Myc and Trp53 were also higher in melanoma. Moreover, transcriptional variants resulted from alternative transcription start sites or alternative polyadenylation sites were found in Ras and genes encoding adhesion or cytoskeleton proteins such as integrin, beta-catenin, alpha-catenin, and actin. CONCLUSION: The highly correlated results unmistakably point to a systematic downregulation of mitochondrial activities, which we hypothesize aims to downgrade the mitochondria-mediated apoptosis and the dependency of cancer cells on angiogenesis. Our results also demonstrate the advantage of using the PET approach in conjunction with KEGG database for systematic pathway analysis.

J Org Chem. 2007 Mar 30; 72(7): 2682-5
Palacios F, Vicario J, Maliszewska A, Aparicio D

An efficient synthesis of alpha,beta-unsaturated imines derived from alpha-Aminophosphonates is achieved through aza-Wittig reaction of P-trimethyl phosphazenes with beta,gamma-unsaturated alpha-ketophosphonates. Selective 1,2-reduction of such 1-azadienes affords beta,gamma-unsaturated alpha-Aminophosphonates, phosphorylated analogs of vinylglycines, which are hydrogenated to yield saturated alpha-Aminophosphonate derivatives.

Chemistry. 2007; 13(1): 203-14
Dieltiens N, Moonen K, Stevens CV

A new tandem reaction sequence has been developed for the synthesis of 2-phosphono pyrroles. The sequence consists of ring-closing enyne metathesis of a substituted Aminophosphonate, containing a terminal alkyne and an internal alkene, in combination with in situ oxidation of the produced 3-pyrrolines using tetrachloroquinone. By analyzing the formation of the end and certain byproducts, taking into account the difference in reactivity of different substrates and carefully studying spectroscopic data, it was found that the reaction proceeds by means of the "yne-then-ene" pathway. During the initiation phase, a new ruthenium carbene is formed which continues the propagation cycle.

J Hazard Mater. 2006 Sep 21; 137(2): 925-33
Deepatana A, Valix M

This study examined the recovery of nickel and cobalt from organic acid complexes using a chelating Aminophosphonate Purolite S950 resin. These metal complexes are generated by bioleaching nickel laterite ores, a commercial nickel and cobalt mineral oxide, with heterotrophic organism and their metabolites or organic acid products. Equilibrium adsorption tests were conducted as a function of Ni and Co concentrations (15-2000 mg/L), solution pH (0.01 and 0.1 M acids) and three metabolic complexing agents (citrate, malate and lactate). It was shown that the adsorption of the various Ni- and Co-complexes on Purolite were quite low, 16-18 and 5.4-9 mg/g of resin, respectively, in comparison to the smaller nickel ions and nickel sulfate. This was attributed to the bulky organic ligands which promoted crowding effect or steric hindrance. The adsorption of these complexes was further hampered by the strong affinity of the resin to H+ ions under acidic conditions. Mechanisms of adsorption, as inferred from the fitted empirical Langmuir and Freundlich models, were correlated to the proposed steric hindrance and competitive adsorption effects. Nickel and cobalt elution from the resin were found be effective and were independent of the type of metal complexes and metal concentrations. This study demonstrated the relative challenges involved in recovering nickel and cobalt from bioleaching solutions.

Genome Inform. 2004; 15(2): 266-75
Nikitin F, Rance B, Itoh M, Kanehisa M, Lisacek F

We have studied the projection of protein family data onto single bacterial translated genome as a solution to visualise relationships between families restricted to bacterial sequences. Any member of any type of family as defined in the Pfam database (domains, signatures, etc.) is considered as a protein module. Our first goal is to discover rules correlating the occurrence of modules with biochemical properties. To achieve this goal we have developed a platform to quantify information found in protein databases and to support the analysis of the nature of modules, their position and corresponding frequencies of occurrence (in isolation or in combination) in association with pathway knowledge as found in KEGG.This paper focuses on two pathways: the two-component system and the Aminophosphonate metabolism, that are partially but not completely documented. Proteins involved in those pathways were listed separately in each organism to analyse module composition and rules constraining pathway interactions were identified. It is shown how these results can be used to update KEGG pathways and orthologue tables.

Chem Commun (Camb). 2004 May 7; 1132-3
Drag M, Jezierski A, Kafarski P

Oxidative, chemical cleavage of the C-P bond in 1-amino-1-(3,4-dihydroxyphenyl)methylphosphonic acid upon the action of NaIO(4) have been the subject of the NMR, EPR and UV-Vis investigations in acidic and basic conditions.

J Org Chem. 2002 Nov 15; 67(23): 8123-9
Moore JD, Sprott KT, Hanson PR

A transition metal-catalyzed/Curtius rearrangement sequence toward the development of conformationally constrained alpha-Boc-Aminophosphonates 2-6 is described. An approach using the versatile tert-butylphosphonoacetate moieties 1a and 1b to derive an array of mono- and bicyclic alpha-Boc-Aminophosphonate systems is presented. Conformational constraint is incorporated using either the ring-closing metathesis reaction catalyzed by the first generation Grubbs catalyst or intramolecular cyclopropanation mediated by Rh2(OAc)4. Using the tert-butyl ester functionality in 1a or 1b as a potential amino group, the Curtius rearrangement provides an efficient route toward the target alpha-Boc-Aminophosphonates.

Z Naturforsch [C]. 2001 Nov-Dec; 56(11-12): 999-1002
Kleszczyńisk H, Bonarska D, Sarapuk J, Bielecki K

Hemolysis and fluidization of erythrocytes (RBC) membranes by some newly synthesized Aminophosphonates as well as their potency to induce electrolyte efflux from cucumber (Cucumis sativus cv "Wisconsin") cotyledons were studied. Also, the chlorophyll content in Aminophosphonate-treated cotyledons was affected. The compounds studied differed mainly in hydrophobicity of their substituents at the carbon, nitrogen and phosphorus atoms. It was found that Aminophosphonate potency to fluidize RBC membranes depended on the combination of its overall lipophilicity and/or the kind of substituent at the P atom. Especially, iso-propyl groups enhanced that potency. The sequence of Aminophosphonates that exhibited the strongest fluidization activity was paralelled by their physiological and hemolytic activities; in the latter case for these compounds that hemolyzed RBC under used concentrations. A general conclusion is that both the stereochemistry and lipophilicity determine the efficiency of the Aminophosphonates studied. This efficiency is most probably related to the interaction of Aminophosphonates with the lipid phase of biological objects.

Nucl Med Commun. 2002 Jan; 23(1): 67-74
Chakraborty S, Das T, Unni PR, Sarma HD, Samuel G, Banerjee S, Venkatesh M, Ramamoorthy N, Pillai MR

Polyphosphonate ligands labelled with radioisotopes decaying by moderate energy beta emission have shown utility as palliative agents for painful bone metastasis. 177Lu (T(1/2)=6.71 d, Ebetamax=497 keV) has radionuclidic properties suitable for use in palliative therapy of bone metastasis. 177Lu was produced at a high specific activity and excellent radionuclidic purity by thermal neutron bombardment of a target prepared from natural Lu. Three polyaminomethylene phosphonate ligands, abbreviated as EDTMP, DTPMP and TTHMP, were synthesized and radiolabelled with 177Lu. Complexation parameters were optimized to achieve maximum yields (97-99.5%). All the complexes were found to retain their stability at room temperature even 14 days after preparation. Biodistribution studies of the complexes were carried out in Wistar rats. All the complexes showed significant bone uptake (6-6.5%/g in tibia at 3 h post-injection (p.i.)) with rapid clearance from blood and minimum uptake in soft tissues. These studies reveal that 177Lu complexes with the synthesized ligands have a potential use in palliative treatment of painful bone metastasis.

Cell Mol Biol Lett. 2001; 6(2A): 271-5
Kleszczyńska H, Sarapuk J, Bonarska D

A series of ten Aminophosphonate derivatives were assayed for their hemolytic activity as a preliminary screening for the detection of herbicides. The data obtained indicate: 1. A clear correlation between the hemolytic capacity of the test compounds and their plant growth inhibition and an increase in membrane fluidity was demonstrated. 2. It was found that the most active compounds revealed at least one of the following structural features: an iso-propyl substituent at the phosphorus atom, a tert-butyl group attached to their hexane ring or a long hydrocarbon chain. 3. Ring substituents at the phosphorus (phenyl ring), carbon or nitrogen atoms (hexane) removed the hemolytic activity of compounds. 4. It may be concluded that the hemolytic toxicity of the Aminophosphonates studied is related to their ability to incorporate and fuse into the lipid phase of the erythrocyte membrane. The general conclusion is that both stereochemistry and hydrophobicity are deciding factors for the efficiency of the interaction of the studied compounds studied with erythrocytes, and that the most possible location of the Aminophosphonates is in the lipid phase of the RBC membrane.

Z Naturforsch [C]. 2001 May-Jun; 56(5-6): 349-52
Grzyś E, Bielecki K, Sarapuk J

Betacyanine and ionic leakage from red beet (Beta vulgaris ssp. L. rapacea) roots and lilac (Syringa vulgaris L.) leaves under the influence of new Aminophosphonates were studied by spectroscopic and conductometric methods. It was found that the leakage of dye or electrolytes depended both on the concentration of the compounds used and their structural features. The results compared to those obtained for the well known herbicide Buminafos (dibutyl 1-butylamino-1-cyclohexanephosphonate) enabled to conclude that some of the compounds studied exhibited comparable or better activity than this herbicide. That makes them potentially good herbicides. It is possible that the effects observed are the result of action on cell membranes of the tissues used. The possible role of the structural features of Aminophosphonates in this action is discussed.

J Cardiovasc Pharmacol. 2000 Nov; 36(5 Suppl 1): S40-3
Trapani AJ, Beil ME, Bruseo CW, De Lombaert S, Jeng AY

The purpose of this study was to examine the pharmacologic properties of CGS 35066, a novel Aminophosphonate inhibitor of endothelin-converting enzyme-1 (ECE-1). CGS 35066 inhibited the activity of human ECE-1 and rat kidney neutral endopeptidase 24.11 (NEP) in vitro with IC50 values of 22 +/- 0.9 nM and 2.3 +/- 0.03 microM, respectively. The in vivo effects of CGS 35066 were characterized in conscious, catheterized rats. At 30 and 120 min after treatment with vehicle, big endothelin-1 (big ET-1, 0.3 nmol/kg i.v.) produced increases in mean arterial pressure (MAP) of 982 +/- 31 and 992 +/- 43 mmHg x min (area under the curve), respectively. Doses of 0.3, 1.0, 3.0 and 10.0 mg/kg i.v., of CGS 35066 blocked these pressor responses by 61 +/- 7, 78 +/- 4, 93 +/- 4 and 98 +/- 2% at 30 min (p < 0.05 compared with vehicle controls, all doses), and by 29 +/- 7, 63 +/- 5, 63 +/- 5 and 84 +/- 10% at 120 min (p < 0.05, all doses). In contrast, the pressor effect (58 +/- 6 mmHg) of angiotensin-I (300 ng/kg i.v.) was unaffected by the ECE-1 inhibitor (10 mg/kg i.v.) indicating the absence of activity against angiotensin-converting enzyme. In rats infused with atrial natriuretic peptide (ANP), CGS 35066, at 1 mg/kg, had no effect on plasma irANP; however, irANP levels were doubled at a dose of 30 mg/kg. These results demonstrate that CGS 35066 is the most potent and selective ECE inhibitor identified to date.

Bioorg Med Chem Lett. 2000 Aug 7; 10(15): 1749-50
Lintunen T, Yli-Kauhaluoma JT

Two 2-Aminophosphonate haptens derived from methyl alpha-D-glucopyranoside were synthesized to mimic the transition-state of a transesterification reaction between methyl alpha-D-glucopyranoside and 4-nitrophenylester of tert-BOC-beta-alanine. Two sets of monoclonal antibodies were generated against these haptens.

Bioorg Med Chem. 1999 Dec; 7(12): 2671-82
Du S, Faiger H, Belakhov V, Baasov T

The design and two synthetic pathways to Aminophosphonate 4 which mimics the ionic and steric properties of putative oxocarbenium intermediate 3 in the Kdo8P synthase-catalyzed reaction are reported. It was found that 4 is a slow-binding, most potent inhibitor of the enzyme yet tested, with a Ki value of 0.4 microM.

Res Commun Mol Pathol Pharmacol. 1995 Feb; 87(2): 211-20
Ghai RD, De Lombaert S, Ksander GM, Berry C, Sakane Y, Trapani AJ

The selection of therapeutic agents for clinical development is principally based upon pharmacodynamic and pharmacokinetic criteria. Although many compounds are routinely tested in pharmacologic assays, direct pharmacokinetic assessment is difficult and not applicable to a large number of agents. Therefore, we have developed a rapid indirect method based on enzyme inhibition for determining the unbound concentration of NEP 24.11 inhibitors in rat plasma. In the present study, drug levels of compounds from three different classes of NEP 24.11 inhibitors: mercaptoalkyl, carboxyalkyl and Aminophosphonates were compared. Studies were carried out in conscious, unrestrained rats. Arterial blood samples were obtained 10, 30, 60, 120, and 240 min after drug administration at 10 mg/kg i.v. or 30 mg/kg p.o. The blood was collected in EDTA and plasma prepared immediately. Protein bound NEP inhibitor was separated from plasma by centrifugation through an ultrafiltration membrane. Following acidification and serial dilution, the concentration of unbound inhibitor was determined in the plasma ultrafiltrate using the in vitro assay for NEP 24.11 inhibition. The results of this study indicated that the mercaptoalkyl inhibitor thiorphan was cleared rapidly from plasma, whereas, the plasma concentrations of the carboxyalkyl inhibitor CGS 23880A (UK-69,578), and the plasma concentrations of the Aminophosphonate, CGS 24128, were maintained at high levels for at least 4 hours. Furthermore, the ratio of the NEP inhibitor concentration/IC50 value correlated well with the pharmacologic activity of these compounds.

Cancer Res. 1993 Aug 1; 53(15): 3536-40
Lelievre E, Guillaudeux J, Cardona H, Bourguignat A, Lokiec F, Solere P, Lucas C, Sauveur C

S 12363 is a new Vinca alkaloid derivative, characterized by the grafting of an alpha-Aminophosphonate, onto the Vinca nucleus, facilitating drug penetration and increasing intracellular drug retention. As a high cytotoxic activity had been demonstrated in in vitro and in vivo models recommended by the National Cancer Institute, a phase I trial was initiated in cancer patients. In order to quantify S 12363 systemic levels in humans, two monoclonal antibody-based immunoassays, RIA (radio-) and EIA (enzyme immunoassay) were developed. The gamma-emitting probe used in the RIA, 125I-(deacetyl-O4-vinblastine)-tyramine, bound very tightly to the monoclonal antibody (dissociation constant, Kd = 2.5 x 10(-11) M), demonstrating a high affinity mainly directed toward the catharantine nucleus (vindesine, vincristine, vinblastine, 100% cross-reactivity; vinorelbine, 0.3% cross-reactivity). In the EIA, a deacetyl O4-vinblastine/ovalbumine conjugate was used as the competing antigen. Its binding to the monoclonal antibody was revealed by an anti-mouse immunoglobulin G conjugated to biotin which interacts with streptavidin labeled with alkaline phosphatase. This method permitted obtaining nearly the same sensitivity and reproducibility with EIA as with RIA, their respective minimum quantitation limits being 0.100 and 0.040 ng/ml (106 and 42 pM) of S 12363 in plasma. These assays allowed the study of S 12363 systemic pharmacokinetics in cancer patients during a phase I trial up to 72 h after dosing. As determined by RIA, the S 12363 plasma profile was triphasic with a terminal half-life; t1/2 gamma = 49 +/- 16 h, a plasma clearance, CL = 0.14 +/- 0.04 liter/h/kg, and a volume of distribution at steady state, Vdss = 5.0 +/- 2.8 liter/kg. The pharmacokinetics of S 12363 is linearly related to dose when increased from 0.08 up to 0.84 mg/m2 in humans. Its plasma profile and pharmacokinetic parameters are close to those of other Vinca alkaloids with clearance and terminal half-life being intermediate between those of vinblastine and vincristine. Therapeutic doses are 4 to 10 times lower and should be a direct consequence of the higher uptake and retention by the cells of this new Aminophosphonate Vinca alkaloid derivative.

Blood. 1992 Sep 15; 80(6): 1608-13
Appelbaum FR, Brown PA, Sandmaier BM, Storb R, Fisher DR, Shulman HM, Graham TC, Schuening FG, Deeg HJ, Bianco JA

166Holmium ethylenediaminetetramethylene phosphonic acid (166Ho-EDTMP) is a short-lived beta-emitting radionuclide complexed to an Aminophosphonate ligand that we have investigated in a canine model as a potential agent for specific marrow ablation before marrow transplantation. After intravenous injections, 166Ho-EDTMP distributed principally to bone and after 24 hours the concentrations of 166Ho-EDTMP in bone were more than 200-fold higher than in any other organ. Increasing dosages of 166Ho-EDTMP led to increasingly prolonged and severe myelosuppression, but myeloablation was not achieved. Histologic examination of recovering animals suggested that the spleen may have acted as a reservoir for circulatory hematopoietic precursors. Four splenectomized animals administered 20 to 30 mCi/kg 166Ho-EDTMP without marrow transplantation died with marrow aplasia, while four splenectomized animals administered similar dosages of 166Ho-EDTMP followed by autologous transplantation recovered. The dose-limiting toxicity of 166Ho-EDTMP appeared to be marrow stromal damage resulting in myelofibrosis, which was reversible. These results suggest that 166Ho-EDTMP can be used to specifically ablate marrow function before marrow transplantation.

Anticancer Res. 1990 Jan-Feb; 10(1): 139-44
Pierré A, Lavielle G, Hautefaye P, Seurre G, Leonce S, Saint-Dizier D, Boutin JA, Cudennec CA

S 12363 is a new vinca alkaloid derivative obtained by grafting an optically active alpha-Aminophosphonate at the C23 position of O4-deacetyl vinblastine. This compound was as potent as Vincristine (VCR), and less potent than Vinblastine (VLB), in inhibiting in vitro tubulin polymerization. However, S 12363 was found to be 7 to 553 and 12 to 74-fold more cytotoxic than VCR and VLB, respectively, when tested on a panel of 2 murine and 6 human tumor cell lines using the Microculture Tetrazolium Assay. S 12362, which differs only by the configuration of the asymmetric carbon atom of the side chain, was 18 to 59-fold less cytotoxic. At equitoxic doses, all these compounds induced a "G2 + M" phase accumulation of L1210 cells, suggesting a similar mechanism of action. S 12363, administered i.p. or i.v., was at least as active as reference compounds on two murine transplantable tumors (P388 leukemia and B16 melanoma) while the optimal dosage was 20-fold lower: 0.15-0.20 mg/kg versus 2-5 mg/kg, respectively. S 12362 was practically inactive at 1-3 mg/kg. The hematological toxicity of S 12363 (0.1 mg/kg) was similar to that of VLB (4 mg/kg). The exceptionally high potency of S 12363 did not appear to be due to a better interaction with tubulin, its intracellular target, but rather to some properties conferred by the alpha-aminophosphonic acid, such as a facilitated uptake and/or a better cellular retention.