One-Pot Synthesis of Phosphinylphosphonate Derivatives and Their Anti-Tumor Evaluations

This paper reports on the synthesis of new hydroxymethylene-(phosphinyl)phosphonates (HMPPs). A methodology has been developed to propose an optimized one-pot procedure without any intermediate purifications. Various aliphatic and (hetero)aromatic HMPPs were synthesized in good to excellent yields (53–98%) and the influence of electron withdrawing/donating group substitution on aromatic substrates was studied. In addition, the one-pot synthesis of HMPP was monitored by 31P NMR spectroscopy, allowing effective control of the end of the reaction and identification of all phosphorylated intermediate species, which enabled us to propose a reaction mechanism. Optimized experimental conditions were applied to the preparation of biological relevant aminoalkyl-HMPPs. A preliminary study of the complexation to hydroxyapatite (bone matrix) was carried out in order to verify its lower affinity towards bone compared to bisphosphonate molecules. Moreover, in vitro anti-tumor activity study revealed encouraging antiproliferative activities on three human cancer cell lines (breast, pancreas and lung).

Synthetic and Structural Study of peri-Substituted Phosphine-Arsines

A series of phosphorus-arsenic peri-substituted acenaphthene species have been isolated and fully characterised, including single crystal X-ray diffraction. Reactions of EBr3 (E = P, As) with iPr2PAcenapLi (Acenap = acenaphthene-5,6-diyl) afforded the thermally stable peri-substitution supported donor–acceptor complexes, iPr2PAcenapEBr23 and 4. Both complexes show a strong P→E dative interaction, as observed by X-ray crystallography and 31P NMR spectroscopy. DFT calculations indicated the unusual As∙∙∙As contact (3.50 Å) observed in the solid state structure of 4 results from dispersion forces rather than metallic interactions. Incorporation of the excess AsBr3 in the crystal structure of 3 promotes the formation of the ion separated species [iPr2PAcenapAsBr]+Br− 5. A decomposition product 6 containing the rare [As6Br8]2– heterocubane dianion was isolated and characterised crystallographically. The reaction between iPr2PAcenapLi and EtAsI2 afforded tertiary arsine (BrAcenap)2AsEt 7, which was subsequently lithiated and reacted with PhPCl2 and Ph2PCl to afford cyclic PhP(Acenap)2AsEt 8 and acyclic EtAs(AcenapPPh2)2 9.

Gold(I) Complexes with P-Donor Ligands and Their Biological Evaluation

Gold(I) complexes with phosphine ligands—[Au(TrippyPhos)Cl] (1) (TrippyPhos = 1-[2-[bis(tert-butyl)phosphino]phenyl]-3,5-diphenyl-1H-pyrazole), [Au(BippyPhos)Cl]0.5CH2Cl2 (2) (BippyPhos = 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole), and [Au(meCgPPh)Cl] (3) (meCgPPh = 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane—were investigated as types of bioactive gold metallodrugs. Complexes (1)–(3) were characterized using IR, 1H, 13C, 31P NMR spectroscopy, elemental analysis and mass spectrometry (FAB-MS). Complexes of (1) and (2) exhibited substantial in vitro cytotoxicity (IC50 = 0.5–7.0 μM) against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the A549 human lung carcinoma, K562 chronic myelogenous leukemia, and HeLa (human cervix carcinoma) cells. However, among the compounds studied, complex (2) showed the most promising biological properties: the highest stability in biologically relevant media, selectivity towards cancer cells over the non-cancer cells (HUVEC, human umbilical vein endothelial cells), and the highest inhibitory effect on cytosolic NADPH-dependent reductases in A2780 and A2780cis cells among the gold complexes under analysis.

Phosphonates as Unique Components of Plant Seeds—A Promising Approach to Use Phosphorus Profiles in Plant Chemotaxonomy

Phosphorus is one of the most important elements essential for all living beings. Plants accumulate and store phosphorous in various forms that have diverse physiological and biochemical functions. In this study,we determine and then examine the phosphorus profiles of seeds of plants belonging to different taxa based on extractable inorganic phosphates and organic forms of phosphorus. We paid particular attention to the presence of natural phosphonates in the tested materials. The inorganic phosphates were determined colorimetrically, whereas phosphorus profiles were created by using 31P NMR spectroscopy. Our study on phosphorus profiles revealed that the obtainedsets of data vary significantly among the representatives of different taxa and were somehow specific for families of plants. It should be emphasised that the measurements obtained using 31P NMR spectroscopy undoubtedly confirmed—for the first time—the presence of phosphonates among the natural components of plant seeds. Hence, the classification of plants considering the phosphorus profiles, including the presence of phosphonates, may be a new additional chemotaxonomic feature.

Selective Esterification of Phosphonic Acids

Here, we report straightforward and selective synthetic procedures for mono- and diesterification of phosphonic acids. A series of alkoxy group donors were studied and triethyl orthoacetate was found to be the best reagent as well as a solvent for the performed transformations. An important temperature effect on the reaction course was discovered. Depending on the reaction temperature, mono- or diethyl esters of phosphonic acid were obtained exclusively with decent yields. The substrate scope of the proposed methodology was verified on aromatic as well as aliphatic phosphonic acids. The designed method can be successfully applied for small- and large-scale experiments without significant loss of selectivity or reaction yield. Several devoted experiments were performed to give insight into the reaction mechanism. At 30 °C, monoesters are formed via an intermediate (1,1-diethoxyethyl ester of phosphonic acid). At higher temperatures, similar intermediate forms give diesters or stable and detectable pyrophosphonates which were also consumed to give diesters. 31P NMR spectroscopy was used to assign the structure of pyrophosphonate as well as to monitor the reaction course. No need for additional reagents and good accessibility and straightforward purification are the important aspects of the developed protocols.

Lipid Polymorphism of the Subchloroplast—Granum and Stroma Thylakoid Membrane–Particles. II. Structure and Functions

In Part I, by using 31P-NMR spectroscopy, we have shown that isolated granum and stroma thylakoid membranes (TMs), in addition to the bilayer, display two isotropic phases and an inverted hexagonal (HII) phase; saturation transfer experiments and selective effects of lipase and thermal treatments have shown that these phases arise from distinct, yet interconnectable structural entities. To obtain information on the functional roles and origin of the different lipid phases, here we performed spectroscopic measurements and inspected the ultrastructure of these TM fragments. Circular dichroism, 77 K fluorescence emission spectroscopy, and variable chlorophyll-a fluorescence measurements revealed only minor lipase- or thermally induced changes in the photosynthetic machinery. Electrochromic absorbance transients showed that the TM fragments were re-sealed, and the vesicles largely retained their impermeabilities after lipase treatments—in line with the low susceptibility of the bilayer against the same treatment, as reflected by our 31P-NMR spectroscopy. Signatures of HII-phase could not be discerned with small-angle X-ray scattering—but traces of HII structures, without long-range order, were found by freeze-fracture electron microscopy (FF-EM) and cryo-electron tomography (CET). EM and CET images also revealed the presence of small vesicles and fusion of membrane particles, which might account for one of the isotropic phases. Interaction of VDE (violaxanthin de-epoxidase, detected by Western blot technique in both membrane fragments) with TM lipids might account for the other isotropic phase. In general, non-bilayer lipids are proposed to play role in the self-assembly of the highly organized yet dynamic TM network in chloroplasts.