Phosphorus-containing Dendrimers Research Articles

Phosphorus-carrying cascade molecules: inner architecture to biomedical applications.

Cascade molecules are nearly uniform-sized macromolecules of small molecules or linear polymer cores built around symmetric branching units. A wide range of biological properties can be achieved with phosphorus-containing dendrimers, depending on their terminal functions, ranging from biomaterials to imaging, drug delivery, and acting as a drug by themselves. This feature article presents significant examples of phosphorus-containing dendrimers used to develop biochips, support cell cultures, carry or deliver biomacromolecules and drugs, bioimaging, and combinational benefits. Because of the thermal stability, ferrocene function, and physical and chemical properties of phosphorus, dendrimers show greater rigidity, mobility, and strength. These dendrimers will be discussed as having a favorable effect on cell growths, especially on neuronal cells, as well as human immune cells like natural killer cells and monocytes, which have a crucial part in preventing cancerous and viral infections. Several phosphorus dendrimers are effective as drugs by themselves (drug per se) and show their activity against neurodegenerative diseases, cancer, inflammation, ocular hypertension, and transmissible spongiform encephalopathies (TSEs) in both in vivo and in vitro. The present review discusses the synthetic route, fabrications, and biomedical applications of phosphorus-containing dendrimers. The toxicity of these dendrimers was also reported.

Expanding Chitosan Reticular Chemistry Using Multifunctional and Thermally Stable Phosphorus-Containing Dendrimers

Chitosan is an astonishing building block that is extracted from marine crustacean waste, features randomly distributed amino and acetamido groups in its backbone, and can be handled in different forms, giving rise to an impressive diversity of functional nanomaterials. Hitherto, its reticular chemistry, although mandatory to circumvent its main drawback of instability, has been dominated by the use of glutaraldehyde. Unfortunately, the toxicity and inherent chemistry of the latter narrow further development of such cross-linked materials and constitute an impediment for their massive spreading and real implementation, especially in nanomedicine and related healthcare applications. Prompted by the well-established advantages of dendrimers, more distinctively those containing phosphorus in their skeleton, we herein explore the use of second- and third-generation phosphorus-containing dendrimers as cross-linkers to provide an extended covalent dendritic framework grown inside of the carbohydrate network. The presence of residual amine and aldehyde defects was explored to conjugate other chemicals (viologen-based ionic liquid and aminopropyltriethoxysilane) thereby adding more functional diversity to the assembled framework. We also leveraged on the film-forming ability of chitosan to shape the reticular network as flexible films. Despite the bulkiness of the used phosphorus dendrimers, the film-forming memory of chitosan was preserved, allowing successful preparation of highly functional, transparent, and flexible micrometer-thick bioplastics. The cross-linking seems to delay the half-weight degradation temperature of the plastics, with a significant increase in the char residue and a reduced heat release rate. Ternary objects (Congo red dye and gold nanoparticles) could also be entrapped within the transparent films without leaching or degradation, thereby expanding the usefulness of these transparent coatings as multifunctional sensors, flame retardants, biofoulants, etc.

Liquid-Crystalline Order in the Phosphorus-Containing DenDrimers

The structure of phosphorus-containing dendrimers has been studied by IR spectroscopy and optical polarization microscopy. The repeating units of dendrimer molecules are mesogens. This property arises from the conjugation of the aromatic ring and the hydrazone group. An analysis of the IR spectra showed that, with an increase in the generation number, the width of the stretching vibration bands ν(PN) and ν(PO) increases. Difficulties in packing molecules of higher generations cause conformational diversity. The shape of the dendrimer molecules was determined by analyzing the increments of dipole moments. Additionally, the modeling of the stacking of repeating links was performed. The spherical model of molecules does not satisfy the experimental dipole moments of the dendrimers. The flat disk model is more suitable for explaining step changes in dipole moments. The liquid-crystalline ordering of dendrimers under the action of applied pressure was found. With simultaneous heating and uniaxial compression, optical anisotropy appears in dendrimers. It is associated with the formation of liquid-crystalline order. However, a thermodynamically stable liquid-crystalline phase is not formed in this case. Dendrimers most likely have disk-shaped molecules.

Analysis of Dendrimer Generation by Sombor Indices

Dendrimers are highly branched, star-shaped macromolecules with nanometer-scale dimensions. Dendrimers are defined by three components: a central core, an interior dendritic structure (the branches), and an exterior surface with functional surface groups. Topological indices are numerical numbers that help us to understand the topology of different dendrimers and can be used to predict the properties without performing experiments in the wet lab. In the present paper, we computed the Sombor index and the reduced version of the Sombor index for the molecular graphs of phosphorus-containing dendrimers, porphyrin-cored dendrimers, PDI-cored dendrimers, triazine-based dendrimers, and aliphatic polyamide dendrimers. We also plotted our results by using Maple 2015 which help us to see the dependence of the Sombor index and reduced Sombor index on the involved parameters. Our results may help to develop better understanding about phosphorus-containing dendrimers, porphyrin-cored dendrimers, PDI-cored dendrimers, triazine-based dendrimers, and aliphatic polyamide dendrimers. Our results are also useful in the pharmaceutical industry and drug delivery.

The Usefulness of Trivalent Phosphorus for the Synthesis of Dendrimers.

Dendrimers are hyperbranched macromolecules, which are synthesized step-by-step by the repetition of a series of reactions. While many different types of dendrimers are known, this review focusses on the use of trivalent phosphorus derivatives (essentially phosphines and phosphoramidites) for the synthesis of dendrimers. The first part presents dendrimers constituted of phosphines at each branching point. The other parts display the use of trivalent phosphorus derivatives during the synthesis of dendrimers. Different types of reactions have been applied to phosphines. The very first examples of phosphorus-containing dendrimers were obtained by the alkylation of phosphines. Then, several families of dendrimers were elaborated by reaction of phosphoramidites. Such a type of reaction is the base of the solid phase synthesis of oligonucleotides; it has been applied in particular for the synthesis of dendrimers constituted of oligonucleotides. Finally, the Staudinger reaction between phosphines and azides afforded different families of dendrimers, and was at the origin of accelerated methods of synthesis of dendrimers. Besides, the reactivity of the P=N-P=S linkages created by this reaction led to very original dendritic structures.

Straightforward synthesis of gold nanoparticles by adding water to an engineered small dendrimer.

A small water-soluble phosphorus-containing dendrimer was engineered for the complexation of gold(I) and for its reduction under mild conditions. Gold nanoparticles were obtained as colloidal suspensions simply and only when the powdered form of this dendrimer was dissolved in water, as shown by transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDX) analyses. The dendrimers acted simultaneously as mild reducers and as nanoreactors, favoring the self-assembly of gold atoms and promoting the growth and stabilization of isolated gold nanoparticles. Thus, an unprecedented method for the synthesis of colloidal suspensions of water-soluble gold nanoparticles was proposed in this work.

On Eccentricity-Based Topological Indices and Polynomials of Phosphorus-Containing Dendrimers

In the study of the quantitative structure–activity relationship and quantitative structure-property relationships, the eccentric-connectivity index has a very important place among the other topological descriptors due to its high degree of predictability for pharmaceutical properties. In this paper, we compute the exact formulas of the eccentric-connectivity index and its corresponding polynomial, the total eccentric-connectivity index and its corresponding polynomial, the first Zagreb eccentricity index, the augmented eccentric-connectivity index, and the modified eccentric-connectivity index and its corresponding polynomial for a class of phosphorus containing dendrimers.

Vibrational spectroscopic investigation of the gold complexation within the cascade structure of phosphorus-containing dendrimer

The interaction of the phosphoric dendrimer with gold was performed by means of vibrational spectroscopy and quantum chemistry. Stable complexes are formed with a PN−PS linkage, whereas with an isolated PS bond this does not occur.The change in geometric parameters and delocalization of electric charge under the influence of gold was discovered. The classification of bands in the experimental vibrational spectra of the dendrimer and its complex was carried out.HOMO of molecule of the dendrimer is localized on the SPNP linkage, whereas the LUMO is located on the terminal group. In the SPNP linkage there is a noticeable delocalization of the charge which leads to a change in the reactivity of this group. Interaction energy was estimated as the difference between the energies of the complex and the energies of the molecules of the dendrimer G′0 and two molecules AuCl and is equal to 25.2 eV. The ionization energy IE and electron affinity EA for AuCl are higher than for dendrimer, therefore, when the complex is formed, these quantities increases. Chemical potential and the electrophilicity index in the complex also increases.

Engineering CNDP’s of dendrimers containing phosphorous interior compositions to produce new emerging properties

Phosphorus-containing dendrimers are defined as dendrimers having at least one phosphorus atom at each branching point. In this review, we will show how phosphorhydrazone dendrimers can be modified at will at the level of the core and of the branches, to afford specific properties, such as fluorescence to image biological events. Accelerated methods of synthesis of phosphorus (one step for one generation) will be also displayed, as well as the specific reactivity of P=N–P=S linkages obtained in most of these accelerated method of synthesis, which has led to particularly original dendritic architectures, such as dendrons included in dendrimers. Finally, we will display how modifications of the internal structure of a series of dendrimers having the same type and number of terminal functions can deeply modify their biological anti-inflammatory properties. Among the six critical nanoscale design parameters (CNDP), we will show how two of them, i.e., architecture and elemental composition, have been particularly engineered to modify phosphorus-containing dendrimers, in order to fulfill the desired properties.

Synthesis and study of the vibrational spectra of a first generation phosphorus-containing dendrimer with pyridyl functional groups

A new phosphorus-containing dendrimer of the first-generation with potential pharmacological activity was synthesized and studied by spectral methods. The FTIR, FT Raman, 1H and 31P NMR spectra of the first generation dendrimer G1 with a cyclotriphosphazene core, six branches OC6H4CHNN(CH3)P(S) < and twelve 4-oxyphenethylamidopyridyl end groups OC6H4(CH2)2NHCOC5NH4 were recorded. Amide groups of the dendrimer participate in the formation of an intermolecular hydrogen bond. Structure, geometric parameters, the frequency and intensity of the bands in the vibrational spectra were calculated using DFT with PBE functional and TZ2P basis set. Spectral characteristics, charge distribution and reactivity of the core, repeating units and terminal groups of the dendrimer were determined. The first-generation dendrimer molecule has the shape of a concave lens with a slightly non-planar cyclotriphosphazene core and flat repeating units. Repeating units are arranged symmetrically on three on each side of the core, there are no steric hindrances in it and the end groups are able to enter into subsequent reactions and dendrimer has a sufficiently large cavity for accommodating guest molecules. The HOMO covers the repeating units with a noticeable conjugation and the LUMO belongs to the terminal groups.

DFT study of structure, IR and Raman spectra of the first generation dendrimer built from cyclotriphosphazene core with terminal pyrazine groups

A phosphorus-containing dendrimer with pyrazine end groups that can be used for biological purposes has been synthesized. The vibrational spectra of the first generation dendrimer G1 constructed from the cyclotriphosphazene core, six repeating units OC6H4–CHNN(CH3)–P(S)< and twelve 4-oxyphenethylamidopyrazine end groups OC6H4–(CH2)2–NHCOC4N2H3 were registered. Analysis of the IR spectra of G1 shows that the amide groups form an intermolecular hydrogen bond. Optimization of the structure and analysis of normal vibrations were carried out for dendrimer G1 using the density functional theory (DFT). The six repeating units are arranged in a symmetric manner about the cyclophosphazene ring; each side of the ring contains three repeating units. It turned out that dendrimer G1 is a double bowl with almost flat repeating units which represent the concave surface and a core as a bottom of the bowl. The assignment of bands in the vibrational spectra was carried out by analyzing the distribution of the potential energy. Amide groups show bands at 3393, 1675cm−1 in the IR spectrum of G1. The line at 1577cm−1 in the Raman spectrum is characteristic of repeating units.

Symmetrical and unsymmetrical incorporation of active biological monomers on the surface of phosphorus dendrimers

Phosphorus-containing dendrimers are attractive carriers for the delivery of bioactive molecules due to their very particular architecture, globular shape and chemical and physical properties. Herein we report a simple synthetic approach of ethacrynic acid derivatives loaded-phosphorus dendrimers by symmetrical grafting of ethacrynic acid analogues by nucleophilic substitution of each chlorine of P(S)Cl2 end groups. We report also for the first time an unsymmetrical grafting of two different phenol derivatives by a selective substitution of one chlorine of P(S)Cl2 end group followed by the grafting of the second phenol.

Physico-chemical properties of β-diketone phosphorus-containing dendrimers

Protolytic, absorbance and fluorescence properties of β-diketone phosphorus-containing dendrimers based on cyclotriphosphazene core were studied. Dendrimer solutions in acetone are characterized by intense absorbance band at ≈ 340 nm (ε340≈ 8.5·104L/mol·сm) and fluorescence band with maximum at 440 nm. Position of these maxima does not change in various solvents, unlike the bands of monomer β-diketone. It was found that dendrimer aggregation is accompanied by appearance of a second absorbance band ε400≈ 4.5·103L/mol·сm, by red shift of emission spectra ∆λ ≈ 10 nm and also by decrease in surface tension of acetone solution. Ability of dendrimer aggregates to solubilize organic substrates was observed with the fluorescent indicator acridine.

Bifunctional Phosphorus Dendrimers and Their Properties.

Dendrimers are hyperbranched and monodisperse macromolecules, generally considered as a special class of polymers, but synthesized step-by-step. Most dendrimers have a uniform structure, with a single type of terminal function. However, it is often desirable to have at least two different functional groups. This review will discuss the case of bifunctional phosphorus-containing dendrimers, and the consequences for their properties. Besides the terminal functions, dendritic structures may have also a function at the core, or linked off-center to the core, or at the core of dendrons (dendritic wedges). Association of two dendrons having different terminal functions leads to Janus dendrimers (two faces). The internal structure can also possess functional groups on one layer, or linked to one layer, or on several layers. Finally, there are several ways to have two types of terminal functions, besides the case of Janus dendrimers: either each terminal function bears two functions sequentially, or two different functions are linked to each terminal branching point. Examples of each type of structure will be given in this review, as well as practical uses of such sophisticated structures in the fields of fluorescence, catalysis, nanomaterials and biology.

Editorial to the Organophosphorus Chemistry Special Issue of Molecules (2012–2014)

The review entitled “Organophosphorus Chemistry for the Synthesis of Dendrimers” gives an overview of the methods of synthesis of phosphorus-containing dendrimers, with emphasis on the various roles played by the chemistry of phosphorus [1]. It is demonstrated that the presence of phosphorus atom(s) at each branching point of the dendrimeric structure is particularly important and highly valuable.

Interaction of phosphorus dendrimers with HIV peptides—Fluorescence studies of nano-complexes formation

In this study, dendrimers emerge as an alternative approach for delivery of HIV peptides to dendritic cells. Gp160, NH-EIDNYTNTIYTLLEE-COOH; P24, NH-DTINEEAAEW-COOH and Nef, NHGMDDPEREVLEWRFDSRLAF-COOH peptides were complexed with two types of positively charged phosphorus-containing dendrimers (CPD). Fluorescence polarization, dynamic light scattering, transmission and electron microscopy (TEM) techniques were chosen to evaluate the dendriplexes stability. We were able to show that complexes were stable in time and temperature. This is crucial for using these peptide/dendrimer nano-complexes in a new vaccine against HIV-1 infection.

Comparative DFT study of Raman spectra of phosphorus-containing dendrimers built from thiophosphoryl, cyclotriphosphazene and phthalocyanine cores

The FT Raman spectra of the zero and first generations of phosphorus-containing dendrimers built from thiophosphoryl, cyclotriphosphazene and phthalocyanine core with terminal oxybenzaldehyde groups have been recorded and analyzed. The structural optimization and normal mode analysis were performed for dendrimers on the basis of the density functional theory (DFT). The calculated geometrical parameters, harmonic vibrational frequencies and Raman scattering activities are predicted in a good agreement with the experimental data. The experimental Raman spectra of dendrimers were interpreted by means of potential energy distribution. Relying on DFT calculations the lines of the cores, repeating units and terminal groups of dendrimers were assigned.The influence of the encirclement on the line frequencies and intensities was studied and due to the predictable, controlled and reproducible structure of dendrimers the information, usually inaccessible is obtained. The strong line at 1600cm−1 show marked changes of intensity in dependence of aldehyde (CHO) or azomethyne (CHN) substituents in the aromatic ring. The polarizabilities and lipophilicity of dendrimers were estimated.

DFT study of Raman spectra of phosphorus-containing dendrimers built from thiophosphoryl core

The FT-Raman spectra of the first and second generations of phosphorus-containing dendrimers with terminal benzaldehyde and P–Cl groups have been recorded and analyzed. The structural optimization and normal mode analysis were performed for dendrimers on the basis of the density functional theory (DFT). The calculated geometrical parameters, harmonic vibrational frequencies and Raman scattering activities are predicted in a good agreement with the experimental data. The experimental Raman spectra of dendrimers were interpreted by means of potential energy distribution. Relying on DFT calculations the lines of the core, repeating units and terminal groups of dendrimers were assigned.The influence of the encirclement on the line frequencies and intensities was studied and due to the predictable, controlled and reproducible structure of dendrimers the information, usually inaccessible is obtained. The strong line at 1600cm−1 show marked changes of intensity in dependence of aldehyde (CHO) or azomethyne (CHN) substituents in the aromatic ring. The polarizabilities and lipophilicity of the eleven generations of dendrimers were estimated based on the calculated values of the first generations.

Cytotoxicity and Genotoxicity of Cationic Phosphorus-Containing Dendrimers

Cationic phosphorus-containing dendrimers (CPDs) are a class of highly-branched polymers with potential medical relevance. However, little is known about CPD modes of interactions with cell and its components, including DNA. In the present work we investigated cytotoxicity and genotoxicity of CPDs generation 3 and 4 (CPD G3 and CPD G4) in human mononuclear blood cells, A549 human cancer cells and human gingival fibroblasts (HGFs). CPD G3 and CPD G4 at concentrations up to 10 μM induced a concentration-dependent decrease in cell viability as assessed by flow cytometry. Both compounds did not induce breaks in isolated DNA as evaluated by the plasmid relaxation assay but they induced DNA cross-links in the cells, as examined by comet assay. CPD G3 and 4 induced slight perturbations in the cell cycle leading to a decrease in the G2/M cell population accompanied by an increase in the S cell population. Upon treatment with CPDs, the cells showed changes in their morphology, including loss of cell attachment, disruption of cell membrane and nucleus condensation. Our results indicate that CPD G3 and G4 are cytotoxic and genotoxic for the assorted human cells. Therefore, CPDs may form stable complexes with DNA and interfere with cellular processes.

Organophosphorus chemistry for the synthesis of dendrimers.

Dendrimers are multifunctional, hyperbranched and perfectly defined macromolecules, synthesized layer after layer in an iterative manner. Besides the nature of the terminal groups responsible for most of the properties, the nature of the internal structure, and more precisely of the branching points, is also of crucial importance. For more than 15 years, we have demonstrated that the presence of phosphorus atom(s) at each branching point of the dendrimeric structure is particularly important and highly valuable for three main reasons: (i) the versatility of phosphorus chemistry that allows diversified organochemistry for the synthesis of dendrimers; (ii) the use of 31P-NMR, which is a highly valuable tool for the characterization of dendrimers; (iii) some properties (in the fields of catalysis, materials, and especially biology), that are directly connected to the nature of the internal structure and of the branching points. This review will give an overview of the methods of synthesis of phosphorus-containing dendrimers, as well on the ways to graft phosphorus derivatives as terminal groups, with emphasis on the various roles played by the chemistry of phosphorus.