Divergent synthesis of benzoxaphospholenes and phosphacoumarins via the reaction of 2-alkenylphenols with phosphorus(III/V) chlorides.

The divergent synthesis of benzo[e]-1,2-oxaphosphinines or benzo[d]-1,2-oxaphospholenes along with spirocyclic quasiphosphonium compounds based on 2-alkenylphenols and phosphorus(III/V) chlorides is presented. The reaction is condition-dependent and determined by the biphility of the phosphorus(III) derivative and the dual reactivity of 2-alkenylphenol. The procedures are applicable for obtaining benzo[e]-1,2-oxaphosphinines substituted at position 4 and disubstituted at positions 4 and 5 as well as 3,3-disubstituted benzo[d]-1,2-oxaphospholenes with good to high yields.

Bifunctionalized Betulinic Acid Conjugates with C-3-Monodesmoside and C-28-Triphenylphosphonium Moieties with Increased Cancer Cell Targetability.

A convenient synthesis is presented for a new class of bioactive bifunctionalized conjugates of lupane-type triterpenoids with triphenylphosphonium (TPP) and glycopyranosyl targeting moieties. The main synthesis steps include glycosylation of haloalkyl esters of the triterpene acid at the C-3 position by the imidate derivatives of glycopyranose followed by the product modification at the C-28 position with triphenylphosphine. The conjugates of betulinic acid (BetA) with TPP and d-glucose, l-rhamnose, or d-mannose moieties were thus synthesized as potential next-generation BetA-derived anticancer compounds. LC-MS/MS analysis in glucose-free physiological solution indicated that the glycosides showed better accumulation in PC-3 prostate cancer cells than both BetA and TPP-BetA conjugate, while the transporting effect of monosaccharide residues increased as follows: d-mannose < l-rhamnose ≈ d-glucose. At saturated concentrations, the glycosides caused a disturbing effect on mitochondria with a more drastic drop in transmembrane potential but weaker overproduction of mitochondrial reactive oxygen species (ROS) compared to TPP-BetA conjugate. Cytotoxicity of the glycosides in culture medium was comparable with or higher than that of the nonglycosylated conjugate, depending on the cancer cell line, whereas the compounds were less active toward primary fibroblasts. Glycosylation tended to increase pro-apoptotic and decrease pro-autophagic activities of the BetA derivatives. Cytotoxicity of the synthesized glycosides was considered in comparison with the summarized data on the natural and modified BetA glycosides. The results obtained are important for the development of bifunctionalized conjugates of triterpenoids with an increased cancer cell targetability.

Synthesis, biological evaluation and structure-activity relationship of 2-(2-hydroxyaryl)alkenylphosphonium salts with potency as anti-MRSA agents.

Here we report the synthesis, in vitro antimicrobial activity, preliminary toxicity and mechanism study of a new series of 2-(2-hydroxyaryl)alkenylphosphonium salts with the variation of phosphonium moiety obtained by a two-step synthetic method from phosphine oxides. The salts showed pronounced activity against Gram-positive bacteria, including MRSA strains, and some fungi. Mechanism of action against S. aureus was studied by CV test, TEM and proteomic assay. No cell wall integrity loss was observed while proteomic assay results suggested interference in different metabolic processes of S. aureus. For this series, lipophilicity was determined as a key factor for the inhibition of Gram-positive bacteria growth and S. aureus killing. Biological properties of methylated derivatives were notably different with manifested action against Gram-negative bacteria.

Isatin-3-acylhydrazones with Enhanced Lipophilicity: Synthesis, Antimicrobial Activity Evaluation and the Influence on Hemostasis System.

Water-soluble trialkylammonium isatin-3-hydrazone derivatives bearing phenolic substituent were easily synthesized with high yields. XRD studies confirmed the presence of these compounds as trans-(Z)-isomers in a crystal. It was shown that an increase in the lipophilicity of the cationic center leads to an increase in activity against Gram-positive bacteria Staphylococcus aureus and Bacillus cereus, including methicillin-resistant Staphylococcus aureus (MRSA) strains. The MIC values of all compounds turned out to be 2-100 times higher than the MIC of norfloxacin against the MRSA strains in the absence of hemo- and cytotoxicity. Antiaggregation and anticoagulation properties were in vitro better than for acetylsalicylic acid and sodium heparin drugs. It has been shown by UV spectroscopy and fluorescence microscopy that the mechanism of antimicrobial action of new acylhydrazones is associated with their ability to destroy the bacterial cell membrane.

Rational Design 2-Hydroxypropylphosphonium Salts as Cancer Cell Mitochondria-Targeted Vectors: Synthesis, Structure, and Biological Properties.

It has been shown for a wide range of epoxy compounds that their interaction with triphenylphosphonium triflate occurs with a high chemoselectivity and leads to the formation of (2-hydroxypropyl)triphenylphosphonium triflates 3 substituted in the 3-position with an alkoxy, alkylcarboxyl group, or halogen, which were isolated in a high yield. Using the methodology for the disclosure of epichlorohydrin with alcohols in the presence of boron trifluoride etherate, followed by the substitution of iodine for chlorine and treatment with triphenylphosphine, 2-hydroxypropyltriphenylphosphonium iodides 4 were also obtained. The molecular and supramolecular structure of the obtained phosphonium salts was established, and their high antitumor activity was revealed in relation to duodenal adenocarcinoma. The formation of liposomal systems based on phosphonium salt 3 and L-α-phosphatidylcholine (PC) was employed for improving the bioavailability and reducing the toxicity. They were produced by the thin film rehydration method and exhibited cytotoxic properties. This rational design of phosphonium salts 3 and 4 has promising potential of new vectors for targeted delivery into mitochondria of tumor cells.

Recent advances in the application of isoindigo derivatives in materials chemistry.

In this review, the data on the application of isoindigo derivatives in the chemistry of functional materials are analyzed and summarized. These bisheterocycles can be used in the creation of organic solar cells, sensors, lithium ion batteries as well as in OFET and OLED technologies. The potentials of the use of polymer structures based on isoindigo as photoactive component in the photoelectrochemical reduction of water, as matrix for MALDI spectrometry and in photothermal cancer therapy are also shown. Data published over the past 5 years, including works published at the beginning of 2021, are given.

Design and synthesis of amphiphilic 2-hydroxybenzylphosphonium salts with antimicrobial and antitumor dual action.

Here we report the synthesis and biological evaluation of a series of new 2-hydroxybenzylphosphonium salts (QPS) with antimicrobial and antitumor dual action. The most active compounds exhibit antimicrobial activity at a micromolar level against Gram-positive bacteria Sa (ATCC 209p and clinical isolates), Bc (1-2 µM) and fungi Tm and Ca, and induced no notable hemolysis at MIC. The change in nature of substituents of the same length led to a drastic change of biological activity. Self-assembly behavior of the octadecyl and oleyl derivatives was studied. QPS demonstrated self-assembly within the micromolar range with the formation of nanosized aggregates capable of the solubilizing hydrophobic probe. The synthesized phosphonium salts were tested for cytotoxicity. The most potent salt was active against on M-Hela cell line with IC50 on the level of doxorubicin and good selectivity. According to the cytofluorimetry analysis, the salts induced mitochondria-dependent apoptosis.

Synthesis and Antimicrobial Properties of Novel Phosphonium Salts Bearing 1,4-Dihydroxyaryl Fragment.

A versatile two-step pathway to the synthesis of triaryl(2,5-dihydroxy-6-methyl-3-(propan-2-yl)phenyl)- and triaryl(1,4-dihydroxynaphthyl)phosphonium salts from triarylphosphonium trifluoroacetates was developed. The reaction proceeds under mild conditions (20 °C, CH2 Cl2 ) with high yields (88-95 %). Some representatives of this series possess low hemolytic and high bactericidal activity against Gram-positive bacteria.

Synthesis and Antimicrobial Study of Novel 1-Benzylated Water-Soluble Isatin-3-hydrazones.

A high-yield synthesis of some novel isatin-3-acylhydrazones on the base of 5-ethylisatin derivatives and Girard's reagent T is described. Antimicrobial activity preliminary SAR study of both 1-benzylated isatins and water-soluble hydrazones was established. The most active against Staphylococcus aureus and Bacillus cereus are ammonium salts bearing 3,4-dichloro- or 4-CF3 substituents in benzyl fragment.

Design, Synthesis, and Cancer Cell Growth Inhibitory Activity of Triphenylphosphonium Derivatives of the Triterpenoid Betulin.

A series of new triphenylphosphonium (TPP) derivatives of the triterpenoid betulin (1, 3-lup-20(29)-ene-3ß,28-diol) have been synthesized and evaluated for cytotoxic effects against human breast cancer (MCF-7), prostate adenocarcinoma (PC-3), vinblastine-resistant human breast cancer (MCF-7/Vinb), and human skin fibroblast (HSF) cells. The TPP moiety was applied as a carrier group through the acyl linker at the 28- or 3- and 28-positions of betulin to promote cellular and mitochondrial accumulation of the resultant compounds. A structure-activity relationship study has revealed the essential role of the TPP group in the biological properties of the betulin derivatives produced. The present results showed that a conjugate of betulin with TPP (3) enhanced antiproliferative activity toward vinblastine-resistant MCF-7 cells, with an IC50 value as low as 0.045 µM.

Stereoselective PCO/POC-Rearrangement of P-C-Cage Phosphorane in the Reaction of 4,5-Dimethyl-2-(2-oxo-1,2-diphenyl)ethoxy-1,3,2-dioxaphospholane with Hexafluoroacetone.

Interaction of 4,5-dimethyl-2-(2-oxo-1,2-diphenyl)ethoxy-1,3,2-dioxaphospholane, bearing a carboxyl group in the γ-position with respect to the phosphorus atom and obtained from d,l-butanediol, with hexafluoroacetone (CCl4, -40 °C) leads to the simultaneous formation of regio- and stereoisomeric cage-like phosphoranes with phosphorus-carbon and phosphorus-oxygen bonds with a high stereoselectivity (>95%), whose structure was determined by 1D and 2D NMR spectroscopy and XRD. When stored as a solution in dichloromethane for one month, the PCO-isomer rearranges into the thermodynamically more stable POC-isomer of the cage-like phosphorane. Mild hydrolysis of the PCO/POC-isomers proceeds with a high chemoselectivity and leads to the formation of P(IV)-dioxaphospholane derivatives. Acidic hydrolysis of the POC-isomer leads to the formation of an oxirane derivative with an unexpectedly high stereoselectivity (>95%). DFT calculations (using the PBE functional) allowed us to obtain structures and energies of the initial phospholane, reaction products (PCO/POC-isomers), and an intermediate P(V)-oxaphosphirane.

Triphenylphosphonium Cations of the Diterpenoid Isosteviol: Synthesis and Antimitotic Activity in a Sea Urchin Embryo Model.

A series of novel triphenylphosphonium (TPP) cations of the diterpenoid isosteviol (1, 16-oxo-ent-beyeran-19-oic acid) have been synthesized and evaluated in an in vivo phenotypic sea urchin embryo assay for antimitotic activity. The TPP moiety was applied as a carrier to provide selective accumulation of a connected compound into mitochondria. When applied to fertilized eggs, the targeted isosteviol TPP conjugates induced mitotic arrest with the formation of aberrant multipolar mitotic spindles, whereas both isosteviol and the methyltriphenylphosphonium cation were inactive. The structure-activity relationship study revealed the essential role of the TPP group for the realization of the isosteviol effect, while the chemical structure and the length of the linker only slightly influenced the antimitotic potency. The results obtained using the sea urchin embryo model suggested that TPP conjugates of isosteviol induced mitotic spindle defects and mitotic arrest presumably by affecting mitochondrial DNA. Since targeting mitochondria is considered as an encouraging strategy for cancer therapy, TPP-isosteviol conjugates may represent promising candidates for further design as anticancer agents.

Novel indolin-2-one-substituted methanofullerenes bearing long n-alkyl chains: synthesis and application in bulk-heterojunction solar cells.

An easy, high-yield and atom-economic procedure of a C60 fullerene modification using a reaction of fullerene C60 with N-alkylisatins in the presence of tris(diethylamino)phosphine to form novel long-chain alkylindolinone-substituted methanofullerenes (AIMs) is described. Optical absorption, electrochemical properties and solubility of AIMs were studied. Poly(3-hexylthiophene-2,5-diyl) (P3HT)/AIMs solar cells were fabricated and the effect of the AIM alkyl chain length and the P3HT:AIM ratio on the solar cell performance was studied. The power conversion efficiencies of about 2% were measured in the P3HT/AIM devices with 1:0.4 P3HT:AIM weight ratio for the AIMs with hexadecyl and dodecyl substituents. From the optical and AFM data, we suggested that the AIMs, in contrast to [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), do not disturb the P3HT crystalline domains. Moreover, the more soluble AIMs do not show a better miscibility with the P3HT crystalline phase.

Novel triphenylphosphonium amphiphilic conjugates of glycerolipid type: synthesis, cytotoxic and antibacterial activity, and targeted cancer cell delivery.

This work deals with the creation of new cationic triphenylphosphonium amphiphilic conjugates of glycerolipid type (TPP-conjugates), bearing a pharmacophore terpenoid fragment (abietic acid and betulin) and a fatty acid residue in one hybrid molecule as a new generation of antitumor agents with high activity and selectivity. The TPP-conjugates showed high mitochondriotropy leading to the development of mitochondriotropic delivery systems such as TPP-pharmacosomes and TPP-solid lipid particles. Introducing the betulin fragment into the structure of a TPP-conjugate (compound 10) increases the cytotoxicity 3 times towards tumor cells of prostate adenocarcinoma DU-145 and 4 times towards breast carcinoma MCF-7 compared to TPP-conjugate 4a in the absence of betulin. TPP-hybrid conjugate 10 with two pharmacophore fragments, betulin and oleic acid, has significant cytotoxicity toward a wide range of tumor cells. The lowest IC50 of 10 is 0.3 µM toward HuTu-80. This is at the level of the reference drug doxorubicin. TPP-pharmacosomes (10/PC) increased the cytotoxic effect approximately 3 times toward HuTu-80 cells, providing high selectivity (SI = 480) compared to the normal liver cell line Chang liver.

Terpenes-Modified Lipid Nanosystems for Temozolomide, Improving Cytotoxicity against Glioblastoma Human Cancer Cells In Vitro.

Currently, increasing the efficiency of glioblastoma treatment is still an unsolved problem. In this study, a combination of promising approaches was proposed: (i) an application of nanotechnology approach to create a new terpene-modified lipid system (7% w/w), using soybean L-α-phosphatidylcholine, N-carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine for delivery of the chemotherapy drug, temozolomide (TMZ, 1 mg/mL); (ii) use of TMZ associated with natural compounds-terpenes (1% w/w) abietic acid and Abies sibirica Ledeb. resin (A. sibirica). Different concentrations and combinations of terpene-lipid systems were employed to treat human cancer cell lines T 98G (glioblastoma), M-Hela (carcinoma of the cervix) and human liver cell lines (Chang liver). The terpene-lipid systems appeared to be unilamellar and of spherical shape under transmission electron microscopy (TEM). The creation of a TMZ-loaded terpene-lipid nanosystem was about 100 nm in diameter with a negative surface charge found by dynamic light scattering. The 74% encapsulation efficiency allowed the release time of TMZ to be prolonged. The modification by terpenes of TMZ-loaded lipid nanoparticles improved by four times the cytotoxicity against human cancer T 98G cells and decreased the cytotoxicity against human normal liver cells. Terpene-modified delivery lipid systems are of potential interest as a combination therapy.

Phosphineoxide-Chelated Europium(III) Nanoparticles for Ceftriaxone Detection.

The present work demonstrates the optimization of the ligand structure in the series of bis(phosphine oxide) and ß-ketophosphine oxide representatives for efficient coordination of Tb3+ and Eu3+ ions with the formation of the complexes exhibiting high Tb3+- and Eu3+-centered luminescence. The analysis of the stoichiometry and structure of the lanthanide complexes obtained using the XRD method reveals the great impact of the bridging group nature between two phosphine oxide moieties on the coordination mode of the ligands with Tb3+ and Eu3+ ions. The bridging imido-group facilitates the deprotonation of the imido- bis(phosphine oxide) ligand followed by the formation of tris-complexes. The spectral and PXRD analysis of the separated colloids indicates that the high stability of the tris-complexes provides their safe conversion into polystyrenesulfonate-stabilized colloids using the solvent exchange method. The red Eu3+-centered luminescence of the tris-complex exhibits the same specificity in the solutions and the colloids. The pronounced luminescent response on the antibiotic ceftriaxone allows for sensing the latter in aqueous solutions with an LOD value equal to 0.974 µM.

Novel Mitochondria-Targeted Amphiphilic Aminophosphonium Salts and Lipids Nanoparticles: Synthesis, Antitumor Activity and Toxicity.

The creation of mitochondria-targeted vector systems is a new tool for the treatment of socially significant diseases. Phosphonium groups provide targeted delivery of drugs through biological barriers to organelles. For this purpose, a new class of alkyl(diethylAmino)(Phenyl) Phosphonium halides (APPs) containing one, two, or three diethylamino groups was obtained by the reaction of alkyl iodides (bromides) with (diethylamino)(phenyl)phosphines under mild conditions (20 °C) and high yields (93-98%). The structure of APP was established by NMR and XRD. A high in vitro cytotoxicity of APPs against M-HeLa, HuTu 80, PC3, DU-145, PANC-1, and MCF-7 lines was found. The selectivity index is in the range of 0.06-4.0 µM (SI 17-277) for the most active APPs. The effect of APPs on cancer cells is characterized by hyperproduction of ROS and depolarization of the mitochondrial membrane. APPs induce apoptosis, proceeding along the mitochondrial pathway. Incorporation of APPs into lipid systems (liposomes and solid lipid nanoparticles) improves cytotoxicity toward tumor cells and decrease toxicity against normal cell lines. The IC50s of lipid systems are lower than for the reference drug DOX, with a high SI (30-56) toward MCF-7 and DU-145. APPs exhibit high selective activity against Gram-positive bacteria S. aureus 209P and B. segeus 8035, including methicillin-resistant S. aureus (MRSA-1, MRSA-2), comparable to the activity of the fluoroquinolone antibiotic norfloxacin. A moderate in vivo toxicity in CD-1 mice was established for the lead APP.

Deoxygenation of some α-dicarbonyl compounds by tris(diethylamino)phosphine in the presence of fullerene C60.

The reactions of such cyclic α-diketones as acenaphthenequinone, aceanthrenequinone, and N-alkylisatins, with hexaethyltriaminophosphine in the presence of the fullerene C(60), lead to the formation of methanofullerene derivatives under mild conditions. This process proceeds via deoxygenation of the dicarbonyl compound by the P(III) derivative and is likely to involve the intermediate formation of α-ketocarbenes. The structure of some methanofullerenes has been confirmed by NMR and XRD. The electrochemical behavior of the methanofullerenes was also investigated.

The formation of cage phosphoranes and their rearrangements in the reactions of substituted 2-(3-oxo-3-phenyl)ethoxybenzo[d]-1,3,2-dioxaphospholes with perfluorodiacetyl.

The Kukhtin-Ramirez reaction of 2-(3-oxo-3-phenyl)ethoxy-benzo[d]-1,3,2-dioxaphospholes with perfluorodiacetyl was monitored by NMR methods. To our surprise the initial stage involved a kinetically controlled [4+4]-cycloaddition with the formation of a cage phosphorane containing a 2',5',8',9'-tetraoxa-2λ5-phosphaspiro[benzo[d][1,3,2]dioxaphosphole-2,1'-bicyclo[4.2.1]nonan]-3'-ene (compound 5) scaffold. Intermediate 5 then converts to spirophosphorane-4',5'-bis(trifluoromethyl)-2λ5-spiro[benzo[d] [1,3,2]dioxaphosphole-2-yl-2,2'-[1,3,2] dioxaphosphole (compound 4). Compound 4 further rearranges into a cage phosphorane derivative containing a [2,5]epoxybenzo[d][1,3,6,2]trioxaphosphocine] (compound 3) backbone.

Trialkyl(vinyl)phosphonium Chlorophenol Derivatives as Potent Mitochondrial Uncouplers and Antibacterial Agents.

Trialkyl phosphonium derivatives of vinyl-substituted p-chlorophenol were synthesized here by a recently developed method of preparing quaternary phosphonium salts from phosphine oxides using Grignard reagents. All the derivatives with a number (n) of carbon atoms in phosphonium alkyl substituents varying from 4 to 7 showed pronounced uncoupling activity in isolated rat liver mitochondria at micromolar concentrations, with a tripentyl derivative being the most effective both in accelerating respiration and causing membrane potential collapse, as well as in provoking mitochondrial swelling in a potassium-acetate medium. Remarkably, the trialkyl phosphonium derivatives with n from 4 to 7 also proved to be rather potent antibacterial agents. Methylation of the chlorophenol hydroxyl group suppressed the effects of P555 and P444 on the respiration and membrane potential of mitochondria but not those of P666, thereby suggesting a mechanistic difference in the mitochondrial uncoupling by these derivatives, which was predominantly protonophoric (carrier-like) in the case of P555 and P444 but detergent-like with P666. The latter was confirmed by the carboxyfluorescein leakage assay on model liposomal membranes.