The kinetics of alkyldiphenylphosphine addition to electron-deficient alkenes in the presence of carboxylic acids as the proton source has been studied. The reactivity of phosphines was found to follow the trend: PPh2Me > PPh2Et > PPh2n-Pr > PPh2Cy > PPh2i-Pr > PPh2t-Bu, regardless of the nature of the alkene and the solvent used. The effect of the alkyl group was analyzed using linear free energy relationships, which revealed poor correlation with the steric descriptors of the substituents. More strong correlations were observed between the rate constants and 13C and 31P NMR spectroscopic parameters of the phosphonium adducts, giving evidence for the crucial role of hyperconjugation in determining the reactivity of alkyldiphenylphosphines.

Cholinesterases (ChEs) are irreversibly inhibited by organophosphorous compounds (OP). Then, OP-inhibited ChEs undergo a reaction that progressively decreases reactivatability. This process called “aging” results from dealkylation of the adduct. Aged ChEs are resistant to antidotal oximes. Structural and conformational changes in the aged phosphylated ChE active site pocket impair enzyme reactivatability. Thus, reactivation of aged ChEs was a challenge for more than 70 years. However, it was postulated that realkylation of aged adducts could lead to reactivation of enzymes. This hypothesis was confirmed in 2018 when a new generation of reactivators, electrophilic quinone methide precursors (QMPs), capable of resuscitating or resurrecting aged ChEs were synthesized. The QMP-mediated resurrection process of ChEs by these first “resurrectors” is still very slow. Thus, substantial optimization in the chemical design of new drugs and drug-targeted delivery are needed before the resurrection approach can be translated into clinically viable therapies. However, despite limitations, the first achievements resolving the non-reactivatability issue of OP-aged cholinesterases and successful administration of these new reactivators can be regarded as a major step forward in improving the therapy of OP poisoning.

A convenient approach to the synthesis of quaternary phosphonium salts, bearing a diterpenoid fragment is proposed. This highly regioselective synthesis is based on the reaction of quinopimaric and dehydroquinopimaric acids with P─H-phosphonium salts. The structures of obtained quaternary phosphonium salts based on quinopimaric and dehydroquinopimaric acid were confirmed by NMR and IR spectroscopy, mass spectrometry, and XRD. Compounds possess both antibacterial activity and in vitro cytotoxicity against human cancer cell lines. Selectivity of cytotoxic action depends on substituents in the aromatic moieties of phosphonium salts. Also, phosphonium derivatives of quinopimaric acid, possessing a hydroxyvinyl fragment bound directly to the phosphorus atom, show a higher cytotoxicity than dehydroquinopimaric acid phosphonium derivatives. Highest cytotoxicity is for the phosphonium derivatives of quinopimaric acid, containing 4-methoxyphenyl substituents (IC50 = 1.5-2.8 µM). Apoptosis test suggests that the cytotoxic mechanism involves a substantial contribution of the mitochondrial pathway of apoptosis.

The smart design and stimulus-sensitive control of the properties of mitochondria-targeted systems are at the forefront of advanced and promising therapies for numerous diseases. We report a series of amphiphilic 3-alkoxy-2-hydroxypropyl triphenylphosphonium salts (RO-HP-TPPSs, where R = CnH2n+1 and n = 1-18) that act as new mitochondrial agents and molecular regulators of liposome membrane permeability, with low melting points of <100 degrees C. The dodecyl (R = C12H25) and tetradecyl (R = C14H29) derivatives of RO-HP-TPPSs, with Krafft points close to 36 degrees C and 58 degrees C, respectively, form micelle-like associates at concentrations of 400 and 150 & micro;M, respectively. The lipid film hydration method is used to prepare RO-HP-TPPS-decorated soy phosphatidylcholine-based liposomes and PEG-liposomes with a size of 100 nm, a charge of +40 mV and good stability. The cytotoxicity of RO-HP-TPPS-containing PEGylated liposomes is comparable to that of doxorubicin against tumor cell lines and 10 times lower against normal cell lines. The tuning of their hydrophilic cargo release properties is done at physiological temperature and hyperthermia conditions at 45 degrees C.

The reaction of (-)-menthyl/(-)-bornyl glycidyl ethers with H-triphenylphosphonium or H-triphenylarsonium triflates proceeds as a regioselective oxirane-opening at the terminal CH2 fragment with the formation of the corresponding 2-hydroxy-3-terpenyloxypropylphosphonium or arsonium triflates. The salts thus prepared demonstrate high antimicrobial (MIC 1.9-3.9 & micro;M S. aureus) and antitumor (IC50 0.1-1.1 & micro;M HuTu 80) activities.

A convenient synthetic approach to the synthesis of TPP-conjugated derivatives of 9,10-anthraquinone from naturally occurring diterpene levopimaric acid and 1,4-naphthoquinone in four stages has been developed. A series of quaternary phosphonium salts differed by a length of an alkyl linker has been synthesized. The obtained compounds showed cytotoxic (IC50 ≥ 0.20 μM) and bactericidal (MIC ≥ 0.90 μM) activity comparable to that of reference drugs.

Delocalized positive charge and high hydrophobicity of triarylphosphonium (TPP) groups facilitate a penetration of the TPP-conjugated molecules through the cell and mitochondrial membranes, which result in their accumulating in tumor cells. Combining mitochondrial strategies with nanotechnology-based delivery systems is a challenge to the new cancer therapy approaches. Using synthetic approach for targeted delivery of small molecules with antitumor activity into mitochondria, the quaternary γ-oxoalkylphosphonium salts (TPP-alantolactone, TPP-AL) were synthesized under mild conditions with high yields. First time mitochondria-targeted lipid nanosystems, namely, liposomes and solid lipid nanoparticles (SLN) modified with TPP-AL were prepared and characterized. TPP-alantolactones showed a high in vitro cytotoxicity. The highest cytotoxicity against human duodenal adenocarcinoma cell lines (HuTu 80) occurred at IC50 = 0.4 µM with a high selectivity of 17.5. Cytotoxicity is increased up to 520-fold when tested TPP-alantolactone-SLN (TPP-AL-SLN) against M-HeLa cancer cell lines. The enhanced cellular uptake and accumulation of curcumin-labeled-TPP-AL-SLN were shown by confocal microscopy. TPP-AL caused a significant depolarization of mitochondrial membrane in the HuTu 80 cancer cells, increased ROS production and over expression of caspase-9, suggesting an intrinsic mitochondrial mechanism for triggering apoptosis. A significant delay of cells in the G0/G1 phase compared to the control was revealed. In addition to the anti-tumor effect TPP-AL exhibit a bactericidal activity, i.e. they are dual-action drugs. TPP-AL are noticeably active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), with a minimum bactericidal concentration (MBC) of 7.8 µM, which is close to the antibiotic norfloxacin. TPP-derived sesquiterpene lactones-decorated nanosystems showed a high potential as antitumor agents for the targeted delivery to the mitochondria of tumor cells.

A series of silver-polygalacturonate complexes with improved structure and activity against bacterial infections was developed. Pure sodium polygalacturonate was obtained by saponification of a pectin precursor and identified by NMR as predominantly homogalacturonan (uronide content 95%). Polygalacturonate complexes with ionic and borohydride-reduced silver with a controllable metallic component were synthesized; the role of spontaneous Ag+ reduction was revealed. The presence of uniform 5 nm nanoparticles and negligible particulate by-products in the reduced complexes was verified. The complexes showed similar silver-normalized activity against non-resistant bacteria, irrespective of complex stoichiometry/silver state. Pharmaceutical silver proteinate with a similar nanoparticle profile exhibited the same silver-normalized activity, indicating the lack of a ligand effect. The Ag+ complex was more effective against some hospital drug-resistant strains. The cytotoxicity of the complexes depended on fibroblast type, silver state, ligand type, exposure time, presumably in association with cellular availability and glutathione depletion. The complexes were administered to rats with excisional wounds persistently infected with S. aureus. Swab/histological analyses of the treated wounds revealed decreased bacterial burden/tissue damage, along with promotion of wound contraction/closure and matrix formation. The nanoparticle complexes that were compared had similar antibacterial/regenerative effects, while the Ag+ complex demonstrated higher efficacy in vivo. These results encourage the use of the developed silver-polygalacturonate complexes as antibacterial substances.

A series of alkyl[2-(5-chloro-2-hydroxyphenyl)hex-1-en-1-yl]diphenylphosphonium salts were synthesized based on the predicted lipophilicity (logP). The synthesized salts exhibited high antimicrobial activity against gram-positive bacterial and fungal strains and high activity against the antibiotic-resistant Staphylococcus aureus (MRSA) strains. The most active compounds showed low cytotoxicity against human erythrocytes and liver cells and exhibited high selectivity indices.

Using triterpenoid betulin as an example, a convenient method for the synthesis of 5,6-dihydropyran derivatives containing a nor-triterpenoid fragment at position 4 was proposed. The method involves the reaction of lupane triterpenoids with paraformaldehyde in dioxane in the presence of sulfuric acid. Approaches to the synthesis of triterpene derivatives of 5,6-dihydropyran-2-one and penta-2,4-dienoic acid were developed based on the obtained 4-(3,28-diacetoxy-20,29,30-tri-nor-lupan-19-yl)-5,6-dihydropyran. Triterpene-substituted penta-2,4-dienoic acid heated with triphenylphosphonium triflate formed a quaternary phosphonium salt, which showed cytotoxicity against human cancer cells MCF-7 (breast cancer) and HCT116 (colon cancer) with IC50 4–19 µmol L−1, with its activity against these cell lines being superior to the activity of the comparison drug camptothecin.

Coordination complexes of cobalt represent a potential alternative to anticancer platinum-derived drugs owing to multiple activities and better toxicity profile. This work is aimed at generation of novel cobalt complexes based on peptide-conjugated diethylentriamine (Dien) ligand. Dien derivatives including SPPS-compliant Boc-protected N,N′-di(2-aminoethyl)glycine and its conjugate with RGD peptide derivative (compound 6) were synthesized. Cobalt(III) complexes of Dien and 6 were obtained and characterized. Both complexes exhibited comparable ATP-depleting activity in solution and in PC-3 and OVCAR-4 cancer cells. The complex of 6 showed profoundly increased prooxidant, cytotoxic, and apoptotic in vitro effects compared to the non-targeted counterpart. Both complexes bound DNA and caused its significant damage in the presence of glutathione or hydrogen peroxide. These results provide an important background for development of bioactive cobalt complexes conjugated with biospecific oligopeptides.

The reactions of 1,1,1,2,3-pentachloro-1-phosphaindene (1) with phenylacetylene and catechol were found to lead to the regioselective formation of the addition product, 1,1,2,3-tetrachloro-1-(2-chloro-2-phenylvinyl)-1-phosphaindene (6), and spirophosphorane, 1,2-bis(2′,3′-dichloro-2H-2λ5-spiro[benzo[d][1,3,2]dioxaphosphole-2,1′-phosphaindene]-2-yl)oxybenzene (13). The hydrolysis of compound 6 proceeds through the intermediate formation of (Z)-2,3-dichloro-1-(2-chloro-2-phenylvinyl)phosphaindene 1-oxide (9) and affords the P—C bond cleavage product, [(Z)-2-chloro-2-phenylvinyl]-(2-[(Z)-1,2-dichlorovinyl]phenylphosphinic acid (10). The structures of compounds 1, 6, and 13 were determined by X-ray diffraction. Compound 6 is the first example of monocyclic phosphoranes containing the phosphorus atom in a nearly ideal trigonal-bipyramidal configuration with an antiapicophilic (diequatorial) arrangement of the five-membered ring at the base. Quantum chemical calculations showed that this structure is favorable due to conjugation effects. Compound 13 has a planar chirality in the crystal (space group P21).

The reaction of quinopimaric acid with P–H-phosphonium salts yielded quaternary phosphonium salts containing enol moiety at the phosphorus atom. The reaction proceeded with high regioselectivity. The structures of the resulting compounds were confirmed by NMR and IR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction.

The reaction of alantolactone, a sesquiterpene α,β-unsaturated lactone, with H-phosphonium or H-arsonium triflates proceeds as P–H or As–H addition at the terminal =CH2 moiety to afford novel triphenyl(sesquiterpenyl)phosponium or -arsonium triflates. Their diastereoisomerism at the formed C11 chiral center has been simulated by quantum chemical calculations.

Cholinesterases (ChEs) display a non-michaelian behavior with positively charged substrates. In the steady-state rate equation, the b factor describes this behavior: if b > 1 there is substrate activation, if b < 1 there is substrate inhibition. The mechanistic significance of the b factor was investigated to determine whether this behavior depends on acylation, deacylation or on both steps. Kinetics of human acetyl- (AChE) and butyryl-cholinesterase (BChE) were performed under steady-state conditions and using a time-course of complete substrate hydrolysis. For the hydrolysis of short acyl(thio)esters, where acylation and deacylation are partly rate-limiting, steady-state kinetic analysis could not decide which step determines b. However, the study of the hydrolysis of an arylacylamide, 3-(acetamido)-N,N,N-trimethylanilinium (ATMA), where acetylation is rate-limiting, showed that b depends on the acylation step. The magnitude of b and opposite b values between AChE and BChE for the hydrolysis of acetyl(thio)- versus benzoyl-(thio) esters, then indicated that the productive adjustment of substrates in the active center at high concentration depends on motions of both the Ω and the acyl-binding loops. Benzoylcholine was shown to be a poor substrate of AChE, and steady-state kinetics showed a sudden inhibition at high concentration, likely due to the non-dissociation of hydrolysis products. The poor catalytic hydrolysis of this bulky ester by AChE illustrates the importance of the fine adjustment of substrate acyl moiety in the acyl-binding pocket. Molecular modeling and QM/MM simulations should definitively provide evidence for this statement.

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.

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.

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.

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.

Mitochondrial dysfunctions lead to the emergence and development of a large number of diseases. The present review gives the first systematic survey of various aspects of studies of mitochondria-targeted nanosystems containing triphenylphosphonium vector groups providing targeted delivery of drug substances to these organelles. Approaches to the design of components and various nanoparticles bearing these groups are summarized and analyzed. The relationship between the key parameters of triphenylphosphonium nanoparticles (chemical composition, size, shape, ζ-potential, drug loading, drug encapsulation efficiency, etc.) and the biological action is discussed; in some cases, the mechanism of mitochondria targeting is given. The design principles and preparation methods for mitochondria-targeted triphenylphosphonium delivery nanosystems are of interest to researchers in the field of nanomaterials, nanotechnology, molecular biology, biotechnology and pharmaceutical chemistry. The bibliography includes 243 references.