Discovery of Di(het)arylmethane and Dibenzoxanthene Derivatives as Potential Anticancer Agents.

A family of bifunctional dihetarylmethanes and dibenzoxanthenes is assembled via a reaction of acetals containing a 2-chloroacetamide moiety with phenols and related oxygen-containing heterocycles. These compounds demonstrated selective antitumor activity associated with the induction of cell apoptosis and inhibition of the process of glycolysis. In particular, bis(heteroaryl)methane containing two 4-hydroxy-6-methyl-2H-pyran-2-one moieties combine excellent in vitro antitumor efficacy with an IC50 of 1.7 µM in HuTu-80 human duodenal adenocarcinoma models with a high selectivity index of 73. Overall, this work highlights the therapeutic potential of dimeric compounds assembled from functionalized acetals and builds a starting point for the development of a new family of anticancer agents.

Synthesis, cytotoxicity and antioxidant activity of new conjugates of N-acetyl-d-glucosamine with α-aminophosphonates.

A series of the first conjugates of N-acetyl-d-glucosamine with α-aminophosphonates was synthesized using the Kabachnik-Fields reaction, the Pudovik reaction, a copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) and evaluated for the in vitro cytotoxicity against human cancer cell lines M - HeLa, HuTu-80, A549, PANC-1, MCF-7, T98G and normal lung fibroblast cells WI-38. The tested conjugates, with exception of compound 21b, considered as a lead compound, were either inactive against the used cancer cells or showed moderate cytotoxicity in the range of IC50 values 33-80 µM. The lead compound 21b, being non cytotoxic against normal human cells WI-38 (IC50 = 90 µM), demonstrated good activity (IC50 = 17 µM) against breast adenocarcinoma cells (MCF-7) which to be 1.5 times higher than the activity of the used reference anticancer drug tamoxifen (IC50 = 25.0 µM). A flexible receptor molecular docking simulation showed that the cytotoxicity of the synthesized conjugates of N-acetyl-d-glucosamine with α-aminophosphonates against breast adenocarcinoma MCF-7 cell line is due to their ability to inhibit EGFR kinase domain. In addition, it was found that conjugates 22a and 22b demonstrated antioxidant activity that was not typical for α-aminophosphonates.

Phosphine-Catalyzed Synthesis and Cytotoxic Evaluation of Michael Adducts of the Sesquiterpene Lactone Arglabin.

A general method for chemo- and diastereoselective modification of anticancer natural product arglabin with nitrogen- and carbon-centered pronucleophiles under the influence of nucleophilic phosphine catalysts was developed. The locked s-cis-geometry of α-methylene-γ-butyrolactone moiety of arglabin favors for the additional stabilization of the zwitterionic intermediate by electrostatic interaction between phosphonium and enolate oxygen centers, leading to the unprecedentedly high efficiency of the phosphine-catalyzed Michael additions to this sesquiterpene lactone. Using n-Bu3P as the catalyst, pyrazole, phthalimide, 2-oxazolidinone, 4-quinazolinone, uracil, thymine, cytosine, and adenine adducts of arglabin were obtained. The n-Bu3P-catalyzed reaction of arglabin with active methylene compounds resulted in the predominant formation of bisadducts bearing a new quaternary carbon center. All synthesized Michael adducts and previously obtained phosphorylated arglabin derivatives were evaluated in vitro against eleven cancer and two normal cell lines, and the results were compared to those of natural arglabin and its dimethylamino hydrochloride salt currently used as anticancer drugs. 2-Oxazolidinone, uracil, diethyl malonate, dibenzyl phosphonate, and diethyl cyanomethylphosphonate derivatives of arglabin exhibited more potent antiproliferative activity towards several cancer cell lines and lower cytotoxicity towards normal cell lines in comparison to the reference compounds, indicating the feasibility of the developed methodology for the design of novel anticancer drugs with better therapeutic potential.

Towards Antibacterial Agents: Synthesis and Biological Activity of Multivalent Amide Derivatives of Thiacalix[4]arene with Hydroxyl and Amine Groups.

Antimicrobial resistance to modern antibiotics stimulates the search for new ways to synthesize and modify antimicrobial drugs. The development of synthetic approaches that can easily change different fragments of the molecule is a promising solution to this problem. In this work, a synthetic approach was developed to obtain multivalent thiacalix[4]arene derivatives containing different number of amine and hydroxyl groups. A series of macrocyclic compounds in cone, partial cone, and 1,3-alternate stereoisomeric forms containing -NHCH2CH2R (R = NH2, N(CH3)2, and OH) and -N(CH2CH2OH)2 terminal fragments, and their model non-macrocyclic analogues were obtained. The antibacterial activity against Gram-positive (Staphylococcus aureus, Bacillus cereus, and Enterococcus faecalis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains and cytotoxicity of the obtained compounds were studied. Structure-activity relationships were established: (1) the macrocyclic compounds had high antibacterial activity, while the monomeric compounds had low activity; (2) the compounds in cone and partial cone conformations had better antibacterial activity compared to the compounds in 1,3-alternate stereoisomeric form; (3) the macrocyclic compounds containing -NHCH2CH2N(CH3)2 terminal fragments had the highest antibacterial activity; (4) introduction of additional terminal hydroxyl groups led to a significant decrease in antibacterial activity; (5) the compounds in partial cone conformation had significant bactericidal activity against all studied cell strains; the best selectivity was observed for the compounds in cone conformation. The mechanism of antibacterial activity of lead compounds with terminal fragments -NHCH2CH2N(CH3)2 was proved using model negatively charged POPG vesicles, i.e., the addition of these compounds led to an increase in the size and zeta potential of the vesicles. The obtained results open up the possibility of using the synthesized macrocyclic compounds as promising antibacterial agents.

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.

ROS-producing nanomaterial engineered from Cu(I) complexes with P2N2-ligands for cancer cells treating.

The work presents core-shell nanoparticles (NPs) built from the novel Cu(I) complexes with cyclic P2N2-ligands (1,5-diaza-3,7-diphosphacyclooctanes) that can visualize their entry into cancer and normal cells using a luminescent signal and treat cells by self-enhancing generation of reactive oxygen species (ROS). Variation of P- and N-substituents in the series of P2N2-ligands allows structure optimization of the Cu(I) complexes for the formation of the luminescent NPs with high chemical stability. The non-covalent modification of the NPs with triblock copolymer F-127 provides their high colloidal stability, followed by efficient cell internalization of the NPs visualized by their blue (⁓450 nm) luminescence. The cytotoxic effects of the NPs toward the normal and some of cancer cells are significantly lower than those of the corresponding molecular complexes, which correlates with the chemical stability of the NPs in the solutions. The ability of the NPs to self-enhanced and H2O2-induced ROS generation is demonstrated in solutions and intracellular space by means of the standard electron spin resonance (ESR) and fluorescence techniques correspondingly. The anticancer specificity of the NPs toward HuTu 80 cancer cells and the apoptotic cell death pathway correlate with the intracellular level of ROS, which agrees well with the self-enhancing ROS generation of the NPs. The enhanced level of ROS revealed in HuTu 80 cells incubated with the NPs can be associated with the significant level of their mitochondrial localization.

Oxygen-Containing Quaternary Phosphonium Salts (oxy-QPSs): Synthesis, Properties, and Cellulose Dissolution.

In the present study, the synthesis of oxygen-containing quaternary phosphonium salts (oxy-QPSs) was described. Within this work, structure-property relationships of oxy-QPSs were estimated by systematic analysis of physical-chemical properties. The influence of the oxygen-containing substituent was examined by comparing the properties of oxy-QPSs in homology series as well as with phosphonium analog-included alkyl side chains. The crystal structure analysis showed that the oxygen introduction influences the conformation of the side chain of the oxy-QPS. It was found that oxy-QPSs, using an aprotic co-solvent, dimethylsulfoxide (DMSO), can dissolve microcrystalline cellulose. The cellulose dissolution in oxy-QPSs appeared to be dependent on the functional group in the cation and anion nature. For the selected conditions, dissolution of up to 5 wt% of cellulose was observed. The antimicrobial activity of oxy-QPSs under study was expected to be low. The biocompatibility of oxy-QPSs with fermentative microbes was tested on non-pathogenic Saccharomyces cerevisiae, Lactobacillus plantarum, and Bacillus subtilis. This reliably allows one to safely address the combined biomass destruction and enzyme hydrolysis processes in one pot.

Mitochondria-Targeted Lipid Nanoparticles Loaded with Rotenone as a New Approach for the Treatment of Oncological Diseases.

This research is based on the concept that mitochondria are a promising target for anticancer therapy, including thatassociated with the use of oxidative phosphorylation blockers (mitochondrial poisons). Liposomes based on L-α-phosphatidylcholine (PC) and cholesterol (Chol) modified with cationic surfactants with triphenylphosphonium (TPPB-n, where n = 10, 12, 14, and 16) and imidazolium (IA-n(OH), where n = 10, 12, 14, and 16) head groups were obtained. The physicochemical characteristics of liposomes at different surfactant/lipid molar ratios were determined by dynamic/electrophoretic light scattering, transmission electron microscopy, and spectrophotometry. The hydrodynamic diameter of all the systems was within 120 nm with a polydispersity index of no more than 0.24 even after 2 months of storage. It was shown that cationization of liposomes leads to an increase in the internalization of nanocontainers in pancreatic carcinoma (PANC-1) and duodenal adenocarcinoma (HuTu 80) cells compared with unmodified liposomes. Also, using confocal microscopy, it was shown that liposomes modified with TPPB-14 and IA-14(OH) statistically better colocalize with the mitochondria of tumor cells compared with unmodified ones. At the next stage, the mitochondrial poison rotenone (ROT) was loaded into cationic liposomes. It was shown that the optimal loading concentration of ROT is 0.1 mg/mL. The Korsmeyer-Peppas and Higuchi kinetic models were used to describe the release mechanism of ROT from liposomes in vitro. A significant reduction in the IC50 value for the modified liposomes compared with free ROT was shown and, importantly, a higher degree of selectivity for the HuTu 80 cell line compared with the normal cells (SI value is 307 and 113 for PC/Chol/TPPB-14/ROT and PC/Chol/IA-14(OH)/ROT, respectively) occurred. It was shown that the treatment of HuTu 80 cells with ROT-loaded cationic liposomal formulations leads to a dose-dependent decrease in the mitochondrial membrane potential.

Anticancer and Antiphytopathogenic Activity of Fluorinated Isatins and Their Water-Soluble Hydrazone Derivatives.

A series of new fluorinated 1-benzylisatins was synthesized in high yields via a simple one-pot procedure in order to explore the possible effect of ortho-fluoro (3a), chloro (3b), or bis-fluoro (3d) substitution on the biological activity of this pharmacophore. Furthermore, the new isatins could be converted into water-soluble isatin-3-hydrazones using their acid-catalyzed reaction with Girard's reagent P and its dimethyl analog. The cytotoxic action of these substances is associated with the induction of apoptosis caused by mitochondrial membrane dissipation and stimulated reactive oxygen species production in tumor cells. In addition, compounds 3a and 3b exhibit platelet antiaggregation activity at the level of acetylsalicylic acid, and the whole series of fluorine-containing isatins does not adversely affect the hemostasis system as a whole. Among the new water-soluble pyridinium isatin-3-acylhydrazones, compounds 7c and 5c,e exhibit the highest antagonistic effect against phytopathogens of bacterial and fungal origin and can be considered useful leads for combating plant diseases.

Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis.

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.

Synthesis, Properties, and Biomedical Application of Dicationic Gemini Surfactants with Dodecane Spacer and Carbamate Fragments.

A synthesis procedure and aggregation properties of a new homologous series of dicationic gemini surfactants with a dodecane spacer and two carbamate fragments (N,N'-dialkyl-N,N'-bis(2-(ethylcarbamoyloxy)ethyl)-N,N'-dimethyldodecan-1,6-diammonium dibromide, n-12-n(Et), where n = 10, 12, 14) were comprehensively described. The critical micelle concentrations of gemini surfactants were obtained using tensiometry, conductometry, spectrophotometry, and fluorimetry. The thermodynamic parameters of adsorption and micellization, i.e., maximum surface excess (Гmax), the surface area per surfactant molecule (Amin), degree of counterion binding (ß), and Gibbs free energy of micellization (∆Gmic), were calculated. Functional activity of the surfactants, including the solubilizing capacity toward Orange OT and indomethacin, incorporation into the lipid bilayer, minimum inhibitory concentration, and minimum bactericidal and fungicidal concentrations, was determined. Synthesized gemini surfactants were further used for the modification of liposomes dual-loaded with α-tocopherol and donepezil hydrochloride for intranasal treatment of Alzheimer's disease. The obtained liposomes have high stability (more than 5 months), a significant positive charge (approximately + 40 mV), and a high degree of encapsulation efficiency toward rhodamine B, α-tocopherol, and donepezil hydrochloride. Korsmeyer-Peppas, Higuchi, and first-order kinetic models were used to process the in vitro release curves of donepezil hydrochloride. Intranasal administration of liposomes loaded with α-tocopherol and donepezil hydrochloride for 21 days prevented memory impairment and decreased the number of Aß plaques by 37.6%, 40.5%, and 72.6% in the entorhinal cortex, DG, and CA1 areas of the hippocampus of the brain of transgenic mice with Alzheimer's disease model (APP/PS1) compared with untreated animals.

Diverse Biological Activity of Benzofuroxan/Sterically Hindered Phenols Hybrids.

Combining two pharmacophores in a molecule can lead to useful synergistic effects. Herein, we show hybrid systems that combine sterically hindered phenols with dinitrobenzofuroxan fragments exhibit a broad range of biological activities. The modular assembly of such phenol/benzofuroxan hybrids allows variations in the phenol/benzofuroxan ratio. Interestingly, the antimicrobial activity only appears when at least two benzofuroxan moieties are introduced per phenol. The most potent of the synthesized compounds exhibit high cytotoxicity against human duodenal adenocarcinoma (HuTu 80), human breast adenocarcinoma (MCF-7), and human cervical carcinoma cell lines. This toxicity is associated with the induction of apoptosis via the internal mitochondrial pathway and an increase in ROS production. Encouragingly, the index of selectivity relative to healthy tissues exceeds that for the reference drugs Doxorubicin and Sorafenib. The biostability of the leading compounds in whole mice blood is sufficiently high for their future quantification in biological matrices.

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.

The Formation of Morphologically Stable Lipid Nanocarriers for Glioma Therapy.

Cerasomes are a promising modification of liposomes with covalent siloxane networks on the surface that provide outstanding morphological stability while maintaining all the useful traits of liposomes. Herein, thin film hydration and ethanol sol injection methods were utilized to produce cerasomes of various composition, which were then evaluated for the purpose of drug delivery. The most promising nanoparticles obtained by the thin film method were studied closely using MTT assay, flow cytometry and fluorescence microscopy on T98G glioblastoma cell line and modified with surfactants to achieve stability and the ability to bypass the blood-brain barrier. An antitumor agent, paclitaxel, was loaded into cerasomes, which increased its potency and demonstrated increased ability to induce apoptosis in T98G glioblastoma cell culture. Cerasomes loaded with fluorescent dye rhodamine B demonstrated significantly increased fluorescence in brain slices of Wistar rats compared to free rhodamine B. Thin film hydration with Tween 80 addition was established as a more reliable and versatile method for cerasome preparation. Cerasomes increased the antitumor action of paclitaxel toward T98G cancer cells by a factor of 36 and were able to deliver rhodamine B over the blood-brain barrier in rats.

(2-Hydroxy-3-Methoxybenzylidene)thiazolo[3,2-a]pyrimidines: Synthesis, Self-Assembly in the Crystalline Phase and Cytotoxic Activity.

A series of new 2-hydroxy-3-methoxybenzylidenethiazolo[3,2-a]pyrimidines with different aryl substituents at the 5 position are synthesized and characterized by 1H/ 13C NMR and IR-spectroscopy and mass-spectrometry, as well as single crystal X-ray diffraction (SCXRD). It was demonstrated that the type of hydrogen bonding can play a key role in the chiral discrimination of these compounds in the crystalline phase. The hydrogen bond of the O-H...N type leads to 1D supramolecular heterochiral chains or conglomerate crystallization in the case of the formation of homochiral chains. The hydrogen bond of O-H...O type gave racemic dimers, which are packed into 2D supramolecular layers with a parallel or angular dimers arrangement. Halogen bonding of the N...Br or O...Br type brings a new motif into supramolecular self-assembly in the crystalline phase: the formation of 1D supramolecular homochiral chains instead 2D supramolecular layers. The study of cytotoxicity against various tumor cells in vitro was carried out. It was found that 2-hydroxy-3-methoxybenzylidenethiazolo[3,2-a]pyrimidines with 3-nitrophenyl substituent at C5 carbon atom demonstrated a high efficiency against M-HeLa (cervical adenocarcinoma) and low cytotoxicity against normal liver cells.

Thymine-Modified Nanocarrier for Doxorubicin Delivery in Glioblastoma Cells.

Brain tumor glioblastoma is one of the worst types of cancer. The blood-brain barrier prevents drugs from reaching brain cells and shields glioblastoma from treatment. The creation of nanocarriers to improve drug delivery and internalization effectiveness may be the solution to this issue. In this paper, we report on a new nanocarrier that was developed to deliver the anticancer drug doxorubicin to glioblastoma cells. The nanocarrier was obtained by nanoemulsion polymerization of diallyl disulfide with 1-allylthymine. Diallyl disulfide is a redox-sensitive molecule involved in redox cell activities, and thymine is a uracil derivative and one of the well-known bioactive compounds that can enhance the pharmacological activity of doxorubicin. Doxorubicin was successfully introduced into the nanocarrier with a load capacity of about 4.6%. Biological studies showed that the doxorubicin nanocarrier composition is far more cytotoxic to glioblastoma cells (T98G) than it is to cancer cells (M-HeLa) and healthy cells (Chang liver). The nanocarrier improves the penetration of doxorubicin into T98G cells and accelerates the cells' demise, as is evident from flow cytometry and fluorescence microscopy data. The obtained nanocarrier, in our opinion, is a promising candidate for further research in glioblastoma therapy.

Transdermal Delivery of 2-PAM as a Tool to Increase the Effectiveness of Traditional Treatment of Organophosphate Poisoning.

For the first time, the efficacy of post-exposure treatment of organophosphate (OP) poisoning was increased by transdermal delivery of acetylcholinesterase (AChE) reactivator pyridine-2-aldoxime methochloride (2-PAM) as a preventive countermeasure. By selecting the optimal ratio of components, classical transfersomes (based on soybean phosphatidylcholine and Tween 20) and modified transfersomes (based on soybean phosphatidylcholine, Tween 20 and pyrrolidinium cationic surfactants with different hydrocarbon tail lengths) were obtained for 2-PAM encapsulation. Transfersomes modified with tetradecylpyrrolidinium bromide showed the best results in encapsulation efficiency and sustained release of 2-PAM from vesicles. Using Franz cells, it was found that the incorporation of surfactants into PC liposomes results in a more prolonged release of 2-PAM through the rat skin. Transfersomes containing 2-PAM, after exhaustive physical and chemical characterization, were embedded in a gel based on Carbopol® 940. A significantly high degree of erythrocyte AChE reactivation (23 ± 7%) was shown for 2-PAM in unmodified transfersomes in vivo. Preliminary transdermal administration of 2-PAM 24 h before emergency post-exposure treatment of OP poisoning leads to an increase in the survival rate of rats from 55% to 90%.

Calix[4]Resorcinarene Carboxybetaines and Carboxybetaine Esters: Synthesis, Investigation of In Vitro Toxicity, Anti-Platelet Effects, Anticoagulant Activity, and BSA Binding Affinities.

As a result of bright complexation properties, easy functionalization and the ability to self-organize in an aqueous solution, amphiphilic supramolecular macrocycles are being actively studied for their application in nanomedicine (drug delivery systems, therapeutic and theranostic agents, and others). In this regard, it is important to study their potential toxic effects. Here, the synthesis of amphiphilic calix[4]resorcinarene carboxybetaines and their esters and the study of a number of their microbiological properties are presented: cytotoxic effect on normal and tumor cells and effect on cellular and non-cellular components of blood (hemotoxicity, anti-platelet effect, and anticoagulant activity). Additionally, the interaction of macrocycles with bovine serum albumin as a model plasma protein is estimated by various methods (fluorescence spectroscopy, synchronous fluorescence spectroscopy, circular dichroic spectroscopy, and dynamic light scattering). The results demonstrate the low toxicity of the macrocycles, their anti-platelet effects at the level of acetylsalicylic acid, and weak anticoagulant activity. The study of BSA-macrocycle interactions demonstrates the dependence on macrocycle hydrophilic/hydrophobic group structure; in the case of carboxybetaines, the formation of complexes prevents self-aggregation of BSA molecules in solution. The present study demonstrates new data on potential drug delivery nanosystems based on amphiphilic calix[4]resorcinarenes for their cytotoxicity and effects on blood components.

Diastereoselective Synthesis of Novel Spiro-Phosphacoumarins and Evaluation of Their Anti-Cancer Activity.

Herein we present the regio- and diastereoselective synthesis of novel pyrrolidine-fused spiro-dihydrophosphacoumarins via intermolecular [3 + 2] cycloaddition reaction. The presented approach is complementary to existing ones and provides an easy entry to the otherwise inaccessible derivatives. Additionally, the unprecedented pathway of the reaction of 4-hydroxycoumarin with azomethine ylides is described. The anti-cancer activity of the obtained compounds was tested in vitro, the most potent compound being 2.6-fold more active against the HuTu 80 cell line than the reference 5-fluorouracil, with a selectivity index > 32.