Lipophilic Complex Research Articles

Photostimulated Anticancer Activity of Mitochondria Localized Rhenium(I) Tricarbonyl Complexes Bearing 1H-imidazo[4,5-f][1,10]phenanthroline Ligands Against MDA-MB-231 Cancer Cells.

We have introduced Re(I) tricarbonyl complexes (ReL1 - ReL6) [Re(CO)3(N^N)Cl] where N^N = extensive π conjugated imidazo-[4,5-f]1,10-phenanthroline derivatives that helps in strong DNA intercalation, enhanced photophysical behavior, increase the 3π-π* character of T1 state for PDT and high value of lipophilicity for cell membrane penetration. These complexes exhibited prominent intraligand/ligand-centered (π - π*/ 1LC) absorption bands at λ 260 - 350 nm and relatively weak metal-to-ligand charge-transfer (1MLCT) bands within the λ 350 - 550 nm range. Among the six synthesized complexes, [(CO)3ReICl(K2-N,N-2-(4-(1-benzyl-1H-tetrazol-5-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline] (ReL6) exhibited outstanding potency (IC50 ~ 6 µM, PI > 9) under yellow light irradiation compared to dark conditions. Importantly, extremely lipophilic complex ReL6 showed effective penetration through the cell membrane and localized primarily in mitochondria (Pearson's correlation coefficient, PCC = 0.918) of MDA-MB-231 cells. Complex ReL6 exhibited more than 9 times higher photo-toxicity in normoxic and hypoxic environment of tumor by inducing 1O2 generation (type II PDT), radical generation triggered by NADH oxidation (type I PDT). This complex is a promising candidate for TNBC treatment in hypoxic tumors, with efficacy comparable to photofrin and have demonstrated CO release ability under UV light irradiation.

Modulation of intestinal permeability of 5-fluorouracil via phospholipid interaction based lipophilic complex designing and pharmacokinetic assessment

Modulation of intestinal permeability of 5-fluorouracil via phospholipid interaction based lipophilic complex designing and pharmacokinetic assessment

Hyphenation of lipophilic ruthenium(II)-diphosphine core with 5-fluorouracil: an effective metallodrug against glioblastoma brain cancer cells.

Glioblastoma multiforme (GBM) is the most common highly aggressive malignant brain tumor, with a very limited chance for survival post-diagnosis and post-treatment. Despite significant advancement in GBM genomics implicated in molecularly targeted chemotherapies, the prognosis remains poor and requires new drug discovery approaches. We used fluoropyrimidine 5-fluorouracil (5-FU), an antimetabolite anticancer drug conjugated or 'caged' within a lipophilic Ru(II)-diphosphine (dppe) core formulated as [RuII(dppe)2(5-FU)]PF6 (Ru-DPPE-5FU), where dppe = 1,2-bis(diphenylphosphino)ethane, and evaluated its in vitro cytotoxicity in depth with aggressive GBM cells (LN229). The hydrophilic nature of 5-FU limits its passage through the blood-brain barrier (BBB), which prevents its effective accumulation and efficacy for GBM tumors. Herein, we attempted to modulate the lipophilicity of 5-FU by inserting it within a well-designed lipophilic {Ru(dppe)2}-core with anticipated higher efficiency towards GBM. The physicochemical properties of [RuII(dppe)2(5-FU)]PF6 (Ru-DPPE-5FU) were studied using various spectroscopic and analytical techniques. The molecular structure was determined using X-ray crystallography, showing a distorted {RuP4NO} octahedral geometry with bidentate (N, O) binding of 5-FU and its aromatization in the Ru(II)-bound form. The 31P-NMR spectra of Ru-DPPE-5FU showed four closely spaced distinct 31P-signals, indicating four unique chemical environments around P, and the strong coupling constants between them make it a second-order spectrum. The RuII/RuIII redox potential in Ru-DPPE-5FU shifted by ∼0.91 V towards the anodic region as compared to its precursor complex cis-[Ru(dppe)2Cl2] (Ru-DPPE-Cl). DFT-based theoretical calculations have been performed to correlate the experimental electronic absorption spectra and redox behaviours of the complexes. The electrostatic potential (ESP) plots indicate the delocalization of the charge density on the O-/F-atom from the 5-FU ligand towards Ru(II) upon its complexation. The antioxidant properties of all the compounds were quantified by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The hyphenation of the 5-fluorouracil (5-FU) ligand to the lipophilic {Ru(dppe)2}-core endowed lipophilicity to Ru-DPPE-5FU with higher in vitro cytotoxicity (IC50 = 2.37 μM) against the LN229 GBM cells as compared to the hydrophilic 5-FU, suggesting efficient cellular uptake. Further biological assays indicated that the complex is highly potent in inhibiting significant proliferation and spheroid formation and restricting the migratory potentials of the GBM cells. Increased caspase 3/7 activity and the presence of apoptotic bodies at the center of 3-D GBM spheroids as revealed by AO/EB dual staining indicated a deeper penetration of the lipophilic complex. The Ru-DPPE-5FU complex displayed lower cytotoxicity in HaCaT normal cells (IC50 = 7.27 μM) in comparison to LN229 cancer cells with a selectivity index (S.I.) of ≥3. Overall, the synergism and caging of 5-FU within the hydrophobic {Ru(dppe)2}-core improves the pharmacokinetic profile of Ru-DPPE-5FU as a potent anticancer agent for glioblastoma.

Удосконалення комплексного підходу до лікування функціональних закрепів у дітей

Functional constipation in children has become a serious medical issue that needs to be addressed immediately. They can significantly limit children’s physical activity and social integration, which emphasizes the importance of providing them with effective care. Purpose - to analyze and improve the results of the complex use of a lactulose-based drug and prophylactic phytocylinders with a lipophilic complex of rose hips and chamomile extract in the treatment of functional constipation in children. Materials and methods. We examined 78 children with constipation over the past 3 years. They were divided into two groups. The first group included 36 (46.2%) patients, the second - 42 (53.8%). Patients of the first group received standard treatment according to the protocols of the Ministry of Health of Ukraine, patients of the second group received similar treatment and additionally lactulose in the form of syrup and a preparation based on prophylactic phytocylinders with a lipophilic complex of rose hips and chamomile extract during the course of treatment daily in the form of rectal suppositories. Results. Most patients were female (60.2%), had average physical development parameters. The duration of constipation ranged from 1 to 3 months, and stool retention - from 3 to 5 days. At the beginning of the observation, there were complaints of changes in the shape and consistency of stools, painful defecation, flatulence, periodic abdominal pain, strong straining during defecation, fear or anxiety in children before the act of defecation. An analysis of anamnestic data showed that in one third of patients, constipation was observed during the transition from breastfeeding to artificial feeding. Conclusions. The analysis of the addition to the complex of treatment of functional constipation, in addition to lactulose, of preparations based on prophylactic phytocylinders with a lipophilic complex of rose hips and chamomile extract is a safe and quite effective method of correcting these disorders in young children, as evidenced by the results obtained. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Self-Emulsifying Drug Delivery Systems (SEDDS) Containing Reverse Micelles: Advanced Oral Formulations for Therapeutic Peptides.

Alternative methods to hydrophobic ion pairing for the formation of lipophilic complexes of peptide drugs to incorporate them in lipid-based nanocarriers such as self-emulsifying drug delivery systems (SEDDS) for oral administration are highly on demand. Such an alternative might be reverse micelles. Within this study, SEDDS containing dry reverse micelles (dRMsPMB ) formed with an anionic (sodium docusate; AOT), cationic (dimethyl-dioctadecyl-ammonium bromide; DODAB), amphoteric (soy lecithin; SL), or non-ionic (polysorbate 85; P85) surfactant loaded with the model peptide drug polymyxin B (PMB) are developed. They are characterized regarding size, payload, release kinetics, cellular uptake, and peptide activity. SEDDS exhibit sizes from 22.2±1.7 (AOT-SEDDS-dRMsPMB ) to 61.7±3.2nm (P85-SEDDS-dRMsPMB ) with payloads up to 2% that are approximately sevenfold higher than those obtained via hydrophobic ion pairing. Within 6h P85-SEDDS-dRMsPMB and AOT-SEDDS-dRMsPMB show no release of PMB in aqueous medium, whereas DODAB-SEDDS-dRMsPMB and SL-SEDDS-dRMsPMB show a sustained release. DODAB-SEDDS-dRMsPMB improves uptake by Caco-2 cells most efficiently reaching even ≈100% within 4h followed by AOT-SEDDS-dRMsPMB with ≈20% and P85-/SL-SEDDS-dRMsPMB with ≈5%. The peptide drug maintains its antimicrobial activity in all SEDDS-dRMsPMB . According to these results, SEDDS containing dRMs might be a game changing strategy for oral peptide drug delivery.

Selective ischemic-hemisphere targeting Ginkgolide B liposomes with improved solubility and therapeutic efficacy for cerebral ischemia-reperfusion injury

Cerebral ischemia-reperfusion injury (CI/RI) remains the main cause of disability and death in stroke patients due to lack of effective therapeutic strategies. One of the main issues related to CI/RI treatment is the presence of the blood-brain barrier (BBB), which affects the intracerebral delivery of drugs. Ginkgolide B (GB), a major bioactive component in commercially available products of Ginkgo biloba, has been shown significance in CI/RI treatment by regulating inflammatory pathways, oxidative damage, and metabolic disturbance, and seems to be a candidate for stroke recovery. However, limited by its poor hydrophilicity and lipophilicity, the development of GB preparations with good solubility, stability, and the ability to cross the BBB remains a challenge. Herein, we propose a combinatorial strategy by conjugating GB with highly lipophilic docosahexaenoic acid (DHA) to obtain a covalent complex GB-DHA, which can not only enhance the pharmacological effect of GB, but can also be encapsulated in liposomes stably. The amount of finally constructed Lipo@GB-DHA targeting to ischemic hemisphere was validated 2.2 times that of free solution in middle cerebral artery occlusion (MCAO) rats. Compared to the marketed ginkgolide injection, Lipo@GB-DHA significantly reduced infarct volume with better neurobehavioral recovery in MCAO rats after being intravenously administered both at 2 h and 6 h post-reperfusion. Low levels of reactive oxygen species (ROS) and high neuron survival in vitro was maintained via Lipo@GB-DHA treatment, while microglia in the ischemic brain were polarized from the pro-inflammatory M1 phenotype to the tissue-repairing M2 phenotype, which modulate neuroinflammatory and angiogenesis. In addition, Lipo@GB-DHA inhibited neuronal apoptosis via regulating the apoptotic pathway and maintained homeostasis by activating the autophagy pathway. Thus, transforming GB into a lipophilic complex and loading it into liposomes provides a promising nanomedicine strategy with excellent CI/RI therapeutic efficacy and industrialization prospects.

Delayed Release of Amiodarone Causing Late-Onset Thyrotoxicosis

Introduction: Amiodarone is an antiarrhythmic medication associated with a wide range of adverse effects, including thyroid dysfunction.1 Thyrotoxicosis without underlying Graves' disease or nodules is classified as Type II, or destructive, amiodarone-induced thyrotoxicosis (AIT).2 However, few cases have been reported in whom AIT occurs months after cessation of medication use. We describe a case of late-onset Type II AIT, diagnosed in the setting of atrial fibrillation (AF), 10 months after last known dose of amiodarone. Description of the Case: A 51-year-old man presented with palpitations and an electrocardiogram showing AF with rapid ventricular response. His history was notable for a diagnosis of AF, treated with ablation and multiple courses of amiodarone, most recently 1 year prior with a cumulative dose of 22.4 g for 12 weeks. Serum laboratory tests showed newly suppressed thyroid-stimulating hormone <0.02 (0.3–4.7 mcIU/mL) and elevated free thyroxine 1.9 (0.8–1.7 ng/dL). Thyroid autoantibodies to thyroid peroxidase and thyrotropin receptor and thyroid-stimulating immunoglobulins were absent. He had no recent exposure to biotin or iodinated contrast and reported no recent viral illness or neck pain. He had a 9 kg weight loss in the preceding few months secondary to decreased appetite. Family history was significant for mother and nephew with autoimmune thyroid disease. Thyroid ultrasonography showed no nodules. An iodine-123 uptake scan showed homogeneous bilateral decreased uptake most consistent with destructive thyroiditis. Methimazole treatment, started empirically at presentation, was discontinued. Thyroid function tests normalized within 3 months with no therapy needed. Discussion: Delayed-onset AIT may occur after cessation of amiodarone therapy. To our knowledge, only one case series of eight patients has been reported in whom late-onset thyrotoxicosis occurred after amiodarone cessation.3 Amiodarone contains a significant amount of iodine and releases about 100 to 300 times of the recommended daily intake. It is a lipophilic complex primarily stored within adipose tissue, with a long half-life of up to 100 days. Our patient's rapid weight loss may have contributed to a delayed release of amiodarone from lipid stores, thereby triggering Type II AIT. This case emphasizes the importance of considering AIT in all patients with history of amiodarone use, even months after cessation of therapy, when supported by presentation and diagnostic tests. Patient Consent: Authors have received and archived patient consent for video recording/publication in advance of video recording of procedure. No competing financial interests exist for any of the authors. Runtime of video: 4 mins 12 secs

Sulfonamide-Derived Dithiocarbamate Gold(I) Complexes Induce the Apoptosis of Colon Cancer Cells by the Activation of Caspase 3 and Redox Imbalance.

Two new families of dithiocarbamate gold(I) complexes derived from benzenesulfonamide with phosphine or carbene as ancillary ligands have been synthesized and characterized. In the screening of their in vitro activity on human colon carcinoma cells (Caco-2), we found that the more lipophilic complexes—those with the phosphine PPh3—exhibited the highest anticancer activity whilst also displaying significant cancer cell selectivity. [Au(S2CNHSO2C6H5)(PPh3)] (1) and [Au(S2CNHSO2-p-Me-C6H4)(IMePropargyl)] (8) produce cell death, probably by intrinsic apoptosis (mitochondrial membrane potential modification) and caspase 3 activation, causing cell cycle arrest in the G1 phase with p53 activation. Besides this, both complexes might act as multi-target anticancer drugs, as they inhibit the activity of the enzymes thioredoxin reductase (TrxR) and carbonic anhydrase (CA IX) with the alteration of the redox balance, and show a pro-oxidant effect.

Інноваційний підхід до індивідуалізації лікування дітей з гострими респіраторними інфекціями

Під нашим спостереженням перебували 27 дітей віком від 10 міс. до 10 років, хворих на гострі респіраторні інфекції, з яких 14 пацієнтам введено до харчового раціону функціональний харчовий продукт із рослинної сировини «Пилок квітковий з розчинною клітковиною» та продукти для спеціального харчування «Олія вівса, ліпофільний комплекс», «Олія чорного кмину, ліпофільний комплекс». Проведений аналіз клінічної симптоматики показав відсутність відмінностей у перебігу захворювання, тривалості симптомів гострих респіраторних інфекцій та терапії при обох способах лікування за дуже подібної клінічної картини на старті хвороби. Обсяг лікувального комплексу в другій групі (13 хворих) був вірогідно більшим за кількістю застосованих препаратів, а вартість — суттєво вищою, ніж у групі порівняння. Тому запропонована схема лікування з корекцією харчування функціональними харчовими продуктами з рослинної сировини може бути рекомендована для практичного застосування.

Oxorhenium(V) and Oxotechnetium(V) Complexes of N3S Tetradentate Ligands with a Styrylpyridyl Functional Group: Toward Imaging Agents to Assist in the Diagnosis of Alzheimer's Disease.

Alzheimer's disease (AD) is associated with the presence of amyloid plaques in the brain mainly comprised of aggregated forms of amyloid-β (Aβ). Molecules radiolabeled with technetium-99m that cross the blood-brain barrier (BBB) and selectively bind to Aβ plaques have the potential to assist in the diagnosis of AD using single-photon emission computed tomography imaging. In this work, three new tetradentate ligands of pyridyl, amide, amine and thiol donors, featuring a styrylpyridyl group that is known to interact with amyloid plaques, were prepared. The new ligands formed charge-neutral and lipophilic complexes with the [Tc═O]3+ and [Re═O]3+ motifs, and two rhenium complexes were characterized by X-ray crystallography. The rhenium(V) complexes interact with synthetic Aβ1-40 and amyloid plaques on human brain tissue. Two of the new ligands were radiolabeled with 99mTc using a kit-based approach, and their biodistribution in wild-type mice was evaluated. The presence of amide donors in the tetradentate ligand increased the stability of the respective [Tc═O]3+ complexes but reduced brain uptake. While the complexes were able to cross the BBB, the degree of uptake in the brain was not sufficient to justify further investigation of these complexes.

Hypoxia-targeted cupric-tirapazamine liposomes potentiate radiotherapy in prostate cancer spheroids

In this study, novel cupric-tirapazamine [Cu(TPZ)2]-liposomes were developed as an effective hypoxia-targeted therapeutic, which potentiated radiotherapy in a three dimensional (3D) prostate cancer (PCa) model. To overcome the low water solubility of the Cu(TPZ)2, a remote loading method was developed to efficiently load the lipophilic complex into different liposomal formulations. The effect of pH, temperature, PEGylation, lipid composition, liposome size, lipid: complex ratio on the liposome properties, and drug loading was evaluated. The highest loading efficiency was obtained at neutral pH, which was independent of lipid composition and incubation time. In addition, enhanced drug loading was achieved upon decreasing the lipid:complex molar ratio with minimal effects on liposomes’ morphology. Interestingly, the in vitro potency of the developed liposomes was easily manipulated by changing the lipid composition. The hydrophilic nature of our liposomal formulations improved the complex’s solubility, leading to enhanced cellular uptake and toxicity, both in PCa monolayers and tumour spheroids. Moreover, Cu(TPZ)2-loaded liposomes combined with radiation, showed a significant reduction in PCa spheroids growth rate, compared to the free complex or radiation alone, which could potentiate radiotherapy in patients with localised advanced PCa.

The bile acid composition analysis of the lipophilic complex of animal bile

Using gas chromatography, the qualitative composition and the quantitative content of bile acids in the lipophilic complexes of animal bile was studied. As a result of the studies, 6 steroids were identified in the lipophilic complexes of bile, 5 of which are bile acids. It was defined that cholic and deoxycholic acid predominate in all the studied objects, while their amount depends on the used raw materials.

Development and Evaluation of Sustained Release Lipid Nanocarriers for Curcumin

Background: Lipid based excipients have increased acceptance nowadays in the development of novel drug delivery systems in order to improve their pharmacokinetic profiles. Drugs encapsulated in lipids have enhanced stability due to the protection they experience in the lipid core of these nano-formulations. Phytosomes are newly discovered drug delivery systems and novel botanical formulation to produce lipophilic molecular complex which imparts stability, increases absorption and bioavailability of phytoconstituent. Curcumin, obtained from turmeric (Curcuma longa), has a wide range of biological activities. The poor solubility and wettability of curcumin are responsible for poor dissolution and this, in turn, results in poor bioavailability. To overcome these limitations, the curcumin-loaded nano phytosomes were developed to improve its physicochemical stability and bioavailability. Objective: The objective of the present research work was to develop nano-phytosomes of curcumin to improve its physicochemical stability and bioavailability. Methods: Curcumin-loaded nano phytosomes were prepared by using phospholipid Phospholipon 90 H using a modified solvent evaporation method. The developed curcumin nano phytosomes were evaluated by particle size analyzer and differential scanning calorimetry (DSC). Results: Results indicated that phytosomes prepared using curcumin and lipid in the ratio of 1:2 show good entrapment efficiency. The obtained curcumin phytosomes were spherical in shape with a size less than 100 nm. The prepared nano phytosomal formulation of curcumin showed promising potential as an antioxidant. Conclusion: The phytosomal complex showed sustained release of curcumin from vesicles. The sustained release of curcumin from phytosome may improve its absorption and lowers the elimination rate with an increase in bioavailability.

Interactions of Cationic Diruthenium Trithiolato Complexes with Phospholipid Membranes Studied by NMR Spectroscopy.

To apprehend the possible mechanisms involved in the cellular uptake and the membrane interactions of cytotoxic dinuclear p-cymene trithiolato ruthenium(II) complexes, the interactions of the complexes [(η6-p-MeC6H4Pri)2Ru2(R1)2(R2)]+ (R1 = R2 = SC6H4-m-Pri:1; R1 = SC6H4-p-OMe, R2 = SC6H4-p-OH:2; R1 = SCH2C6H4-p-OMe, R2 = SC6H4-p-OH:3) with 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) vesicles and 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) micelles were studied using nuclear magnetic resonance (NMR) spectroscopy. 1H NMR, nuclear Overhauser effect (NOE), diffusion ordered spectroscopy (DOSY), and T1 and T2 relaxation data provided information on interactions between the complexes and the model membranes and on the submolecular localization of the complexes at the membrane interface. The results suggest that (a) the interaction takes place without new covalent adduct formation, (b) the cationic diruthenium complexes interact with DOPC head groups most likely involving electrostatic interactions while remaining structurally unchanged, (c) the changes indicating interactions are more pronounced for the most lipophilic complex 1, and (d) the diruthenium complexes remain at the exterior vesicle surface and are unlikely inserted between the phospholipid chains. The complexes also interact with micellar/free DHPC and seem to induce micellization or aggregation in solutions below critical micelle concentration (CMC). Our study suggests high affinity of the Ru complexes for the membrane surface that likely plays a key role in cellular uptake and possibly also in redistribution in mitochondria.

Facile synthesis of heterobimetallic [FeII(µ-diphosphine)RuII] and homobimetallic [FeII(µ-diphosphine)FeII] complexes and their in vitro cytotoxic activity on cisplatin-resistant cancer cells

A series of heterobimetallic [Fe,Ru] and homobimetallic [Fe,Fe] complexes, featuring µ -diphosphine bridges between the two metal centres, are reported along with their in vitro cytotoxicity activity on the A2780cisR cell-line. The known starting material [CpFe(CO)2(CH3)] (Cp = η5-C5H5) (1) was reacted with dppe (1,2-bis(diphenylphosphino)ethane) forming the known mononuclear κ1-dppe complex: [CpFe(CO)(COCH3)(κ1-dppe)] (2) and the known dinuclear complex: and [[CpFe(CO)(COCH3)]2(µ-dppe)] (3). Dimer cleavage reactions between complex 2 and two ruthenium arene complexes [(η6-p-cymene)RuCl2]2 and [(η6-benzene)RuCl2]2 formed two new heterobimetallic complexes: [CpFe(CO)(COCH3)(µ-dppe)Ru(η6-cymene)Cl2] (4) and [CpFe(CO)(COCH3)(µ-dppe)Ru(η6-C6H6)Cl2] (5). A homobimetallic system, [[CpFe(CO)(I)]2(µ-dppb)] (6) was obtained by the facile reaction between of [CpFe(CO)2I] and 1,4-bis(diphenylphosphino)butane (dppb). Complex 6 was methylated using MeLi to generate the more lipophilic complex [[CpFe(CO)(CH3)]2(µ-dppb)] (7). All of the complexes were fully characterized by spectroscopy (1H, 13C {1H}, 31P {1H} NMR; FTIR, UV–Vis), and high resolution mass spectrometry (HRMS). Density functional theory calculations (DFT) (Level of theory B3LYP, basis set for H, C, P, O, Cl is 6-31+G(d,p) and for Ru, Fe, I is DGDZVP) on complexes 5 and 6 are also reported. An excellent agreement between the DFT calculated infra-red (IR) spectra of the optimised geometries of 5 and 6 was found with the experimentally determined spectra. In vitro cytotoxicity studies of all complexes was carried out on A2780cisR (cisplatin resistant ovarian cancer cell-line) and compared to cisplatin as a positive control and RAPTA-C as a negative control. Although limited to only one cell-line, the results show that the heterobimetallic complexes 4 and 5 are the most cytotoxic (IC50 = 4.9 ± 0.4 µM and 6.5 ± 0.1 µM respectively), whilst the dinculear [Fe,Fe] complexes exhibit no, or very low cytotoxicity.

Synthesis, structure and biological evaluation of ruthenium(III) complexes of triazolopyrimidines with anticancer properties.

Six novel ruthenium(III) complexes of general formula [RuCl3(L)3] (1,3,5) and [RuCl3(H2O)(L)2] (2,4,6), where L stands for three different triazolopyrimidine-derived ligands, are reported. The compounds have been structurally characterized (IR, EPR, SCXRD), and their magnetic moments have been determined. The single-crystal X-ray diffraction study revealed a slightly distorted octahedral geometry of the Ru(III) complexes with mer configuration in 1 and 5, and fac configuration in 3. In 2 and 4, three chloride ions are in mer configuration and the two triazolopyrimidines are oriented trans mutually with the water molecule playing the role of the sixth ligand. All complexes have been thoroughly screened for their in vitro cytotoxicity against human breast cancer cell line MCF-7, human cervical cancer cell line HeLa, and L929 murine fibroblast cells, uncovering among others that the most lipophilic complexes 5 and 6, containing the bulky ligand dptp (5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine), display high cytotoxic activity against MCF-7, and HeLa cells. Moreover, it was also revealed that during the interaction of the complexes 1-6 with the cancer MCF-7 cell line, reactive oxygen species are released intracellularly, which could indicate that they are involved in cell apoptosis. Furthermore, extensive studies have been carried out to reveal the mechanism by which complexes 1-6 interact with DNA, albumin, and apotransferrin. The biological studies were complemented by detailed kinetic studies of the hydrolysis of the complexes in the pH range 5-8, to determine the stability of the complexes in solution. Six novel ruthenium(III) complexes with triazolopyrimidine derivatives demonstrated the potential for use as anticancer agents by maintaining the toxic effect on MCF-7 and HeLa cells.

Incorporation of Antisense Oligonucleotides into Lipophilic Concatemeric Complexes Provides Their Effective Penetration into Cells

The development of highly effective molecular and biological tools to facilitate the penetration of therapeutic nucleic acids into cells opens a direct way to their successful application as drugs. It has been shown that the incorporation of single-stranded antisense oligonucleotides into concatemeric complexes enhances their binding to the membrane structures of eukaryotic cells, and the use of a cholesterol residue attached to one of the oligonucleotide strands considerably improves the delivery of concatemeric complexes of oligonucleotides to their intracellular target. In the present work, the efficiency of the formation of concatemeric structures from oligonucleotides carrying lipophilic fragments such as lithocholic acid, oleylamide of lithocholic acid, and cholesterol, attached to the 5′-end of the oligonucleotide through oligomethylene linkers of different length has been studied. It has been found that all modified oligonucleotides are capable of effectively “assembling” into concatemeric complexes; however, effective delivery into cells was observed only in the case of concatemeric complexes formed by oligonucleotides carrying a cholesterol residue attached through an aminohexanol linker. It has been shown that antisense oligonucleotides delivered to cells as part of these cholesterol-containing concatemeric complexes effectively inhibit the expression of the target gene.

Different bonding of triazolopyrimidine to platinum(IV). Structural and in vitro cytotoxicity studies

The reactions of H2PtCl6 with 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) and 5-methyl-7-isobutyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp) yielded two novel Pt(IV) compounds. The structures of both platinum(IV) coordination compounds have been solved by single-crystal X-ray diffraction. The complexes confirmed different bonding modes of heterocycle ligands to platinum(IV). The coordination units of cis-[PtCl4(ibmtp)2] (1) are built from two monodentate ibmtp molecules coordinated via N3 located in equatorial positions and four chloride ions. In contrast, the X-ray crystal structures of (Hdmtp)2[PtI6] (2) confirmed that this platinum(IV) compound is an ionic pair consisting of one octahedral [PtI6]2− anion and two N3-monoprotonated Hdmtp+ cations. In addition, the stable in solution lipophilic complex (1) has been tested for in vitro cytotoxic activity against three human tumour cell lines T47D (breast cancer), A549 (non-small cell lung carcinoma), and LoVo (colon cancer), and one mouse healthy cell line, BALB/3T3 (mouse embryonic fibroblast). The tests indicate significant in vitro cytotoxicity against the non-small cell lung carcinoma (A549) cancer cell line (IC50 = 3.44 μM).

Дослідження жирнокислотного складу деяких рослин родини айстрові (Аsteraceae)

Introduction. Recently, much attention has been paid to the study of medicinal plants’ lipophilic complexes, part of which is fatty acids, which play an important role in the life activities of a human body. The plants of the Asteraceae family — yacon (the Smallanhus sonchifolius (Poepp. and Endl.) H. Robinson), stevia rebaudiana (Bertoni) Hemsley and cat’s paw (Antennaria dioica (L.) Gaertn.) contain the complex of biologically active substances, among which a significant place is given to lipophilic components (fatty acids, carotenoids, chlorophylls, etc.). In the sources of scientific literature, there is not enough information about the studied species’ fatty acid composition. Therefore, the purpose of our research is to study the lipophilic fractions of stevia leaves, yacon root tubers and leaves, cat’s paw herbs, and to determine the content of fatty acids in their composition.Research Methods. Lipophilic fractions of the studied species are obtained by exhaustive extraction of raw materials with chloroform in the Soxhlet apparatus. Determination of qualitative composition and quantitative content of fatty acids in the investigated medicinal plant material is carried out by the gas-liquid chromatographic/mass spectrometric method of fatty acids methyl esters on the gas chromatographic/mass spectrometric system Agilent 6890N/5973inert (Agilent Technologies, USA). The identification of fatty acid methyl esters in the test mixture is carried out by comparing the retention time of fatty acids methyl esters standard mixture (Supelco, USA). The NIST 02 mass spectrum library is used.Results and Discussion. The isolated lipophilic fraction from yacon root tubers – a thick oily homogeneous mass of brown colour with a pleasant specific odor; not soluble in water and ethanol, is readily soluble in chloroform. Lipophilic fractions of stevia leaves are of dark green colour; cat’s paw herbs – light green colour; according to other physical indicators, the obtained substances do not differ. It is established that the yield of lipophilic substances from yacon and stevia leaves are almost the same – (9.55±0.09)% and (9.05±0.07) %, from yacon roots – in 2.4 and 2.2 times smaller than leaves, respectively. The yield of the lipophilic fraction from cat’s paw herbs is (8.25 ± 0.09) %.9 fatty acids are detected in the lipophilic extract of yacon leaves and cat’s paw herbs, 2 of which are polyunsaturated (linoleic and linolenic). 8 fatty acids are detected in the lipophilic extract of stevia leaves, where linolenic acid is present in the largest number. The lipophilic extract of stevia leaves and cat’s paw herbs contains the saturated palmitic acid. The content of unsaturated fatty acids in the studied lipophilic extracts predominates over saturated. Their ratio in yacon leaves is 55.35:8.63; stevia leaves – 3.04:1.87; cat’s paw herbs – 29.09:20.26, respectively. Only the linoleic and linolenic acids are identified in the lipophilic extract of yacon root tubers.Conclusions. 1. The fatty acid composition of the lipophilic fractions of stevia leaves, yacon root tubers and leaves, and cat’s paw herbs is determined by the gas-liquid chromatographic/mass spectrometric method for the first time.2. The content of unsaturated fatty acids in stevia and yacon leaves, and cat’s paw herbs predominates over saturated. Polyunsaturated fatty acids (linoleic and linolenic) are dominant in the investigated objects.3. Only the linoleic and linolenic acids are identified in yacon root tubers.

Використання фітоциліндрів профілактичних з ліпофільним комплексом плодів шипшини та екстрактом ромашки для лікування анальних тріщин та запорів у дітей

Використання фітоциліндрів профілактичних з ліпофільним комплексом плодів шипшини та екстрактом ромашки для лікування анальних тріщин та запорів у дітей