Cytostatic Activity Research Articles

Novel Glu-based pyrazolo[3,4-d]pyrimidine analogues: design, synthesis and biological evaluation as DHFR and TS dual inhibitors

A novel series of multifunctional pyrazolo[3,4-d]pyrimidine-based glutamate analogs (6a–l and 7a,b) have been designed and synthesized as antifolate anticancer agents. Among the tested compounds, 6i exhibited the most potent anti-proliferative activity towards NSCLC, CNS, Ovarian, Prostate, Colon, Melanoma, Breast, and Renal cancers with good to weak cytostatic activity and non-lethal actions. 6i demonstrated higher selectivity for cancer than normal cells. 6i could significantly increase the accumulation of S-phase cells during the cell cycle distribution of cancer cells with high potency in the induction of apoptosis. The results unveiled that 6i probably acts through dual inhibition of DHFR and TS enzymes (IC50 = 2.41 and 8.88 µM, correspondingly). Docking studies of 6i displayed that N1-p-bromophenyl and C3-Methyl groups participate in substantial hydrophobic interactions. The drug-likeness features inferred that 6i met the acceptance criteria of Pfizer. Taking together, 6i could be a promising prototype for further optimization as an effective anticancer drug.

Synthesis and anti-SARS-CoV-2 evaluation of lipid prodrugs of β-D-N4-hydroxycytidine (NHC) and a 3′-fluoro-substituted analogue of NHC

β-D-N4-hydroxycytidine (NHC, EIDD-1931) is a nucleoside analogue that exhibits broad spectrum antiviral activity against a variety of RNA viruses. Herein, we report the synthesis of a series of lipid prodrugs of NHC and a novel 3′-fluoro modified NHC analogue, and evaluation of their antiviral activity against five variants of SARS-CoV-2. All lipid prodrugs showed potent antiviral activity against the tested SARS-CoV-2 variants with EC50 values in the range of 0.31–3.51 μM, which were comparable to those of NHC or higher than those of remdesivir and molnupiravir. An increase in the cytostatic activity of the lipid prodrugs was found, but prodrug 2d proved equally selective as molnupinavir. The 3′-F analogue of NHC (6) only displayed minor antiviral activity against the SARS-CoV-2 Omicron variant (EC50 = 29.91 μM), while no activity was found for other variants at the highest concentration tested. The promising antiviral data of the lipid prodrugs of NHC suggest that they deserve further investigation as new anti-SARS-CoV-2 drugs.

In Vitro Study of Cytostatic Activity of Baicalin, Baicalein, and Chlorophyllipt on HeLa-v Cell Line

Cytostatic activity of baicalin, baicalein, and neogalenical drug Chlorophyllipt was studied in vitro on HeLa-v cells. Standard samples of Eucalimin, baicalin, and baicalein, as well as Chlorophyllipt and paclitaxel (reference drug Taxacad) were used. The cell deaths were determined by MTT assay in a Multiskan FC microplate reader with incubator. The effective inhibition concentration (IC50) of the tested substances were: paclitaxel (4.0±0.4 μM)-baicalein (10.5±1.1 μM)-baicalin (16.5±1.7 μM)-sum of euglobals in Chlorophyllipt (24.1±2.5 μM). Chlorophyllipt was found to exhibit cytostatic activity. Cytostatic activity of baicalein, baicalin, and Chlorophyllipt was lower than cytostatic activity of the reference drug by 2.6, 4.1, and 6 times, respectively. The prospects of further evaluation of the synergetic effect of baicalin, baicalein, and chlorophyllipt used in combinations with different cytostatic agents for finding the most effective combination have been shown.

Type I interferon signaling in malignant blasts contributes to treatment efficacy in AML patients

While type I interferon (IFN) is best known for its key role against viral infection, accumulating preclinical and clinical data indicate that robust type I IFN production in the tumor microenvironment promotes cancer immunosurveillance and contributes to the efficacy of various antineoplastic agents, notably immunogenic cell death inducers. Here, we report that malignant blasts from patients with acute myeloid leukemia (AML) release type I IFN via a Toll-like receptor 3 (TLR3)-dependent mechanism that is not driven by treatment. While in these patients the ability of type I IFN to stimulate anticancer immune responses was abolished by immunosuppressive mechanisms elicited by malignant blasts, type I IFN turned out to exert direct cytostatic, cytotoxic and chemosensitizing activity in primary AML blasts, leukemic stem cells from AML patients and AML xenograft models. Finally, a genetic signature of type I IFN signaling was found to have independent prognostic value on relapse-free survival and overall survival in a cohort of 132 AML patients. These findings delineate a clinically relevant, therapeutically actionable and prognostically informative mechanism through which type I IFN mediates beneficial effects in patients with AML.

Antiproliferative Activity of Natural Flavonoid Fustin Isolated from the Heartwood of Cotinus Coggygria Scop. Against Breast and Colon Cancer Cell Lines

Abstract Background and objective Cotinus coggygria Scop. is a valuable medicinal plant species with pronounced pharmacological potential due to its numerous biological activities. The herb is characterized by a high content of polyphenols among which is fustin. The anticancer activities of fustin, however, are extremely weakly studied. The aim of the present study was to investigate the in vitro antiproliferative potential of fustin isolated from the heartwood of C. coggygria against cell lines originating from two of the most common cancer types – breast (MDA-MB-231 and MCF7), and colon cancer (Colon 26). Materials and methods Cell growth inhibitory properties of fustin were examined by MTT assay. Subsequently, phase-contrast and fluorescence microscopy analysis as well as colonyforming assay were carried out on the most sensitive to the cytostatic action of the fustin cell line. Results The obtained results showed that fustin reduced the proliferation of all studied cell lines. The highest cytostatic effect was registered towards breast cancer MDA-MB-231 cells with a half maximal inhibitory concentration (IC50) value of 56.02 μg/ml followed by colon cancer cells with an IC50 of 78.07 μg/ml. MCF7 cell proliferation was least affected with a calculated IC50 of 187.8 μg/ml. Further investigations on breast cancer MDA-MB-231 cells indicated decreased density of cell monolayer and some morphological alterations, significant attenuation in the number of viable cells, and diminished clonogenic ability of cells after fustin exposure. Conclusion It could be concluded that fustin isolated from the heartwood of medicinal plant C. coggygria possesses marked antiproliferative properties against breast cancer cell line MDA-MB-231 which will be a subject of our more detailed future investigations.

Four organotin(IV) complexes derived from 2,6-difluoro-3-(propylsulfonamido)benzoic acid: synthesis, structure, in vitro cytostatic activity and antifungal activity evaluation

Four new organotin(IV) complexes, [(Me2Sn)4O2(C10H10F2NO4S)4] (1), [(n-Bu2Sn)4O2(C10H10F2NO4S)4] (2), [Me3SnC10H10F2NO4S] (3) and [n-Bu3SnC10H10F2NO4S] (4) have been synthesized by the reactions of 2,6-difluoro-3-(propylsulfonamido)benzoic acid with R2SnO (R = Me, and n-Bu) or R3SnCl (R = Me, and n-Bu). The four complexes have been characterized by elemental analysis, FT-IR, NMR (1H, 13C and 119Sn), and X-ray crystallography. The X-ray crystallography analyses revealed that the complexes 1 and 2 represent tetranuclear tin ladder-like geometries. In comparison, complexes 3 and 4 exhibit 1D zig-zag chains. Complex 1 constructs a 2D planar structure by NH···O and CH···O intermolecular hydrogen bonding. Complex 2 constructs a 3D supramolecular framework via the CH···O and CH···F intermolecular hydrogen bonding. The 3D supramolecular frameworks of complexes 3 and 4 were formed by SO···H intermolecular hydrogen bonding, respectively. Furthermore, in vitro cytostatic activity of complexes 1–4 against the cervical carcinoma (HeLa) and the hepatocellular carcinoma (HepG-2) cell lines were examined by MTT screening. Results indicated that complexes 2 and 4 exhibited strong cytostatic activity. Meanwhile, the inhibition of complexes 1–4 against five common plant pathogenic fungi in vitro was obtained by the mycelial growth inhibition method, and the results revealed that complex 4 exhibited much stronger inhibition. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) micrographs were used to study changes on the fungal morphology for the treatments with complex 4.

Library Screening and Preliminary Characterization of Synthetic Cannabinoids Against Prostate and Pancreatic Cancer Cell Lines.

Background: Our previous screening efforts with colorectal cancer cell lines suggested potential cannabinoid therapeutic leads for other solid cancers. Objectives: The aim of this study was to identify cannabinoid lead compounds that have cytostatic and cytocidal activities against prostate and pancreatic cancer cell lines and profile cellular responses and molecular pathways of select leads. Materials and Methods: A library of 369 synthetic cannabinoids was screened against 4 prostate and 2 pancreatic cancer cell lines with 48 h of exposure at 10 μM in medium with 10% fetal bovine serum using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) viability assay. Concentration titration of the top 6 hits was carried out to identify their concentration-response patterns and calculate IC50 values. Three select leads were examined for cell cycle, apoptosis, and autophagy responses. The role of cannabinoid receptors (CB1 and CB2) and noncanonical receptors in apoptosis signaling was examined with selective antagonists. Results: Two independent screening experiments in each cell line detected growth inhibitory activities against all six or a majority of cancer cell lines for HU-331 (a known cannabinoid topoisomerase II inhibitor), (±)5-epi-CP55,940, and PTI-2, each previously identified in our colorectal cancer study. 5-Fluoro NPB-22, FUB-NPB-22, and LY2183240 were novel hits. Morphologically and biochemically, (±)5-epi-CP55,940 elicited caspase-mediated apoptosis of PC-3-luc2 (a PC-3 subline with luciferase) prostate cancer and Panc-1 pancreatic cancer cell lines, each the most aggressive of the respective organ site. The apoptosis induced by (±)5-epi-CP55,940 was abolished by the CB2 antagonist, SR144528, but not modulated by the CB1 antagonist, rimonabant, and GPR55 antagonist, ML-193, nor TRPV1 antagonist, SB-705498. In contrast, 5-fluoro NPB-22 and FUB-NPB-22 did not cause substantial apoptosis in either cell line, but resulted in cytosolic vacuoles and increased LC3-II formation (suggestive of autophagy) and S and G2/M cell cycle arrests. Combining each fluoro compound with an autophagy inhibitor, hydroxychloroquine, enhanced the apoptosis. Conclusions: 5-Fluoro NPB-22, FUB-NPB-22, and LY2183240 represent new leads against prostate and pancreatic cancer cells in addition to the previously reported compounds, HU-331, (±)5-epi-CP55,940, and PTI-2. Mechanistically, the two fluoro compounds and (±)5-epi-CP55,940 differed regarding their structures, CB receptor involvement, and death/fate responses and signaling. Safety and antitumor efficacy studies in animal models are warranted to guide further R&D.

Valproic acid inhibits cell growth in both MCF-7 and MDA-MB231 cells by triggering different responses in a cell type-specific manner

BackgroundBreast cancer is the second leading cause of death among women after lung cancer. Despite the improvement in prevention and in therapy, breast cancer still remains a threat, both for pre- and postmenopausal women, due to the development of drug resistance. To counteract that, novel agents regulating gene expression have been studied in both hematologic and solid tumors. The Histone Deacetylase (HDAC) inhibitor Valproic Acid (VA), used for epilepsy and other neuropsychiatric diseases, has been demonstrated a strong antitumoral and cytostatic activity. In this study, we tested the effects of Valproic Acid on the signaling pathways involved in breast cancer cells viability, apoptosis and in Reactive Oxygen Species (ROS) production using ER-α positive MCF-7 and triple negative MDA-MB-231 cells.MethodsCell proliferation assay was performed by MTT Cell cycle, ROS levels and apoptosis were analyzed by flow cytometry, protein levels were detected by Western Blotting.ResultsCell treatment with Valproic Acid reduced cell proliferation and induced G0/G1 cell cycle arrest in MCF-7 and G2/M block in MDA-MB-231 cells. In addition, in both cells the drug enhanced the generation of ROS by the mitochondria. In MCF-7 treated cells, it has been observed a reduction in mitochondrial membrane potential, a down regulation of the anti-apoptotic marker Bcl-2 and an increase of Bax and Bad, leading to release of cytochrome C and PARP cleavage. Less consistent effects are recorded in MDA-MB-231 cells, in which the greater production of ROS, compared to MCF-7cells, involves an inflammatory response (activation of p-STAT3, increased levels of COX2).ConclusionsOur results have demonstrated that in MCF-7 cells the Valproic Acid is a suitable drug to arrest cell growth, to address apoptosis and mitochondrial perturbations, all factors that are important in determining cell fate and health. In a triple negative MDA-MB 231 cells, valproate directs the cells towards the inflammatory response with a sustained expression of antioxidant enzymes. Overall, the not always unequivocal data between the two cellular phenotypes indicate that further studies are needed to better define the use of the drug, also in combination with other chemotherapy, in the treatment of breast tumors.

Evaluation of Cellular Toxicity and Preclinical Safety of Using an Inhalable Liposomal form of Dexamethasone.

A liposomal form of dexamethasone was obtained. Liposomal vesicles were formed. The efficiency of incorporating dexamethasone into the liposomes was 99.7%. The cytotoxicity of the obtained liposomes was studied on a culture of human lung fibroblast cells using the MTT assay. The toxicity of liposomal dexamethasone was less than that of dexamethasone solution after a 24-h incubation. The half-maximum inhibitory concentration (IC50) was not achieved after 24 h when exposed to liposomal dexamethasone whereas IC50 was 27.5 mg/mL for lecithin (empty liposomes) and 177 µg/mL for dexamethasone solution. The toxicity of liposomal dexamethasone increased much more than that of dexamethasone solution after 48 h of incubation with IC50 values of 36 and 156 µg/mL, respectively. Thus, the liposomal form of dexamethasone has a latent period for implementation of the cytostatic (antiproliferative) action. Experiments on laboratory white rats of both sexes revealed that the inhalation use of liposomal dexamethasone insignificantly changed the functional parameters of their respiratory and cardiovascular systems. The study results could be used for conducting clinical trials.

HER2-Specific Peptide (LTVSPWY) and Antibody (Herceptin) Targeted Core Cross-Linked Micelles for Breast Cancer: A Comparative Study.

This study aims to prepare a novel breast cancer-targeted micelle-based nanocarrier, which is stable in circulation, allowing intracellular drug release, and to investigate its cytotoxicity, apoptosis, and cytostatic effects, in vitro. The shell part of the micelle is composed of zwitterionic sulfobetaine ((N-3-sulfopropyl-N,N-dimethylamonium)ethyl methacrylate), while the core part is formed by another block, consisting of AEMA (2-aminoethyl methacrylamide), DEGMA (di(ethylene glycol) methyl ether methacrylate), and a vinyl-functionalized, acid-sensitive cross-linker. Following this, a targeting agent (peptide (LTVSPWY) and antibody (Herceptin®)), in varying amounts, were coupled to the micelles, and they were characterized by 1H NMR, FTIR (Fourier-transform infrared spectroscopy), Zetasizer, BCA protein assay, and fluorescence spectrophotometer. The cytotoxic, cytostatic, apoptotic, and genotoxic effects of doxorubicin-loaded micelles were investigated on SKBR-3 (human epidermal growth factor receptor 2 (HER2)-positive) and MCF10-A (HER2-negative). According to the results, peptide-carrying micelles showed a higher targeting efficiency and better cytostatic, apoptotic, and genotoxic activities than antibody-carrying and non-targeted micelles. Also, micelles masked the toxicity of naked DOX on healthy cells. In conclusion, this nanocarrier system has great potential to be used in different drug-targeting strategies, by changing targeting agents and drugs.

1,2,3-Triazole-Containing 1,5,6,7-Tetrahydro-4<i>h-</i>indazol-4-ones and 6,7-Dihydrobenzo[<i>d</i>]isoxazol-4(5<i>h</i>)-ones: Synthesis and Biological Activity

Triazole-containing 1,5,6,7-tetrahydro-4 H- indazol-4-ones and 6,7-dihydrobenzo[ d ]isoxazol-4(5 H )-ones were synthesized by cyclocondensation of 2-[(1 H -1,2,3-triazol-1-yl)acetyl]cyclohexane-1,3-diones with phenylhydrazine (4-fluorophenylhydrazine) or hydroxylamine, respectively. SStructure and composition of the obtained compounds were confirmed by 1H, 13C, 19F NMR spectroscopy methods and by data of elemental analysis. Cytotoxic and cytostatic activities of the series of obtained compounds were investigated in vitro against human hepatocellular carcinoma cells HepG2, mammary adenocarcinoma cells MCF-7 and laryngeal cancer cells Hep2.

1,2,3-Triazole-Containing 1,5,6,7-Tetrahydro-4H-indazol-4-ones and 6,7-Dihydrobenzo[d]isoxazol-4(5H)-ones: Synthesis and Biological Activity

Triazole-containing 1,5,6,7-tetrahydro-4H-indazol-4-ones and 6,7-dihydrobenzo[d]isoxazol-4(5H)-ones were synthesized by cyclocondensation of 2-[(1H-1,2,3-triazol-1-yl)acetyl]cyclohexane-1,3-diones with phenylhydrazine (4-fluorophenylhydrazine) or hydroxylamine, respectively. Structure and composition of the obtained compounds were confirmed by 1H, 13C, 19F NMR spectroscopy methods and by data of elemental analysis. Cytotoxic and cytostatic activities of the series of obtained compounds were investigated in vitro against human hepatocellular carcinoma cells HepG2, mammary adenocarcinoma cells MCF-7, and laryngeal cancer cells Hep2.

Half sandwich-type osmium, ruthenium, iridium and rhodium complexes with bidentate glycosyl heterocyclic ligands induce cytostasis in platinum-resistant ovarian cancer cells and bacteriostasis in Gram-positive multiresistant bacteria.

The toxicity of and resistance to platinum complexes as cisplatin, oxaliplatin or carboplatin calls for the replacement of these therapeutic agents in clinical settings. We have previously identified a set of half sandwich-type osmium, ruthenium and iridium complexes with bidentate glycosyl heterocyclic ligands exerting specific cytostatic activity on cancer cells but not on non-transformed primary cells. The apolar nature of the complexes, conferred by large, apolar benzoyl protective groups on the hydroxyl groups of the carbohydrate moiety, was the main molecular feature to induce cytostasis. We exchanged the benzoyl protective groups to straight chain alkanoyl groups with varying length (3 to 7 carbon units) that increased the IC50 value as compared to the benzoyl-protected complexes and rendered the complexes toxic. These results suggest a need for aromatic groups in the molecule. The pyridine moiety of the bidentate ligand was exchanged for a quinoline group to enlarge the apolar surface of the molecule. This modification decreased the IC50 value of the complexes. The complexes containing [(η6-p-cymene)Ru(II)], [(η6-p-cymene)Os(II)] or [(η5-Cp*)Ir(III)] were biologically active unlike the complex containing [(η5-Cp*)Rh(III)]. The complexes with cytostatic activity were active on ovarian cancer (A2780, ID8), pancreatic adenocarcinoma (Capan2), sarcoma (Saos) and lymphoma cell lines (L428), but not on primary dermal fibroblasts and their activity was dependent on reactive oxygen species production. Importantly, these complexes were cytostatic on cisplatin-resistant A2780 ovarian cancer cells with similar IC50 values as on cisplatin-sensitive A2780 cells. In addition, the quinoline-containing Ru and Os complexes and the short chain alkanoyl-modified complexes (C3 and C4) proved to be bacteriostatic in multiresistant Gram-positive Enterococcus and Staphylococcus aureus isolates. Hereby, we identified a set of complexes with submicromolar to low micromolar inhibitory constants against a wide range of cancer cells, including platinum resistant cells and against multiresistant Gram-positive bacteria.

Novel 3,9-Disubstituted Acridines with Strong Inhibition Activity against Topoisomerase I: Synthesis, Biological Evaluation and Molecular Docking Study.

A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives 17a-17j, in a moderate yield. The principles of cheminformatics and computational chemistry were applied in order to study the relationship between the physicochemical properties of the 3,9-disubstituted acridines and their biological activity at a cellular and molecular level. The selected 3,9-disubstituted acridine derivatives were studied in the presence of DNA using spectroscopic (UV-Vis, circular dichroism, and thermal denaturation) and electrophoretic (nuclease activity, relaxation and unwinding assays for topoisomerase I and decatenation assay for topoisomerase IIα) methods. Binding constants (2.81-9.03 × 104 M-1) were calculated for the derivatives from the results of the absorption titration spectra. The derivatives were found to have caused the inhibition of both topoisomerase I and topoisomerase IIα. Molecular docking simulations suggested a different way in which the acridines 17a-17j can interact with topoisomerase I versus topoisomerase IIα. A strong correlation between the lipophilicity of the derivatives and their ability to stabilize the intercalation complex was identified for all of the studied agents. Acridines 17a-17j were also subjected to in vitro screening conducted by the Developmental Therapeutic Program of the National Cancer Institute (NCI) against a panel of 60 cancer cell lines. The strongest biological activity was displayed by aniline acridine 17a (MCF7-GI50 18.6 nM) and N,N-dimethylaniline acridine 17b (SR-GI50 38.0 nM). The relationship between the cytostatic activity of the most active substances (derivatives 17a, 17b, and 17e-17h) and their values of KB, LogP, ΔS°, and δ was also investigated. Due to the fact that a significant correlation was only found in the case of charge density, δ, it is possible to assume that the cytostatic effect might be dependent upon the structural specificity of the acridine derivatives.

Secondary Metabolites with Anti-Inflammatory Activity from Laurencia majuscula Collected in the Red Sea.

The chemical investigation of the organic extract of the red alga Laurencia majuscula collected from Hurghada reef in the Red Sea resulted in the isolation of five C15 acetogenins, including four tricyclic ones of the maneonene type (1-4) and a 5-membered one (5), 15 sesquiterpenes, including seven lauranes (6-12), one cuparane (13), one seco-laurane (14), one snyderane (15), two chamigranes (16, 17), two rearranged chamigranes (18, 19) and one aristolane (20), as well as a tricyclic diterpene (21) and a chlorinated fatty acid derivative (22). Among them, compounds 1-3, 5, 7, 8, 10, 11 and 14 are new natural products. The structures and the relative configurations of the isolated natural products have been established based on extensive analysis of their NMR and MS data, while the absolute configuration of maneonenes F (1) and G (2) was determined on the basis of single-crystal X-ray diffraction analysis. The anti-inflammatory activity of compounds 1, 2, 4-8, 10, 12-16, 18 and 20-22 was evaluated by measuring suppression of nitric oxide (NO) release in TLR4-activated RAW 264.7 macrophages in culture. All compounds, except 6, exhibited significant anti-inflammatory activity. Among them, metabolites 1, 4 and 18 did not exhibit any cytostatic activity at the tested concentrations. The most prominent anti-inflammatory activity, accompanied by absence of cytostatic activity at the same concentration, was exerted by compounds 5 and 18, with IC50 values of 3.69 μM and 3.55 μΜ, respectively.

Phosphine chalcogenides and their derivatives from red phosphorus and functionalized pyridines, imidazoles, pyrazoles and their antimicrobial and cytostatic activity

Tertiary phosphine oxides, phosphine sulfides, and phosphine selenides containing pyridine, imidazole, and pyrazole groups have been synthesized via the reaction of elemental phosphorus or secondary phosphine oxides with functional pyridines, imidazoles, and pyrazoles. Alkyl tris(2-pyridylethyl)phosphonium iodide and bromide are also obtained by quaternization of the corresponding phosphine. Antimicrobial activity of the synthesized compounds, including nitrogen-containing heterocycles, phosphorus, selenium, and sulfur, with respect to Enterococcus durans, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa microorganisms is evaluated. It is found that phosphine chalcogenides bearing imidazole (14, 19), pyrazole (13), and pyridine fragments (5, 9) and phosphonium salts (11, 12) can be considered as new promising antibacterial agents. For some synthesized compounds, LC50 is determined. Phosphine oxide with methylpyrazole fragments (13) and phosphonium salts (11, 12) show strong profile of antimicrobial activity, and cytotoxic effect of phosphonium bromide having a long chain radical (12) is by order of magnitude higher than that of cisplatin. We believe that the results obtained may contribute to the development of highly effective agents for the treatment and prevention of bacterial infections and cancers.

Cytotoxic, cytostatic, and keratolytic activity of anti-dandruff shampoo formulations

Background: Dandruff is characterized by increased sebum production, yeast colonization, and hyper-keratinization leading to an itchy-flaky scalp. Ancillary non-microbial reasons for flaky scalp include ultraviolet rays and excessive heat from the sun. Thus, apart from traditional anti-fungal activity, anti-dandruff formulations should also possess the keratolytic activity and should be safe to use. Methods: Selsun, a shampoo formulation with 2.5% selenium sulfide (SS2.5), was tested in-vitro for its cytotoxic and cytostatic activities via cell viability of primary human dermal fibroblasts (HDFs). Its keratolytic activity was determined by assessing anti-proliferative activity on immortalized human keratinocyte (HaCaT) cell line. The shampoo was compared with 3 other shampoo formulations, one containing 2% ketoconazole (K2), second containing 2% ketoconazole with 1% zinc pyrithione (K2ZP1), and third containing 1% zinc pyrithione (ZP1). Results: Of the tested samples, SS2.5 and K2ZP1 showed cytostatic and keratolytic activity where the IC50 values on normal HDFs i.e., 0.521 mg/ml and 0.220 mg/ml, respectively, were higher than those on HaCaT cells (0.162 mg/ml and 0.198 mg/ml, respectively). SS2.5 displayed the highest keratolytic activity at IC50 of 0.162 mg/ml, followed by K2ZP1 (0.198 mg/ml) and K2 (0.267 mg/ml). On normal HDFs, SS2.5 showed the highest IC50 value (0.521 mg/ml), followed by K2 at 0.264 mg/mL, K2ZP1 at 0.220 mg/ml, and ZP1 at 0.139 mg/ml. Conclusions: SS2.5 was found to possess the highest cytostatic and keratolytic activities among all the shampoo formulations tested, thereby confirming its safety profile.

ФАРМАКОЛОГИЧЕСКИЕ СВОЙСТВА И КОМПОНЕНТНЫЙ СОСТАВ БОРЩЕВИКА СОСНОВСКОГО (HERACLEUM SOS-NOWSKI MANDEN)

The article presents a literature review regarding the composition and pharmacological properties of Heracleum Sosnowski Manden. The dominant group of biologically active substances of Heracleum Sosnowski are furano-coumarins, which are represented by angelicin, bergapten, isobergapten, iso-pimpinellin, methoxsalen, osthole, pimpinellin, sfondin, umbelliferone, isoimperatorin, marmesin, oxypeucedanin and pangelin. In addition to this group of biologically active substances, Heracleum Sosnowski contains terpe-noids, phenols and their derivatives, organic acids, aliphatic hydrocarbons, al-cohols, aldehydes, fatty acids and their esters, carbohydrates, proteins and amino acids, vitamins and alkaloids. The essential oil contains predominantly aliphatic esters and has an antibacterial effect. For Heracleum Sosnowski described photosensitizing, antihypertensive, an-tispasmodic, diuretic, antioxidant and antibacterial action. The photosensitiz-ing effect of Heracleum Sosnowski is associated with the presence of coumarins in it. Methods for obtaining galenic drugs (tinctures, extracts), suspensions of the amount of furanocoumarins and essential oil emulsions from Heracleum Sosnowski herbal raw materials have been developed under laboratory condi-tions. The toxic properties of Heracleum Sosnowski on the skin, cytotoxic, geno-toxic and mutagenic effects were noted. The phototoxicity of Heracleum Sos-nowski manifests itself in the form of photodermatitis, for the treatment of which there are currently no clinical guidelines and protocols. Medicinal plant materials Heracleum Sosnowskyi are not included in interna-tional, regional and national pharmacopoeias and, therefore, do not have ap-proved express and high-precision standardization methods, incl. methods of identification and quantitative determination of the active group of biologically active substances - furanocoumarins. Thus, the pharmacological potential of Heracleum Sosnowskyi is not well understood. There is no evidence base necessary to obtain safe and effective drugs based on it. At the same time, in order to obtain dosage forms from Her-acleum Sosnowskyi, it is necessary to develop safe methods for the procure-ment and processing of raw materials. Given the presence of cytotoxic properties, a promising direction in the study of the pharmacological properties of extracts from Heracleum Sos-nowskyi may be the assessment of their cytostatic activity against tumor cell lines in vitro.

Mechanism of action of oxazaphosphorine cytostatics and anti metastatic experimental therapy with SUMIAP a new Ifosfamide derivative adapted

Mechanism of action of oxazaphosphorine cytostatics and anti metastatic experimental therapy with SUMIAP a new Ifosfamide derivative adapted

1,3-Dipolar cycloaddition of cycloimmonium salts and 4-(trimethylsilyl)-3-butyn-2-one to access new functionalized indolizines with potential cytostatic activity

4-(Trimethylsilyl)-3-butyn-2-one is an effective dipolarophile in the [3+2] cycloaddition reaction with cycloimmonium salts to obtain bioactive non-silicon adducts, namely 1-acetylindolizines, but also trimethylsilyl-containing adducts.