Search

A series of 19 synthetic alkyl and thioalkyl glycosides derived from d -mannose, d -glucose and d -galactose and having C 10 –C 16 aglycone were investigated for cytotoxic activity against 7 human cancer and 2 non-tumor cell lines as well as for antimicrobial potential on 12 bacterial and yeast strains. The most potent compounds were found to be tetradecyl and hexadecyl β- d -galactopyranosides (18, 19), which showed the best cytotoxicity and therapeutic index against CCRF-CEM cancer cell line. Similar cytotoxic activity showed hexadecyl α- d -mannopyranoside (5) but it also inhibited non-tumor cell lines. Because these two galactosides (18, 19) were inactive against all tested bacteria and yeast strains, they could be a target-specific for eukaryotic cells. On the other hand, β-D-glucopyranosides with tetradecyl (11) and hexadecyl (12) aglycone inhibited only Gram-positive bacterial strain Enterococcus faecalis. The studied glycosides induce changes in the lipid bilayer thickness and lateral phase separation at high concentration, as derived from SAXS experiments on POPC model membranes. In general, glucosides and galactosides exhibit more specific properties. Those with longer aglycone show high cytotoxicity and therefore, they are more promising candidates for cancer cell line targeted inhibition. Image 1 • β-Hexopyranosides having C14-16 aglycone were the most potent glycosides. • Such two β-D-glucosides selectively inhibited a G+ strain Enterococcus faecalis. • Such two β- d -galactosides could be an agent specific for eukaryotic cells. • Tetradecyl β- d -galactoside was the most cytotoxic (IC 50 9.4 μM, CCRF-CEM line). [ABSTRACT FROM AUTHOR]

After cardiovascular diseases, cancer, a non-communicable pathology, has been considered the second cause of death each year globally and as the most important barrier to increasing life expectancy in the 21st century. Advances of great relevance have been made in its prevention and treatment, however, there is still a long way to go to achieve an eff ective treatment for each type of cancer. This paper describes approaches to reposition and synthesis of hybrid molecules with potential antineoplastic activity. To obtain the key intermediate aldehyde, the Dess-Martin oxidation methodology was used, which was coupled with the corresponding ketones using LDA. The fi nal hybrid compounds were obtained as a racemic mixture. The in vitro antiproliferative activity of the fi nal compounds was evaluated against eight cell lines derived from human solid tumors, and four non-cancerous cell lines. The compound 11d turned out to be the most eff ective and with the highest safety index. The results suggested that these compounds could block the cell cycle and induce apoptosis and death in CCRF-CEM cells in a dose-dependent manner in vitro. [ABSTRACT FROM AUTHOR]

A series of 78 synthetic 7-chloro-(4-thioalkylquinoline) derivatives were investigated for cytotoxic activity against eight human cancer as well as 4 non-tumor cell lines. The results showed, with some exceptions, that sulfanyl 5–40 and sulfinyl 41–62 derivatives exhibited lower cytotoxicity for cancer cell lines than those of well-described sulfonyl N-oxide derivatives 63–82. As for compound 81, the most pronounced selectivity (compared against BJ and MRC-5 cells) was observed for human cancer cells from HCT116 (human colorectal cancer with wild-type p53) and HCT116p53−/− (human colorectal cancer with deleted p53), as well as leukemia cell lines (CCRF-CEM, CEM-DNR, K562, and K562-TAX), lung (A549), and osteosarcoma cells (U2OS). A good selectivity was also detected for compounds 73 and 74 for leukemic and colorectal (with and without p53 deletion) cancer cells (compared to MRC-5). At higher concentrations (5 × IC50) against the CCRF-CEM cancer cell line, we observe the accumulation of the cells in the G0/G1 cell phase, inhibition of DNA and RNA synthesis, and induction of apoptosis. In addition, X-ray data for compound 15 is being reported. These results provide useful scientific data for the development of 4-thioalkylquinoline derivatives as a new class of anticancer candidates. [ABSTRACT FROM AUTHOR]

A series of triterpenoid pyrones was synthesized and subsequently modified to introduce phthalimide or phthalate moieties into the triterpenoid skeleton. These compounds underwent in vitro cytotoxicity screening, revealing that a subset of six compounds exhibited potent activity, with IC 50 values in the low micromolar range. Further biological evaluations, including Annexin V and propidium iodide staining experiment revealed, that all compounds induce selective apoptosis in cancer cells. Measurements of mitochondrial potential, cell cycle analysis, and the expression of pro- and anti-apoptotic proteins confirmed, that apoptosis was mediated via the mitochondrial pathway. These findings were further supported by cell cycle modulation and DNA/RNA synthesis studies, which indicated a significant increase in cell accumulation in the G0/G1 phase and a marked reduction in S-phase cells, alongside a substantial inhibition of DNA synthesis. The activation of caspase-3 and the cleavage of PARP, coupled with a decrease in the expression of Bcl-2 and Bcl-XL proteins, underscored the induction of apoptosis through the mitochondrial pathway. Given their high activity and pronounced effect on mitochondria function, trifluoromethyl pyrones 1f and 2f , and dihydrophthalimide 2h have been selected for further development. [Display omitted] • A set of novel triterpenoid pyrones, phthalimides and phthalates was synthesized. • Six compounds with high in vitro cytotoxicity in CCRF-CEM cells was identified. • All compounds induce apoptosis via the mitochondrial intrinsic pathway. • Pyrones 1f , 2f , and dihydrophthalimide 2h were selected for further development. [ABSTRACT FROM AUTHOR]

[Display omitted] • Triazole-Based Estradiol dimers inhibit tubulin assembly in vitro. • Triazole-Based Estradiol dimers reversibly disrupt microtubule structures in U2OS cells. • Triazole-Based Estradiol dimers show cytotoxic activities on cancer cell lines, arrest cells in the G2/M phase of the cell cycle and attenuate DNA/RNA synthesis. • Structural changes in the bridge are essential for the activity of estradiol dimers at the cytoskeletal level. • Simple linkers seem more suitable than more complex ones, bulky groups (benzyl pendants), are reducing the activity. Microtubule dynamic is exceptionally sensitive to modulation by small-molecule ligands. Our previous work presented the preparation of microtubule-targeting estradiol dimer (ED) with anticancer activity. In the present study, we explore the effect of selected linkers on the biological activity of the dimer. The linkers were designed as five-atom chains with carbon, nitrogen or oxygen in their centre. In addition, the central nitrogen was modified by a benzyl group with hydroxy or methoxy substituents and one derivative possessed an extended linker length. Thirteen new dimers were subjected to cytotoxicity assay and cell cycle profiling. Dimers containing linker with benzyl moiety substituted with one or more methoxy groups and longer branched ones were found inactive, whereas other structures had comparable efficacy as the original ED (e.g. D1 with IC 50 = 1.53 µM). Cell cycle analysis and immunofluorescence proved the interference of dimers with microtubule assembly and mitosis. The proposed in silico model and calculated binding free energy by the MM-PBSA method were closely correlated with in vitro tubulin assembly assay. [ABSTRACT FROM AUTHOR]

In this work, a large set of betulinic acid derivatives modified with various aromatic substituents at the position C-3 were prepared via Suzuki-Myiaura cross-coupling. All compounds were tested for their in vitro cytotoxic activity in 8 cancer and 2 healthy cell lines. Derivatives 6h , 6i , and 6o had the lowest IC 50 in the CCRF-CEM cell line (0.69–4.0 μM) and had high selectivity. In addition, 6h and 6i also showed significant activity in daunorubicin-resistant CEM and taxol-resistant K562 cell lines; therefore, they were selected for the evaluation of the mechanism of action. First, the effect of 6h , 6i , and 6o on cell death induction was studied. To our surprise, we have not detected almost any apoptotic cells, even following a long-time exposure of CCRF-CEM cells to the compounds. On the other hand, a dramatic cell number decrease was observed, proportional to the time of the compound's exposure. Based on this data it was concluded that the effect of compounds is cytostatic rather than cytotoxic, which was further confirmed by subsequent studies of the impact of 6h , 6i , and 6o on the cell cycle. Detailed cell cycle analysis revealed a block in the G1 phase accompanied by reduced expression of phosphorylated forms of the RB protein as well as cyclin A protein. Evaluation of the pharmacological properties of the most promising compounds revealed their high stability in the presence of phosphate buffer, human plasma, and microsomes and limited permeability determined using permeability through artificial membrane (PAMPA) and cell permeability assay: Caco-2 and MDCK-MDR1 cell lines. Compounds 6h , 6i , and 6o were selected for further drug development; their cytostatic effect may be advantageous in this process since we expect fewer non-specific interactions and toxicity than in highly cytotoxic compounds. In addition, the activity of 6h and 6i against resistant CEM-DNR and K562-TAX leukemic cell lines makes them promising as a possible future alternative to currently used therapies. [Display omitted] • Arylated lupane derivatives were prepared and their cytotoxicity tested. • Pharmacological parameters and selectivity were measured. • Most active compounds were cytostatic against leukemic cells including resistant. • Compounds 6h , 6i , 6o were selected for further drug development. [ABSTRACT FROM AUTHOR]

A set of new substituted dienes were synthesized from betulinic acid by its oxidation to 30-oxobetulinic acid followed by the Wittig reaction. Cytotoxicity of all compounds was tested in vitro in eight cancer cell lines and two noncancer fibroblasts. Almost all dienes were more cytotoxic than betulinic acid. Compounds 4.22 , 4.30 , 4.33 , 4.39 had IC 50 below 5 μmol/L; 4.22 and 4.39 were selected for studies of the mechanism of action. Cell cycle analysis revealed an increase in the number of apoptotic cells at 5 × IC 50 concentration, where activation of irreversible changes leading to cell death can be expected. Both 4.22 and 4.39 led to the accumulation of cells in the G0/G1 phase with partial inhibition of DNA/RNA synthesis at 1 × IC 50 and almost complete inhibition at 5 × IC 50. Interestingly, compound 4.39 at 5 × IC 50 caused the accumulation of cells in the S phase. Higher concentrations of tested drugs probably inhibit more off-targets than lower concentrations. Mechanisms disrupting cellular metabolism can induce the accumulation of cells in the S phase. Both compounds 4.22 and 4.39 trigger selective apoptosis in cancer cells via intrinsic pathway, which we have demonstrated by changes in the expression of the crucial apoptosis-related protein. Pharmacological parameters of derivative 4.22 were superior to 4.39 , therefore 4.22 was the finally selected candidate for the development of anticancer drug. [Display omitted] • Forty new triterpenoids were prepared from 30-oxobetulinic acid by Wittig reaction • Four compounds had high selective cytotoxicity to cancer cells • Compounds 4.22 and 4.39 were selected for further development • Both compounds cause selective apoptosis in cancer cells via the intrinsic pathway • Diene 4.22 has appropriate pharmacological parameters and will be further developed [ABSTRACT FROM AUTHOR]

We have synthesized a series of 2-phenyl-3-hydroxy-4(1 H)-quinolinone derivatives substituted with one or more fluorine atoms on the quinolone backbone as well as on phenyl ring. The derivatives bearing more fluorine atoms were subjected to modification by nucleophilic substitutions by thiophenol, morpholine, and piperazine derivative. We have tested the prepared compounds in cytotoxic activity assay against cancer cell lines. Four derivatives exhibited micromolar values of IC 50 against some of the cancer cell lines, and we have subjected them to cell cycle analysis on CCRF-CEM. Moreover, most active 7-fluoro-3-hydroxy-2-phenyl-6-(phenylthio)quinolin-4(1 H)-one inhibits mitosis progression. Cell cycle analysis, in vitro tubulin polymerization assay, and tubulin imaging in cells indicated that the anticancer activity of thiophenol derivative is associated with its ability to inhibit microtubule formation. Image 1 • Fluorine in 2-phenyl-3-hydroxy-4(1 H)-quinolinone improves biological activity. • Difluoroderivatives of 3-hydroxy-4(1 H)-quinolinone enable nucleophilic substitution. • 2-phenyl-3-hydroxy-4(1 H)-quinolinones can inhibit tubulin polymerization. [ABSTRACT FROM AUTHOR]