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Sesquiterpene lactone trilobolide is a sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) inhibitor, thus depleting the Ins(1,4,5)P3-sensitive intracellular calcium stores. Here, we describe a synthesis of a series of 6 trilobolide-steroids conjugates (estradiol, pregnene, dehydroepiandrosterone, and testosterone). We found that the newly synthesized Tb-based compounds possess different remarkable biological activities. Cancer cell cytotoxicity and preferential selectivity is represented in our study by a Tb-pregnene derivative. The most cytotoxic clickates of estradiol and pregnene were studied by FACS where impact on cell cycle and RNA synthesis was observed; live-cell microscopy revealed the impact on cell organelle morphology particularly endoplasmic reticulum, mitochondria and nucleus. Further, we have studied the estrogenic and androgenic properties of the clickate molecules using cell-based luciferase assays. Finally, antimycobacterial tests revealed that testosterone and estradiol derivatives potentiated the antimycobacterial activity up to IC50 of 10.6 μM. [ABSTRACT FROM AUTHOR]

Abstract: There were synthesized new types of ribbon type steroidal dimers derived from three types of steroidal skeletons (cholic acid, etienic acid, estrone) using CuI catalyzed 1, 3-dipolar cycloaddition reaction. Steroid parts of the molecular “ribbons” are linked by heterocyclic moiety, namely by 2,6-bis((1H-1,2,3-triazol-1-yl)-methyl)pyridine. Compounds synthesized possess different cytotoxic and hormone receptor modulating activities. [Copyright &y& Elsevier]

Abstract: A number of 5-alkoxymethyluracil analogues were synthesized to evaluate their cytotoxic activity. 5-Alkoxymethyluracil derivatives 1 were prepared via known nucleophilic substitution of 5-chloromethyluracil 5 and subsequently transformed to their corresponding nucleosides 2. All prepared compounds were submitted to cytotoxic activity testing against drug sensitive and drug resistant leukaemia cells and solid tumour derived cell lines. In addition, the cytotoxic activity of 5-alkoxymethyluracil analogues 1 and 2 was compared with the previously published 5-[alkoxy(4-nitrophenyl)methyl]uracil analogues 3 and 4. Extensive structure–cytotoxic activity relationship studies are reported. [Copyright &y& Elsevier]

Abstract: A series of uridine analogues modified at the 5-position with the 5-[alkoxy-(4-nitrophenyl)-methyl] moiety was synthesized. Nucleosides were formed as a mixture of two diastereoisomers, which were separated and tested for their cytotoxic activity in vitro against different cancer cell lines and for antimicrobial activity. Relationships between structure and the above mentioned activities were studied. The cytotoxic activity was slightly increased in some cases by transformation of bases to nucleosides. Depending on the length of the alkyl chain increased cytotoxic and antimicrobial activity were noted. The cytotoxic activity of the nucleosides was not due to cell cycle alterations, DNA and/or RNA synthesis. [ABSTRACT FROM AUTHOR]

Abstract: The preparation of various 5-[alkoxy-(4-nitro-phenyl)-methyl]-uracils with alkyl chain lengths C1–C12 is described. The synthesis is based on the preparation of 5-[chloro-(4-nitro-phenyl)-methyl]-uracil and subsequent substitution of chlorine with appropriate alcohols. The resulting ethers were tested for their cytotoxic activity in vitro against five cancer cell lines. The compounds were less active in lung resistance protein expressing cell lines, suggesting the involvement of this multidrug resistant protein in control of the biological activity. Cytotoxic substances induced rapid inhibition of DNA and modulation of RNA synthesis followed by induction of apoptosis. The data indicate that the biological activity of 5-[alkoxy-(4-nitro-phenyl)-methyl]-uracils depends on the alkyl chain length. [Copyright &y& Elsevier]

Abstract: Large series of O-alkyl derivatives (methyl and benzyl) of silybin and 2,3-dehydrosilybin was prepared. Selective alkylation of the silybin molecule was systematically investigated. For the first time we present here, for example, preparation of 19-nor-2,3-dehydrosilybin. All prepared silybin/2,3-dehydrosilybin derivatives were tested for cytotoxicity on a panel of drugs sensitive against multidrug resistant cell lines and the ability to inhibit P-glycoprotein mediated efflux activity. We have identified effective and relatively non-cytotoxic inhibitors of P-gp derived from 2,3-dehydrosilybin. Some of them were more effective inhibitors at concentrations lower than a standard P-gp efflux inhibitor cyclosporin A. Another group of 2,3-dehydrosilybin derivatives also had better inhibitory effects on P-gp efflux but a cytotoxicity comparable with that of parent 2,3-dehydrosilybin. Structural requirements for improving inhibitory activity and reducing toxicity of 2,3-dehydrosilybin were established. Effect of E-ring substitution as well as an influence of the substituent size at the C-7-OH position of A-ring on P-gp-inhibitory activity was evaluated for the first time in this study. [Copyright &y& Elsevier]

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]

A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of β-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA in this study. The compounds significantly reduced haeme crystallization, with IC50 values < 10 µM. The values were comparable to chloroquine's, with an IC50 of 1.50 ± 0.01 µM. The compounds 4c and 4e prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds 4b, 4c, and 4e on another important human parasite, Leishmania mexicana, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC50 < 10 µM. Concerning the possible mechanism of action of these compounds on Lesihmania mexicana, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber's rules, and except for 2 and 4i, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo. [ABSTRACT FROM AUTHOR]

A series of benzofuro‐fused 7‐deazapurine (6H‐furo[2,3‐e]pyrimido[4,5‐b]indole) 2'‐deoxyribo‐ and ribonucleosides was designed and synthesized. The synthesis of key compound 10‐chloro‐6H‐furo[2,3‐e]pyrimido[4,5‐b]indole was based on the Negishi cross‐coupling of iodobenzofurane with zincated 4,6‐dichloropyrimidine followed by azidation and photochemical cyclization. Glycosylation of the heterocycle with either Hoffer's chlorodeoxyribose or protected ribose followed by cross‐coupling or substitution reactions at position 10 gave the desired two sets of final nucleosides that showed moderate to weak cytostatic activity and interesting fluorescence properties. [ABSTRACT FROM AUTHOR]

P2X7 sites are emerging targets for molecular imaging research, notably in the context of neurodegeneration and inflammatory conditions. Therefore, we prepared a precursor for (radio)iodination of the P2X7 ligand VPGIS191. We then developed a radioiodination method with 123I for SPECT with a radiochemical yield of 71 ± 13% and 125I for autoradiography with a radiochemical yield of 85 ± 6% Autoradiography of [125I]VPGIS191 in mouse brain cryostat sections demonstrated approximately 36 nM binding affinity and Bmax of approximately 400 pmol/gram tissue for P2X7 binding sites. VPGIS191 (cis) had a two-fold lower affinity compared to its geometric trans-isomer TZ6019. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects normal functions of the brain. Currently, AD is one of the leading causes of death in developed countries and the only one of the top ten diseases without a means to prevent, cure, or significantly slow down its progression. Therefore, newer therapeutic concepts are urgently needed to improve survival and the quality of life of AD patients. Microtubule affinity-regulating kinases (MARKs) regulate tau-microtubule binding and play a crucial role in neurons. However, their role in hyperphosphorylation of tau makes them potential druggable target for AD therapy. Despite the relevance of MARKs in AD pathogenesis, only a few small molecules are known to have anti-MARK activity and not much has been done to progress these compounds into therapeutic candidates. But given the diverse role of MARKs, the specificity of novel inhibitors is imperative for their successful translation from bench to bedside. In this regard, a recent co-crystal structure of MARK4 in association with a pyrazolopyrimidine-based inhibitor offers a potential scaffold for the development of more specific MARK inhibitors. In this manuscript, we review the biological role of MARKs in health and disease, and draw attention to the largely unexplored area of MARK inhibitors for AD. [ABSTRACT FROM AUTHOR]

Cervical mucus (CM) is a viscous fluid that is produced by the cervical glands and functions as a uterine cervix plug. Its viscosity decreases during ovulation, providing a window for non-invasive sampling. This study focuses on proteomic characterization of CM to evaluate its potential as a non-invasively acquired source of biomarkers and in understanding of molecular (patho)physiology of the female genital tract. The first objective of this work was to optimize experimental workflow for CM processing and the second was to assess differences in the proteomic composition of CM during natural ovulatory cycles obtained from intrauterine insemination (IUI) cycles and in vitro fertilization (IVF) cycles with controlled ovarian hyperstimulation. Proteomic analysis of CM samples revealed 4370 proteins involved in processes including neutrophil degranulation, cellular stress responses, and hemostasis. Differential expression analysis revealed 199 proteins enriched in IUI samples and 422 enriched in IVF. The proteins enriched in IUI were involved in phosphatidic acid synthesis, responses to external stimulus, and neutrophil degranulation, while those enriched in IVF samples were linked to neutrophil degranulation, formation of a cornified envelope and hemostasis. Subsequent analyses clarified the protein composition of the CM and how it is altered by hormonal stimulation of the uterus. [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]

Aryl hydrocarbon receptor (AHR) plays pivotal roles in intestinal physiology and pathophysiology. Intestinal AHR is activated by numerous dietary, endogenous, and microbial ligands. Whereas the effects of individual compounds on AHR are mostly known, the effects of real physiological mixtures occurring in the intestine have not been studied. Using reporter gene assays and RT-PCR, we evaluated the combinatorial effects (3520 combinations) of 11 microbial catabolites of tryptophan (MICTs) on AHR. We robustly (n = 30) determined the potencies and relative efficacies of single MICTs. Synergistic effects of MICT binary mixtures were observed between low- or medium-efficacy agonists, in particular for combinations of indole-3-propionate and indole-3-lactate. Combinations comprising highly efficacious agonists such as indole-3-pyruvate displayed rather antagonist effects, caused by saturation of the assay response. These synergistic effects were confirmed by RT-PCR as CYP1A1 mRNA expression. We also tested mimic multicomponent and binary mixtures of MICTs, prepared based on the metabolomic analyses of human feces and colonoscopy aspirates, respectively. In this case, AHR responsiveness did not correlate with type of diet or health status, and the indole concentrations in the mixtures were determinative of gross AHR activity. Future systematic research on the synergistic activation of AHR by microbial metabolites and other ligands is needed. [ABSTRACT FROM AUTHOR]

The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8–23 were obtained using the classical base-catalyzed Claisen–Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments. [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]

Abstract: The targeted solid-phase synthesis of 3-hydroxyquinolin-4(1H)-one derivatives is described. Primary and secondary amines, 3-amino-4-(methoxycarbonyl)benzoic acid and 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone were used as starting materials. The structures of the final compounds were designed in accordance with previous information obtained from structure–activity relationship studies of similar cytotoxic derivatives. Representative prepared compounds were subjected to in vitro screening of cytotoxic activity against various cancer cell lines; the results obtained are discussed. Fluorescence properties of selected compounds were also studied to compare the data with those obtained in analogous derivatives. [Copyright &y& Elsevier]

A key objective in immuno-oncology is to reactivate the dormant immune system and increase tumour immunogenicity. Adenosine is an omnipresent purine that is formed in response to stress stimuli in order to restore physiological balance, mainly via anti-inflammatory, tissue-protective, and anti-nociceptive mechanisms. Adenosine overproduction occurs in all stages of tumorigenesis, from the initial inflammation/local tissue damage to the precancerous niche and the developed tumour, making the adenosinergic pathway an attractive but challenging therapeutic target. Many current efforts in immuno-oncology are focused on restoring immunosurveillance, largely by blocking adenosine-producing enzymes in the tumour microenvironment (TME) and adenosine receptors on immune cells either alone or combined with chemotherapy and/or immunotherapy. However, the effects of adenosinergic immunotherapy are not restricted to immune cells; other cells in the TME including cancer and stromal cells are also affected. Here we summarise recent advancements in the understanding of the tumour adenosinergic system and highlight the impact of current and prospective immunomodulatory therapies on other cell types within the TME, focusing on adenosine receptors in tumour cells. In addition, we evaluate the structure- and context-related limitations of targeting this pathway and highlight avenues that could possibly be exploited in future adenosinergic therapies. [ABSTRACT FROM AUTHOR]

The combination of cytotoxic amino‐BODIPY dye and 2‐phenyl‐3‐hydroxy‐4(1H)‐quinolinone (3‐HQ) derivatives into one molecule gave rise to selective activity against lymphoblastic or myeloid leukemia and the simultaneous disappearance of the cytotoxicity against normal cells. Both species′ conjugation can be realized via a disulfide linker cleavable in the presence of glutathione characteristic for cancer cells. The cleavage liberating the free amino‐BODIPY dye and 3‐HQ derivative can be monitored by ratiometric fluorescence or by the OFF‐ON effect of the amino‐BODIPY dye. A similar cytotoxic activity is observed when the amino‐BODIPY dye and 3‐HQ derivative are connected through a non‐cleavable maleimide linker. The work reports the synthesis of several conjugates, the study of their cleavage inside cells, and cytotoxic screening. [ABSTRACT FROM AUTHOR]

The synthesis and anticancer activity evaluation of new quinazoline alkaloids rutaecarpine and evodiamine semisynthetic derivatives and their molecular hybrids with lupinine moiety is described. Newly synthesized compounds were elucidated based on elemental analyses and spectral data (1H and 13C NMR). Anticancer cytotoxicity was studied toward some cell lines of lung cancer, T-lymphoblastic leukemia, colon cancer, myeloid leukemia, and osteosarcoma. Among the tested compounds, the highest activity with a specific sensitivity profile toward the Leukemia cell lines CCRF-CEM and K-562 was demonstrated by the starting compound evodiamine. Structural modifications of the studied quinazoline alkaloids did not lead to the improvement of anticancer activity. [ABSTRACT FROM AUTHOR]

The interleukin‐2‐inducible kinase (ITK) and Bruton tyrosine kinase (BTK) are two crucial Tec family kinase members with important roles in the development of hematopoietic malignancies, autoimmune disorders and other diseases in humans. Thus, ITK and BTK are key targets for drug development. Spirooxindoles are important scaffolds for the synthesis of small molecules with broad and potent biological activities. In this study, we performed a structure‐activity relationship study of a new series of 5′‐(benzo[d][1,3]dioxol‐5‐yl)spiro[piperidine‐4,3′‐pyrrolo[2,3–b]pyridin]‐2′(1′H)‐one linked with N‐acyl and C‐5 aryl‐substituted scaffolds in a panel of ITK and BTK cancer cell lines. Four compounds 11, 12, 14, and 15 showed high antiproliferative activity against ITK and BTK cell lines. Compounds 11 and 12 with a C‐5 benzodioxole group and gem‐dialkyl group attached to carbonyl on piperidine were highly effective in ITK‐high Jurkat and CEM cell lines, and compound 14, a biotin analogue, was identified as a good inhibitor of BTK‐high RAMOS cells. Compound 15 with cyclopropyl group attached to carbonyl on piperidine also showed good activity in ITK and BTK cell lines. [ABSTRACT FROM AUTHOR]

All four isomeric series of novel 4‐substituted pyrido‐fused 7‐deazapurine ribonucleosides possessing the pyridine nitrogen atom at different positions were designed and synthesized. The total synthesis of each isomeric fused heterocycle through multistep heterocyclization was followed by glycosylation and derivatization at position 4 by cross‐coupling reactions or nucleophilic substitutions. All compounds were tested for cytostatic and antiviral activity. The most active were pyrido[4′,3′:4,5]pyrimidine nucleosides bearing MeO, NH2, MeS, or CH3 groups at position 4, which showed submicromolar cytotoxic effects and good selectivity for cancer cells. The mechanism involved activation by phosphorylation and incorporation to DNA where the presence of the modified ribonucleosides causes double‐strand breaks and apoptosis. [ABSTRACT FROM AUTHOR]

20-Hydroxyecdysterone – (2β,3β,5β,22 R)-2,3,14,20,22,25-hexahydroxycholest-7-en-6-one was isolated in satisfactory yield using ethanol extraction from the aerial part of Silene wolgensis (Hornem.) Otth; sometimes Silene wolgensis (Willd.) Bess. ex Spreng. The complexation of the phytoecdysteroid with β-cyclodextrin was studied by NMR spectroscopy. By studying the changes in chemical shifts of protons of substrates and receptors it was found that ecdysterone interacts with cyclodextrins to form supramolecular inclusion complexes of stoichiometric composition of 1:1 or 1:2. Ecdysterone-β-cyclodextrin complexes exhibit 100 times higher solubility in water than the parent compound. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of pentamethinium salts with benzothiazolium and indolium side units. • Affinity to sulfated polysaccharides correlated with their biological activity. • Side heteroaromates responsible for cytotoxicity and selectivity to cancer cells. • Charged salts with benzothiazole high efficacy against taxol-resistant cancer cells. Abstract A series of pentamethinium salts with benzothiazolium and indolium side units comprising one or two positive charges were designed and synthesized to determine the relationships among the molecular structure, charge density, affinity to sulfated polysaccharides, and biological activity. Firstly, it was found that the affinity of the pentamethinium salts to sulfated polysaccharides correlated with their biological activity. Secondly, the side heteroaromates displayed a strong effect on the cytotoxicity and selectivity towards cancer cells. Finally, doubly charged pentamethinium salts possessing benzothiazolium side units exhibited remarkably high efficacy against a taxol-resistant cancer cell line. [ABSTRACT FROM AUTHOR]

Two series of substituted benzo[g]‐ or benzo[e]pyrimido[4,5‐b]indole (naphtho‐fused 7‐deazapurine) ribonucleosides were synthesized. The heterocyclic nucleobases were obtained by Negishi cross‐coupling reaction of zincated pyrimidines with naphthyl iodides, nucleophilic substitution to tetrazoles/azides and thermal cyclization or photocyclization. Nucleosides were obtained by glycosylation followed by substitution reactions and deprotection. Resulting ribonucleosides were tested for their cytotoxic activity against cancer cell lines and antiviral activities. Some derivatives showed micromolar cytotoxic activities and moderate anti‐hepatitis C virus activities. Naphtho‐fused 7‐deazapurine 2′‐deoxyribonucleoside triphosphate was successfully incorporated into DNA oligonucleotides by KOD XL DNA polymerase. Fluorescence properties of naphtho‐fused 7‐deazapurine nucleosides and oligonucleotides were also studied. Two isomeric series of bulky naphtho‐fused 7‐deazapurine nucleosides were prepared and shown to exert moderate cytostatic and antiviral activity and interesting fluorescent properties. The 2′‐deoxyribonucleoside triphosphates were substrates for KOD XL DNA polymerase. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Estradiol dimer inhibits tubulin assembly in vitro. • Estradiol dimer reversibly disrupts microtubule structures in U2OS cells. • Estradiol dimer inhibits microtubule dynamics in U2OS cells. • Estradiol dimer shows cytotoxic activities on cancer cell lines, arrests cells in the G2/M phase of the cell cycle and attenuates DNA/RNA synthesis. • Estradiol dimer has no effect on the transactivation by estrogen receptor α. Abstract Microtubule dynamics is one of the major targets for new chemotherapeutic agents. This communication presents the synthesis and biological profiling of steroidal dimers based on estradiol, testosterone and pregnenolone bridged by 2,6-bis(azidomethyl)pyridine between D rings. The biological profiling revealed unique properties of the estradiol dimer including cytotoxic activities on a panel of 11 human cell lines, ability to arrest in the G2/M phase of the cell cycle accompanied with the attenuation of DNA/RNA synthesis. Thorough investigation precluded a genomic mechanism of action and revealed that the estradiol dimer acts at the cytoskeletal level by inhibiting tubulin polymerization. Further studies showed that estradiol dimer, but none of the other structurally related dimeric steroids, inhibited assembly of purified tubulin (IC 50 , 3.6 μM). The estradiol dimer was more potent than 2-methoxyestradiol, an endogenous metabolite of 17β-estradiol and well-studied microtubule polymerization inhibitor with antitumor effects that was evaluated in clinical trials. Further, it was equipotent to nocodazole (IC 50 , 1.5 μM), an antimitotic small molecule of natural origin. Both estradiol dimer and nocodazole completely and reversibly depolymerized microtubules in interphase U2OS cells at 2.5 μM concentration. At lower concentrations (50 nM), estradiol dimer decreased the microtubule dynamics and growth life-time and produced comparable effect to nocodazole on the microtubule dynamicity. In silico modeling predicted that estradiol dimer binds to the colchicine-binding site in the tubulin dimer. Finally, dimerization of the steroids abolished their ability to induce transactivation by estrogen receptor α and androgen receptors. Although other steroids were reported to interact with microtubules, the estradiol dimer represents a new structural type of steroid inhibitor of tubulin polymerization and microtubule dynamics, bearing antimitotic and cytotoxic activity in cancer cell lines. [ABSTRACT FROM AUTHOR]

Abstract: Three isomeric series of 4‐substituted thieno‐fused 7‐deazapurine nucleobases were synthesized by palladium catalyzed couplings or nucleophilic substitutions from protected key‐intermediate 4‐chlorothienopyrrolopyrimidines. Most final nucleobases exerted micromolar activity against hepatitis C virus and respiratory syncytial virus, as well as some in vitro cytostatic activities against several cancer and leukemia cell lines. Three new nucleosides derived from 8H‐thieno[3′, 4′:4,5]pyrrolo[2, 3‐d]pyrimidine were also synthesized and were significantly more cytostatic than corresponding nucleobases, with activities in submicromolar range and low toxicity to normal cycling fibroblasts. [ABSTRACT FROM AUTHOR]

The advanced-stage colon cancer spreads from primary tumor site to distant organs where the colon-unassociated stromal population provides a favorable niche for the growth of tumor cells. The heterocellular interactions between colon cancer cells and colon-unassociated fibroblasts at distant metastatic sites are important, yet these cell-cell interactions for therapeutic strategies for metastatic colon cancer remain underestimated. Recent studies have shown the therapeutic potential of DNA-demethylating epi-drugs 5-azacytidine (AZA) and 5-aza-2′-deoxycytidine (DAC) for the treatment of solid tumors. While the effects of these epi-drugs alone or in combination with other anticancer therapies are well described, the influence of stromal cells and their secretome on cancer cell response to these agents remain elusive. In this study, we determined the effect of normal and senescent colon-unassociated fibroblasts and their conditioned medium on colorectal cancer (CRC) cell response to AZA and DAC using a cell-based DNA demethylation reporter system. Our data show that fibroblasts accelerate cell proliferation and differentially regulate the expression of DNA methylation-regulating enzymes, enhancing DAC-induced demethylation in CRC cells. In contrast, the conditioned medium from senescent fibroblasts that upregulated NF-κB activity altered deoxycytidine kinase levels in drug-untreated CRC cells and abrogated DAC effect on degradation of DNA methyltransferase 1. Similar to 2D cultures, senescent fibroblasts increased DNA demethylation of CRC cells in coculture spheroids, in addition to increasing the stemness of CRC cells. This study presents the first evidence of the effect of normal and senescent stromal cells and their conditioned medium on DNA demethylation by DAC. The data show an increased activity of DAC in high stromal cell cocultures and suggest the potential of the tumor-stroma ratio in predicting the outcome of DNA-demethylating epigenetic cancer therapy. [ABSTRACT FROM AUTHOR]

Background Hypoxia is a prominent feature of solid tumors, dramatically remodeling microtubule structures and cellular pathways and contributing to paclitaxel resistance. Peloruside A (PLA), a microtubule-targeting agent, has shown promising anti-tumor effects in preclinical studies. Although it has a similar mode of action to paclitaxel, it binds to a distinct site on β-tubulin that differs from the classical taxane site. In this study, we examined the unexplored effects of PLA in hypoxia-conditioned colorectal HCT116 cancer cells. Methods Cytotoxicity of PLA was determined by cell proliferation assay. The effects of a pre-exposure to hypoxia on PLA-induced cell cycle alterations and apoptosis were examined by flow cytometry, time-lapse imaging, and western blot analysis of selected markers. The hypoxia effect on stabilization of microtubules by PLA was monitored by an intracellular tubulin polymerization assay. Results Our findings show that the cytotoxicity of PLA is not altered in hypoxia-conditioned cells compared to paclitaxel and vincristine. Furthermore, hypoxia does not alter PLA-induced microtubule stabilization nor the multinucleation of cells. PLA causes cyclin B1 and G2/M accumulation followed by apoptosis. Conclusions The cellular and molecular effects of PLA have been determined in normoxic conditions, but there are no reports of PLA effects in hypoxic cells. Our findings reveal that hypoxia preconditioning does not alter the sensitivity of HCT116 to PLA. General significance These data report on the cellular and molecular effects of PLA in hypoxia-conditioned cells for the first time, and will encourage further exploration of PLA as a promising anti-tumor agent. [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]

Cytokinin ribosides (N 6 -substituted adenosines) have demonstrated anticancer activity in various cultured cell lines, several xenografts and even a small clinical trial. Effects of kinetin riboside, N 6 -benzyladenosine (BAR) and N 6 -isopentenyladenosine on various parameters related to apoptosis have also been reported, but not directly compared with those of the highly active naturally occurring aromatic cytokinins oTR ( ortho -topolin riboside) and 2OH3MeOBAR (N 6 -(2-hydroxy-3-methoxybenzyl)adenosine). Here we show that 2OH3MeOBAR is the most active cytokinin riboside studied to date (median, 1st quartile, 3rd quartile and range of GI50 in tests with the NCI60 cell panel: 0.19, 0.10, 0.43 and 0.02 to 15.7 μM, respectively) and it differs from other cytokinins by inducing cell death without causing pronounced ATP depletion. Analysis of NCI60 test data suggests that its activity is independent of p53 status. Further we demonstrate that its 5′-monophosphate, the dominant cancer cell metabolite, inhibits the candidate oncogene DNPH1. Synthesis, purification, HPLC-MS identification and HPLC-UV quantification of 2OH3MeOBAR metabolites are also reported. [ABSTRACT FROM AUTHOR]

Two isomeric series of new thieno-fused 7-deazapurine ribonucleosides (derived from 4-substituted thieno[2',3':4,5]pyrrolo[2,3-d]pyrimidines and thieno[3',2':4,5]pyrrolo[2,3-d]pyrimidines) were synthesized by a sequence involving Negishi coupling of 4,6-dichloropyrimidine with iodothiophenes, nucleophilic azidation, and cyclization of tetrazolopyrimidines, followed by glycosylation and cross-couplings or nucleophilic substitutions at position 4. Most nucleosides (from both isomeric series) exerted low micromolar or submicromolar in vitro cytostatic activities against a broad panel of cancer and leukemia cell lines and some antiviral activity against HCV. The most active were the 6-methoxy, 6-methylsulfanyl, and 6-methyl derivatives, which were highly active to cancer cells and less toxic or nontoxic to fibroblasts. [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 fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid, moronic acid, ursonic acid, heterobetulonic acid, and allobetulone). Cytotoxicity of all compounds was tested in eight cancer and two non-cancer cell lines. Evaluation of the structure-activity relationships revealed that the triterpenoid core determined whether the final molecule is active or not, while the heterocycle is able to increase the activity and modulate the specificity. Five compounds (1b , 1c , 2b , 2c , and 8) were found to be preferentially and highly cytotoxic (IC 50 ≈ 1 μM) against leukemic cancer cell lines (CCRF-CEM, K562, CEM-DNR, or K562-TAX). Surprisingly, compounds 1c , 2b , and 2c are 10-fold more active in multidrug-resistant leukemia cells (CEM-DNR and K562-TAX) than in their non-resistant analogs (CCRF-CEM and K562). Pharmacological parameters were measured for the most promising candidates and two types of prodrugs were synthesized: 1) Sugar-containing conjugates, most of which had improved cell penetration and retained high cytotoxicity in the CCRF-CEM cell line, unfortunately, they lost the selectivity against resistant cells. 2) Medoxomil derivatives, among which compounds 26 – 28 gained activities of IC 50 0.026–0.043 μM against K562 cells. Compounds 1b , 8 , 21 , 22 , 23 , and 24 were selected for the evaluation of the mechanism of action based on their highest cytotoxicity against CCRF–CEM cell line. Several experiments showed that the majority of them cause apoptosis via the mitochondrial pathway. Compounds 1b , 8 , and 21 inhibit growth and disintegrate spheroid cultures of HCT116 and HeLa cells, which would be important for the treatment of solid tumors. In summary, compounds 1b , 1c , 2b , 2c , 24 , and 26 – 28 are highly and selectively cytotoxic against cancer cell lines and were selected for future in vivo tests and further development of anticancer drugs. [Display omitted] • Triterpenoid pyridines and pyrazines were prepared and their cytotoxicity tested. • Pharmacological parameters and selectivity were optimized by prodrug synthesis. • Most active compounds cause apoptosis via the intrinsic pathway. • Compounds 1b , 1c , 2b , 2c , 24 , and 26 – 28 were selected for further development. [ABSTRACT FROM AUTHOR]

A series of 1-aryl-4-(phthalimidoalkyl) piperazines and 1-aryl-4-(naphthalimidoalkyl) piperazines were retrieved from a proprietary library based on their high structural similarity to haloperidol, an antipsychotic with antiparasitic activity, and assessed as potential antileishmanial scaffolds. Selected compounds were tested for antileishmanial activity against promastigotes of Leishmania major and Leishmania mexicana in dose-response assays. Two of the 1-aryl-4-(naphthalimidoalkyl) piperazines (compounds 10 and 11) were active against promastigotes of both Leishmania species without being toxic to human fibroblasts. Their activity was found to correlate with the length of their alkyl chains. Further analyses showed that compound 11 was also active against intracellular amastigotes of both Leishmania species. In promastigotes of both Leishmania species, compound 11 induced collapse of the mitochondrial electrochemical potential and increased the intracellular Ca2+ concentration. Therefore, it may serve as a promising lead compound for the development of novel antiparasitic drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

Quercetin and phenylpropanoids are well known chemoprotective compounds identified in many plants. This study was aimed at determining their effects on activation of Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (Nrf2-ARE) signalling pathway and expression of its important downstream effector phase II detoxification enzyme glutathione-S-transferase P1 (GSTP1) in BJ foreskin fibroblasts and skin HaCaT keratinocytes. Cell lines and their corresponding Nrf2-ARE luciferase reporter cells were treated by ginger phenylpropanoids and quercetin for 10 h and the level of Nrf2 activity was subsequently determined. Both, ginger phenylpropanoids and quercetin, significantly increased the level of Nrf2 activity. Subsequent western blot analyses of proteins showed the increased expression level of glutathione-S-transferase P1 (GSTP1) in BJ cells but not in HaCaT cells. Such phenomenon of unresponsive downstream target expression in HaCaT cells was consistent with previous studies showing a constitutive expression of their GSTP1. Thus, while both ginger phenylpropanoids and quercetin have the property of increasing the level of Nrf2 both in HaCaT and in BJ cells, their effects on its downstream signalling were mediated only in BJ cells. [ABSTRACT FROM AUTHOR]

The synthesis and biological activity profiling of a large series of diverse pyrrolo[2,3- d ]pyrimidine 4′- C -methylribonucleosides bearing an (het)aryl group at position 4 or 5 is reported as well as the synthesis of several phosphoramidate prodrugs. These compounds are 4′-C-methyl derivatives of previously reported cytostatic hetaryl-7-deazapurine ribonucleosides. The synthesis is based on glycosylation of halogenated 7-deazapurine bases with 1,2-di- O -acetyl-3,5-di- O -benzyl-4- C -methyl-β- d -ribofuranose followed by cross-coupling and nucleophilic substitution reactions. The final compounds showed low cytotoxicity and several derivatives exerted antiviral activity against HCV or Dengue viruses at micromolar concentrations. [ABSTRACT FROM AUTHOR]

This work describes the synthesis of 8-iodoimidazo[1,2- c]pyrimidin-5(6 H)-one 2 from 5-iodocytosine 1. This compound was subjected to Suzuki with aryl and heteroarylboronic acids. After optimization, 10 products 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j were obtained in good yields 61-90%. Cytotoxic activity of all new products was evaluated on seven tumor cell lines including resistant variants and on normal human fibroblasts. Two derivatives showed promising and good therapeutic index in the case of 3h. [ABSTRACT FROM AUTHOR]

We report design and synthesis of set of novel anticancer agents based on caffeine–hydrazones bearing 2-hydroxyaryl- or 2-N-heteroaryl moiety. Anticancer activity evaluation using seven cancer cell lines and two non-malignant cell lines demonstrated that several derivatives display significant anticancer activity and great selectivity index toward T-lymphoblastic leukaemia cells. In general, hydrazones bearing 2-N-heteroaryl moiety are more active and selective than those with 2-hydroxyaryl moiety. Tested compounds exhibit dose-dependent inhibition of both RNA and DNA synthesis, with some exceptions. Antimicrobial activities were tested on set of twelve bacterial and yeast strains, however prepared compounds were not active, suggesting for a molecular target specific for eukaryotic cells. [ABSTRACT FROM AUTHOR]

We report the design and synthesis of novel anticancer agents based on bis-hydrazones separated by a rigid Tröger’s base skeleton. This novel approach combines a biologically active moiety (hydrazone) with this scaffold (Tröger’s base) to construct DNA intercalators. Evaluation of the anticancer activity of these agents using seven cancer cell lines and two healthy cell lines found that several derivatives had potent anticancer activity and excellent selectivity indexes toward cancer cells. The antimicrobial activities were tested on a set of thirteen bacterial stains, but the prepared compounds were not active. Complexation studies using biologically important metal ions demonstrated that these compounds are able to bind Cu 2+ , Fe 3+ , Co 2+ , Ni 2+ and Zn 2+ . DNA intercalation studies showed that the compounds themselves do not interact with DNA, but their metallocomplexes do interact, most likely via intercalation into DNA. [ABSTRACT FROM AUTHOR]

Adenosine kinase (ADK) from Mycobacterium tuberculosis(Mtb) was selected as a targetfor design of antimycobacterial nucleosides.Screening of 7-(het)aryl-7-deazaadenine ribonucleosides with Mtb andhuman (h) ADKs and testing with wild-type and drug-resistantMtb strains identified specific inhibitors of Mtb ADK with micromolarantimycobacterial activity and low cytotoxicity. X-ray structuresof complexes of Mtb and hADKs with 7-ethynyl-7-deazaadenosineshowed differences in inhibitor interactions in the adenosine bindingsites. 1D 1H STD NMR experiments revealed that these inhibitorsare readily accommodated into the ATP and adenosine binding sitesof Mtb ADK, whereas they bind preferentially into the adenosine siteof hADK. Occupation of the Mtb ADK ATP site withinhibitors and formation of catalytically less competent semiopenconformation of MtbADK after inhibitor binding in the adenosine siteexplain the lack of phosphorylation of 7-substituted-7-deazaadenosines.Semiempirical quantum mechanical analysis confirmed different affinityof nucleosides for the Mtb ADK adenosine and ATP sites. [ABSTRACT FROM AUTHOR]

A series of 80 7-(het)aryl-and 7-ethynyl-7-deazapurine ribonucleosidesbearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl,or oxo group at position 6, or 2,6-disubstituted derivatives bearinga methyl or amino group at position 2, were prepared, and the biologicalactivity of the compounds was studied and compared with that of theparent 7-(het)aryl-7-deazaadenosine series. Several of the compounds,in particular 6-substituted 7-deazapurine derivatives bearing a furylor ethynyl group at position 7, were significantly cytotoxic at lownanomolar concentrations whereas most were much less potent or inactive.Promising activity was observed with some compounds against Mycobacterium bovis and also against hepatitis C virus ina replicon assay. [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]

Novel analogues of (+)-varitriol have been synthesised via Julia-Kocienski olefination from γ-D-ribonolactone. Newly prepared compounds were screened for their in vitro cytotoxicity towards certain human tumours and NCI60 cancer cell line panel. [ABSTRACT FROM AUTHOR]

A structure-activity relationship of some derivatives of 2-phenyisubstituted- hydroxyquinoun-4(lH)-one-7-carboxarnid(;s was systematically studied using combinatorial solid-phase synthesis and in vitro cytotoxic activity screening on representative cancer lines. The effect of subsetituent type in position 2 as well as of the carboxamide group was investigated via synthesis of generic libraries constructed with respect to polarity and bulkiness of appropriate substituents. The process of development afforded a set of compounds with, significant cytotoxic activity. Subsequently, corresponding 2-phenylsubstituted-3-hydroxyquinolin-4(l,h)-one-6-carboxamides and 2-phenylsubstitutted- 3-hydroxyquinolin 4-(lH)-one-8-carboxamides were prepared to evaluate the influence of the carboxamide group position on the resulting biological activity. [ABSTRACT FROM AUTHOR]

Abstract: Cytokinin ribosides (N6-substituted adenosine derivatives) have been shown to have anticancer activity both in vitro and in vivo. This study presents the first systematic analysis of the relationship between the chemical structure of cytokinins and their cytotoxic effects against a panel of human cancer cell lines with diverse histopathological origins. The results confirm the cytotoxic activity of N6-isopentenyladenosine, kinetin riboside, and N6-benzyladenosine and show that the spectrum of cell lines that are sensitive to these compounds and their tissues of origin are wider than previously reported. The first evidence that the hydroxylated aromatic cytokinins (ortho-, meta-, para-topolin riboside) and the isoprenoid cytokinin cis-zeatin riboside have cytotoxic activities is presented. Most cell lines in the panel showed greatest sensitivity to ortho-topolin riboside (IC50 =0.5–11.6μM). Cytokinin nucleotides, some synthesized for the first time in this study, were usually active in a similar concentration range to the corresponding ribosides. However, cytokinin free bases, 2-methylthio derivatives and both O- and N-glucosides showed little or no toxicity. Overall the study shows that structural requirements for cytotoxic activity of cytokinins against human cancer cell lines differ from the requirements for their activity in plant bioassays. The potent anticancer activity of ortho-topolin riboside (GI50 =0.07–84.60μM, 1st quartile=0.33μM, median=0.65μM, 3rd quartile=1.94μM) was confirmed using NCI60, a standard panel of 59 cell lines, originating from nine different tissues. Further, the activity pattern of oTR was distinctly different from those of standard anticancer drugs, suggesting that it has a unique mechanism of activity. In comparison with standard drugs, oTR showed exceptional cytotoxic activity against NCI60 cell lines with a mutated p53 tumour suppressor gene. oTR also exhibited significant anticancer activity against several tumour models in in vivo hollow fibre assays. [Copyright &y& Elsevier]

Abstract: A series of the 3,7-diaryl-5-(3,4,5-trimethoxyphenyl)pyrazolo[4,3-e][1,2,4]triazines (17a–20f) have been synthesized in five steps. The cytotoxic activity of all of the newly synthesized compounds has been tested in vitro against five cancer cell lines. Several compounds demonstrated significant broad cytotoxic activity in low micromolar range, while others were selectively active against lung adenocarcinoma cell line A549. [Copyright &y& Elsevier]

Carbonic anhydrase IX (CA IX) is a transmembrane enzyme overexpressed in hypoxic tumors, where it plays an important role in tumor progression. Specific CA IX inhibitors potentially could serve as anti -cancer drugs. We designed a series of sulfonamide inhibitors containing carborane clusters based on prior structural knowledge of carborane binding into the enzyme active site. Two types of carborane clusters, 12-vertex dicarba- closo -dodecaborane and 11-vertex 7,8-dicarba- nido -undecaborate (dicarbollide), were connected to a sulfonamide moiety via aliphatic linkers of varying lengths (1–4 carbon atoms; n = 1–4). In vitro testing of CA inhibitory potencies revealed that the optimal linker length for selective inhibition of CA IX was n = 3. A 1-sulfamidopropyl-1,2-dicarba- closo -dodecaborane (3) emerged as the strongest CA IX inhibitor from this series, with a K i value of 0.5 nM and roughly 1230-fold selectivity towards CA IX over CA II. X-ray studies of 3 yielded structural insights into their binding modes within the CA IX active site. Compound 3 exhibited moderate cytotoxicity against cancer cell lines and primary cell lines in 2D cultures. Cytotoxicity towards multicellular spheroids was also observed. Moreover, 3 significantly lowered the amount of CA IX on the cell surface both in 2D cultures and spheroids and facilitated penetration of doxorubicin. Although 3 had only a moderate effect on tumor size in mice, we observed favorable ADME properties and pharmacokinetics in mice, and preferential presence in brain over serum. Image 1 • Carborane alkylsulfonamides are potent and selective inhibitors of human CA IX. • Inhibitory potency and specificity is driven by a length of alkyl linker. • Selective inhibition of CA IX with a subnanomolar K i value. • Moderate effect on tumor size in mice. • Favorable ADME properties and pharmacokinetics in mice. [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]