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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]

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]

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]

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]

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]

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]

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]

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]