Synthesis of non-natural C2-homo-ceramide and its apoptotic activity against HL-60 cells

Non-natural ceramide analogues, C2-homo-ceramide and C2-homo-dihydroceramide, were prepared from L-aspartic acid via L-homo-serine. The apoptotic activities of the synthesized ceramide analogues were examined in HL-60 human leukemia cells. C2-homo- and C2-bishomo-ceramide indicate low but considerable apoptotic activities in comparison with C2-ceramide.     

2,2'-Pyridoin derivatives protect HL-60 cells against oxidative stress

Focusing on 2,2'-pyridoin (1, 1,2-di(2-pyridyl)-1,2-ethenediol) and its synthetic derivatives as the lead compound of the potent antioxidative enediol, their protective effect against oxidative stress was evaluated on the HL-60 cell system. 2,2'-Pyridoins showed no remarkable cytotoxic effect on HL-60 cells. The derivatives 1, 2, 3, 5, and 6 inhibited H(2)O(2)-induced cell death and intracellular oxidative stress more significantly than ascorbic acid. Since 2,2'-pyridoins are oxidized to the diketones, 2,2'-pyridils, in a protic solvent, the antioxidant activity of 2,2'-pyridils was also investigated. 2,2'-Pyridils showed antioxidant activity in the cell; however, the activity was lower than that of 2,2'-pyridoins. These results suggested that 2,2'-pyrdoin derivatives can be good cytoprotective agents against oxidative stress.     

Synthesis and anticancer activity studies of cyclopamine derivatives

A diversity-oriented synthesis has been developed for facile construction of a library of carbohydrate-cyclopamine conjugates. The synthetic protocol is suitable for generating cyclopamine derivatives with various structural motifs for exploring the desired activity. From this initial library, we have observed one derivative that exhibits improved activity against lung cancer cell as compared to cyclopamine.     

S-Adenosylhomocysteine hydrolase activity during differentiation of HL-60 cells

Early changes in S-adenosylhomocysteine (SAH) hydrolase activity during DMSO-induced granulocytic differentiation of HL-80 ceils were followed. Within 24 h a decrease of activity of SAH hydrolase could be detected in induced cultures but not in control cultures. This decrease could be shown to be associated with G1 phase of the cell cycle and was detected prior to phenotypic changes of the ceils.     

Synthesis and anticancer activity of novel 9,13-disubstituted berberine derivatives

Novel berberine derivatives with disubstituents on positions C9 and C13 were synthesized and evaluated for antiproliferative activities against human prostate cancer cell lines (PC3 and DU145), breast cancer cell line (MDA-MB-231) and human colon cancer cell lines (HT29 and HCT116). All compounds showed significantly enhanced antiproliferative activities compared with berberine. Notably, compound 18e exhibited the strongest cytotoxicity against PC3 cells with an IC₅₀ value of 0.19 μM, and the highest selectivity index (SI^PC3 > 20). Further studies showed that 18e could arrest the cell cycle at G1 phase, and significantly inhibit tumor cell colony forming and migration even at low concentrations. Interestingly, 18e could significantly induce cytoplasmic vacuolation, suggesting a different mode of action from berberine.     

Synthesis and anticancer activity of some 1,2,3-trisubstituted pyrazinobenzimidazole derivatives

Abstract

The synthesis of some new pyrazino[1,2-a]benzimidazole derivatives and investigation of their anticancer activities were aimed in this work. Thus, 2-acetylbenzimidazole was reacted with appropriate α-bromoacetophenones and potassium carbonate in acetone to give 2-(2-acetyl-1H-benzimidazol-1-yl)-1-phenylethanone derivatives (3a–d). These diketone compounds were reacted with varied benzylamines in acetic acid to obtain 2-benzyl-1-methylidene-3-aryl-1,2-dihydropyrazino[1,2-a]benzimidazole derivatives (4a–t). The structures of the obtained compounds were elucidated by using IR, ¹H-NMR, ¹³C-NMR, MS spectral data and elemental analyses results. Anticancer activities of the selected compounds were investigated in National Cancer Institute, Bethesda, MD. 3c and 4n showed remarkable anticancer activity comparing with standard drugs, melphalan and cisplatin.     

Synthesis and evaluation of naphthalene-based thiosemicarbazone derivatives as new anticancer agents against LNCaP prostate cancer cells

Fourteen new naphthalene-based thiosemicarbazone derivatives were designed as anticancer agents against LNCaP human prostate cancer cells and synthesized. MTT assay indicated that compounds 6, 8 and 11 exhibited inhibitory effect on LNCaP cells. Among these compounds, 4-(naphthalen-1-yl)-1-[1-(4-hydroxyphenyl)ethylidene)thiosemicarbazide (6), which caused more than 50% death on LNCaP cells, was chosen for flow cytometric analysis of apoptosis. Flow cytometric analysis pointed out that compound 6 also showed apoptotic effect on LNCaP cells. Compound 6 can be considered as a promising anticancer agent against LNCaP cells owing to its potent cytotoxic activity and apoptotic effect.     

Synthesis and anticancer activity of novel amide derivatives of non-acetal deoxoartemisinin

Novel amide derivatives of C-12 non-acetal deoxoartemisinin were synthesized. Some of the derivatives had potent in vitro anticancer activity against major human cancer cell lines. The deoxoartemisinin amide trimer had potent in vivo antiangiogenic activity, according to the mouse matrigel plug assay.     

19-Nor-1alpha,25-dihydroxyvitamin D2 (paricalcitol) exerts anticancer activity against HL-60 cells in vitro at clinically achievable concentrations

19-Nor-1alpha,25-dihydroxyvitamin D2 (paricalcitol) is an analogue of 1,25(OH)2D3 with reduced calcemic effects that is approved in the United States for the suppression of parathyroid hormone in chronic renal failure. Paricalcitol has anticancer activity in prostate cancer cells. We tested the effects of paricalcitol on the HL-60 leukemia cells, studying cellular differentiation, cell cycle changes, apoptosis and cellular proliferation. Paricalcitol at 10(-8)M concentration induced the maturation of HL-60 cells in a time-dependent manner, as shown by increased expression of CD11b differentiation surface antigen. The ability of HL-60 cells to reduce nitroblue tetrazolium (NBT) was markedly increased after exposure to paricalcitol at 10(-8)M for 72 h. Paricalcitol inhibited colony formation of HL-60 cells in a soft agar semisolid media after 10-day incubation (estimated IC50 of 5 x 10(-9) M. Exposure to 10(-8)M paricalcitol for 72 h increased the number of cells in G0/G1 phase, and decreased the number of cells in S phase, and significantly increased the number of HL-60 cells undergoing apoptosis. The concentration required to achieve inhibition of growth of HL-60 cells is comparable to clinically achievable levels. These findings support the clinical evaluation of paricalcitol as an antileukemia agent.     

Intracellular alkalinization induced by amphotericin B derivatives in HL-60 leukemia cells

The effects on intra- and extracellular pH of two polyenic derivatives of amphotericin B, N-fructosyl amphotericin B and N-fructosyl amphotericin B methyl-ester, were tested on HL-60 promyelocytic leukemia cells. Both derivatives raised the internal pH and reduced the external pH in weakly buffered medium. These results support the idea that both derivatives induce outward proton movement from the cell to the external solution. In this respect, the non-esterified derivative proved to be more powerful that the esterified one. Under the present conditions, there was little or no regulation of pH in HL-60 cells, which exhibited an almost constant pH gradient between the external and internal pH (acid inside relative to outside). This deficiency in pH homeostasis might be due to the immature state of the HL-60 cells.     

Synthesis of 5-enamine-4-thiazolidinone derivatives with trypanocidal and anticancer activity

A series of novel 2-(5-aminomethylene-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropionic acid ethyl esters has been synthesized. Target compounds were evaluated for their trypanocidal activity towards Trypanosoma brucei brucei and Trypanosoma brucei gambiense. Several hit-compounds (8, 10, 12) inhibited growth of the parasites at sub-micromolar concentrations (IC₅₀ 0.027–1.936 µM) and showed significant selectivity indices (SI = 108–1396.2) being non-toxic towards the human primary fibroblasts. The screening of anticancer activity in vitro within NCI DTP protocol allowed to identify active 2-(5-{[5-(2,4-dichlorobenzyl)-thiazol-2-ylamino]-methylene}-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropionic acid ethyl ester 14 that demonstrated inhibition against all 59 human tumor cell lines with the average GI₅₀ value of 2.57 μM. It was established that the activity type (antitrypanosomal or anticancer) as well as its level depends on the character of enamine fragment in the C5 position of thiazolidinone core.     

Synthesis and SAR studies of bis-chromenone derivatives for anti-proliferative activity against human cancer cells

A novel family of 3-((4-oxo-4H-chromen-3-yl)methyl)-4H-chromen-4-one (bis-chromone) derivatives were designed, synthesized and studied for their anti-cancer activity using the XTT assay for the growth inhibition against various human cancer cells. Among them, 3-((5-(cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)methyl)-7-methoxy-4H-chromen-4-one and 3-((5-(cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)methyl)-7-hydroxy-4H-chromen-4-one showed micromolar level of in vitro anti-proliferative activity against human cancer cell lines. The SAR studies indicated bis-chromone as a basic scaffold to design anticancer agents. The 5-cyclohexylmethoxy on the first chromenone ring and electron donating group such as CH₃, OCH₃ or hydrogen bonding group (OH) on the other chromenone ring of bis-chromone increased the activity. However, saturation of one of chromenone to chromanone in bis-chromones decreased the activity.     

PAF-acether transfer activity in HL-60 cells is induced during differentiation

Platelet-activating factor is a proinflammatory lipid active at subnanomolar concentrations. The intermembrane transfer of a biologically active PAF analog has been previously demonstrated in macrophages. Here we demonstrate that the specific activity of this transfer activity increases when HL-60 cells are induced to differentiate by treatment with dimethyl sulfoxide, dibutyryl cAMP or phorbol diester. In undifferentiated HL-60 cells, methylcarbamyl-PAF transfer activity was only 0.56 U.min-1.mg-1. This basal value was increased 2.6 and 6.7 times upon granulocytic and macrophagic differentiation, respectively. On the other hand, the transfer of 2-O-methyl-PAF, a cytotoxic analog with no PAF biological activity, remained very low and did not vary during differentiation.     

Synthesis and anticancer effect of chrysin derivatives

A series of chrysin derivatives, prepared by alkylation, halogenation, nitration, methylation, acetylation and trifluoromethylation, were tested in vitro against human gastric adenocarcinoma cell line (SGC-7901) and colorectal adenocarcinoma (HT-29) cells. Among these derivatives of chrysin, 5,7-dimethoxy-8-iodochrysin 3 and 8-bromo-5-hydroxy-7-methoxychrysin 11 have the strongest activities against SGC-7901 and HT-29 cells, respectively. 5,7-Dihydroxy-8-nitrochrysin 12 were found to have strong activities against both SGC-7901 and HT-29 cells.     

Alterations in insulin receptor kinase activity during differentiation of HL-60 cells

Differentiation of the human promyelocytic leukemia cell line HL-60 into monocytes or macrophages is associated with increased expression of cell surface insulin receptors, while differentiation of these cells into granulocytes is associated with receptor loss. Here we demonstrate that differentiation of HL-60 cells into monocytes or granulocytes induced by 1;25(OH)2vitD3 or Bt2cAMP, respectively, has no major effect on the specific activity of the insulin receptor kinase (IRK). By contrast, when HL-60 cells are incubated with a combination of 1;25(OH)2vitD3 and Bt2cAMP, their differentiation into adherent macrophages-like cells is accompanied by a 50% reduction in the specific activity of IRK. These findings suggest that acquisition or loss of insulin receptors during differentiation of HL-60 involves selective alterations in the functional aspects of these receptors. Our results also implicate the generation of specific regulatory signals that inhibit IRK activity when HL-60 cells are stimulated with a combination of 1;25(OH)2vitD3 and Bt2cAMP.     

Synthesis and evaluation of in vitro anticancer activity of some novel isopentenyladenosine derivatives

The present study describes the synthesis, the characterization and the evaluation of some derivatives of N⁶-isopentenyladenosine on T24 human bladder carcinoma cells. In particular we have modified the hydroxyl groups in the ribose moiety, the position of the isopentenyl chain in the purine ring and the base moiety. The structures of the compounds were confirmed by standard studies of NMR, MS and elemental analysis. We here show that only two derivatives, 1-(3-methyl-2-butenylamino)-9-(3′-deoxy-β-d-ribofuranosyl)-purine hydrobromide and 2-amino-6-(3-methyl-2- butenylamino)-9-(β-d-ribofuranosyl)-purine, inhibit the growth of T24 cells, although to a lower extent than N⁶-isopentenyladenosine. We conclude that the integrity of ribosidic and purine moiety and the N⁶ position of the chain are essential for maintaining the antiproliferative activity.     

Synthesis and biological evaluation of novel 2,4,5-substituted pyrimidine derivatives for anticancer activity

A series of novel 2,4,5-substituted pyrimidine derivatives were synthesized and evaluated for inhibition against the human hepatocellular carcinoma BEL-7402 cancer cell line. Several compounds showed potent inhibition with an IC₅₀ value less than 0.10 μM. Structure–activity relationships for this class of compounds at the 2- and 5-position of the pyrimidine scaffold have been elucidated. The most active compound 7gc showed good inhibition of several different human cancer cell lines with IC₅₀ values from 0.024 to 0.55 μM.     

Discovery of 1,2,4-triazine-based derivatives as novel neddylation inhibitors and anticancer activity studies against gastric cancer MGC-803 cells

Neddylation modification is often over-expressed in a variety of human tumor cells. Therefore, targeting neddylation pathway may represent a potential approach to the treatment of human tumors. Herein, we describe the discovery of a hit scaffold from our in-house library and further structure-based optimizations. In this work, compound V11 could block the neddylation and inhibit the activity of NAE (with an EC₅₀ value of 3.56 µM), and a dose-dependent reduction of the Ubc12-NEDD8 conjugations was also observed. Molecular docking results suggest compound V11 could bind tightly to NAE via hydrogen bonds and hydrophobic interactions. Compound V11 showed the best antiproliferative ability with an IC₅₀ value of 8.22 μM against gastric cancer MGC-803 cells. Further anticancer activity studies suggested that compound V11 inhibited MGC-803 cell growth, caused a cell cycle arrestment at G2/M phase and induced apoptosis via extrinsic and intrinsic apoptosis pathways. All the findings suggest that 1,2,4-triazine scaffold might provide a novel scaffold for the further development of neddylation inhibitors and compound V11 might be a potential neddylation inhibitor with anticancer activity.     

Synthesis of novel ribavirin hydrazone derivatives and anti-proliferative activity against A549 lung cancer cells

A series of novel ribavirin hydrazone derivatives were synthesized by the reaction of ribavirin hydrazone with benzaldehyde or acetophenone derivatives. The structures of the compounds were determined by IR, ¹H NMR, and HRESIMS. Preliminary biological evaluation showed that one compound (7h) inhibits the growth of A549 cells at 20 μM.