A new series of antiproliferative casein kinase 2a (CK2a) inhibitors were synthesized incorporating either a hydrophilic group (carboxylic or hydrazide) or a hydrophobic group (ester) at N1 or N2 of 4,5,6,7-tetrabromobenzotriazole (TBBt). New compounds were prepared via N-alkylation of TBBt followed by base-catalysed hydrolysis or hydrazinolysis. All the compounds demonstrated low sub-micromolar inhibition of CK2a and antiproliferative activity against both breast and lung cancer cell lines (MCF-7, and A549, respectively), at low micromolar concentrations with N2-regioisomers exhibiting higher activity than their corresponding N1-isomers. The most active compound incorporates an acetic acid hydrazide moiety at the N2 of the TBBt triazole nucleus with IC50 at 0.131 mM (CK2a), 9.1 mM (MCF-7) and 6.3 mM (A549). It induced apoptosis in the MCF-7 cell line through upregulation of bax (pro-apoptotic gene) four to five times higher than the corresponding ester or acid analogues. Molecular docking suggests that the hydrophilic group at N2 of the TBBt triazole nucleus provides binding with important residues (Asp175, Lys68 and Trp176) in the ATP binding site of the CK2a enzyme. We are the first to experimentally estimate the lipophilicity of TBBt derivatives. Our study demonstrated that TBBt hydrazides are more lipophilic than their corresponding acids in contrast to the contradicting calculated lipophilicity using four well-known software programs. This may explain the higher anticancer activity of the most active hydrazide over its corresponding acid despite their nearly equipotent enzyme inhibition.

A new series of antiproliferative casein kinase 2a (CK2a) inhibitors were synthesized incorporating either a hydrophilic group (carboxylic or hydrazide) or a hydrophobic group (ester) at N1 or N2 of 4,5,6,7-tetrabromobenzotriazole (TBBt). New compounds were prepared via N-alkylation of TBBt followed by base-catalysed hydrolysis or hydrazinolysis. All the compounds demonstrated low sub-micromolar inhibition of CK2a and antiproliferative activity against both breast and lung cancer cell lines (MCF-7, and A549, respectively), at low micromolar concentrations with N2-regioisomers exhibiting higher activity than their corresponding N1-isomers. The most active compound incorporates an acetic acid hydrazide moiety at the N2 of the TBBt triazole nucleus with IC50 at 0.131 mM (CK2a), 9.1 mM (MCF-7) and 6.3 mM (A549). It induced apoptosis in the MCF-7 cell line through upregulation of bax (pro-apoptotic gene) four to five times higher than the corresponding ester or acid analogues. Molecular docking suggests that the hydrophilic group at N2 of the TBBt triazole nucleus provides binding with important residues (Asp175, Lys68 and Trp176) in the ATP binding site of the CK2a enzyme. We are the first to experimentally estimate the lipophilicity of TBBt derivatives. Our study demonstrated that TBBt hydrazides are more lipophilic than their corresponding acids in contrast to the contradicting calculated lipophilicity using four well-known software programs. This may explain the higher anticancer activity of the most active hydrazide over its corresponding acid despite their nearly equipotent enzyme inhibition.

A new series of antiproliferative casein kinase 2a (CK2a) inhibitors were synthesized incorporating either a hydrophilic group (carboxylic or hydrazide) or a hydrophobic group (ester) at N1 or N2 of 4,5,6,7-tetrabromobenzotriazole (TBBt). New compounds were prepared via N-alkylation of TBBt followed by base-catalysed hydrolysis or hydrazinolysis. All the compounds demonstrated low sub-micromolar inhibition of CK2a and antiproliferative activity against both breast and lung cancer cell lines (MCF-7, and A549, respectively), at low micromolar concentrations with N2-regioisomers exhibiting higher activity than their corresponding N1-isomers. The most active compound incorporates an acetic acid hydrazide moiety at the N2 of the TBBt triazole nucleus with IC50 at 0.131 mM (CK2a), 9.1 mM (MCF-7) and 6.3 mM (A549). It induced apoptosis in the MCF-7 cell line through upregulation of bax (pro-apoptotic gene) four to five times higher than the corresponding ester or acid analogues. Molecular docking suggests that the hydrophilic group at N2 of the TBBt triazole nucleus provides binding with important residues (Asp175, Lys68 and Trp176) in the ATP binding site of the CK2a enzyme. We are the first to experimentally estimate the lipophilicity of TBBt derivatives. Our study demonstrated that TBBt hydrazides are more lipophilic than their corresponding acids in contrast to the contradicting calculated lipophilicity using four well-known software programs. This may explain the higher anticancer activity of the most active hydrazide over its corresponding acid despite their nearly equipotent enzyme inhibition.

A new series of antiproliferative casein kinase 2a (CK2a) inhibitors were synthesized incorporating either a hydrophilic group (carboxylic or hydrazide) or a hydrophobic group (ester) at N1 or N2 of 4,5,6,7-tetrabromobenzotriazole (TBBt). New compounds were prepared via N-alkylation of TBBt followed by base-catalysed hydrolysis or hydrazinolysis. All the compounds demonstrated low sub-micromolar inhibition of CK2a and antiproliferative activity against both breast and lung cancer cell lines (MCF-7, and A549, respectively), at low micromolar concentrations with N2-regioisomers exhibiting higher activity than their corresponding N1-isomers. The most active compound incorporates an acetic acid hydrazide moiety at the N2 of the TBBt triazole nucleus with IC50 at 0.131 mM (CK2a), 9.1 mM (MCF-7) and 6.3 mM (A549). It induced apoptosis in the MCF-7 cell line through upregulation of bax (pro-apoptotic gene) four to five times higher than the corresponding ester or acid analogues. Molecular docking suggests that the hydrophilic group at N2 of the TBBt triazole nucleus provides binding with important residues (Asp175, Lys68 and Trp176) in the ATP binding site of the CK2a enzyme. We are the first to experimentally estimate the lipophilicity of TBBt derivatives. Our study demonstrated that TBBt hydrazides are more lipophilic than their corresponding acids in contrast to the contradicting calculated lipophilicity using four well-known software programs. This may explain the higher anticancer activity of the most active hydrazide over its corresponding acid despite their nearly equipotent enzyme inhibition.

A new series of hybrid structures 14a–l containing thiohydantoin as anti-cancer moiety and pyrazole core possessing SO2Me pharmacophore as selective COX-2 moiety was designed and synthesized to be evaluated for both anti-inflammatory and anti-cancer activities. The synthesized compounds were evaluated for their COX inhibition, in vivo anti-inflammatory activity, ulcerogenic liability, in vitro cytotoxic activity and human topoisomerase-1 inhibition. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Also, all derivatives were significantly less ulcerogenic (ulcer indexes=2.64–3.87) than ibuprofen (ulcer index=20.25) and were of acceptable ulcerogenicity when compared with the non-ulcerogenic reference drug celecoxib (ulcer index=2.99). Regarding anti-cancer activity, most of the target derivatives showed activities against A-549, MCF-7 and HCT-116 cell lines (IC50=5.32–17.90, 3.67–19.04 and 3.19–14.87 μM respectively) in comparison with doxorubicin (IC50=0.20, 0.50 and 2.44 μM respectively). Compound 14a inhibited the human topoisomerase-1 with IC50=29.7 μg/ml while 14b and 14c showed more potent inhibitory activity with IC50=26.5 and 23.3 μg/ml. respectively in comparison with camptothecin (IC50=20.2 μg/ml). Additionally, COX-2 and human topoisomerase-1 docking studies were carried out to explain the interaction of the synthesized hybrid structures 14a–l with the target enzymes.

Simple, small, drug-like molecules bearing aryl azide and aryl sulfonamide moieties were designed and synthesized. The cytotoxic activity of these compounds was measured on colon cancer HCT116, lung cancer A549, and normal fibroblast cells F180 cell lines. All the synthesized compounds showed a significant cytotoxic activity below 100 μM in both HCT116 and A549 cells. Compounds 10e and 10f exhibited the most potent activity with IC50 values of 2.20 and 6.27 μM on A549 and HCT116 cells, respectively. Also, compounds 10e and 10f showed significant tumor selectivity on HCT116 and A549 cell lines when compared with the reference cytotoxic agent staurosporine. This indicated the promising safety of these compounds on normal cells. In addition, flow cytometry studies showed that HCT116 cell lines treated with the most active compound 10f were arrested in the G2/M phase of the cell cycle. 10f boosted both early and late apoptosis at HCT116 cells. A hypothetical pharmacophore model was built using 14 reported potent carbonic anhydrase I inhibitors. The pharmacophoric study revealed that the tested sulfonamide derivatives 10e and 10f showed significant fitting on the pharmacophore query with reasonable RMSD values. Molecular docking study showed a chelation reaction with the key Zn atom, in addition to different hydrogen bonding, and van der Waals interactions with several important amino acids inside the CA Ι active site.

tSulfated steroids function as a storage reservoir of biologically active steroid hormones. The sulfatedsteroids themselves are biologically inactive and only become active in vivo when they are convertedinto their desulfated (unconjugated) form by the enzyme steroid sulfatase (STS). Inhibitors of STS areconsidered to be potential therapeutics for the treatment of steroid-dependent cancers such as breast,prostate and endometrial cancer. The present review summarizes steroid derivatives as inhibitors of STScovering the literature from the early years of STS inhibitor development to October of 2012. A briefdiscussion of the function, structure and mechanism of STS and its role in estrogen receptor-positive(ER+) hormone-dependent breast cancer is also presented.

Steroid sulfatase (STS) catalyzes the hydrolysis of the sulfate ester group in biologically inactive sulfated steroids to give biologically active steroids. Inhibitors of STS are considered to be potential therapeutics for treating hormone-dependent cancers such as ER+ breast cancer. A series of 4-substituted 17b-arylsulfonamides of 17b-aminoestra-1,3,5(10)-trien-3-ol were prepared and examined as STS inhibitors. The presence of a NO2 or Br at the 2-position of the A-ring resulted in a decrease in potency compared to their A-ring-unsubstituted counterparts. However the presence of a nitro group or fluorine atom at the 4-position of the A-ring resulted in an increase in potency and one of these compounds exhibited a Ki app value of 1 nM. Modeling studies provided insight into how these compounds interact with active site residues. The anti-proliferative activity of the 30-Br, 30-CF3, 4-NO2-30-Br and 4-NO2-30-CF3 derivatives were examined using the NCI 60-cell-line panel and found to have mean graph midpoint values of 1.9–3.4 lM.

Steroid sulfatase (STS) catalyzes the desulfation of biologically inactive sulfated steroids to yield biologically active desulfated steroids and is currently being examined as a target for therapeutic intervention for the treatment of breast and other steroid-dependent cancers. Here we report the synthesis of a series of 17b-arylsulfonamides of 17b-aminoestra-1,3,5(10)-trien-3-ol and their evaluation as inhibitors of STS. Some of these compounds are among the most potent reversible STS inhibitors reported to date. Introducing n-alkyl groups into the 40-position of the 17b-benzenesulfonamide derivative resulted in an increase in potency with the n-butyl derivative exhibiting the best potency with an IC50 of 26 nM. A further increase in carbon units (to n-pentyl) resulted in a decrease in potency. Branching of the 40-n-propyl group resulted in a decrease in potency while branching of the 40-n-butyl group (to a tert-butyl group) resulted in a slight increase in potency (IC50 = 18 nM). Studies with 30- and 40-substituted substituted 17b-benzenesulfonamides with small electron donating and electron withdrawing groups revealed the 30-bromo and 30-trifluoromethyl derivatives to be excellent inhibitors with IC50’s of 30 and 23 nM, respectively. The 17b-20-naphthalenesulfonamide was also an excellent inhibitor (IC50 = 20 nM) while the 17b-40-phenylbenzenesulfonamide derivative was the most potent inhibitor of all the compounds studied with an IC50 of 9 nM.

Certain new derivatives of 1,2,4-triazolo[1,5-a]pyrimidines were synthesized through the reaction of 1,2,4-triazolo[1,5-a]pyrimidine-7-ol with ethyl bromoacetate to afford the ethyl acetate ester, which upon hydrazinolysis gives the corresponding hydrazide. The hydrazide is the key intermediate which was used for the synthesis of the target compounds. The structures of the new compounds were assigned by spectral and elemental methods of analyses. The synthesized compounds were tested for their in vitro antibacterial and antifungal activities. Most of the tested compounds showed comparable results with those of ampicillin and fluconazole reference drugs.