ß-MoO3 Whiskers in 99Mo/99mTc Radioisotope Production and 99Mo/99mTc Extraction Using Hot Atoms.

ß-MoO3 whiskers prepared by a thermal evaporation method and α-MoO3 particles were irradiated in a nuclear reactor to produce 99Mo/99mTc radioisotopes via neutron capture. The irradiated targets were then dispersed in water to extract the 99Mo/99mTc isotopes. Of the 99Mo formed in the ß-MoO3 whiskers, 64.0 ± 7.4% was extracted with water; by contrast, only 8.8 ± 2.6% of the 99Mo formed in α-MoO3 was extracted. By comparing these data to the 98Mo concentration dissolved in water, we confirmed the hot-atom effect on both ß-MoO3 whisker and α-MoO3 particle targets to transfer 99Mo isotopes from irradiated samples to water. In addition, the ß-MoO3 whiskers exhibited a prominent hot-atom effect to transfer a higher ratio of 99Mo isotopes into water. To the best of our knowledge, this research is the first demonstration of ß-MoO3 being used as an irradiation target in the neutron capture method. On the basis of the results, ß-MoO3 is considered a promising irradiation target for producing 99Mo/99mTc by neutron capture and using water for the radioisotope extraction process in the future.

Design, synthesis and evaluation of novel indirubin-based N-hydroxybenzamides, N-hydroxypropenamides and N-hydroxyheptanamides as histone deacetylase inhibitors and antitumor agents.

Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common human cancer cell lines (SW620, PC-3 and NCI-H23) with IC50 values ranging from 0.09 to 0.007 µM. The cytotoxicity of the compounds was equipotent or even up to 10-times more potent than adriamycin and up to 205-times more potent than SAHA. Among the series of N-hydroxypropenamides, compounds 10a-d were the most potent HDAC inhibitors as well as cytotoxicity toward the cell lines tested. In addition, the strong inhibitory activites toward HDAC of our compounds were observed with IC50 values of below-micromolar range. Especially, compound 4a inhibited HDAC6 with an IC50 value of 29-fold lower than that against HDAC2 isoform. Representative compounds 4a and 7a were found to significantly arrest SW620 cells at G0/G1 phase. Compounds 7a and 10a were found to strongly induce apoptosis in SW620 cells. Docking studies revealed some important features affecting the selectivity against HDAC6 isoform. The results clearly demonstrate the potential of the indirubin-hydroxamic acid hybrids and these compounds should be very promising for further development.

Exploration of certain 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents.

Several novel series of hydroxamic acids bearing 2-benzamidooxazole/thiazole (5a-g, 6a-g) or 2-phenylsulfonamidothiazole (8a-c) were designed and synthesized. The compounds were obtained straightforwards via a two step pathway, starting from commercially available ethyl 2-aminooxazole-4-carboxylate or ethyl 2-aminothiazole-4-carboxylate. Biological evaluation showed that these hydroxamic acids generally exhibited good cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer), with IC50 values in low micromolar range and comparable to that of SAHA. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range (0.010-0.131 µM) and some compounds (e.g 5f, IC50, 0.010 µM) were even more potent than SAHA (IC50, 0.025 µM) in HDAC inhibition. Representative compounds 6a and 8a appeared to arrest the SW620 cell cycle at G2 phase and significantly induced both early and late apoptosis of SW620 colon cancer cells. Docking experiments on HDAC2 and HDAC6 isozymes revealed favorable interactions at the tunnel of the HDAC active site which positively contributed to the inhibitory activity of synthesized compound. The binding affinity predicted by docking program showed good correlation with the experimental IC50 values. This study demonstrates that simple 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids are also promising as antitumor agents and HDAC inhibitors and these results should provide valuable information for further design of more potent HDAC inhibitors and antitumor agents.

Design, synthesis, and evaluation of novel N'-substituted-1-(4-chlorobenzyl)-1H-indol-3-carbohydrazides as antitumor agents.

In continuity of our search for novel anticancer agents acting as procaspase activators, we have designed and synthesised two series of (E)-N'-benzylidene-carbohydrazides (4a-m) and (Z)-N'-(2-oxoindolin-3-ylidene)carbohydrazides (5a-g) incorporating 1-(4-chlorobenzyl)-1H-indole core. Bioevaluation showed that the compounds, especially compounds in series 4a-m, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Within series 4a-m, compounds with 2-OH substituent (4g-i) exhibited very strong cytotoxicity in three human cancer cell lines assayed with IC50 values in the range of 0.56-0.83 µM. In particular, two compounds 4d and 4f bearing 4-Cl and 4-NO2 substituents, respectively, were the most potent in term of cytotoxicity with IC50 values of 0.011-0.001 µM. In caspase activation assay, compounds 4b and 4f were found to activate caspase activity by 314.3 and 270.7% relative to PAC-1. This investigation has demonstrated the potential of these simple acetohydrazides, especially compounds 4b, 4d, and 4f, as anticancer agents.

Design, Synthesis and Bioevaluation of Two Series of 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines.

Two series of 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-benzylpiperidin-4-yl)quinazolin-4-amines were designed initially as potential acetylcholine esterase inhibitors. Biological evaluation demonstrated that N-(1-benzylpiperidin-4-yl)quinazolin-4-amines significantly inhibited AChE activity. Especially, two compounds of them were found to be the most potent with relative AChE inhibition percentages of 87 % in comparison to donepezil. The docking studies with AChE showed similar interactions between donepezil and four derivatives. N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines also exhibited significant DPPH scavenging effects. The two series of compound also exerted moderate to good cytotoxicity against three human cancer cell lines, including SW620 (human colon cancer), PC-3 (prostate cancer), and NCI-H23 (lung cancer), with 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one being the most cytotoxic agent. 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one significantly induced early apoptosis and arrested the SW620 cells at G2/M phase. From this study, two compounds of N-(1-benzylpiperidin-4-yl)quinazolin-4-amines could serve as new leads for further design and AChE inhibitors, while 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one could serve as a new lead for the design and development of more potent anticancer agents.

Novel N-hydroxybenzamides incorporating 2-oxoindoline with unexpected potent histone deacetylase inhibitory effects and antitumor cytotoxicity.

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized two series of novel N-hydroxybenzamides incorporating 2-oxoindolines (4a-g, 6a-g). Biological evaluation showed that these benzamides potently inhibited HDAC2 with IC50 values in sub-micromolar range. In three human cancer cell lines the synthesized compounds were up to 4-fold more cytotoxic than SAHA. Docking experiments indicated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA. Our present results demonstrate that these novel and simple N-hydroxybenzamides are potential for further development as anticancer agents and further investigation of similarly simple N-hydroxybenzamides should be warranted to obtain more potent HDAC inhibitors.

Synthesis, bioevaluation and docking study of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents.

Since the first histone deacetylase (HDAC) inhibitor (Zolinza®, widely known as suberoylanilide hydroxamic acid; SAHA) was approved by the Food and Drug Administration for the treatment of T-cell lymphoma in 2006, the search for newer HDAC inhibitors has attracted a great deal of interest of medicinal chemists worldwide. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. A number of compounds in this series, for example, N(1)-hydroxy-N(8)-(5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5b), N(1)-hydroxy-N(8)-(5-(3-chlorophenyl-1,3,4-thiadiazol-2-yl)octandiamide (5c) and N(1)-hydroxy-N(8)-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5d), were found to possess potent anticancer cytotoxicity and HDAC inhibition effects. Compounds 5b-d were generally two- to five-fold more potent in terms of cytotoxicity compared to SAHA against five cancer cell lines tested. Docking studies revealed that these hydroxamic acid displayed higher affinities than SAHA toward HDAC8.

Design, Synthesis and Evaluation of Novel (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as Antitumor Agents.

BACKGROUND: Herein, we have designed and synthesized a series of the novel (E)-N'-((1-(4-chlorobenzyl)- 1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5) as potent small molecules activating procaspase- 3. The compounds were designed by the amalgamation of structural features of PAC-1 (the first procaspase-3 activator) and oncrasin-1, one potential anticancer agent. METHODS: The target acetohydrazides (5a-m) were prepared via the Niementowski condensation of anthranilic acid (1a) or 5-substituted-2-aminobenzoic acid (1b-m) and formamide. The compound libraries were evaluated for their cytotoxicity, caspase-3 activation, cell cycle analysis, and apoptosis. In addition, computational chemistry is also performed. RESULTS: A biological evaluation revealed that all thirteen compounds designed and synthesized showed strong cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer) with eight compounds (5a, 5c-i, 5k), which were clearly more potent than both PAC-1 and oncrasin-1. In this series, four compounds, including 5c, 5e, 5f, and 5h, were the most potent members with approximately 4- to 5-fold stronger than the reference compounds PAC-1 and oncrasin-1 in terms of IC50. In comparison to 5-FU, these compounds were even 18- to 29-fold more potent in terms of cytotoxicity in three human cell lines tested. In the caspase activation assay, the caspase activity was activated to 285% by compound 5e compared to PAC-1, the first procaspase activating compound, which was used as a control. Our docking simulation revealed that compound 5e was a potent allosteric inhibitor of procaspase-3 through chelation of inhibitory zinc ion. Physicochemical and ADMET calculations for 5e provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent. CONCLUSION: Compound 5e has emerged as a potential hit for further design and development of caspases activators and anticancer agents.

5-aryl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents: synthesis, bioevaluation and docking study.

The search for newer histone deacetylase (HDAC) inhibitors has attracted a great deal of interest of medicinal chemists worldwide, especially after the first HDAC inhibitor (Zolinza(®), widely known as SAHA or Suberoylanilide hydroxamic acid) was approved by the FDA for the treatment of Tcell lymphoma in 2006. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-aryl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. Most of the compounds in this series, e.g. compounds with 5-aryl moiety being 2- furfuryl (5a), 5-bromofuran-2-yl (5b), 5-methylfuran-2-yl (5c), thiophen-2-yl (5d), 5-methylthiophen-2-yl (5f) and pyridyl (5g-i), were found to have potent anticancer cytotoxicity with IC50 values of generally 5- to 10-fold lower than that of SAHA in 4 human cancer cell lines assayed. Those compounds with potent cytotoxicity were also found to have strong HDAC inhibition effects. Docking studies revealed that compounds 5a and 5d displayed high affinities towards HDAC2 and 8.

Novel isatin-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents.

Accumulated clinical studies have demonstrated that histone deacetylase (HDAC) inhibitors show great potential for the treatment of cancer. SAHA (Vorinostat, trade name Zolinza) was approved by the FDA in 2006 for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma. As a continuity of our ongoing effort to identify novel small molecules targeting these important enzymes, we designed and synthesized two series of isatin-3'-oxime- and isatin-3'-methoxime-based hydroxamic acids (3a-g and 6a-g) as analogues of SAHA. Generally in both series it was found that, compounds bearing no substituent or with 5'-F, 5'-Cl, 7'-Cl substitutents on the isatin moiety exhibited good inhibition against histone-H3 and histone-H4 deacetylation at the concentrations of 1 µM, as evaluated by Western Blot assay. The compounds also displayed potent cytotoxicity against five cancer cell lines with IC50 values of as low as 0.08 µM, more than 45-fold lower than that of SAHA. Docking study performed with selected compounds 3a and 6a revealed that these compounds bound to HDAC8 with higher affinities compared to SAHA. Compounds 3a and 6a also bound to HDAC2 at the binding site with high binding affinity. These findings should encourage further elaboration with the isatin moiety to produce more potent HDAC inhibitors with potential anticancer activity.