Novel 4-Oxoquinazoline-Based N-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation.

Two series of novel 4-oxoquinazoline-based N-hydroxypropenamides (9a-m and 10a-m) were designed, synthesized, and evaluated for their inhibitory and cytotoxicity activities against histone deacetylase (HDAC). The compounds showed good to potent HDAC inhibitory activity and cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). In this series, compounds with the N-hydroxypropenamide functionality impeded at position 7 on the 4-oxoquinazoline skeleton (10a-m) were generally more potent than compounds with the N-hydroxypropenamide moiety at position 6 (9a-m). Also, the N 3-benzyl-substituted derivatives (9h-m, 10h-m) exhibited stronger bioactivity than the N 3-alkyl-substituted ones (9a-e, 10a-e). Two compounds 10l and 10m were the most potent ones. Their HDAC inhibitory activity (IC50 values, 0.041-0.044 µM) and cytotoxicity (IC50 values, 0.671-1.211 µM) were approximately 2- to 3-fold more potent than suberoylanilide hydroxamic acid (SAHA). Some compounds showed up to 10-fold more potent HDAC6 inhibition compared to their inhibitory activity in total HDAC extract assay. Analysis of selected compounds 10l and 10m revealed that these compounds strongly induced both early and late apoptosis and arrested SW620 cells at the G2/M phase. Docking studies were carried out on the HDAC6 isoform for series 10a-m and revealed some important features contributing to the inhibitory activity of synthesized compounds.

Molecular Shapes, Orientation, and Packing of Polyoxometalate Arrays Imaged by Scanning Tunneling Microscopy.

Reported here are both STM images and spatially resolved tunneling spectra of four different polyoxometalate (POM) structural class members: Keggin structure, H(3)[PW(12)O(40)] (spherical); Finke-Droege (FD) structure, Na(16)[Cu(4)(H(2)O)(2)(P(2)W(15)O(56))(2)] (prolate spheroidal); Wells-Dawson (WD) structure, H(7)[P(2)Mo(17)VO(62)] (prolate spheroidal); and Pope-Jeannin-Preyssler (PJP) structure, K(12.5)Na(1.5)[NaP(5)W(30)O(110)] and (NH(4))(14) [NaP(5)W(30)O(110)] (oblate spheroidal). In all four cases, the results demonstrate the formation of well-ordered 2-D inorganic POM anion arrays (composed of catalytically active molecular constituents) on graphite. Importantly, the image shapes and lattice spacings accurately reflect the POM anisotropies, permitting the determination of anion orientation with respect to the surface plane.

H3PW12O40-functionalized tip for scanning tunneling microscopy.

Recent reports of C(60)-functionalized metal tips [Kelly, K. F., Sarkar, D., Hale, G. D., Oldenburg, S. J. & Halas, N. J. (1996) Science 273, 1371-1373] and carbon nanotube tips [Dai, H., Hafner, J. H., Rinzler, A. G., Colbert, D. T. & Smalley, R. E. (1996) Nature (London) 384, 147-151] demonstrate the potential of controlling the chemical identity and geometric structure of tip atoms in scanning tunneling microscopy (STM). This work reports the performance of a heteropolyacid (HPA)-functionalized Pt/Ir tip, which was formulated by contacting a mechanically formed tip with a solution of H(3)PW(12)O(40) molecules. Attachment of an H(3)PW(12)O(40) molecule on the metal tip was confirmed by observing the characteristic negative differential resistance (NDR) behavior of H(3)PW(12)O(40) in tunneling spectroscopy. Atomic resolution images of bare graphite as well as of H(6)P(2)W(18)O(62) HPA monolayers on graphite were successfully obtained with a Pt/Ir-HPA tip. In the H(3)PW(12)O(40) molecule on a metal tip, it is likely that a terminal oxygen of WO (an oxygen species projecting outward from the pseudospherical H(3)PW(12)O(40) molecule) serves as an atomically sharp and stable tip. Additionally, superimposed superperiodic structures commensurate with the underlying graphite lattice were regularly observed with the modified tips. This result suggests that tip functionalization with these metal oxide molecules may enhance resolution in a fashion analogous to functionalization with C(60).

Nanoscale characterization of redox and acid properties of keggin-type heteropolyacids by scanning tunneling microscopy and tunneling spectroscopy: effect of heteroatom substitution.

Nanoscale characterization of acid and redox properties of Keggin-type heteropolyacids (HPAs) with different heteroatoms, H(n)MW(12)O(40) (M = P, Si, B, Co), was carried out by scanning tunneling microscopy (STM) and tunneling spectroscopy (TS) in this study. HPA samples were deposited on highly oriented pyrolytic graphite surfaces to obtain images and tunneling spectra by STM before and after pyridine adsorption. All HPA samples formed well-ordered 2-dimensional arrays on graphite before and after pyridine exposure. NDR (negative differential resistance) peaks were observed in the tunneling spectra. Those measured for fresh HPA samples appeared at less negative voltages with increasing reduction potential of the HPAs and with increases in the electronegativity of the heteroatom, but with decreases in the overall negative charge of the heteropolyanions. These results support the conclusion that more reducible HPA samples show NDR behavior at less negative applied voltages in their tunneling spectra. Introduction of pyridine into the HPA arrays increased the lattice constants of the 2-dimensional HPA arrays by ca. 6 A. Exposure to pyridine also shifted NDR peak voltages of H(n)MW(12)O(40) (M = P, Si, B, Co) samples to less negative values in the TS measurements. The NDR shifts of HPAs obtained before and after pyridine adsorption were correlated with the acid strengths of the HPAs, suggesting that tunneling spectra measured by STM could serve to probe acid properties of HPAs. These results show how one can relate the bulk acid and redox properties of HPAs to surface properties of nanostructured HPA monolayers determined by STM.