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Solid-phase total syntheses of highly methylated cyclic azacoibamide A and its O-desmethyl analogue were achieved. Two ester linkages of natural coibamide A were replaced by amide bonds to improve its pharmacokinetic properties. The synthetic strategy consists of the key on-resin macrocyclization, N,N-dimethylation, and final solution phase O-methylation reactions. Compared to the naturally occurring coibamide A, azacoibamide A and its O-desmethyl analogue displayed low micromolar activities against tested cancer cell lines.

The solid-phase total synthesis of the proposed structure of cyclic depsipeptide coibamide A and its derivative O-desmethyl coibamide A is reported. In this study, we demonstrate the solid-phase synthetic strategy and final solution-phase O-methylation for highly N-methylated cyclic depsipeptides. On-resin macrocyclization, N,N-dimethylation and solution-phase O-methylation were the key steps of these syntheses. The mass of synthetic coibamide A is consistent with that of the natural product according to liquid chromatography-mass spectroscopy (LCMS) analysis but significant differences are observed upon 1H and 13C NMR analysis. The 2D NMR analysis and modeling studies of the synthetic compound compared with the isolated natural compound revealed that either they are conformationally different or the stereochemistry of the natural product was incorrectly assigned.

α-Tocopheryl succinate (TOS), a vitamin E analog, is a promising anticancer agent due to its abilities to inhibit proliferation and to induce apoptosis in a variety of human malignant cell lines, while being relatively less active toward normal cells. However, the molecular mechanisms underlying the apoptotic effects of TOS are not precisely understood. Reports that TOS can generate reactive oxygen species (ROS) prompted us to investigate the role of ROS in TOS-induced apoptosis in cancer cells. We found that the human lung cancer A549 and H460 cell lines were much more sensitive to TOS-induced apoptosis than the human glioblastoma T98G and U87MG cell lines. Our data suggested that the differential TOS sensitivity was not caused by differences in the uptake and retention of TOS between TOS-sensitive and –resistant cancer cells. The differential ability of cancer cells to generate ROS in response to TOS appears to be an important factor in determining the susceptibility of cells to TOS-induced apoptosis. Our results further suggest that TOS-induced generation of ROS is involved in caspase-independent apoptosis. Taken together, our findings suggest an important role of ROS generation in TOS-induced, caspase-independent apoptosis of cancer cells. © 2004 Wiley-Liss, Inc.

4HPR, an analogue of ATRA, effectively induces growth inhibition and apoptosis in breast cancer cell lines and animal models but is ineffective against advanced human breast tumors. Different compounds, including tamoxifen, are currently being tested to increase 4HPR efficacy in the clinic. Here, we report that cyclosporin A selectively increases the ability of 4HPR, but not ATRA, to induce growth inhibition and apoptosis in ER+ and ER− breast cancer cell lines. Increased apoptosis by the 4HPR and cyclosporin A combination was correlated with increased production of the free radical nitric oxide. Thus, the 4HPR and cyclosporin A combination may potentially be a novel therapeutic modality against breast tumors. © 2002 Wiley-Liss, Inc.

In this study a novel series of isoindol-1-one and isoindol-1,3-dione derivatives for β-amyloid-specific binding agents is described. Twelve compounds were synthesized and evaluated via a competitive binding assay with [125I]TZDM against β-amyloid 1–42 (Aβ42) aggregates. Two new [18F]-labeled isoindole derivatives were synthesized and evaluated as potential β-amyloid imaging probes based on the in vivo pharmacokinetic profiles. The preliminary results suggest that these [18F]18b and [18F]18c are promising positron emission tomography (PET) imaging probes for studying accumulation of Aβ fibrils in the brains of Alzheimer’s disease (AD) patients.

Vol. 29, No. 9 1767In conclusion, functionalized benzoxazole derivatives basedon the structural features of PIB and FDDNP showed ex-cellent binding affinities to aggregated Aβ42 fibrils. Thesecompounds could be considered as ligands for molecularimaging agents to monitor Aβ42 fibrils in AD brain due totheir high binding affinity.

Based on the structural features of Indoprofen and PIB, a series of isoindol-1,3-diones 1a-k and isoindol-1-ones 2a-l were designed and synthesized. These 23 compounds were evaluated by competitive binding assay against aggregated Abeta42 fibrils using [(125)I]TZDM. All the isoindolone derivatives showed very good binding affinities with K(i) values in the subnanomolar range (0.42-0.94 nM). Among them, isoindol-1,3-diones 1i and 1k and isoindol-1-ones 2c and 2i exhibited excellent binding affinities (K(i)=0.42-0.44 and 0.46-0.49 nM) than those of Indoprofen (K(i)=0.52 nM) and PIB (K(i)=0.70 nM). These results suggest that isoindolones could be served as a scaffold for potential AD diagnostic probes to monitor Abeta fibrils.