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A preliminary experiment for microwave thorax imaging is conducted. A low-profile symmetrical meandering dipole antenna operating at 915MHz is designed and a rectangular water tank with 16 antennas is built for experiments. A graduated cylinder is placed in water as a target. Each antenna in turn acts as transmitter and the others work as receivers. Transmission coefficients are measured. With One-Step Gauss Newton Method, the size and position of the target can be reconstructed. The experiment results verify the feasibility of microwave thorax imaging.

Cyclosporin A (CsA) was converted into cyclosporin methyl vinyl ketone (Cs-MVK) by either a biocatalytic method utilizing 1-hydroxybenzotriazole-mediated laccase oxidation or by a chemical oxidation using t-butyl hydroperoxide and potassium periodate as co-oxidants. Cs-MVK is a novel, versatile synthetic intermediate that can be used for the preparation of many novel cyclosporin analogues possessing therapeutic potential as immunosuppressive agents.

The diacylglycerol signaling pathway, involving protein kinase C (PKC) and RasGRP, is a promising therapeutic target for both cancer and other indications. The phorbol esters, ultrapotent diacylglycerol analogues, bind to and activate PKC and RasGRP. Here, using fluorescent phorbol esters and complementary fluorescent PKC and RasGRP constructs, we determined the localization of the phorbol ester as a function of time after addition and how the resultant PKC or RasGRP3 translocation related to ligand localization. For these studies, we prepared fluorescently labeled phorbol esters of varying lipophilicities based on the BODIPY FL (green) or BODIPY 581/591 (red) fluorophores, and by using fusion constructs of green fluorescent protein or DsRed with PKC isoforms or RasGRP3 expressed in Chinese hamster ovary cells, we simultaneously compared the kinetics and pattern of localization of PKC or RasGRP3 with that of the fluorescent red or green phorbol esters. Binding assays showed that the fluorescent derivatives were potent ligands. Uptake followed a one-compartment pharmacokinetic model with a half-time of minutes to hours, depending on the ligand, and all of the fluorescent phorbol esters localized primarily to intracellular membranes, with little plasma membrane localization. The fluorescent phorbol esters induced translocation of and generally colocalized with PKCδ or RasGRP3. However, PKCα and, initially, PKCδ, translocated to the plasma membrane, in which little phorbol ester accumulated. The findings argue that the rate of uptake of phorbol esters influences the subsequent pattern of PKCδ translocation, and that the specificity for PKCα translocation is dominated by factors other than the localization of the ligand.

The addition of stabilized carbon nucleophiles to tricarbonyl(1-methoxycarbonylpentadienyl)iron(1+) cation (1a) proceeds via attack at C2 on the face of the ligand opposite the Fe(CO)(3) group to generate tricarbonyl(pentenediyl)iron complexes 2. Oxidation of complexes 2 affords vinylcyclopropanecarboxylates in good yield. In general, the relative stereochemistry about the cyclopropane ring reflects reductive elimination with retention of configuration. In cases where the C2 substituent is bulky (i.e., 2b) the major cyclopropane product 9b represents ring closure with inversion at C3. A mechanism involving pi-sigma-pi rearrangement of the initially oxidized (pentenediyl)iron species is proposed to account for these results. Experiments which probe the stereochemistry of deuterium labeling in the vinyl group of the vinylcyclopropanecarboxylate products were carried out, and these results are consistent with the proposed mechanism. This methodology for the preparation of vinylcyclopropanecarboxylates was applied to the synthesis of 2-(2'-carboxycyclopropyl)glycines (+)-22 and (-)-23 and the cyclopropane triester (-)-26.

The reaction of ethyl dimethylsulfonium acetate bromide with aromatic enones 5a or 5b derived from (S)-glyceraldehyde acetonide under the action of DBU provides cyclopropanation products in excellent yield and good diastereoselectivity (10/1). High geometry-selectivity (>95/1) can be reached when the reaction is carried out at lower temperature in toluene. The cis-enone 5a gives better geometry-selectivity than trans-enone 5b. The ylides with amide groups can also be used for cyclopropanation reaction but neither the yields nor the geometry-selectivity are satisfactory. Based on this reaction a new synthetic protocol for (2S,1′R,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine ( l -DCG-IV), an isotype-selective agonist of metabotropic glutamate, is developed.

Aldo-keto reductase family 1 member C3 (AKR1C3) catalyzes the reduction of a diverse group of substrates, including prostaglandin (PG) D2 and PGH2. It has been reported that AKR1C3 is overexpressed in the majority of hepatocellular carcinomas (HCC) with 58% of HCC patient surgical tumor samples having strong expression of the enzyme1. Tumors overexpressing AKR1C3 can be resistant to radiation therapy2 and chemotherapies3. AKR1C3 is also expressed in normal tissues,but its expression is much lower than in HCC tissue1. HCC is the sixth most common cause of cancer. It has very poor prognosis, and is the second leading cause of cancer death in all cancers. Treatment options for late stage liver cancer are very limited, with Sorafenib, a multi-tyrosine kinase inhibitor, being the only approved drug with limited efficacy. More effective therapies are urgently needed. TH3424 is a prodrug which selectively releases a DNA alkylating agent upon exposure to activated AKR1C3. In vitro cell proliferation tests with TH3424 in several HCC cell lines showed that it is very potent (IC50 ≤ 10 nM with 2 hour exposure) in killing cancer cells with high levels of AKR1C3, but less active (IC50 ≥ 10 μM) in killing cells with low or no AKR1C3 reductase. The activity of TH3424 correlates with the expression level of AKR1C3 as the potency of TH3424 is inhibited when used with a specific AKR1C3 inhibitor:4 (IC50: 4 nM vs 6.3 μM with SN33638) in a non-small cell lung cancer cell line (H460). In vivo orthotopic and patient derived disease (PDX) liver cancer model studies have shown promising efficacy with TH3424 being administer weekly with doses as low as 1.5mg/kg. TH3424 showed better efficacy than Sorafenib in an orthotopic HepG2 mouse model. Three of 8 mice treated with TH3424 at 2.5 mg/kg, Q7Dx3, and 8 of 8 mice treated with TH3424 at 5 mg/kg, Q7Dx3 were tumor free at day 35. Reference:1: Guise C. P.; Abbattista M. R.; Singleton R. S.; Holford S. D.; Connolly J.; Dachs G. U.; Fox S. B.; Rollock R.; Harvey J.; Guiford P.; Daňate F.; Wilson W. R.; and Patterson A. V.; Cancer Res.70(4), 2010, 1573 2: Xiong W.; Zhao J.; Yu H.; Li X.; Sun S.; Li Y.; Xia Q.; Zhang C.; He Q.; Gao X.; Zhang L.; Zhou D.; Plos One, V. 9 (11), 2014, e111911 3: Liu C.; Lou W.; Zhu Y.; Yang J.; Nadiminty N.; Gaikwad N.; Evans C.; Gao A.; Cancer Res.; 2015, 75(7), 1413 4: Flanagan J. U.; Atwell G. J.; Heinrich D. M.; Brooke D. G.; Silva S.; Rigoreau L. J. M.; Trivier E.; Turnbull A. P.; Raynham T.; Jamieson S. M. F.; Denny W. A.; Bioorg. Med. Chem.; 22(2014); 967 Citation Format: Jianxin Duan, Zhong Wang, Qing Li, Yeyu Cao, Ping He, Fanying Meng, Changhua Zhou, Yanhong Wang, Gavin Qu, Henry Li, Jiang Li, Meng Yang, Hui Qi, Don Jung, Mei Song, Mark Matteucci. In vitro and in vivo antitumor activity of TH3424: Preclinical rationale for a highly selective AKR1C3 prodrug for treating hepatocellular carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1369.

Background and objective. Overactivation of AKT1 and gene amplification of AKT2 are frequently detected in ovarian cancer. Activated AKT kinases provide a cell survival signal that may confer resistance to apoptosis induced by conventional therapies in cancer cells. Therefore, development of potent inhibitors that block AKT pathway is an attractive therapeutic strategy for treating ovarian carcinoma. Methods. Ovarian cancer cell lines, A2780, MDAH2774, OVCAR-8, Caov-3, and normal murine fibroblasts (NIH3T3) were used. Cells were treated with different doses of a non-peptide small molecule compound, 9-methoxy-2-methylellipticinium acetate (termed API-59-OME) that potentially inhibit AKT pathway. Kinase assays and the phosphorylation of AKT, GSK-3α/β, PDK1, ERK1/2, SGK, p38, FAK, EGFR, JAK2, PKC isoforms, and the cleavage of poly (ADP-ribose) polymerase (PARP) were examined in treated and untreated cell lines. Further, cells treated with API-59-OME were analyzed for induction of apoptosis using sub-G1 profile with propidium iodide staining. Results. API-59-OME inhibited AKT kinase activity but did not inhibit ERK or JNK kinase activities in A2780, MDAH2774, and OVCAR-8 cell lines. API-59-OME did not reduce phosphorylation of other protein kinases in these cell lines. API-59-OME induced apoptosis and the cleavage of PARP in A2780, MDAH2774, and OVCAR-8 ovarian cancer cell lines that express elevated levels of phosphorylated AKT. In contrast, in Caov-3 and NIH3T3 cell lines, which lack constitutive AKT activity, API-59-OME only had minimal effect to induce apoptosis. Conclusion. These data suggest that API-59-OME may be a potent agent to target constitutively activated AKT pathway in ovarian cancer cells.

The PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumour suppressor is mutated in 40–50% of human endometrial cancers. PTEN exerts its effects in part via inhibition of the antiapoptotic protein AKT. We demonstrate that two endometrial cancer cell lines that harbour PTEN mutations, Ishikawa and RL95-2, have high levels of phosphorylated AKT and high AKT kinase activity. Two additional endometrial cancer cell lines that express wild-type PTEN, Hec1A and KLE, have little phosphorylated AKT and minimal demonstrable AKT kinase activity. We tested a potential inhibitor of the AKT pathway, API-59CJ-OMe, in these four cell lines. We found that API-59CJ-OMe inhibits AKT kinase activity and induces apoptosis in the Ishikawa and RL95-2 cell lines with high AKT activity, but has little effect on Hec1A and KLE cells without AKT activity. API-59CJ-OMe may therefore have therapeutic potential for those endometrial cancers that harbour PTEN mutations and AKT activation.

The C11–C17 segment of the antifungal agent soraphen A1α was prepared from glyceraldehyde acetonide in nine steps. The C12 stereocenter is derived from glyceraldehyde, while the C17 stereocenter as introduced by 1,6-asymmetric control via the coordinated Fe(CO)3.

Bcl-2 belongs to a growing family of proteins which regulates programmed cell death (apoptosis). Overexpression of Bcl-2 has been observed in 70% of breast cancer, 30-60% of prostate cancer, 80% of B-cell lymphomas, 90% of colorectal adenocarcinomas, and many other forms of cancer. Thereby, Bcl-2 is an attractive new anti-cancer target. Herein, we describe the discovery of novel classes of small-molecule inhibitors targeted at the BH3 binding pocket in Bcl-2. The three-dimensional (3D) structure of Bcl-2 has been modeled on the basis of a high-resolution NMR solution structure of Bcl-X(L), which shares a high sequence homology with Bcl-2. A structure-based computer screening approach has been employed to search the National Cancer Institute 3D database of 206 876 organic compounds to identify potential Bcl-2 small-molecule inhibitors that bind to the BH3 binding site of Bcl-2. These potential Bcl-2 small-molecule inhibitors were first tested in an in vitro binding assay for their potency in inhibition of the binding of a Bak BH3 peptide to Bcl-2. Thirty-five potential inhibitors were tested in this binding assay, and seven of them were found to have a binding affinity (IC(50) value) from 1.6 to 14.0 microM. The anti-proliferative activity of these seven active compounds has been tested using a human myeloid leukemia cell line, HL-60, which expresses the highest level of Bcl-2 protein among all the cancer cell lines examined. Compound 6 was the most potent compound and had an IC(50) value of 4 microM in inhibition of cell growth using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Five other compounds had moderate activity in inhibition of cell growth. Compound 6 was further evaluated for its ability to induce apoptosis in cancer cells. It was found that 6 induces apoptosis in cancer cells with high Bcl-2 expression and its potency correlates with the Bcl-2 expression level in cancer cells. Furthermore, using NMR methods, we conclusively demonstrated that 6 binds to the BH3 binding site in Bcl-X(L). Our results showed that small-molecule inhibitors of Bcl-2 such as 6 modulate the biological function of Bcl-2, and induce apoptosis in cancer cells with high Bcl-2 expression, while they have little effect on cancer cells with low or undetectable levels of Bcl-2 expression. Therefore, compound 6 can be used as a valuable pharmacological tool to elucidate the function of Bcl-2 and also serves as a novel lead compound for further design and optimization. Our results suggest that the structure-based computer screening strategy employed in the study is effective for identifying novel, structurally diverse, nonpeptide small-molecule inhibitors that target the BH3 binding site of Bcl-2.