Ipertrofan Revisited—The Proposal of the Complete Stereochemistry of Mepartricin A and B

Being a methyl ester of partricin, the mepartricin complex is the active substance of a drug called Ipertrofan (Tricandil), which was proven to be useful in treatment of benign prostatic hyperplasia and chronic nonbacterial prostatitis/chronic pelvic pain syndrome. Nevertheless, no direct structural evidence on the stereochemistry of its components has been presented to date. In this contribution, we have conducted detailed, NMR-driven stereochemical studies on mepartricins A and B, aided by molecular dynamics simulations. The absolute configuration of all the stereogenic centers of mepartricin A and B was defined as 3R, 7R, 9R, 11S, 13S, 15R, 17S, 18R, 19S, 21R, 36S, 37R, and 38S, and proposed as 41R. The geometry of the heptaenic chromophore of both compounds has been established as 22E, 24E, 26E, 28Z, 30Z, 32E, and 34E. Our studies on mepartricin ultimately proved that partricins A and B are structurally identical to the previously described main components of the aureofacin complex: gedamycin and vacidin, respectively. The knowledge of the stereochemistry of this drug is a fundamental matter not only in terms of studies on its molecular mode of action, but also for potential derivatization, aiming at improvement of its pharmacological properties.     

The Br,Fe, Rb,Sr, and Zn contents and interrelation in intact and morphologic normal prostate tissue of adult men investigated by energy‐dispersive X‐ray fluorescent analysis

A method for radionuclide‐induced (¹⁰⁹Cd) energy‐dispersive X‐ray fluorescent (EDXRF) was used to determine Br, Fe, Rb, Sr, and Zn contents in intact and morphologic normal prostate tissues. Prostates were removed at necropsy from 64 men (mean age 36.5 years, range 13–60) who had died suddenly. All materials were divided into two parts. One part was morphologically examined, whereas chemical element contents of the other were estimated. Mean values (M ± SΕΜ) for mass fraction of Br, Fe, Rb, Sr, and Zn (mg kg^?1 on dry‐weight basis) in the intact and morphologic normal prostate tissue were 35.5 ± 4.0, 107 ± 5.4, 17.1 ± 0.8, 1.9 ± 0.3, and 850 ± 79, respectively. Mean values (M ± SΕΜ) for Zn/Fe, Zn/Rb, and Zn/Sr ratios of mass fraction were 8.72 ± 0.80, 57.4 ± 7.2, and 567 ± 82, respectively. A strongly pronounced tendency of age‐related exponential increase in Zn mass fraction as well an increase in Zn/Fe, Zn/Rb, and Zn/Sr ratios in prostate was observed. A significant positive correlation was seen between the prostatic zinc and iron contents (p ≤ 0.05, r = 0.22) and between the prostatic zinc and bromine contents (p ≤ 0.01, r = 0.43). Copyright © 2011 John Wiley & Sons, Ltd.     

Tissue distribution and metabolism of the putative cancer chemopreventive agent 3′,4′,5′‐trimethoxyflavonol (TMFol) in mice

3′,4′,5′‐Trimethoxyflavonol (TMFol) is a synthetic flavonol with preclinical cancer chemopreventive properties. The hypothesis was tested that, in mice, p.o. administration of TMFol results in measureable levels of the parent in target tissues. A single oral dose (240 mg/kg) was administered to mice (n = 4 per time point) with time points ranging from 5 to 1440 min. TMFol and its metabolites were identified and quantitated in all tissues by high‐performance liquid chromatography (HPLC). Plasma levels of TMFol were at the limit of quantification or below, although metabolites were identified. Peak levels of TMFol in the gastrointestinal tract and the prostate averaged 1671 ± 265 µg/g (5.3 µmol/g) and 6.0 ± 1.6 µg/g (18.4 nmol/g), and occurred 20 and 360 min post‐dose, respectively. The area under the tissue concentration–time curve (AUC) for TMFol was greater than those of the metabolites, indicating that TMFol is relatively metabolically stable. Micromolar TMFol levels are easily achieved in the prostate and gastrointestinal tract, suggesting that TMFol might exert chemopreventive efficacy at these tissue sites. Further investigations are warranted to elucidate the potential chemopreventive potency of TMFol. Copyright © 2012 John Wiley & Sons, Ltd.     

Alnus sibirica Compounds Exhibiting Anti-Proliferative,Apoptosis-Inducing,and GSTP1 Demethylating Effects on Prostate Cancer Cells

Alnus sibirica (AS) is distributed in Korea, Japan, China, and Russia and has reported anti-oxidant, anti-inflammatory, and reducing activities on atopic dermatitis-like skin lesions, along with other beneficial health properties. In the present study, we tried to prove the cancer-preventive activity against prostate cancer. The extracted and isolated compounds, oregonin (1), hirsutenone (2), and hirsutanonol (3), which were isolated from AS, were tested for anti-proliferative activity. To do this, we used the MTT assay; NF-κB inhibitory activity, using Western blotting; apoptosis-inducing activity using flow cytometry; DNA methylation activity, using methylation-specific polymerase chain reaction in androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cell lines. The compounds (1–3) showed potent anti-proliferative activity against both prostate cancer cell lines. Hirsutenone (2) exhibited the strongest NF-κB inhibitory and apoptosis-inducing activities compared with oregonin (1) and hirsutanonol (3). DNA methylation activity, which was assessed for hirsutenone (2), revealed a concentration-dependent enhancement of the unmethylated DNA content and a reduction in the methylated DNA content in both PC-3 and LNCaP cells. Overall, these findings suggest that hirsutenone (2), when isolated from AS, may be a potential agent for preventing the development or progression of prostate cancer.     

经直肠超声联合前列腺特异抗原密度诊断前列腺癌的临床应用价值研究

为探讨经直肠超声与前列腺特异抗原密度(PSAD)联合检查诊断前列腺癌的临床应用价值,选取本院2013年9月~2018年9月期间内接收的97例血清前列腺特异性抗原(PSA)患者实施研究。所有患者均行经直肠超声与前列腺特异抗原密度(PSAD)联合检查,并与手术病理结果进行对比。观察PSAD检查结果,分析经直肠超声与PSAD联合检查的诊断符合率,并对比病理结果与经直肠超声和PSAD联合检查的准确率、灵敏性、特异性情况,分析前列腺癌患者经直肠超声检查的影像学特征及内部回声情况。与病理结果对比,经直肠超声与PSAD联合检查对前列腺癌、移行细胞癌、黏液腺癌检出率均稍低(P>0.05);经直肠超声与PSAD联合检查的准确率、灵敏性、特异性较病理检查均稍低(P>0.05)。经直肠超声检查后根据图像表现可将疾病分为弥漫性、结节型、无结节型3型,不同类型的影像学特征及内部回声情况表现不同,表明经直肠超声与PSAD联合诊断前列腺癌准确性较高,并且可清晰地对不同疾病类型的内部回声作出反映,临床实用价值较高,值得加以推广。     

The use of matrix coating assisted by an electric field (MCAEF) to enhance mass spectrometric imaging of human prostate cancer biomarkers

In this work, we combined a newly developed matrix coating technique – matrix coating assisted by an electric field (MCAEF) and matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) to enhance the imaging of peptides and proteins in tissue specimens of human prostate cancer. MCAEF increased the signal‐to‐noise ratios of the detected proteins by a factor of 2 to 5, and 232 signals were detected within the m/z 3500–37500 mass range on a time‐of‐flight mass spectrometer and with the sinapinic acid MALDI matrix. Among these species, three proteins (S100‐A9, S100‐A10, and S100‐A12) were only observed in the cancerous cell region and 14 proteins, including a fragment of mitogen‐activated protein kinase/extracellular signal‐regulated kinase kinase kinase 2, a fragment of cAMP‐regulated phosphoprotein 19, 3 apolipoproteins (C‐I, A‐I, and A‐II), 2 S100 proteins (A6 and A8), β‐microseminoprotein, tumor protein D52, α‐1‐acid glycoprotein 1, heat shock protein β‐1, prostate‐specific antigen, and 2 unidentified large peptides at m/z 5002.2 and 6704.2, showed significantly differential distributions at the p < 0.05 (t‐test) level between the cancerous and the noncancerous regions of the tissue. Among these 17 species, the distributions of apolipoprotein C‐I, S100‐A6, and S100‐A8 were verified by immunohistological staining. In summary, this study resulted in the imaging of the largest group of proteins in prostate cancer tissues by MALDI‐MS reported thus far, and is the first to show a correlation between S100 proteins and prostate cancer in a MS imaging study. The successful imaging of the three proteins only found in the cancerous tissues, as well as those showing differential expressions demonstrated the potential of MCAEF‐MALDI/MS for the in situ detection of potential cancer biomarkers. Copyright © 2015 John Wiley & Sons, Ltd.     

概率主成分分析联合支持向量机的前列腺SELDI-TOF质谱数据分析方法研究

基于前列腺癌检测中获取的表面增强激光解吸/离子化飞行时间质谱(SELDI-TOF-MS)数据,提出一种概率主成分分析(PPCA)联合支持向量机(SVM)的分类方法。对临床322例血清样本的质谱数据进行特征提取,以随机选取训练样本集(225例)构造SVM判别模型,对剩余样本集(97例)进行测试。采用均方根误差、识别率与预测率指标,将所构造的PPCA-SVM模型分别与偏最小二乘(Partial least squares,PLS)和PCA-SVM模型进行比较,发现PLS模型的识别率和预测率分别为90.92%和76.38%,PCA-SVM模型分别为99.23%和84.63%,而PPCA-SVM模型分别为99.01%和90.41%。因此SELDI-TOF-MS技术结合PPCA-SVM在样品分类中具有准确、重复性好等优点,为前列腺癌早期诊断提供了一种新方法。     

Preclinical Assessment Addressing Intravenous Administration of a [68Ga]Ga-PSMA-617 Microemulsion: Acute In Vivo Toxicity,Tolerability, PET Imaging,and Biodistribution

It has been herein presented that a microemulsion, known to be an effective and safe drug delivery system following intravenous administration, can be loaded with traces of [⁶⁸Ga]Ga-PSMA-617 without losing its properties or causing toxicity. Following tolerated IV injections the capability of the microemulsion in altering [⁶⁸Ga]Ga-PSMA-617 distribution was presented at 120 min post injection based on its ex vivo biodistribution results.     

Synthesis,cytotoxicity assessment and antioxidant activity of some new thiazol-2-yl carboxamides

Dependence on the biological activity of 2-aminothiazole, the synthesis and chemical reactions of ethyl 3-oxo-3-(thiazol-2-ylamino)propanoate ( 1 ) with some different reagents were described for cytotoxic and antioxidant evaluation. The new derivatives 2–19 could be synthesized and characterized by correct analytical and spectral data. In addition to the thiazole ring, these compounds contain 2H-1,2,3-triazole ( 3 ), 1H-pyrazole ( 5 , 12 ), 1,3-dithiane ( 7 ), benzothiazole ( 10 ), thiazolidine ( 13 ), thiazolidinone ( 14 , 15 ), 2H-chromene ( 17 ), pyridine ( 19 ) moieties. The preparation of compounds 2–19 was performed through the formation of the isolable 2-(2-phenylhydrazineylidene) 2 , 2-dimethylaminomethylidene 4 , 2-phenylcarbamothioyl 9 , 2-(methylthio)(phenylamino) methylidene 11 and non-isolable potassium bis(thiolate) 6 , potassium thiolate 8 intermediates from precursor 1 . The activity of these derivatives 1–19 against human lung fibroblast (WI38) and human prostate cancer (PC3) were examined in vitro using the MTT assay. The assessment of their antioxidant activities was carried out by following the ABTS method to evaluate their pharmaceutical importance.