Recent Advances in the Chemistry and Therapeutic Evaluation of Naturally Occurring and Synthetic Withanolides

Natural products are a major source of biologically active compounds that make promising lead molecules for developing efficacious drug-like molecules. Natural withanolides are found in many flora and fauna, including plants, algae, and corals, that traditionally have shown multiple health benefits and are known for their anti-cancer, anti-inflammatory, anti-bacterial, anti-leishmaniasis, and many other medicinal properties. Structures of these withanolides possess a few reactive sites that can be exploited to design and synthesize more potent and safe analogs. In this review, we discuss the literature evidence related to the medicinal implications, particularly anticancer properties of natural withanolides and their synthetic analogs, and provide perspectives on the translational potential of these promising compounds.     

Phytotherapy in Integrative Oncology—An Update of Promising Treatment Options

Modern phytotherapy is part of today’s conventional evidence-based medicine and the use of phytopharmaceuticals in integrative oncology is becoming increasingly popular. Approximately 40% of users of such phytopharmaceuticals are tumour patients. The present review provides an overview of the most important plants and nature-based compounds used in integrative oncology and illustrates their pharmacological potential in preclinical and clinical settings. A selection of promising anti-tumour plants and ingredients was made on the basis of scientific evidence and therapeutic practical relevance and included Boswellia, gingko, ginseng, ginger, and curcumin. In addition to these nominees, there is a large number of other interesting plants and plant ingredients that can be considered for the treatment of cancer diseases or for the treatment of tumour or tumour therapy-associated symptoms. Side effects and interactions are included in the discussion. However, with the regular and intended use of phytopharmaceuticals, the occurrence of adverse side effects is rather rare. Overall, the use of defined phytopharmaceuticals is recommended in the context of a rational integrative oncology approach.     

β-榄香烯三羰基铼配合物的合成、放射化学合成及抗癌活性研究

以中草药有效成分β-榄香烯为起始原料, 经烯丙位的氯代反应及亲核取代反应在β-榄香烯母体上成功地引入含吡啶基的三齿螯合剂, 并与稳定的三羰基铼配位, 得到了一种新的铼(I)三齿配合物, 在此基础上利用铼的放射性同位素Re-188进行了放射性标记. 反应中间体及最终化合物分别用IR, ¹H NMR, HRMS, HPLC或元素分析进行表征, 并对该化合物进行了初步的体外抗癌活性研究. β-榄香烯三羰基铼配合物的合成、放射化学合成及体外抗癌活性评价, 为探讨β-榄香烯体内靶点和作用机制提供了可能, 并为最终开发基于β-榄香烯的放射性药物奠定了基础.     

Mass spectrometric characterization of 3'-imino[60]fulleryl-3'-deoxythymidine by collision-induced dissociation

The primary structure of 3'-imino[60]fulleryl-3'-deoxythymidine ions is studied using mass spectrometry both in the positive and negative modes. Interaction between the subunits is discussed using collision-induced dissociation (CID) spectra. Collisional activation with argon of the sodiated cations leads to the cleavage of the glycosidic bond and the transfer of a radical hydrogen from the deoxyribose to the thymine. The sodiated thymine is the only fragment observed for low collision energies in the positive mode. In the negative mode, two different ionization mechanisms take place, reduction and deprotonation in the presence of triethylamine. The 2.7 eV electron affinity of C60 and its huge cross section compared to the small cross section and predicted 0.44 eV electron affinity of the thymidine subunit most likely localize the radical electron on the fullerene. On the other hand, deprotonation of the 3'-azido-3'-deoxythymidine (AZT) is known to occur in N-3, the most acidic site of the nucleobase. Consequently, deprotonation causes the negative charge to be initially localized on the thymine. Both types of parent anions give the radical anion C60*- as fragment. The other fragments detected are the dehydrogenated 3'-imino[60]fulleryl-3'-deoxyribose anion, C60NH2-, C60N- and C60H-. Since in negative ion mass spectrometry all fragments include the [60]fullerene unit, this suggests that the fragmentation is driven by the electron affinity of the [60]fullerene, likely responsible for a charge transfer between the deprotonated thymine and the C60.     

Folate-targeted optical and magnetic resonance dualmodality PCL-<Emphasis Type="Italic">b</Emphasis>-PEG micelles for tumor imaging

A biodegradable tumor targeting nano-probe based on poly（ε-caprolactone）-b-poly（ethylene glycol）block copolymer（PCL-b-PEG）micelle functionalized with a magnetic resonance imaging（MRI）contrast agent diethylenetriaminepentaacetic acid-gadolinium(DTPA-Gd³⁺)on the shell and a near-infrared（NIR）dye in the core for magnetic resonance and optical dual-modality imaging was prepared.The longitudinal relaxivity（r₁）of the PCL-b-PEG-DTPA -Gd³⁺micelle was 13.4（mmol/L）^-1s^-1,three folds of that of DTPA-Gd³⁺,and higher than that of many polymeric contrast agents with similar structures.The in vivo optical imaging of a nude mouse bearing xenografted breast tumor showed that the dual-modality micelle preferentially accumulated in the tumor via the folic acid-mediated active targeting and the passive accumulation by the enhanced permeability and retention（EPR）effect.The results indicated that the dualmodality micelle is a promising nano-probe for cancer detection and diagnosis.     

Synthesis and Antitumor Evaluation of Novel Hybrids of Phenylsulfonylfuroxan and Estradiol Derivatives

Fifteen novel furoxan-based nitric oxide (NO) releasing hybrids of estradiol derivatives were synthesized and evaluated in vitro anti-proliferative activity in MDA-MB-231, A2780, Hela and HUVEC cell lines. Most of them displayed potent anti-proliferative effects. Among the compounds, 4-bromo-3-((phenylsulfonyl)-1,2,5-oxadiazole 2-oxide)-oxy-propoxy-estradiol ( 11 b ) exhibited the best activity with IC₅₀ values of 3.58–0.0008 μM. Preliminary pharmacological studies showed that 11 b induced apoptosis and hardly affected the cell cycle of MDA-MB-231 cell line. NO-releasing capacity and inhibition of ERK/MAPK pathway signaling might explain the potent antineoplastic activity of these compounds. The preliminary structure-activity relationship (SAR) showed that steroidal scaffolds with a linker in 3-position were favorable moieties to evidently increase the bioactivities of these hybrids. Overall, these results implied that 11 b merited to be further investigated as a promising anti-cancer candidate.     

Chiral resolution of diphenylalanine by high-performance liquid chromatography on a crown-ether-based chiral stationary phase and by NMR spectroscopy

Summary The enantiomers of diphenylalanine (DPA) were well separated by chiral HPLC and NMR spectroscopy on the chiral stationary phase (CSP) derived from (18-crown-6)-2,3,11,12-tetracarboxylic acid (18-C-6-TA). The chromatographic parameters such as separation factors and retention times were greatly influenced by the mobile phase conditions. The (+)-18-C-6-TA used in the CSP was also employed as a chiral solvating agent for the enantiodiscrimination of the DPA enantiomers by NMR spectroscopy. The proton of the DPA analyte showing the chemical shift nonequivalences was used in determining the enantiomeric composition of the analyte.     

2，2＇－偶氮二异丁酸二甲酯的合成及其热分解反应的研究

本文研究了２，２＇－偶氮二异丁酸二甲酯的合成及其在甲苯、二甲苯中的热分解反应动力学，得到了其热分解反应速度常数与反应温度的关系式：Ｋ＿ｄ＝１．６３×１００￣（－１４）ｅｘｐ（－１２３．３ＫＪ／ＲＴ）２，２＇－偶氮二异丁酸二甲酯作为苯乙烯自由基聚合的引发剂，其单体转化率随引发剂用量的增加而增高，产物分子量则随之下降；引发剂用量在５％以上时，可得到分子量低于１０￣３的含有酯基端基的聚合物。     

Integrated rapid resolution liquid chromatography–tandem mass spectrometric approach for screening and identification of metabolites of the potential anticancer agent 3,6,7-trimethoxyphenanthroindolizidine in rat urine

An integrated approach combining data acquisition using MS^E and multi-period product ion scan (mpMS/MS), with high-resolution characteristic extracted ion chromatograms (hcXIC) as a data mining method, was developed for in vivo drug metabolites screening and identification. This approach is illustrated by analyzing metabolites of a potential anticancer agent, 3,6,7-trimethoxyphenanthroindolizidine (CAT) in rat urine based on rapid resolution liquid chromatography combined with tandem mass spectrometry (RRLC–MS/MS). Untargeted full-scan MS^E enabled the high-throughput acquisition of potential metabolites, and targeted mpMS/MS contributed to the sensitivity and specificity of the acquisition of molecules of interest. The data processing method hcXIC, based on the structure of CAT, was shown to be highly effective for the metabolite discovery. Through the double-filtering effect of the characteristic ion and accurate mass, conventional extracted ion chromatograms that contained a substantial number of false-positive peaks were simplified into chromatograms essentially free of endogenous interferences. As a result, 21 metabolites were detected in rat urine after oral administration of CAT. Based on the characteristic fragmentation patterns of the phenanthroindolizidine alkaloid, the structures of 9 metabolites were identified. Furthermore, the interpretation of the MS/MS spectra of these metabolites enabled the determination of demethylation position as well as the differentiation between N-oxidized and hydroxylated metabolites.