Xanthone derivatives: new insights in biological activities

Xanthones or xanthen-9H-ones (dibenzo-gamma-pirone) comprise an important class of oxygenated heterocycles whose role is well-known in Medicinal Chemistry. The biological activities of this class of compounds are associated with their tricyclic scaffold but vary depending on the nature and/or position of the different substituents. In this review, an array of biological/pharmacological effects is presented for both natural and synthetic xanthone derivatives, with an emphasis on some significant studies on structure-activity relationships. The antitumor activity of some xanthones as well as the related targets, particularly PKC modulation studies, is also discussed in detail. Examples of the "hit" compounds involved in cancer therapy, namely DMXAA, psorospermin, mangiferin, norathyriol, mangostins, and AH6809, a prostanoid receptor antagonist, are also mentioned. Finally, a historical perspective of these xanthonic derivatives, their relevance as therapeutic agents and/or their uses as pharmacological tools and as extract components in folk medicine are also highlighted.     

Synthetic biology: impact on the design of innovative vaccines

Conventional vaccine design strategies mainly focus on live-attenuated vaccines, inactivated microorganisms, and subunits thereof comprising purified components or recombinantly expressed proteins, mostly formulated with adjuvants. Although generally very efficient, these approaches are suboptimal or unfeasible for some infectious diseases. Over the past years new technologies to vaccine development have evolved, often utilizing design principles and construction technologies of synthetic biology. The contribution of synthetic biology to vaccine development comprises algorithms for accelerated in silico identification of relevant protein candidates, in silico design of novel immunogens with improved expression, safety and immunogenicity profiles as well as in silico design of (1) nucleic acid based, (2) vectored and (3) live-attenuated vaccines. Furthermore, synthetic biology enables economic and rapid chemical synthesis of DNA encoding the immunogens designed in silico, and their efficient assembly with delivery systems to obtain vectored vaccines. Altogether, synthetic biology can help to develop improved vaccine candidates in considerably less time compared to conventional approaches.     

A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase

Aromatase (P450arom) is a target of pharmacological interest for the treatment of breast cancer. In this paper, we report the design, synthesis, and in vitro biological evaluation of a series of new (di)benzopyranone-based inhibitors of this enzyme. The design of the new compounds was guided by a CoMFA model previously developed for a series of nonsteroidal aromatase inhibitors. Both the chromone and the xanthone nuclei were taken as molecular skeletons, and the functions supposed to be critical for binding to the aromatase active site - a heterocyclic ring (imidazole or 1,3,4-triazole) linked to the aromatic moiety by a methylene unit and an H-bond accepting function (CN, NO(2), Br) located on the aromatic ring at a suitable distance from the heterocyclic nitrogen carrying the lone pair--were attached to them. The chromone, xanthone, and flavone derivatives were prepared by conventional synthetic methods from the appropriate methyl analogues. Aromatase inhibitory activities were determined by the method of Thompson and Siiteri, using human placental microsomes and [1 beta,2 beta-(3)H]testosterone as the labeled substrate. All the compounds were also tested on 17 alpha-hydroxylase/C17,20-lyase (P450 17), an enzyme of therapeutic interest for the treatment of prostatic diseases. The goal to find new potent inhibitors of aromatase was reached with the xanthone derivatives 22d,e (IC(50) values 43 and 40 nM, respectively), which exceeded the potency of the known reference drug fadrozole and also showed high selectivity with respect to P450 17. Moreover, compounds 22g-i based on the same xanthonic nucleus showed fairly high potency as P450 17 inhibitors (IC(50) values 220, 130, and 42 nM, respectively). Thus, they might be new leads for the development of drug candidates for androgen-dependent diseases.     

Bioactive xanthones with effect on P-glycoprotein and prediction of intestinal absorption

Our research group has been focusing in the discovery of potential antitumor small molecules based on the xanthone scaffold. However, a serious obstacle in the field of cancer therapy is the multidrug resistance (MDR) phenotype, most often caused by the overexpression of P-glycoprotein (P-gp). Another limitation to development of such drug candidates is the reduced information available about the bioavailability of these compounds. We have previously identified four interesting compounds as inhibitors of tumor cell growth namely two dihydroxyxanthones, a xanthonolignoid and a pyranoxanthone. Based on these considerations, it was our aim to: (i) investigate their effect on the P-gp activity; and (ii) estimate their intestinal absorption using Caco-2 cell monolayers as an intestinal model. An HPLC analysis from the in vitro permeation assay with Caco-2 cells monolayer was performed to predict the intestinal permeability of xanthonic derivatives. A rhodamine (Rh123) accumulation assay using P-gp overexpressing leukemia cells, K562Dox, incubated with the four xanthonic derivatives, was performed to investigate their P-gp inhibitory activity. A luminescence-based ATPase assay was performed to differentiate between competitive and noncompetitive P-gp inhibitors. The xanthonolignoid and the pyranoxanthone were found to increase the accumulation of Rh123 in K562Dox cell line, and both were acting by a noncompetitive P-gp inhibitory mechanism. Transport of the four xanthones occurred in the absorptive direction (P_app, 0.012–2.8 nm/s). The behavior of the xanthonolignoid and the pyranoxanthone as P-gp inhibitors and their high apparent permeability coefficients make them promising hit compounds to pursue with further studies.     

以天冬氨酸和丙氨酸为起始原料合成2-甲基-3-羟基吡啶

目的 获得2-甲基-3-羟基吡啶合成方法,降低2-甲基-3-羟基吡啶的合成成本,为常山酮等药物的合成提供了廉价原料。方法 分别以天冬氨酸和丙氨酸为起始原料,经过噁唑中间体,利用Diels-Alder反应,最后脱羧获得2-甲基-3-羟基吡啶,总收率7.4%和30.3%。结果 提供了1种合成2-甲基-3-羟基吡啶的方法,丙氨酸为原料的方法更适合工业化生产,且合成方法简单、原料价格低廉,极大降低了2-甲基-3-羟基吡啶的合成成本,为常山酮等药物的合成提供了廉价原料。     

Structure elucidation of xanthone derivatives: studies of nuclear magnetic resonance spectroscopy

1H and 13C NMR spectra remain the first tool used by chemists to perform the structure elucidation of their products on a routine basis. It is common to provide NMR data on both proton and carbon spectra based on one-dimensional experiments, but often only proton resonances are assigned. The increasing complexity of natural compounds and their synthetic related derivatives imply the use of some more recent 1D and 2D NMR techniques. The purpose of this review is to describe the main NMR features of the most common and important classes of xanthones and also to discuss the application of several 1D and 2D NMR techniques in the structure elucidation of these compounds. A brief discussion of these NMR techniques from the point of view of structure elucidation of organic compounds will also be considered. The calculated NMR chemical shifts in the structure elucidation of xanthones and the use of NMR to study their mode of action in biological activities will be also described.     

Green synthesis of magnesium oxide nanoparticles and its applications: A review

Green synthesis approaches are gaining the attention of researchers and they follow a less hazardous process to obtain nanoparticles. Green synthetic methods are currently used in industry than other physicochemical methods. The magnesium oxide (MgO) nanoparticles have been effectively produced by green synthesis which is environmental friendly, non-toxic with greater stability and has broad range of opportunities for the production of this material in the nanoscale. But still some challenges have been raised for the production of same nanoparticles with huge amount by green synthesis approaches. This is because the biological extracts during the synthesis creates a barrier onto the elucidation of the reactions and their mechanisms. Therefore, this review deals the summing up of variety of biological substrates and different methodologies that can be utilized for the green synthesis of magnesium oxide nanoparticles with impact on their properties. This article also explains the mechanism routes reported in various literatures for better understanding. The energy and environmental applications of the MgO nanoparticles are also dealt with in this article.     

Fueling the Pipeline via Innovations in Organic Synthesis

The paramount importance of synthetic organic chemistry in the pharmaceutical industry arises from the necessity to physically prepare all designed molecules to obtain key data to feed the design–synthesis–data cycle, with the medicinal chemist at the center of this cycle. Synthesis specialists accelerate the cycle of medicinal chemistry innovation by rapidly identifying and executing impactful synthetic methods and strategies to accomplish project goals, addressing the synthetic accessibility bottleneck that often plagues discovery efforts. At AbbVie, Discovery Synthesis Groups (DSGs) such as Centralized Organic Synthesis (COS) have been deployed as embedded members of medicinal chemistry teams, filling the gap between discovery and process chemistry. COS chemists provide synthetic tools, scaffolds, and lead compounds to fuel the pipeline. Examples of project contributions from neuroscience, cystic fibrosis, and virology illustrate the impact of the DSG approach. In the first ten years of innovative science in pursuit of excellence in synthesis, several advanced drug candidates, including ABBV-2222 (galicaftor) for cystic fibrosis and foslevodopa/foscarbidopa for Parkinson’s disease, have emerged with key contributions from COS.     

呫吨酮类衍生物抗肿瘤活性研究进展

呫吨酮是含氧杂环化合物的重要组成部分.此类化合物的生物活性与其三环骨架和骨架上取代基团的性质和位置有关.该文总结了一系列天然与合成的呫吨酮类衍生物的抗肿瘤活性,并且阐述了部分重要的抗肿瘤机制,详细介绍了一些呫吨酮类衍生物的抗肿瘤及其对靶点的作用,尤其是对蛋白激酶C调变作用的研究;还列举了部分具有癌症治疗效果的呫吨酮类化合物,包括DMXAA、普梭草素、芒果苷、降阿赛里奥、曼果斯廷等.     

Neolamellarin A 及其相关吡咯类海洋生物碱合成和结构改造研究进展

Lamellarins 是一类从海洋无脊椎动物中分离的具有生物活性的吡咯生物碱, Neolamellarins,Lukianols, Storniamides, Ningalins 等结构新颖的生物碱都属于该家族。Lamellarins 吡咯类生物碱合成的关键是1,3,4-三取代吡咯环的构建,主要策略有分步构建与一锅法构建吡咯环两类,从中涌现了多种极富创新性与可行性的合成方法,既从结构多样性合成的角度丰富了化合物库,同时又以生物活性为导向提高了该类化合物的生物活性。本文对其结构特点、合成、生物活性进行了综述。     

Recent advances in the synthesis of marine polycyclic ether natural products

For more than twenty years, chemists and biologists have been fascinated by the highly complex molecular architectures and the diverse and potent biological activities of marine polycyclic ether natural products. Given the scarce availability of these intriguing substances from natural sources, total chemical synthesis is the only way to obtain sufficient quantities for biological investigation. This review describes recent synthetic advances in the field of marine polycyclic ether natural products and their successful implementation in total synthesis endeavors.     

Substituted Xanthones as Antimycobacterial Agents,Part 1: Synthesis and Assignment of 1H/13C NMR Chemical Shifts

A series of substituted xanthones was synthesized in order to prove the hypothesis that electron-withdrawing substituents enhance the antimycobacterial activity of these compounds, which is described by means of a QSAR equation with ¹³C NMR chemical shifts as independent parameters. The key step of the synthesis is the formation of substituted 2-phenoxybenzoic acids by Ullmann reaction followed by intramolecular Friedel-Crafts acylation, leading to methyl-, carboxy-, nitro-, cyano-, and aminoxanthones as a test set for QSAR investigations. Spectroscopic data (¹H and ¹³C chemical shifts, IR, UV) of these xanthones are presented and analyzed. Specific shift increments for xanthones depending on the substituent position and on the position of the respective proton/carbon atom as well as additivity rules were developed.     

Reactions in unusual media

This review provides an introduction to three of the most well-developed solvent replacement strategies currently under investigation for synthetic chemistry: Ionic liquids, fluorous phase techniques, and supercritical carbon dioxide. They are all fascinating reaction media, and have considerable potential for use in pharmaceutical synthesis. However, this has to be balanced with problems and limitations of the new methods. This review aims to provide an overall account of recent advances in the use of unusual media for synthetic chemistry, with an emphasis on highlighting potential benefits, but also limitations, of each of the methods described.     

6个小分子海洋药物的全合成方法

骨架新颖、活性独特的海洋天然产物是药物先导化合物的重要来源,但由于海洋样品采集困难、一些高活性天然产物在海洋生物体中含量低微,往往难以获取足够量的化合物进行后续药物的深入研究,成为海洋小分子药物研究的瓶颈之一。现代有机合成尤其是海洋天然产物全合成的迅猛发展,为获取复杂小分子海洋活性天然产物提供了一个重要手段。探究复杂小分子海洋天然产物合成的新策略和新方法,建立高效、高选择性的规模化制备技术,是国际海洋药物研究的热点。本文就6个上市的小分子海洋药物的全合成研究作一概述,重点阐述有机合成对于成药分子规模化制备的途径。     

阿托伐他汀钙的合成研究进展

目的介绍了阿托伐他汀钙的研究背景,作用机制以及合成的研究进展。方法综合国内外报道的文献,阐述阿托伐他汀钙的合成方法。结果重点列出了3条阿托伐他汀钙的合成路线,重点分析了Paal-Knorr合成法。结论 Paal-Knorr合成法中,2种重要中间体的各种合成路线为阿托伐他汀钙的高效合成提供了新的思路。     

Xanthone Derivatives as Potential Anti-cancer Drugs

Xanthone derivatives have been shown to be potent inhibitors of tumour growth. Oxygenated xanthones and [3-(dialkylamino)-2-hydroxypropoxy]xanthones have been prepared and tested for in-vitro inhibition of human PLC/PRF/5, KB and 212 cells. Structure-activity analysis indicated epoxidation of the hydroxyxanthone increased cytotoxicity against tumour cells but ring-opening of the epoxide group with dialkylamine did not enhance the anti-tumour activity. Further evaluation of three of the most active compounds 2, 6-, 3, 6-, and 3, 5-di(2,3-epoxypropoxy)xanthone (compounds 10a, 11a , and 12a , respectively) in DNA, RNA and protein synthesis of tumour cells showed potent inhibitory activity. The 3,5-di(2,3-epoxypropoxy)xanthone also showed potent inhibitory activity against 212 cells, a Ha-ras oncogene-transformed NIH 3T3 cell line. The results indicated that compounds 10a and 12a are potent anti-tumour agents which not only suppressed cellular DNA, RNA and protein synthesis but also specifically inhibited the Ha-ras oncogene in 212 cells.     

Recent cancer drug development with xanthone structures

Objectives Xanthones are simple three‐membered ring compounds that are mainly found as secondary metabolites in higher plants and microorganisms. Xanthones have very diverse biological profiles, including antihypertensive, antioxidative, antithrombotic and anticancer activity, depending on their diverse structures, which are modified by substituents on the ring system. Although several reviews have already been published on xanthone compounds, few of them have focused on the anticancer activity of xanthone derivatives. In this review we briefly summarize natural and synthetic xanthone compounds which have potential as anticancer drugs. Key findings The interesting structural scaffold and pharmacological importance of xanthone derivatives have led many scientists to isolate or synthesize these compounds as novel drug candidates. In the past, extensive research has been conducted to obtain xanthone derivatives from natural resources as well as through synthetic chemistry. Xanthones interact with various pharmacological targets based on the different substituents on the core ring. The anticancer activities of xanthones are also dramatically altered by the ring substituents and their positions. Summary The biological activities of synthetic xanthone derivatives depend on the various substituents and their position. Study of the biological mechanism of action of xanthone analogues, however, has not been conducted extensively compared to the diversity of xanthone compounds. Elucidation of the exact biological target of xanthone compounds will provide better opportunities for these compounds to be developed as potent anticancer drugs. At the same time, modification of natural xanthone derivatives aimed at specific targets is capable of expanding the biological spectrum of xanthone compounds.     

中药藤黄呫吨酮类化合物及其分析测定方法

介绍近年来从中药藤黄中分离得到的笼状呫吨酮类化合物及其分析测定方法,为中药藤黄抗肿瘤活性成分的进一步研究提供参考。笼状呫吨酮类化合物为中药藤黄发挥药理活性的物质基础,但由于其结构复杂,分子稳定性较差,需要借助于新型的分析检测技术方能对其进行定性定量测定。     

CLINICAL TRIALS AND TRANSLATIONAL MEDICINE COMMENTARY: Drug Delivery Trends in Clinical Trials and Translational Medicine: Challenges and Opportunities in the Delivery of Nucleic Acid-Based Therapeutics

The ability to deliver nucleic acids (e.g., plasmid DNA, antisense oligonucleotides, siRNA) offers the potential to develop potent vaccines and novel therapeutics. However, nucleic acid-based therapeutics are still in their early stages as a new category of biologics. The efficacy of nucleic acids requires that these molecules be delivered to the interior of the target cell, which greatly complicates delivery strategies and compromises efficiency. Due to the safety concerns of viral vectors, synthetic vectors such as liposomes and polymers are preferred for the delivery of nucleic acid-based therapeutics. Yet, delivery efficiencies of synthetic vectors in the clinic are still too low to obtain therapeutic levels of gene expression. In this review, we focus on some key issues in the field of nucleic acid delivery such as PEGylation, encapsulation and targeted delivery and provide some perspectives for consideration in the development of improved synthetic vectors.     

Diversity oriented synthesis and branching reaction pathway to generate natural product-like compounds

Combinatorial chemistry can be used to synthesize diversified molecules on a large scale. As with all large-scale experiments, this process requires a major investment in equipment, consumables and time. Therefore, careful design is critical. As the complexity of the libraries to be generated increases, additional considerations become important. What are the issues that should be considered when planning combinatorial chemistry projects? Which features in the design strategy are critical to consider ensuring that all of the potential products will be synthesized? How are the reactants selected to optimize product synthesis and yield? Over the last several years, through an experimental process, we have successfully developed and optimized our synthetic strategy. Our approach incorporates a number of critical components into a tightly controlled process that generates molecules with maximal structural complexity. This complexity emanates from carbon-carbon bond formation, which is extremely stable and it is reminiscent of complex natural product molecules. Our studies have illustrated that transition metal catalysts are powerful reagents that can be used to drive the synthesis of diverse small molecules from less complex starting materials. In this review, we will describe some of our recent efforts to synthesize natural product-like molecules and their derivative structures to successfully create libraries of complex molecules for drug discovery applications. Our diversity-oriented synthesis methods incorporate transition metal catalysts, as a versatile tool for creating carbon-carbon bonds and structural complexity, and the branched reaction pathway, as a method for incorporating diversity into the molecular scaffolds. We will review our combinatorial chemistry program, focusing on the decisions that we made for (1) the scaffold selection; (2) the design of a diversity oriented approach for library synthesis; (3) the incorporation of the branched reaction pathway to generate natural product-like molecules from the same starting material; and (4) the process steps that we selected for chemistry development and library generation.