Quinoline as a privileged scaffold in cancer drug discovery

Quinoline (1-azanaphthalene) is a heterocyclic aromatic nitrogen compound characterized by a double-ring structure that contains a benzene ring fused to pyridine at two adjacent carbon atoms. Quinoline compounds are widely used as "parental" compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain quinoline-based compounds also show effective anticancer activity. This broad spectrum of biological and biochemical activities has been further facilitated by the synthetic versatility of quinoline, which allows the generation of a large number of structurally diverse derivatives. This includes numerous analogues derived from substitution of the quinoline ring system, and derivatization of quinoline ring structure. Quinoline and its analogs have recently been examined for their modes of function in the inhibition of tyrosine kinases, proteasome, tubulin polymerization and DNA repair. In this review, we have summarized our knowledge on quinoline compounds with respect to their anticancer activities, mechanisms of action, structure-activity relationship (SAR), and selective and specific activity against various cancer drug targets. In particular, we focus our review on in vitro and in vivo anticancer activities of quinoline and its analogs in the context of cancer drug development and refinement.     

Molecular target interactions of quinoline derivatives as anticancer agents: A review

One of the leading causes of death worldwide is cancer, which poses substantial risks to both society and an individual's life. Cancer therapy is still challenging, despite developments in the field and continued research into cancer prevention. The search for novel anticancer active agents with a broader cytotoxicity range is therefore continuously ongoing. The benzene ring gets fused to a pyridine ring at two carbon atoms close to one another to form the double ring structure of the heterocyclic aromatic nitrogen molecule known as quinoline (1-azanaphthalene). Quinoline derivatives contain a wide range of pharmacological activities, including antitubercular, antifungal, antibacterial, and antimalarial properties. Quinoline derivatives have also been shown to have anticancer properties. There are many quinoline derivatives widely available as anticancer drugs that act via a variety of mechanisms on various molecular targets, such as inhibition of topoisomerase, inhibition of tyrosine kinases, inhibition of heat shock protein 90 (Hsp90), inhibition of histone deacetylases (HDACs), inhibition of cell cycle arrest and apoptosis, and inhibition of tubulin polymerization.     

喹啉类化合物的合成及活性研究进展

喹啉类化合物在医药和农药领域具有广泛用途,本文综述了喹啉母环的构筑方法及近年来部分喹啉类化合物的合成方法,并对其在抗肿瘤、抗菌和抗HIV方面的活性进行了概述。     

Mannichbasen als Zwischenstufen bei Chinolinsynthesen

Mannich Bases as Intermediates in Quinoline Syntheses The classic quinoline syntheses pass intermediate stages, which can be considered as Mannich bases. This reflexion leads to the preparation of 2-phenyl-quinolines with condensated rings in 3,4-position by ring closure of Mannich bases from the typ of 2-(1-phenyl-1-anilinomethyl)-cycloalcanones.     

抗疟药的剂型研究进展

疟疾是发展中国家尤其是非洲地区所面临的传染病中的头号杀手,严重威胁人类健康。喹啉类、二氢叶酸还原酶抑制剂以及青蒿素类药物是目前治疗疟疾的主要药物,具有良好的临床应用价值,但存在溶解度差、缺乏靶向性等缺点。目前,优化抗疟疾药物剂型已成为研究的热点。现对抗疟药的各种优化剂型,例如固体分散体、环糊精包合物、纳米粒、脂质体等进行综述。     

烟酸合成工艺的改革

本文研究了以对一氨基苯酚为起始原料,先合成6-羟基喹啉;再经氧化、加热脱羧合成烟酸的两项重要工艺改革。两项改革均具有简化流程、节省原料、提高收率、经济效益显著等优越性。     

Synergistic interactions between commonly used food additives in a developmental neurotoxicity test.

Exposure to non-nutritional food additives during the critical development window has been implicated in the induction and severity of behavioral disorders such as attention deficit hyperactivity disorder (ADHD). Although the use of single food additives at their regulated concentrations is believed to be relatively safe in terms of neuronal development, their combined effects remain unclear. We therefore examined the neurotoxic effects of four common food additives in combinations of two (Brilliant Blue and L-glutamic acid, Quinoline Yellow and aspartame) to assess potential interactions. Mouse NB2a neuroblastoma cells were induced to differentiate and grow neurites in the presence of additives. After 24 h, cells were fixed and stained and neurite length measured by light microscopy with computerized image analysis. Neurotoxicity was measured as an inhibition of neurite outgrowth. Two independent models were used to analyze combination effects: effect additivity and dose additivity. Significant synergy was observed between combinations of Brilliant Blue with L-glutamic acid, and Quinoline Yellow with aspartame, in both models. Involvement of N-methyl-D-aspartate (NMDA) receptors in food additive-induced neurite inhibition was assessed with a NMDA antagonist, CNS-1102. L-glutamic acid- and aspartame-induced neurotoxicity was reduced in the presence of CNS-1102; however, the antagonist did not prevent food color-induced neurotoxicity. Theoretical exposure to additives was calculated based on analysis of content in foodstuff, and estimated percentage absorption from the gut. Inhibition of neurite outgrowth was found at concentrations of additives theoretically achievable in plasma by ingestion of a typical snack and drink. In addition, Trypan Blue dye exclusion was used to evaluate the cellular toxicity of food additives on cell viability of NB2a cells; both combinations had a straightforward additive effect on cytotoxicity. These data have implications for the cellular effects of common chemical entities ingested individually and in combination.     

Discovery of phenyl acetic acid substituted quinolines as novel liver X receptor agonists for the treatment of atherosclerosis

A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRbeta and LXRalpha and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.     

Photochemical stability of biologically active compounds: V. Photochemical degradation of primaquine in an aqueous medium

Quinoline antimalarials are photochemically unstable. Several of these drugs cause toxic reactions which may be ascribed to the Photochemical degradation of the substances. The effect of light of wavelengths 320–600 nm on the aminoquinoline primaquine in aqueous solution was investigated. The main photochemical degradation products were isolated by means of preparative TLC. The samples were identified by mass spectrometry (EI, CI and high-resolution), ¹H-NMR spectroscopy and GC/MS.     

Quinolines: a new hope against inflammation

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Highlights? Quinoline has emerged as a new pharmacophore for novel anti-inflammatory agents. ? Various quinolines, for example, substituted or fused analogues have been investigated. ? These include inhibitors of COX, PDE4 and TACE along with TRPV1 antagonists.     

Anti-carcinogenic structural modification by fluorine-substitution in aza-polycyclic aromatic hydrocarbons

One of the major goals of a series of our studies is to explore the availability of a method for anti-genotoxic modification of carcinogens by fluorine-substitution. Quinoline, a hepatocarcinogen, mutates bacterial tester strains in the presence of rat liver microsomal enzymes and induces GST-P (placental glutathione S-transferase)-positive foci in a medium-term bioassay system for hepatocarcinogenesis. On the other hand, 3-fluorinated quinoline (3-FQ) was neither mutagenic nor carcinogenic in the same assay system, whereas 5-fluoroquinoline (5-FQ) was mutagenic and carcinogenic. Quinoline, 3-FQ, and 5-FQ were also tested in an in vivo mutagenicity assay system using a lacZ-transgenic mouse (Muta Mouse). Mutation was induced by quinoline and 5-FQ only in the liver, the target organ of carcinogenesis by quinoline, but not in the other organs examined. 3-FQ was non-mutagenic in all of the organs. The results strongly indicate that fluorine-substitution at the position-3 of quinoline could be an anti-genotoxic structural modification of quinoline in a wide range of its genotoxic end-points. Additionally, seventeen mono- and di-fluorinated derivatives of 1,7-phenanthroline, 1,10-phenanthroline, benzo[h]quinoline, and benzo[f]quinoline were subjected to analysis of their structure-mutagenicity relationship. The results support that the enamine epoxide structure of the pyridine moiety, as well as the bay-region epoxide structure, is responsible for mutagenicity. These results suggest that the introduction of a fluorine atom to the molecule in question may be a useful tool to modify their mutagenic potency and to better understand the mechanism of mutation.     

Efavirenz related compounds preparation by hydrolysis procedure: setting reference standards for chromatographic purity analysis

A simple procedure for obtaining and purifying two degradation products of efavirenz (amino alcohol and quinoline derivatives) from drug substance hydrolysis is described. These impurities are known to exhibit very different UV absorbance properties from those of the parent compound, making determination using a quantitation factor (QF) inaccurate. The obtained hydrolysis products were characterized by physicochemical methods to assure identity, purity and strength. Quinoline derivative was of high purity degree (100%) and amino alcohol was 98.74% pure. Both were set as reference standards in chromatographic related compounds test for efavirenz drug substance and tablets analyses.     

Quinoline antimalarials

Quinoline antimalarial patents and relevant scientific literature concerning their mechanism of action, mechanism of resistance and structure-function relationships are discussed in this review. The review provides a brief history of current antimalarial drugs and describes some salient features about their use, occurrence of drug resistance, their metabolism and known adverse effects. Recent advances in our understanding of the mechanism of action of 4-aminoquinolines, quinoline methanols and 8-aminoquinolines are discussed as is the current state of knowledge regarding the mechanisms of drug resistance. New insights into structure-function relationships in 4-aminoquinolines, both with respect to activity and resistance, are emphasised. Finally, patents registered since 1997 are described and an expert opinion offered. The review emphasises advances made during the last four years.     

高效毛细管区带电泳检测河豚鱼中河豚鱼毒素

目的建立河豚鱼毒素的测定方法。方法采用毛细管区带电泳法 ,运行缓冲液为 0 .0 7mol L硼酸 0 .0 4mol L硼酸钠 (1∶1) ,pH为 9.0 ,自动气压 4s进样 ,分离电压 :30kV ,检测波长 :2 0 0nm。以硝酸喹啉为内标。结果浓度在 10～ 10 0 μg ml范围内吸收度呈良好线性关系 (r=0 .9988) ,平均回收率为 90 .6 % ,RSD为 3.8% (n =5 )。结论此法简单、准确、方便、取样少 ,可作为河豚鱼毒素中毒诊断的有效手段     

Thermofractography of red cinchona bark and its alkaloids (author's transl)

Thermofractography of Red Cinchona Bark and its Alkaloids Quinine and quinidine as well as cinchonine and cinchonidine sublimate under the conditions of Thermofractography (TFG) without decomposition above 180°. The corresponding salts, e.g. sulfates and tannates split at a temperature range of above 220° into likewise blue fluorescent derivatives. These fission products are also obtained on heating the drug (GRAHE's tar test). Quinoline and lepidine are formed in particular as main products from cinchonine- and cinchonidine salts besides small amounts of 4-ethylquinoline and 4-propylquinoline. Mainly 6-methoxyquinoline and 6-methoxylepidine are yielded, and minor amounts of the corresponding 6-hydroxyderivatives from quinine- and quinidine salts. None of these characteristic quinoline derivatives is obtained through fragmentation with 70 eV in a mass spectrograph.     

Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold

One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M(1) muscarinic receptor. A number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M(2) to M(5) subtypes. One strategy to confer selectivity for M(1) is the identification of positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M(1) positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.     

The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types

The impact of carboaromatic, heteroaromatic, carboaliphatic and heteroaliphatic ring counts and fused aromatic ring count on several developability measures (solubility, lipophilicity, protein binding, P450 inhibition and hERG binding) is the topic for this review article. Recent results indicate that increasing ring counts have detrimental effects on developability in the order carboaromatics?heteroaromatics>carboaliphatics>heteroaliphatics, with heteroaliphatics exerting a beneficial effect in many cases. Increasing aromatic ring count exerts effects on several developability parameters that are lipophilicity- and size-independent, and fused aromatic systems have a beneficial effect relative to their nonfused counterparts. Increasing aromatic ring count has a detrimental effect on human bioavailability parameters, and heteroaromatic ring count (but not other ring counts) has increased over time in marketed oral drugs.     

An overview of quinoline as a privileged scaffold in cancer drug discovery

Introduction: The concept of privileged structures is well known and is often used in the process of drug design and development. Although its assumptions are not clear, its overall usefulness remains high. Various substructures have been identified as privileged and quinoline is a prime example of such a structure.

Areas covered: Quinoline drugs that are currently approved or under clinical investigation were reviewed based on a literature search. Their modes of action and outcomes during clinical research are discussed.

Expert opinion: Undoubtedly, quinoline-based compounds have a significant impact on anticancer drugs. Although topoisomerase and kinase inhibitors are the only two different classes of agents that are currently approved for anticancer therapy, more than twenty different drug candidates are being tested on humans. The quinoline moiety offers an easily accessible, well-understood scaffold for designing new drugs. It is also a very druggable molecule with the potency for structure optimization through established synthetic pathways. For these reasons, quinoline-based anticancer drugs have a strong position in modern medicinal chemistry.     

Cyclisierungen von N-(2-Phenylethyl)-2-(2-hydroxyethyl)-benzamiden

Cyclisation of N-(2-Phenylethyl)-2-(2-hydroxyethyl)benzamides The cyclisation of the hydroxyamides 3 according to Bischler-Napieralski proceeds in three ways depending on the substituents at the aromatic rings: The amides 3c and 3d , the phenylethylamine parts (ring A) of which are not activated, close only ring C. The amide 3b , which is activated in ring A but - with regard to nucleophilic attack - deactivated in ring D (lactone part), closes ring B, too, after ring C has been closed. Finally, with 3a activated in ring A only, Bischler-Napieralski cyclisation (formation of ring B) takes place first and intramolecular N-alkylation (formation of ring C) follows.