Antiplatelet α-Methylidene-γ-butyrolactones: Synthesis and evaluation of quinoline,flavone, and xanthone derivatives

As a continuation of our previous studies on the synthesis and antiplatelet activity of coumarin derivatives of α-methylidene-γ-butyrolactones, certain quinoline, flavone, and xanthone derivatives were synthesized and evaluated for antiplatelet activity against thrombin (Thr)-, arachidonic acid (AA)-, collagen (Col)-, and platelet-activating factor (PAF)-induced aggregation in washed rabbit platelets. These compounds were synthesized from quinolin-8-ol, flavon-7-ol, and xanthon-3-ol, respectively, via alkylation and Reformatsky-type condensation (Schemes 1–3). By the comparison with comparison with coumarin α-methylidene-γ-butyrolactone 3a , flavone and xanthone derivatives, 3b and 3c , respectively, are more selective in which only AA- and collagen-induced aggregation are strongly inhibited. Most of the quinoline derivatives ( 9a–e ) exhibited broad-spectrum antiplatelet activities.     

6-取代氨基-2-烷硫基腺苷化合物的合成及抗血小板凝聚活性

以鸟苷(1)为原料, 经过糖环保护得到2',3',5'-三-O-乙酰基鸟嘌呤核苷(2), 化合物2与三氯氧磷反应得到2-氨基-6-氯-9-(2',3',5'-三-O-乙酰基-β-D-呋喃核糖基)嘌呤(3), 化合物3经重氮化后再与二烷基二硫醚反应得到2-烷硫基-6-氯-9-(2',3',5'-三-O-乙酰基-β-D-呋喃核糖基)嘌呤(4a~4d), 化合物4a~4d与胺进行亲核取代反应后, 脱去糖环保护得到12个新型的6-取代氨基-2-烷硫基腺苷化合物(5a~5l). 采用¹H NMR, ¹³C NMR, IR和高分辨质谱(HRMS)对目标化合物的结构进行了确证, 并对所有化合物进行了体外抗血小板聚集活性测试. 结果表明, 当测试浓度为10 μmol/L时, 化合物5a~5l仍具有一定的抗凝活性, 其中, 6-(3-苯基丙基)氨基-2-丙硫基腺苷(5d)活性最为显著, 抑制率可达90.2%.     

Synthesis of Coumarin Derivatives as Inhibitors of Platelet Aggregation

In a search for the inhibitors of platelet aggregation, certain coumarin derivatives were synthesized and evaluated for antiplatelet activity against thrombin(Thr)-, arachidonic acid(AA)-, collagen(Col)-, and platelet-activating-factor(PAF)-induced aggregation in washed rabbit platelets. These compounds were synthesized from 4-hydroxycoumarin ( 1 ) or naphthalen-1-ol via alkylation and Reformatsky-type condensation (Schemes 1–3). Among them, 4-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenylfuran-2-yl)methoxy]-2H-1-benzopyran-2-one ( 6b ) showed potent antiplatelet effects on AA- and PAF-induced aggregation with IC₅₀ values of 8.21 and 103.67 m?M , respectively (see Tables 1 and 2). The antiplatelet potency of 6b against PAF-induced aggregation could be further improved by introducing a proper substituent at the 2-phenyl group of the lactone ring.     

Synthesis and Evaluation of α-Methylidene-γ-butyrolactone bearing flavone and xanthone moieties

In a search for inhibitors of platelet aggregation, a number of α-methylidene-γ-butyrolactones 5 and 6 bearing flavone or xanthone moieties, respectively, were synthesized and evaluated for their antiplatelet activity against thrombin(Thr)-, arachidonic-acid(AA)-, collagen(Col)?, and platelet-activating-factor(PAF)-induced aggregation in washed rabbit platelets. These compounds were synthesized from 7-hydroxyflavone ( 1 ) or 3-hydroxyxanthone ( 2 ) via O-alkylation (→ 3 and 4 , resp.) and Reformatsky-type condensation (Scheme). Most of the flavone-containing α-methylidene-γ-butyrolactones 5a – d showed potent antiplatelet effects on AA- and Col-induced aggregation, while xanthone derivatives 6c – e were found to have the same pharmacological profile than aspirin in which only AA-induced aggregation was inhibited (Table 1). However, 6c – e were approximately three to ten times more potent than aspirin (Table 2). For the vasorelaxing effects, 5a was the only compound which exhibited significant inhibitory activity on the high-K⁺ medium, Ca²⁺-induced vasoconstriction (Table3). Both 5a and 6a , with an aliphatic Me substituent at C(γ) of the lactone, were active against norepinephrine-induced phasic and tonic constrictions while their γ-aryl-substituted counterparts 5b – f and 6b – f were inactive.     

Synthesis and Pharmacological Evaluation of Novel Pyrazolyl Piperidine Derivatives as Effective Antiplatelet Agents

The synthesis and antiplatelet activity of substituted pyrazolyl piperidine derivatives ( 3a–n ) are described. These compounds were synthesized by an improved ring opening reaction of 2‐arylidene quinuclidinone using hydrazine hydrate under mild conditions. They were characterized and screened for their in vitro antiplatelet profile in human platelet aggregation using adenosine diphosphate as agonist. Investigation of structure activity relation revealed interesting results. Among these synthesized derivatives ( 3a–n ), compounds 3a , 3c , 3j , and 3l exhibited excellent activity, while 3c was the most potent one. Based on IC₅₀ values, it was observed that most of the compounds possessed antiplatelet aggregation activity superior to the reference drug Aspirin.     

Studies on Triterpenoid Glycosides from Rhizomes of Panacis majoris and Their Antiplatelet Aggregation Activity

A new triterpenoid glycoside(1) and seven known triterpenoid glycosides, pseudoginsenoside RT2(2), yesanchinoside R2(3), vinaginsenoside R13(4), vinaginsenoside R8(5), notoginsenoside E(6), 6'-O-acetylginsenoside Re(7), 6"-O-acetylginsenoside Rb₁(8), were isolated from the rhizomes of Panacis majoris. The new triterpenoid glycoside was elucidated as 3-O-[β-D-glucopyranosyl-(1→2)-β-D-(6'-O-ethyl)-glucuronopyranosyl]-oleanolic acid-28-O-β-D-glucopyranoside by extensive spectroscopic and phytochemical methods. Compounds 2-8 were obtained from the plant for the first time. Compounds 3 and 4 displayed good activities against adenosine diphosphate (ADP)-induced platelet aggregation, and compounds 1, 5, 6 and 8 showed moderate activities. Compound 6 exhibited moderate antiplatelet aggregation activity induced by arachidonic acid(AA).     

Preparation and antiplatelet activity of glycidic acid derivatives

Arylalkanoic acid derivatives exhibit a variety of biological effects. In the current publication some of new glycidic acid derivatives were prepared via the Darzens condensation. The synthetic approach, analytical and spectroscopic data of all newly synthesized compounds are presented. The prepared compounds were evaluated as potential inhibitors of arachidonic acid-induced platelet aggregation and their activity was compared with that of acetylsalicylic acid as the standard. (±)-Ethyl 3-{4-[(4-methoxyphenyl)sulfanyl]phenyl}-3-methyl-cis-oxirane-2-carboxylate (IC₅₀ = 0.07 mmol L⁻¹) and (±)-3-{4-[(4-methoxyphenyl)sulfanyl]phenyl}-3-methyl-cis-oxirane-2-carboxylic acid (IC₅₀ = 0.06 mmol L⁻¹) showed the highest antiplatelet activity against arachidonic acid-induced platelet aggregation comparable with the standard. Structure-activity relationships between the chemical structure, lipophilicity, and the antiplatelet activity of the evaluated compounds are discussed.     

Prenylated flavonoids with PTP1B inhibitory activity from the root bark of Erythrina mildbraedii

Phytochemical study on an EtOAc-soluble extract of the root bark of Erythrina mildbraedii resulted in the isolation of six prenylated flavonoids 1-6. Based on physicochemical and spectroscopic analyses, their structures were determined to be new natural products licoflavanone-4'-O-methyl ether (1), 2',7-dihydroxy-4'-methoxy-5'-(3-methylbut-2-enyl)isoflavone (2), and (3R)-2',7-dihydroxy-3'-(3-methylbut-2-enyl)-2',2'-dimethylpyrano[5',6' :4',5']isoflavan (3), along with three known compounds erythrinin B (4), abyssinin II (5), and parvisoflavone B (6). All the isolates, except for compound 4, inhibited PTP1B activity in vitro with IC(50) values ranging from 5.3 to 42.6 microM. This result further suggests that the prenyl group on the B ring of flavonoids plays an important role in suppressing the enzyme PTP1B.     

Antiplatelet aggregation coumarins from the leaves of Murraya omphalocarpa

Using a bioactivity-guided fractionation method, two coumarins: minumicroline acetonide (1) and epimurpaniculol senecioate (2), were isolated from the leaves of Murraya omphalocarpa Hayata (Rutaceae). Compound 1 had been previously synthesized and was now isolated from natural sources for the first time, and compound 2, possessing a negative optical rotation value, is new. The structures and their stereochemistry were fully elucidated on the basis of spectroscopic and X-ray crystallographic techniques. Both compounds 1 and 2 are active in the antiplatelet aggregation assay. Interestingly, the possible acetonide artifact 1 displayed significant antiplatelet aggregation induced not only by AA and collagen but also by platelet activating factor (PAF).     

Novel non-peptide GPIIb/IIIa antagonists: synthesis and biological activities of 2-[4-[2-(4-amidinobenzoylamino)-2-(substituted)acetyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyl] acetic acids

To improve the in vitro and in vivo potency of our first low molecular weight GPIIb/IIIa antagonist 1 (TAK-029), a series of 2-[4-[2-(4-amidinobenzoylamino)-2-(substituted)acetyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiper-azinyllacetic acids were synthesized through modification of the glycine moiety of 1 and evaluated for their ability to inhibit in vitro adenosine 5'-diphosphate (ADP)-induced platelet aggregation of guinea pig platelet rich plasma (PRP). Among the compounds examined, the (3S,2S)-4-methoxyphenylalanine derivative 4h showed the most potent antagonistic activity with an IC50 value of 13 nM. Dose-dependent inhibition of ex vivo platelet aggregation was achieved with oral administration of 4h (0.3-1.0 mg/kg) to guinea pigs. Complete inhibition was observed for up to 8 h, and 43% inhibition could still be observed 24 h after oral administration of 1.0 mg/kg. The long-lasting antiplatelet effect of 4h suggests that 4h would be suitable for once-a-day dosing. Structure-activity relationships (SAR) were examined in the series of the phenylalanine derivatives. An increase in the electron density around the 4-position of the phenyl ring of the phenylalanine moiety led to an increase in the antiplatelet activity, suggesting the existence of a hydrophobic and electrostatic interaction site in addition to the ionic binding sites in the GPIIb/IIIa.     

Synthesis and in vitro activities on anti-platelet aggregation of N,N’-di(2-substituted-phenyl)-4-methoxyisophthalamides and benzene- 1,3-disulfonamides

On the propose of searching for the SAR and obtaining novel antiplatelet aggregating drugs,we have described the synthesis procedure and the activities in vitro on antiplatelet aggregation of two series of derivatives,which contain both 18 N.N’-di(2- substitutedphenyl)-4-methoxyisophthalamides(2a-2r) of the 2 series and nine N,N’-di(2-substitutedphenyl)-4-methoxybenzene- 1,3-disulfonamides(3a-3i) of the 3 series.The results showed that three compounds 2e,2i and 3g emerged as significant activities of antiplatelet aggregation,superior to two reference drugs picotamide and aspirin,and eight compounds 2j,2k,21,2o,2p,2q,2r and 3i merely superior to picotamide.The preliminary SAR shows that it is favorable for the 2 series to increase the activities via the steric hindrance substituents attached to the two side chain benzene rings at 2-positions.And the arylamides of the 2 series have better the activity values than the arylsulfonamides of the 3 series respective except for 3b and 3g.On the contrary,electrostatic factors would not contribute evidently to the activities of the two series.The structures of 15 compounds newly synthesized have been established by MS and ~1H NMR and been first reported in this paper.     

Constituents from Rubia Ustulata Diels and R. Yunnanensis Diels and Their Antiplatelet Aggregation Activity

A new anthraquinone glycoside, rubiayannone‐A ( 1 ), and a new coumarin, rubilatin‐A ( 2 ), together with twenty‐two known compounds were isolated and characterized from the roots of Rubia ustulata. A new anthraquinone, 2‐carbomethoxyanthraquinone ( 3 ), and rubiayannone‐A, 2‐formylanthraquinone were obtained from the roots of R. yunnanensis. The structures of those compounds were elucidated by spectroscopic methods. The antiplatelet aggregation activity of the isolated compounds 1, 4～6 were also discussed.     

New stilbenoids from Pholidota yunnanensis and their inhibitory effects on nitric oxide production

Six new stilbenoids, a (bibenzyldihydrophenanthrene) ether designated phoyunnanin D (1), a bis(dihydrophenanthrene) ether designated phoyunnanin E (2), and four stilbenes designated phoyunbene A-D (3-6), were isolated from the air-dried whole plant of Pholidota yunnanensis ROLFE. The new compounds were identified as 7-[2-(3-hydroxyphenethyl)-4-hydroxy-6-methoxyphenoxy]-4-hydroxy-2-methoxy-9,10-dihydrophenanthrene (1), 1-[(9,10-dihydro-4-hydroxy-2-methoxy-7-phenanthrenyl)oxy]-4,7-dihydroxy-2-methoxy-9,10-dihydrophenanthrene (2), trans-3,3'-dihydroxy-2',4',5-trimethoxystilbene (3), trans-3,4'-dihydroxy-2',3',5-trimethoxystilbene (4), trans-3,3'-dihydroxy-2',5-dimethoxystilbene (5), and trans-3-hydroxy-2',3',5-trimethoxystilbene (6) based on spectroscopic evidence. Furthermore, the inhibitory effects of compounds 1-6 on nitric oxide production in a murine macrophage-like cell line (RAW 264.7) activated by lipopolysaccharide and interferon-gamma were examined.     

Phenolic chemical composition of Petroselinum crispum extract and its effect on haemostasis

From the aqueous extract (Pc) of Petroselinum crispum (Mill) flat leaves specimens were isolated and identified the flavonoids apigenin (1), apigenin-7-O-glucoside or cosmosiin (2), apigenin-7-O-apiosyl-(1 --> 2)-O-glucoside or apiin (3) and the coumarin 2",3"-dihydroxyfuranocoumarin or oxypeucedanin hydrate (4). The inhibitory activity toward clotting formation and platelet aggregation was assessed for Pc flavonoids (1) and (2), and the coumarin (4). Pc showed no inhibition on clotting activity when compared with the control. On the other hand, a strong antiplatelet aggregation activity was observed for Pc (IC50 = 1.81 mg/mL), apigenin (IC50 = 0.036 mg/mL) and cosmosiin (IC50 = 0.18 mg/mL). In all cases ADP was used as inductor of platelet aggregation. Our results showed that Pc, apigenin and cosmosiin interfere on haemostasis inhibiting platelet aggregation. To the best of our knowledge this is the first report for the cosmosiin antiplatelet aggregation in vitro activity.     

哌啶并[2,3-b]哌嗪类衍生物的设计、合成及其抗血小板聚集活性研究

以2,3-二氨基吡啶和2,3-丁二酮为起始原料,经环化、催化氢化和亲核取代反应合成了10个新型哌啶并[2,3-b]哌嗪类衍生物(3a~3j),其结构经¹H NMR、¹³C NMR和HR-MS确证。体外抗血小板聚集活性研究表明,化合物3d、3e、3g、3h和3j具有一定的抗血小板聚集作用,其中化合物3h(IC₅₀=1.24mmol/L)的活性显著优于母体化合物川芎嗪(IC₅₀=3.96mmol/L)和阳性药物阿司匹林(IC₅₀=2.41mmol/L)。     

Antiangiogenic polyketides from Peperomia dindygulensis Miq

Two new polyketides: 2Z-(heptadec-12-enyl)-4-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (1) and 2-(heptadec-12-enyl)-5-hydroxy-5,6,7,8-tetrahydrochromen- 4-one (2), together with eleven known compounds: 4-hydroxy-2-[(3,4-methylenedioxy- phenyl)tridecanoyl] cyclohexane-1,3-dione (3), oleiferinone (4), 4-hydroxy-2-[(3,4- methylenedioxyphenyl)undecanoyl]cyclohexane-1,3-dione (5), 4-hydroxy-2-[(11-phenyl- undecanoyl)cyclohexane-1,3-dione (6), proctorione C (7), surinone C (8), 5-hydroxy- 7,8,4'-trimethoxyflavone (9), 5-hydroxy-7,8,3',4'-tetramethoxyflavone (10), 5-hydroxy- 7,3',4'-trimethoxyflavone (11), 5,8-dihydroxy-7,3',4'-trimethoxyflavone (12) and cepharanone B (13) were isolated from the whole plant of Peperomia dindygulensis Miq. Their structures were elucidated by spectroscopic methods, including 2D-NMR techniques. Compounds 2, 3, 5 and 8 inhibited human umbilical vein endothelial cell (HUVEC) proliferation and compounds 5 and 8 sharply suppressed HUVEC tube formation.     

Design, Synthesis, and Activities of Novel Derivatives of Isophthalamide and Benzene-1, 3-disulfonamide

Introduction Themeritsofantiplatelettherapyforthepreven tionofthrombosisincardiovasculardiseaseareevi dent.Meta analysisresultshaveshownthatsecondary preventionbyantiplateletaggregationagentscanreduce theriskofnonfatalmyocardialinfarction(MI)and strokeby2…     

吡嗪类化合物的合成及其抗血小板凝集活性测试

为提高川芎嗪的抗血小板凝集活性,分别以不同的二胺、2,3-丁二酮和硫辛酸为起始原料,采用溴代、水解、环化、氧化、氢化、取代等反应,通过四条路线合成了7个川芎嗪衍生物,其结构经1H NMR、13C NMR及ESI-MS确证。采用Born比浊法初步测试了化合物的体外抗血小板凝集活性,结果显示,化合物1(IC50=0. 26mmol/L)、2(IC50=0. 27mmol/L)和7(IC50=0. 21mmol/L)对由二磷酸腺苷(ADP)诱导的血小板凝集具有一定的抑制活性,优于先导化合物川芎嗪(IC50=0. 49mmol/L)。因此,在不改变川芎嗪药效团的前提下对其进行不同程度的环化,能明显提高川芎嗪的抗血小板凝集活性,此研究为后期化合物的结构修饰提供了一定的参考价值。     

Anti-Platelet Aggregation and Vasorelaxing Effects of the Constituents of the Rhizomes of<em> Zingiber officinale</em>

In the present study, the chemical investigation of the bioactive fractions of the rhizomes of Zingiber officinale has resulted in the identification of twenty-nine compounds including one new compound, O-methyldehydrogingerol (1). Some of the isolates were subjected into the evaluation of their antiplatelet aggregation and vasorelaxing bioactivities. Among the tested compounds, [6]-gingerol (13) and [6]-shogaol (17) exhibited potent anti-platelet aggregation bioactivity. In addition, [10]-gingerol (15) inhibited the Ca²⁺-dependent contractions in high K⁺ medium. According to the results in the present research, the bioactivity of ginger could be related to the anti-platelet aggregation and vasorelaxing mechanism.