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硬度,化学势,电负性各种参数[1]

硬度,化学势,电负性各种参数[1]
硬度,化学势,电负性各种参数[1]

Synthesis,inhibitory activities,and QSAR study of xanthone derivatives as a -glucosidase inhibitors

Yan Liu,Zhuofeng Ke,Jianfang Cui,Wen-Hua Chen,Lin Ma,Bo Wang *

School of Chemistry &Chemical Engineering,Sun Yat-sen University,Guangzhou 510275,PR China

a r t i c l e i n f o Article history:

Received 28April 2008Revised 21June 2008Accepted 24June 2008

Available online 26June 2008

Dedicated to the honor and memory of late Professor Botao Fan in recognition of his encouragement.Keywords:

Xanthone derivatives a -Glucosidase Inhibitory activity QSAR

a b s t r a c t

Xanthones and their derivatives have been reported to exhibit strong inhibitory activities toward a -glu-cosidase.To provide deep insight into the correlation between inhibitory activities and structures of xant-hones,multiple linear regression (MLR)method was employed to establish QSAR models for 43xanthone derivatives that have diverse structures.Among the 38typical descriptors investigated,Hs (number of H-bond forming substituents),N p (number of aromatic rings),and S (softness value)can be utilized to model the inhibitory activity.Thus,inhibitory activities of xanthone derivatives can be regulated by H-bond forming substituents,p -stacking-forming aromatic rings and softness values on the xanthone skel-eton.The accuracy and predictive power of the proposed QSAR model were veri?ed by LOO validation,Y-randomization,and test group validation with newly synthesized xanthone derivatives.

ó2008Elsevier Ltd.All rights reserved.

1.Introduction

Modern diseases,such as diabetes,HIV,and cancers are increasingly threatening the public health,therefore ?nding ef?-cient therapy for these diseases is becoming one of the major goals in modern medicinal chemistry.It is well known that a -glucosidase (EC 3.2.1.20)is a key enzyme that is involved in these diseases,1–6and therefore many efforts have been made in the design and synthesis of agents that are capable of inhib-iting a -glucosidase.7–15Such agents would have potential appli-cations,for example,in developing chemotherapeutic agents for clinic use in the treatment of these diseases.However,tradi-tional trials and error approaches that are used in the discovery of new drugs are time-consuming and costly.To ameliorate this,one practical approach that may be used to rapidly discover more effective drug candidates is to structurally modify natural products whose activities are well established,and then to apply statistic analytical methods (e.g.,the well-known quantitative–structure activity relationship (QSAR)study)to establish correla-tions between chemical structures and the corresponding biolog-ical activities.16–18

As part of our projects to construct small organic molecules targeting biomacromolecules,we have keenly become interested

in the design and synthesis of xanthone-based a -glucosidase inhibitors.Xanthones represent a class of naturally occurring compounds that are widely distributed in nature 19–21and exhibit various pharmacological properties such as antioxi-dant,22,23antimalarial 24and anti-in?ammatory activities,25inhibition of a variety of tumor cell lines’growth,26–28and modulation of PKC isoforms.29Noticeably,recent studies by us 30,31and others 32–35have indicated that xanthones and their synthetic derivatives are capable of inhibiting a -glucosidase.We found that the inhibitory activities toward a -glucosidase of synthetic xanthones could be largely improved by attaching H-bond forming substituents or extending the p -conjugated sys-tems.30,31More recently,Seo et al reported that naturally occurring xanthones from Cudrania tricuspidata displayed potent a -glucosidase inhibition.35These studies have indicated that xanthones are attractive as a versatile platform for the develop-ment of a new class of a -glucosidase inhibitors,and also spurred major efforts aimed at clarifying the structure–activity correlation that can be used to guide the discovery of potent inhibitors for medical use.

Herein,we describe an unprecedented QSAR study on a series of xanthone derivatives X 1–43(Chart 1)with the aim to provide comprehensive insight into the correlation between structures and inhibitory activities of xanthones.Speci?cally,multiple lin-ear regression (MLR)method is employed to establish QSAR models for a training set of compounds X 1–34that have known

0968-0896/$-see front matter ó2008Elsevier Ltd.All rights reserved.doi:10.1016/j.bmc.2008.06.043

*Corresponding authors.Tel.:+862084113083;fax:+862084112245.E-mail address:ceswb@https://www.sodocs.net/doc/9e15483597.html, (B.Wang).Bioorganic &Medicinal Chemistry 16(2008)

7185–7192

Contents lists available at ScienceDirect

Bioorganic &Medicinal Chemistry

j o u r n a l h o m e p a g e :w w w.e l s e v i e r.c o m /l o c a t e /b m

c

inhibitory activities,and then the QSAR model is used to predict the inhibitory activities of X35–43that will be synthesized as test group.The potential of the QSAR model in guiding future effort in the rational design and synthesis of xanthone derivatives that potentially have high-inhibitory activities toward a-glucosidase is brie?y discussed.2.Material and method

2.1.Dataset

In this QSAR study,compounds X1–34from our recent work30,31 serve as training set to build the QSAR models,whereas newly syn-

7186Y.Liu et al./Bioorg.Med.Chem.16(2008)7185–7192

thesized X35–43act as test set to evaluate the predictive ability of the established QSAR models.In order to model and predict the inhibitory activities with accuracy,38descriptors(Table1)includ-ing electronic,constitutional,steric,topological,and physicochem-ical parameters were taken into account as inputs to the model building.

Electronic descriptors1–7were obtained from quantum chem-ical calculations.These global electronic descriptors that are de-?ned on the basis of density functional theory,such as hardness (g),chemical potential(l),softness(S),electrophilicity index(x), and electronegativity(v)36–38have been widely used in SAR/QSAR investigations.39–41All the compounds were fully optimized at the density functional theory(DFT)/B3LYP level of theory,42,43together with the6-31G*basis set.The most stable geometries of each com-pound were con?rmed by frequency analysis,in which no imagi-nary frequency was found for all the minima.All the calculations were performed by using the Gaussian03package of pro-grams.44Using Koopmans’theorem for closed-shell molecules, these electronic descriptors were obtained from the following equations:

I?àe HOMO and A?àe LUMOe1T

g%1

2ee LUMOàe HOMOT?

1

2

eIàATe2T

l%1

2ee LUMOte HOMOT?à

1

2

eItATe3T

S?1=e2gTe4Tv?eItAT=2e5Tx?l2=e2gTe6TIn addition,we have shown in the previous study30,31that(1)xan-thone derivatives having extended p-conjugated systems show greatly improved inhibitory activities most probably through en-hanced p-stacking interaction,and(2)H-bond donating/accepting substituents make greater contribution to the inhibition process than those that can only act as H-bonding acceptors.Therefore, we introduced herein two constitutional descriptors:(1)N p,the number of aromatic rings in the skeleton of the to eval-uate the weight of the possible p-stacking interaction;and(2)Hs, the number of H-bonding substituents,which is de?ned as the fol-lowing equation:

Hs?mtn=2e7Twherein m and n are the numbers H-bond donating/accepting and accepting substituents,respectively.All the other representa-tive29descriptors,including steric,topological,and other physico-chemical parameters,were calculated with Chem3D Ultra(version 8.0)built-in models.

2.2.Stepwise multiple linear regression

The elimination selection-stepwise regression(ES-SWR)vari-able selection method was used to select the most appropriate descriptors.By the combination of forward selection and backward elimination,the independent variables were individually added to or deleted from the model at each step of the regression based on three criteria:correlation coef?cient(R2),Fisher ratio value(F),and standard deviation(SD).The QSAR models are obtained with stan-dardized data of descriptors.

2.3.Cross-validation technique

Since a high-correlation coef?cient only indicates how well the equations?t the data,cross-validation procedure was carried out in order to explore the reliability of the proposed models.In this aspect,the well-known‘‘leave-one-out”(LOO)approach was used in which a number of models were developed with one sample ig-nored each time.Then,the ignored data were predicted by each model and the differences between predicted and observed activity values were evaluated.The LOO cross-validation coef?cient Q2that is given by Eq.8was used as an indicator of the predictive perfor-mance and stability of a model.In general,LOO cross-validated coef?cient Q2being higher than0.5can be considered as a statisti-cal proof of the high-predictive ability.45

Q2?1à

P n

i?1

ey expày predT2

P

i?1

ey expà yT

e8T

wherein y exp and y pred are the observed and predicted values for the dependent variables,respectively,and y is the average observed value.

2.4.Y-Randomization test

A widely used approach to establish the robustness of a given QSAR model is the so-called Y-randomization.46In this approach, dependent variable vector(inhibitory activity in this study)is ran-domly shuf?ed and a new QSAR model is built using the original independent variables.If the new QSAR models have lower R2 and Q2values for several trials,then the given QSAR model is thought to be robust.

2.5.Estimation of the predictive ability of a QSAR model

As indicated in the literatures,45,47,48high value of cross-valida-tion regression coef?cient appears to be necessary but not the

Table1

Electronic,constitutional,steric,topological,and physicochemical descriptors

ID Description Notation

1LUMO energy LUMO

2HOMO energy HOMO

3Total energy E

4Hardness g

5Softness S

6Electronegativity v

7Electrophilicity x

8Dipole moment Dp

9Melting point MP

10Boiling point BP

11Critical pressure Pc

12Critical temperature Tc

13Critical volume Vc

14Principal moment of inertia X PMIX

15Principal moment of inertia Y PMIY

16Principal moment of inertia Z PMIZ

17Molar refractivity MR

18Henry’s law constant HLC

19Molecular weight MW

20log P log P

21Partition coef?cient(octanol water)Clog P

22Number of H-bonding substituents Hs

23number of aromatic rings N p

24Heat of formation HOF

25Gibbs energy G

26Repulsion energy Er

27Balaban index BIndx

28Cluster count ClsC

29Diameter Diam

30Molecular topological index TIndx

31Radius Rad

32Shape attribute ShpA

33Shape coef?cient ShpC

34Sum of degrees SDe

35Sum of valence degrees SVDe

36Total connectivity Tcon

37Total valence connectivity TVCon

38Wiener index Windx

Y.Liu et al./Bioorg.Med.Chem.16(2008)7185–71927187

suf?cient criteria to con?rm the high-predictive power of a QSAR model.Instead,it can only be estimated by an external test group of compounds that are not used in building of the QSAR model.The external R2

CVext

,de?ned in Eq.9by Tropsha and coworkers,45is a convenient criteria to estimate the predictive power of a QSAR model

R2 CVext ?1à

P test

i?1

ey expày predT2

P

i?1

ey expà y trainT

e9T

where y train is the averaged value for the dependent variable for the training set.

All the following criteria should be met for a given QSAR model45:

R2 ext >0:6and R2

CVext

>0:5e10T

eR2

ext àR2

o

T

R2 ext <0:1or

eR2

ext

àR02

o

T

R2

ext

<0:1e11T

0:856k61:15or0:856k061:15e12Twhere R2

ext

refers to the correlation coef?cient between the pre-dicted and observed activities of external compounds.

2.6.Synthesis and biological activities of test group

Compounds X35–43were synthesized to serve as an external test group for the QSAR analysis.The synthetic routes are depicted in Scheme1.Nitration19,25of compounds X2or X27with70%HNO3 in acetic acid gave compounds X35,X39,and X31,49respectively, which were then hydrogenated35,50in the presence of10%Pd–C to give X36,X40,and X41,respectively.Alkylation30,31of X2and X27with1,3-dibromopropane in acetone afforded X37and X42, respectively,treatment of which with K2CO3in DMF gave com-pounds X38and X43,respectively.All these xanthone derivatives were characterized by NMR,mass,IR,and elemental analyses (see Section5).Compounds X35–43statistically represent the distri-bution of data sets,among which X35–X38have three conjugated fused rings;X39–X41,X42,and X43have four extended and conju-gated fused rings;X38and X43have an additional unconjugated ring;X37and X42have a side chain;X35and X39have an additional H-bond accepting substituent NO2and X36,X40,and X41have an additional H-bond donating/accepting substituent NH2.

The inhibitory activities of compounds X35–43toward yeast’s a-glucosidase were evaluated by using similar methods as described in previous studies.30,31The obtained IC50values together with those of compounds X1–34are summarized in Table2.Among the test sets,compound X39has the highest inhibitory activity with IC50being5.9l M,whereas X35has the lowest inhibitory activity with IC50value of235l M.Thus,given the structural diversity and activity range,the design and synthesis of X35–43as the test set was reasonable.

3.Results and discussion

In order to select the predominant descriptors that will affect the inhibitory activities of these compounds,correlation analysis was performed with statistical software SPSS,51taking every calcu-lated descriptor as an independent variable and log(1/IC50)as a dependent variable.Based on the correlation analysis,the afore-mentioned stepwise multiple linear regression technique was used to establish the QSAR model

loge1=IC50T?0:239Hst0:090St0:160N pà1:750

n?34;R2?0:790;Q2?0:733;SD?0:195;

F?37:524;p<0:00001

e13T

wherein n is the number of compounds of training set,compounds X1–34;R2,the correlation coef?cient;Q2,the LOO cross-validated coef?cient;SD,the standard deviation;F,the Fisher’s F-value,and p is the p-value(calculated from F statistics).The predicted values of log(1/IC50)from Eq.13,together with the corresponding residual values are listed in Table2.It can be seen that X9has much higher residual value(0.64)than all the other compounds in training set. Further analysis has indicated that its standardized residual is the highest and greater than two,suggesting that X9is an outlier based on the commonly accepted hypothesis that values of standardized residual above two are characteristic of an outlier.Thus,compound X9was not considered during the course of exploratory data analy-sis.Correspondingly,an alternative QSAR model for the remaining 33compounds was obtained

7188Y.Liu et al./Bioorg.Med.Chem.16(2008)7185–7192

loge1=IC50T?0:261Hst0:122St0:152N pà1:758

n?33;R2?0:872;Q2?0:839;SD?0:154;

F?65:912;p<0:00001

e14T

Generally,a good QSAR model has the feature of large F,small SD, very small p-value,and R2and Q2values that are close to one.Both Eqs.13and14meet these criteria and thus both are statistically acceptable,however,Eq.14has much higher correlation coef?cient R2(0.872)and LOO cross-validated coef?cient Q2(0.839)that is close to R2.Therefore,Eq.14is statistically better,and thus all the discussions that follows will be based on Eq.14.

To establish the robustness,Eq.14was further validated by applying the Y-randomization.Several random shuf?es of the Y vector were performed and the obtained lower R2and Q2values ex-cluded the possibility of chance correlation or structural depen-dency of the training set.

As indicated in Eq.14,the most signi?cant descriptors that af-fect the inhibitory activity are:Hs,the number of H-bonding sub-stituents;S,the softness value and N p,the number of aromatic rings in the skeleton of the xanthones.Their values for all the com-pounds,the predicted values of log(1/IC50),and their correspond-ing residual values,are listed in Table2.In addition,in order to avoid internal correlations,we also performed a correlation analy-sis on these selected descriptors.The obtained correlation matrix (Table3)clearly indicates that the selected descriptors in the QSAR model are in low correlation.

The predictive power of the selected descriptors was explored by external compounds X35–43that were synthesized according to their structural characteristics and biological activity range. With the validation analysis using these compounds,the proposed QSAR model(Eq.14)was proved to meet all the required criteria that are de?ned in Eqs.10–12,that is,R2

ext

?0:825,R2

CVext

?0:735,

eR2

ext

àR2

o

T=R2

ext

?à0:123,eR2

ext

àR02

o

T=R2

ext

?à0:136,k=1.065,and k0=0.911.The observed versus predicted values for all the training and test sets are shown graphically in Figure1.

The aforementioned QSAR model(Eq.14)has clearly indicated that all the three descriptors Hs,N p,and S,have positive correla-tion with the inhibitory activity.This is an interesting observation

Table2

Values of the selected most important descriptors,the experimental/predicted log(1/IC50)values and their corresponding residual values for the training and test set a

Compound IC50Hs N p S Exp.log(1/IC50)Pred.log(1/IC50)

for Eq.13Residual values

for Eq.13

Pred.log(1/IC50)

for Eq.14

Residual values

for Eqs.14

X1177.40.520.124à2.25à2.21à0.04à2.250.00

X2160.8 1.520.118à2.21à1.88à0.33à1.91à0.30

X391.5 1.020.126à1.96à1.980.02à1.990.03

X4131.4 1.520.120à2.12à1.86à0.26à1.88à0.24

X581.8 2.020.121à1.91à1.64à0.27à1.64à0.27

X641.5 2.520.115à1.62à1.52à0.10à1.53à0.08

X714.7 2.520.124à1.17à1.410.24à1.380.21

X817.1 3.020.115à1.23à1.310.08à1.310.07

X931.9 1.020.112à1.50bà2.14b0.64b————

X10138.9 1.020.112à2.14à2.140.00à2.210.07

X1146.5 1.520.115à1.67à1.910.24à1.950.29

X1249.7 2.020.112à1.70à1.740.05à1.780.09

X13172.9 1.020.120à2.24à2.06à0.18à2.10à0.14

X14110.8 1.020.120à2.04à2.050.01à2.100.05

X15130.1 1.020.120à2.11à2.05à0.06à2.09à0.02

X16120.9 1.020.120à2.08à2.05à0.03à2.090.01

X17113.8 1.020.120à2.06à2.050.00à2.090.04

X18123.7 1.020.120à2.09à2.05à0.04à2.090.00

X19115.6 1.020.120à2.06à2.05à0.01à2.090.03

X2098.2 1.020.120à1.99à2.050.06à2.090.10

X2166.6 1.520.119à1.82à1.860.04à1.890.06

X2253.0 1.520.120à1.72à1.860.13à1.880.16

X23115.4 1.020.131à2.06à1.93à0.14à1.92à0.14

X2461.8 1.020.133à1.79à1.900.11à1.880.09

X2563.5 1.520.120à1.80à1.850.05à1.880.07

X26132.7 1.020.130à2.12à1.93à0.19à1.93à0.20

X279.3 1.530.133à0.97à1.330.36à1.330.36

X28 5.8 2.530.141à0.76à0.840.08à0.770.00

X298.0 2.530.139à0.90à0.87à0.03à0.80à0.10

X3031.3 1.030.134à1.50à1.520.02à1.520.03

X3120.1 1.530.134à1.30à1.320.02à1.310.01

X3227.8 2.030.113à1.44à1.36à0.08à1.43à0.02

X3339.9 1.530.126à1.60à1.41à0.19à1.44à0.16

X3434.9 2.030.113à1.54à1.36à0.18à1.42à0.12

X35235.2 1.520.119à2.37———à1.89—à0.48 X36102.3 2.020.120à2.01———à1.66—à0.35 X37146.6 1.020.119à2.17———à2.11—à0.06 X38198.1 1.020.124à2.30———à2.03—à0.27 X39 5.9 1.530.132à0.77———à1.34—0.57 X40 6.3 2.530.133à0.80———à0.89—0.09 X418.3 2.030.133à0.92———à1.11—0.19 X4229.7 1.030.134à1.47———à1.52—0.05 X4367.3 1.030.136à1.83———à1.49—à0.34

a The IC

50

value of each compound was determined against yeast’s a-glucosidase in50mM phosphate buffer(pH6.8)containing5%v/v DMSO at37°C.The experiments were performed in triplicate and repeated at least three times,and the mean values were taken.The data for compounds X1–25and X26–34were selected from Refs.30,31 respectively.

b Compound X

9has the highest standardized residual that is greater than two,and thus was regarded as an outlier.

Y.Liu et al./Bioorg.Med.Chem.16(2008)7185–71927189

and may be used to guide future effort in the rational design and synthesis of xanthone derivatives having potentially potent inhib-itory activity.Thus,as already shown in our previous studies,30,31 it may be constantly a practical approach to improve the inhibitory activity by introducing more H-bond forming substituents(such as hydroxyl and amino groups)and/or more aromatic rings onto the skeleton.It is noteworthy that softness value is positively corre-lated with the inhibitory activity.This may be rationalized by tak-ing into account that the good correlation between softness and polarizability makes it easier for a substrate that has higher soft-ness value to deform its electronic cloud,52–54hence leading to stronger binding af?nity toward the enzyme.If that is the case, the inhibitory activity would be expected to be improved by intro-ducing some hetero atoms with high softness onto the skeleton of xanthones.This is currently under investigation,which will be re-ported in due course.

4.Concluding remarks

Strong QSAR model has been successfully established by using MLR for34xanthone derivatives having inhibitory activities to-ward a-glucosidase.Its predictive power was validated by screen-ing nine external xanthone derivatives that have diverse structures and wide-ranged activity.This,together with the LOO validation and Y-randomization has unambiguously demonstrated the robustness of the QSAR model itself and its power of predicting external data with accuracy.Thus,this QSAR model may be used as an ef?cient tool to predict the inhibitory activities of xanthone derivatives.Among38typical descriptors,three descriptors,Hs, S,and N p can be utilized to model the inhibitory activity.That is, inhibitory activities of xanthone derivatives can be signi?cantly improved by increasing the number of H-bonding substituents, aromatic rings in the skeleton of the xanthone derivatives and softness values onto the xanthone skeleton.Rational design and synthesis of new xanthone derivatives in search of new a-glucosi-dase inhibitors,guided by the QSAR model,is actively under pro-gress in our laboratories.5.Experimental

NMR spectra were recorded on a Varian INOVA300MB NMR spectrometer in either CDCl3or acetone-d6or DMSO-d6,and tetra-methylsilane was used as an internal standard.Mass spectra were measured on a DSQ low resolution mass spectrometer.IR spectra were obtained on a Bruker EQUINOX55Fourier transformation infrared spectrometer.Elemental analyses were carried out on an Elementar Vario EL series elemental analyzer.Melting points were determined on a WRS-1B digital melting point apparatus and were uncorrected.UV spectra were recorded on a Shimadzu UV-3150 scanning spectrophotometer.

p-Nitrophenyl(PNP)glycoside and a-glucosidase(from baker’s yeast)used in this study were purchased from Sigma(St.Louis, MO,USA).All the other reagents were of analytical quality and used as received.

5.1.Synthesis of compounds X35and X39

General procedures:Nitric acid(70%,0.5mL)in acetic acid (5mL)was slowly added to a solution of compound X2or X27 (2mmol)in acetic acid(20mL).The mixture was stirred at60°C for1–4h and then poured into ice-cooled water(200mL).The formed precipitates were?ltered,washed with water,and recrys-tallized from ethanol to give X35and X39as yellow solids, respectively.

5.1.1.1,3-Dihydroxy-4-nitro-9H-xanthen-9-one(X35)

Yield61%from compound X2in1h.Mp227°C(dec);IR(KBr): 3427,2940,1652,1589,1510,1454,1348,1297,1205,1160,1029, 824,756,632cmà1;1H NMR(300MHz,DMSO)d:13.44(s,1H, ArOH),11.34(br s,1H,ArOH),8.25(dd,J=8.1,1.8Hz,1H,ArH), 7.99–7.93(m,1H,ArH),7.67(d,J=8.1Hz,1H,ArH),7.62–7.56 (m,1H,ArH),6.46(s,1H,ArH);EI-MS m/z(%):273([M]+,100).Anal. Calcd for C13H7NO6:C,57.15;H,2.58;N,5.13.Found:C,57.20;H, 2.45;N,5.22.

5.1.2.1,3-Dihydroxy-2-nitro-12H-benzo[b]xanthen-12-one

(X39)

Yield42%from compound X27in4h.Mp281–283°C;IR(KBr): 3421,3044,1641,1592,1491,1411,1351,1308,1187,876, 744cmà1;1H NMR(300MHz,DMSO-d6)d:13.76(s,2H,ArOH), 8.85(s,1H,ArH),8.25(d,J=8.1Hz,1H,ArH),8.11(s,1H,ArH), 8.06(d,J=8.4Hz,1H,ArH),7.72(t,J=8.1Hz,1H,ArH),7.59(t, J=8.3Hz,1H,ArH),6.54(s,1H,ArH);EI-MS m/z(%):323([M]+, 100).Anal.Calcd for C17H9NO6:C,63.16;H,2.81;N,4.33.Found: C,63.01;H,2.82;N,4.09.

5.2.Synthesis of compounds X36,X40,and X41

General procedures:A solution of X35,X39,or X31(1mmol)in THF(20mL)was hydrogenated in the presence of10%palladium on charcoal(20mg)at room temperature for10h.The catalysts were removed by?ltration and the?ltrates were concentrated to give X36,X40,and X41,respectively,as yellow powders.

5.2.1.4-Amino-1,3-dihydroxy-9H-xanthen-9-one(X36)

Yield81%from compound X35.Mp237°C(dec);IR(KBr):3345, 3277,3073,2922,2851,2668,2544,1665,1614,1521,1465,1393, 1340,1286,1198,1145,1058,940,900,822,754,645cmà1;1H NMR(300MHz,acetone-d6)d:8.20(dd,J=8.4,1.5Hz,1H,ArH), 7.85–7.79(m,1H,ArH),7.52(d,J=8.4Hz,1H,ArH),7.48–7.42 (m,1H,ArH),6.34(s,1H,ArH);EI-MS m/z(%):243([M]+,100).Anal. Calcd for C13H9NO4:C,64.20;H,3.73;N,5.76.Found:C,64.45;H, 3.91;N,5.59.

Table3

Correlation matrix for the selected descriptors in Eqs.13and14

Hs N p S

Hs1

N p0.3111

Sà0.02730.4721

7190Y.Liu et al./Bioorg.Med.Chem.16(2008)7185–7192

5.2.2.2-Amino-1,3-dihydroxy-12H-benzo[b]xanthen-12-one (X40)

Yield59%from compound X39.Mp283–285°C;IR(KBr):3345, 3270,3073,2922,2668,1661,1611,1523,1462,1395,1343,1266, 1197,1140,1058,940,903,821,754cmà1;1H NMR(300MHz, acetone-d6)d:13.78(s,2H,ArOH),8.89(s,1H,ArH),8.25(d, J=7.8Hz,1H,ArH),8.11(s,1H,ArH),8.07(d,J=7.8Hz,1H,ArH), 7.75–7.62(m,1H,ArH),7.57–7.46(m,1H,ArH), 6.61(s,1H, ArH);EI-MS m/z(%):293([M]+,100).Anal.Calcd for C17H11NO4: C,69.62;H,3.78;N,4.78.Found:C,69.41;H,3.65;N,4.97.

5.2.3.4-Amino-1,3-dihydroxy-12H-benzo[b]xanthen-12-one (X41)

Yield75%from compound X31.Mp265–267°C;IR(KBr):3345, 3277,3073,2922,2851,2668,2544,1665,1614,1521,1465,1393, 1340,1286,1198,1145,1058,940,900,822,754,645cmà1;1H NMR(300MHz,acetone-d6)d:13.07(s,2H,ArOH),8.85(s,1H, ArH),8.25(d,J=7.8Hz,1H,ArH),8.11(s,1H,ArH),8.07(d, J=7.8Hz,1H,ArH),7.76–7.63(m,1H,ArH),7.55–7.48(m,1H, ArH),6.33(s,1H,ArH);EI-MS m/z(%):293([M]+,100).Anal.Calcd for C17H11NO4:C,69.62;H,3.78;N,4.78.Found:C,69.91;H,3.63; N,4.77.

5.3.Synthesis of compounds X37and X42

General procedures:To a solution of X2or X27(0.2mmol)and 1,3-dibromopropane(2mmol)in acetone(20mL)was added K2CO3(0.25mmol).The mixture was re?uxed under stirring for 2–4h.After cooling,the mixture was?ltered and the organic?l-trate was concentrated.The crude products were puri?ed by chro-matography on a silica gel column to afford X37and X42, respectively,as yellow solids.

5.3.1.3-(3-Bromopropoxy)-1-hydroxy-9H-xanthen-9-one(X37)

Yield91%from compound X2.Mp124–126°C;IR(KBr):3430, 3091,2924,1661,1610,1570,1507,1470,1437,1364,1303, 1223,1162,1082,825,794,761,673cmà1;1H NMR(300MHz, CDCl3)d:12.83(s,1H,OH),8.22(dd,J=1.5Hz,1.8Hz,1H,ArH), 7.73–7.66(m,1H,ArH),7.42–7.33(m,2H,ArH), 6.42(d, J=2.1Hz,1H,ArH), 6.35(d,J=2.1Hz,1H,ArH), 4.20(t, J=6.0Hz,2H,OCH2),3.61(t,J=6.3Hz,2H,–CH2Br),2.41–2.32 (m,2H,CH2);EI-MS m/z:348([M]+,100),350([M+2]+,100).Anal. Calcd.for C16H13BrO4:C,55.04;H,3.75.Found:C,55.21;H,3.88.

5.3.2.3-(3-Bromopropoxy)-1-hydroxy-12H-benzo[b]xanthen-12-one(X42)

Yield73%from compound X27.Mp190–192°C;IR(KBr): 3431,2941,1646,1595,1509,1470,1447,1346,1252,1166, 1034,821,741cmà1;1H NMR(300MHz,CDCl3)d:12.90(s, 1H,ArOH),8.84(s,1H,ArH),8.04(d,J=8.7Hz,1H,ArH),7.90 (d,J=8.7Hz,1H,ArH),7.81(s,1H,ArH),7.65–7.59(m,1H, ArH),7.53–7.47(m,1H,ArH),6.45(d,J=2.4Hz,1H,ArH),6.34 (d,J=2.4Hz,1H,ArH), 4.24(t,J=6.0Hz,2H,OCH2), 3.63(t, J=6.0Hz,2H,–CH2Br),2.43–2.34(m,2H,CH2);EI-MS m/z:398 ([M]+,100),400([M+2]+,100).Anal.Calcd.for C20H15BrO4:C, 60.17;H,3.79.Found:C,60.29;H,3.78.

5.4.Synthesis of compounds X38and X43

General procedures:To a solution of X37or X42(0.5mmol)in DMF(30mL)was added K2CO3(2.0mmol).The mixture was stir-red at60–80°C for0.5–2h.The reaction mixture was poured into ice-water and then extracted with CHCl3.The crude products ob-tained after removal of the solvent were puri?ed by chromatogra-phy on a silica gel column to afford X38and X43,respectively,as yellow solids.5.4.1.6-Hydroxy-2,3-dihydro-1H-pyrano[2,3-c]xanthen-7-one (X38)

Yield27%from compound X37.Mp182–184°C;IR(KBr):3430, 3076,2925,1660,1614,1569,1465,1403,1370,1310,1227,1148, 1098,953,828,758cmà1;1H NMR(300MHz,CDCl3)d:13.18(s, 1H,OH),8.25(dd,J=8.1Hz,1.8Hz,1H,ArH),7.72–7.66(m,1H, ArH),7.43–7.32(m,2H,ArH),6.37(s,1H,ArH),4.28(t,J=5.1Hz, 2H,OCH2), 2.76(t,J=6.3Hz,2H,Ar-CH2), 2.10–2.01(m,2H, CH2);EI-MS m/z:268([M]+,100).Anal.Calcd for C16H12O4:C, 71.64;H,4.51.Found:C,71.75;H,4.60.

5.4.2.6-Hydroxy-2,3-dihydro-1H,7H-benzo[b]pyrano[3,2-

h]xanthen-7-one(X43)

Yield28%from compound X42.Mp241–243°C;IR(KBr):3430, 2924,1641,1605,1470,1444,1353,1293,1251,1174,1112,958, 829,750,655cmà1;1H NMR(300MHz,CDCl3)d:13.25(s,1H, ArOH),8.82(s,1H,ArH),8.03(d,J=8.7Hz,1H,ArH),7.88(d, J=8.7Hz,1H,ArH),7.78(s,1H,ArH),7.60(t,J=8.7Hz,1H,ArH), 7.48(t,J=8.7Hz,1H,ArH),6.37(s,1H,ArH),4.29(t,J=5.4Hz, 2H,OCH2), 2.76(t,J=6.3Hz,2H,Ar-CH2), 2.10–2.02(m,2H, CH2);EI-MS m/z:318([M]+,100).Anal.Calcd for C20H14O4:C, 75.46;H,4.43.Found:C,75.45;H,4.62.

5.5.Enzyme assays

The inhibitory activities of all the xanthone derivatives were measured by using the methods similar to those described previ-ously.30,31Typically,a-glucosidase activity was assayed in50mM phosphate buffer(pH 6.8)containing5%v/v dimethylsulfoxide and the PNP glycoside was used as a substrate.The inhibitors were pre-incubated with the enzyme at37°C for0.5h.The substrate was then added and the enzymatic reaction was carried out at 37°C for60min.The reaction was monitored spectrophotometri-cally by measuring the absorbance at400nm.The assay was per-formed in triplicate with?ve different concentrations around the IC50values that were roughly estimated in the?rst round of exper-iments,and the mean values were adopted.

Acknowledgment

Z.F.Ke is grateful to the State Scholarship Fund of CSC(No. 2007102840)for?nancial support.

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化学选修三,人教版知识点总结

选修三知识点 第一章原子结构与性质 1能级与能层 ⑴构造原理:随着核电荷数递增,大多数元素的电中性基态原子的电子按右图顺序填入核外电子运动轨道(能级),叫做构造原理。 能级交错:由构造原理可知,电子先进入4s轨道,后进入3d轨道,这种现象叫能级交错。说明:构造原理并不是说4s能级比3d能级能量低(实际上4s能级比3d能级能量高),而

是指这样顺序填充电子可以使整个原子的能量最低。 (2)能量最低原理现代物质结构理论证实,原子的电子排布遵循构造原理能使整个原子的能量处于最低状态,简称能量最低原理。构造原理和能量最低原理是从整体角度考虑原子的能量高低,而不局限于某个能级。 (3)泡利(不相容)原理:基态多电子原子中,一个轨道里最多只能容纳两个电子,且电旋方向相反(用“↑↓”表示),这个原理称为泡利(Pauli)原理。 (4)洪特规则:当电子排布在同一能级的不同轨道(能量相同)时,总是优先单独占据一个轨道,而且自旋方向相同,这个规则叫洪特(Hund)规则 洪特规则特例:当p、d、f轨道填充的电子数为全空、半充满或全充满时,原子处于较稳定的状态。 4.基态原子核外电子排布的表示方法 (1)电子排布式①用数字在能级符号的右上角表明该能级上排布的电子数,这就是电子排布式,例如K:1s22s22p63s23p64s1。 ②为了避免电子排布式书写过于繁琐,把内层电子达到稀有气体元素原子结构的部分以相应稀有气体的元素符号外加方括号表示,例如K:[Ar]4s1。 ③外围电子排布式(价电子排布式) (2)电子排布图(轨道表示式)是指将过渡元素原子的电子排布式中符合上一周期稀有气体的原子的电子排布式的部分(原子实)或主族元素、0族元素的内层电子排布省略后剩下的式子。每个方框或圆圈代表一个原子轨道,每个箭头代表一个电子。如基态硫原子的轨道表示式为 二.原子结构与元素周期表

化学螺栓施工工艺

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人教版高中化学选修三 《电负性》随堂练习

课时训练6电负性 1.下列是几种原子的基态电子排布式,电负性最大的原子是( ) 解析:根据四种原子的基态电子排布式可知,选项A有两个电子层,最外层有6个电子,应最容易得到电子,电负性最大。 答案:A 2.按F、Cl、Br、I顺序递增的是( ) A.外围电子 B.第一电离能 C.电负性 D.原子半径 解析:F、Cl、Br、I的外围电子数相同,故A项错误;从F~I第一电离能依次减小,原子半径依次增大,电负性依次减小,故B、C错误,D正确。 答案:D 3.在以离子键为主的化学键中常含有共价键的成分,下列各对原子形成的

化学键中共价键成分最少的是( ) ,F ,F ,Cl ,O 解析: 所以共价键成分最少的为B项。 答案:B 4.对价电子构型为2s22p5的元素描述正确的是( ) A.原子半径最小

B.原子序数为7 C.第一电离能最大 D.电负性最大 解析:价电子构型为2s22p5,可知该元素是F元素,故可判断只有D正确。原子半径最小的是H;F原子序数是9;第一电离能最大的是He。 答案:D 5.下列各组元素性质的递变情况错误的是( ) 、Be、B原子最外层电子数依次增多 、S、Cl元素最高正价依次升高 、O、F电负性依次增大 、K、Rb第一电离能逐渐增大 解析:根据元素周期律可知,同一周期从左到右原子最外层电子数依次增多、元素最高正价依次升高、元素原子的电负性依次增大,故A、B、C正确;同一主族,从上到下随着电子层数的增加,元素的第一电离能逐渐减小,故D错误。 答案:D 和Y都是原子序数大于4的短周期元素,X m+和Y n-两种离子的核外电子排布

相同,下列说法中正确的是( ) 的原子半径比Y小 和Y的核电荷数之差为(m-n) C.电负性:X>Y D.第一电离能:XY,原子半径:X>Y,X和Y的核电荷数之差为(m+n)。X比Y更易失电子,第一电离能:X

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