楊亞星，段曉波，段飛，李勝輝，王書香，張金超

(河北大學(xué) 化學(xué)與環(huán)境科學(xué)學(xué)院，河北 保定 071002)

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2,2’-聯(lián)吡啶和三氟甲基修飾β-二酮金屬鈀(Ⅱ)配合物的合成、表征和體外細(xì)胞毒性

楊亞星，段曉波，段飛，李勝輝，王書香，張金超

(河北大學(xué) 化學(xué)與環(huán)境科學(xué)學(xué)院，河北 保定 071002)

以取代苯乙酮、三氟乙酸乙酯及2,2’-聯(lián)吡啶硝酸鈀為原料，經(jīng)Claisen縮合反應(yīng)和螯合反應(yīng)得到了系列三氟甲基修飾的β-二酮金屬鈀(Ⅱ)配合物.配合物結(jié)構(gòu)通過了NMR、ESI-MS、IR及元素分析的表征，用X線單晶衍射測(cè)定了配合物3g的晶體結(jié)構(gòu).用MTT法對(duì)產(chǎn)物的體外細(xì)胞毒性進(jìn)行了評(píng)價(jià).初步結(jié)果表明：所得配合物對(duì)MCF-7細(xì)胞的毒性明顯高于Hela和A549細(xì)胞,其中配合物3a對(duì)MCF-7的細(xì)胞毒性與順鉑相當(dāng).

Pd(Ⅱ)配合物；β-二酮；三氟甲基；聯(lián)吡啶；細(xì)胞毒性

惡性腫瘤嚴(yán)重威脅人類健康和生命，預(yù)防和治療惡性腫瘤已經(jīng)成為人類迫切需要解決的重大問題.化療是目前治療惡性腫瘤最有效的手段之一.自1967年順鉑的抗癌活性被發(fā)現(xiàn)以后，鉑類抗癌藥物的研究與應(yīng)用得到了迅速發(fā)展.如今，順鉑、卡鉑等鉑類藥物已成為癌癥化療中不可缺少的藥物[1].然而，其嚴(yán)重的毒副作用，如腎毒性、耳毒性以及神經(jīng)毒性和本身耐藥性極大限制了該類藥物在臨床上的應(yīng)用[2-5].

鈀和鉑相似或相同的結(jié)構(gòu)特征及其配合物相近的化學(xué)性質(zhì)，使得金屬鈀配合物成為一類新的潛在抗腫瘤藥物[6-9].β-二酮類化合物不僅是合成雜環(huán)化合物的重要中間體，而且是優(yōu)良的金屬萃取劑.同時(shí)，以β-二酮作為O,O-螯合配體構(gòu)建的金屬配合物也體現(xiàn)出不錯(cuò)的抗腫瘤活性[10-17].近年來(lái),吸電子基團(tuán)三氟甲基功能化的β-二酮金屬配合物以其優(yōu)良的脂溶性、高的細(xì)胞攝取及增強(qiáng)的毒性受到人們的廣泛關(guān)注[11-13,17].本文通過Claisen縮合反應(yīng)制備了三氟甲基功能化的β-二酮化合物，并通過與2,2’-聯(lián)吡啶硝酸鈀進(jìn)行配位組裝，得到了系列三氟甲基功能化的β-二酮金屬鈀配合物.在結(jié)構(gòu)表征基礎(chǔ)上，進(jìn)行了體外細(xì)胞毒性及構(gòu)效關(guān)系的研究.

1 實(shí)驗(yàn)部分

1.1 試劑與儀器

XT-4型顯微熔點(diǎn)測(cè)定儀(溫度計(jì)未校正)；AVANCEⅢ 600 MHz NMR超導(dǎo)核磁共振儀(TMS為內(nèi)標(biāo)，DMSO-d6為溶劑，瑞士Bruker公司)；Model-683型紅外光譜儀(KBr壓片，美國(guó)Perkin-Elmer公司)；Apex Ultra 7.0T 型質(zhì)譜儀(瑞士Bruker公司)；Vario EL Ⅲ型元素分析儀(德國(guó)Elementar公司).DMEM培養(yǎng)基，胰蛋白酶以及胎牛血清購(gòu)自Gibco公司；MTT，芐青霉素和鏈霉素購(gòu)自Sigma公司.實(shí)驗(yàn)所用的所有化學(xué)品及試劑均為分析純.

1.2 配合物3a-3g的合成

1.2.1 配合物合成方法

配合物(3a-3g)的合成路線如式1所示.聯(lián)吡啶硝酸鈀(bipy)Pd(ONO2)2的合成參考文獻(xiàn)[18]進(jìn)行.三氟甲基修飾的β-二酮配體(2a-2g)是由取代苯乙酮(1a-1g)與三氟乙酸乙酯通過Claisen縮合反應(yīng)制備[19].將等摩爾的β-二酮配體(2a-2g)與(bipy)Pd(ONO2)2(21.6 mg,0.1 mmol)加入到水-丙酮(體積比為1∶1)溶液中，室溫?cái)嚢? h，然后升溫至50 °C并加入10倍量的KPF6，立即有黃色固體生成，過濾，用少量冷水洗滌，真空干燥，得產(chǎn)物3(3a-3g).

3a:Ar=Ph；3b:Ar=4-CH3C6H4；3c:Ar=4-CH3OC6H4；3d:Ar=4-CH3CH2OC6H4；3e:Ar=3-CH3OC6H4；3f:Ar=3,4-(CH3O)2C6H3；3g:Ar=3,4,5-(CH3O)3C6H2式1 配合物(3a-3g)的合成路線Scheme 1 Synthetic routine of the complexes(3a-3g)

1.2.2 配合物3g的單晶X-ray結(jié)構(gòu)檢測(cè)

單晶結(jié)構(gòu)測(cè)定使用SMARTAPEXⅡ衍射儀(瑞士Bruker公司)，石墨單色器,Mo-Kα射線(λ=0.071 073 nm)，T=296(2)K，采用ω-θ掃描方式.主要原子坐標(biāo)使用SHELXS-97程序由直接法完成，對(duì)全部非氫原子坐標(biāo)及其各向異性熱參數(shù)進(jìn)行了全矩陣最小二乘法修正(F2).所有非氫原子均為理論加氫，利用幾何參數(shù)對(duì)氫原子坐標(biāo)進(jìn)行結(jié)構(gòu)優(yōu)化.配合物3g晶體學(xué)參數(shù)見表1.

表1 3g的晶體學(xué)參數(shù)

1.3 體外細(xì)胞毒性評(píng)價(jià)

1.3.1 細(xì)胞培養(yǎng)及溶液配制

HeLa,A549和MCF-7 3種不同種類癌細(xì)胞系在含有10%的胎牛血清，100u/mL青霉素和100μg/mL鏈霉素的DMEM培養(yǎng)基中孵育(體積分?jǐn)?shù)5%CO2，37 ℃).將化合物在二甲亞砜中溶解，并配制成5mmol/L母液待用；取一定量的上述母液并用不含血清的培養(yǎng)基逐級(jí)稀釋至不同濃度(1.0,10,100 和500μmol/L)，并使DMSO的體積分?jǐn)?shù)低于0.1%.

1.3.2 體外細(xì)胞毒性

取處于對(duì)數(shù)生長(zhǎng)期的HeLa、A549、MCF-7細(xì)胞懸浮液(1.5×104個(gè)/mL)均勻加入到96孔板中(90μL/孔)，于37 ℃， 體積分?jǐn)?shù)5%CO2的培養(yǎng)箱中孵育.待細(xì)胞貼壁后，加入配合物3a-3g溶液(10 μL/孔，每種化合物設(shè)5個(gè)平行)，使其終濃度為0.1、1、10和50 μmol/L，空白對(duì)照組每孔加10 μL不含血清的培養(yǎng)基.48 h后，每孔加入10 μL (5 mg/mL)的MTT儲(chǔ)備液，37 ℃孵育4 h后，棄去培養(yǎng)基，并加入100 μL/孔DMSO，室溫下震蕩10 min，將細(xì)胞產(chǎn)生的甲瓚充分溶解，使用酶標(biāo)儀在570 nm波長(zhǎng)下測(cè)定每孔OD值.根據(jù)公式：(1-ODtreated/ODcontrol)×100%計(jì)算細(xì)胞生長(zhǎng)抑制率，再計(jì)算IC50值.MTT測(cè)定方法如T.Mosmann[20]所述.

2 結(jié)果與討論

2.1 化合物的合成與表征

3a:黃色固體,產(chǎn)率:93%；IR(KBr,cm-1):3 094,1 593,1 567,1 294,1 155,840,765,557；1H NMR(d6-DMSO,600 MHz)δ:8.65(d,J=7.8 Hz,3H),8.49(t,J=7.8 Hz,2H),8.34(br s,1H),8.24(dd,J1=8.4 Hz,J2=0.6 Hz,2H),7.97(br s,2H),7.80(t,J=7.8 Hz,1H),7.62(t,J=7.8 Hz,1H),6.99(s,1H);13C NMR(d6-DMSO,150 MHz)δ:184.06,165.07,154.49,153.68,147.55,145.53,141.60,126.98,124.27,123.35,123.15,116.94,116.85,114.98,112.98,110.29,109.60,93.92；HRMS(ESI):C20H14F3N2O2Pd[M]+計(jì)算值為477.004 5,實(shí)測(cè)值為 477.004 1.化合物C20H14N2F9O2PPd元素分析理論值為C,38.58；H,2.27；N,4.50.實(shí)測(cè)值為 C,38.19；H,2.46；N,4.80.

3b:黃色固體,產(chǎn)率:95%；IR(KBr,cm-1):3 094,2 993,1 587,1 554,1 292,1 155,840,767,557；1H NMR(d6-DMSO,600 MHz)δ:8.61(d,J=7.8 Hz,2H),8.54(br s,1H),8.46(t,J=7.8 Hz,2H),8.25(br s,1H),8.08(d,J=7.8 Hz,2H),7.94(br s,2H),7.34(d,J=8.4 Hz,2H),6.90(s,1H),2.41(s,3H)；13C NMR(d6-DMSO,150 MHz)δ:186.94,167.60(q,2JCF=33.0 Hz),156.05(q,3JCF=4.5 Hz),147.47,147.11,146.53,143.16,130.86,130.35,129.43,128.72,128.61,124.90,117.33(q,1JCF=280.5 Hz),95.71,21.84；HRMS(ESI):C21H16F3N2O2Pd[M]+計(jì)算值為491.020 1,實(shí)測(cè)值為491.020 0.化合物C21H16N2F9O2PPd元素分析理論值為C,39.61；H,2.53；N,4.40.實(shí)測(cè)值為C,39.72；H,2.53；N,4.24.

3c:黃色固體,產(chǎn)率:93%；IR(KBr,cm-1):3 095,2 938,2 853,1 583,1 562,1 276,1 178,840,771,557；1H NMR(d6-DMSO,600 MHz)δ:8.57-8.63(m,2H),8.55(d,J=4.2 Hz,1H),8.46(d,J=7.8 Hz,2H),8.24(d,J=4.2 Hz,1H),8.20(d,J=9.0 Hz,2H),7.93(t,J=6.6 Hz,2H),7.03(d,J=9.0 Hz,2H),6.86(s,1H),3.90(s,3H)；13C NMR(d6-DMSO,150 MHz)δ:185.59,166.68(q,2JCF=33.0 Hz),165.19,156.00,155.91,147.34,147.02,143.14,132.04,128.66,128.52,125.69,124.87,117.39(q,1JCF=282.0 Hz),115.03,95.21,56.26；HRMS(ESI):C21H16F3N2O3Pd[M]+計(jì)算值為507.015 1,實(shí)測(cè)值為507.014 9.化合物C21H16N2F9O3PPd元素分析理論值為C,38.64；H,2.47；N,4.29.實(shí)測(cè)值為C,38.74；H,2.48；N,4.11.

3d:黃色固體,產(chǎn)率:89%；IR(KBr,cm-1):3 095,1 567,1 311,1 263,1 153,842,765,557；1H NMR(d6-DMSO,600 MHz)δ:8.61(t,J=6.0 Hz,2H),8.56(d,J=4.8 Hz,1H),8.47(d,J=7.2 Hz,1H),8.44(d,J=7.2 Hz,1H),8.25(d,J=4.8 Hz,1H),8.19(d,J=9.0 Hz,2H),7.93(t,J=7.2 Hz,2H),7.01(d,J=9.0 Hz,2H),6.86(s,1H),4.17(q,J=7.2 Hz,2H),1.40(t,J=7.2 Hz,3H)；13C NMR(d6-DMSO,150 MHz)δ:185.68,166.64(q,2JCF=33.0 Hz),164.55,156.12,156.01,147.48,147.10,143.11,132.12,128.66,128.52,125.66,124.85,117.46(q,1JCF=280.5Hz),115.38,95.25,64.46,14.86；HRMS(ESI):C22H18F3N2O3Pd[M]+計(jì)算值為521.030 7,實(shí)測(cè)值為521.030 6.化合物C22H18N2F9O3PPd元素分析理論值為C,39.63；H,2.72；N,4.20.實(shí)測(cè)值為C,39.69；H,2.69；N,3.85.

3e:黃色固體,產(chǎn)率:96%；IR(KBr,cm-1):3 111,2 985,2 938,1 585,1 560,1 295,1 253,1 189,842,771,557；1H NMR(d6-DMSO,600 MHz)δ:8.65(d,J=7.8 Hz,2H),8.57(br s,1H),8.48(t,J=7.8 Hz,2H),8.32(br s,1H),7.98(br s,2H),7.78(d,J=7.8 Hz,1H),7.61(s,1H),7.50(t,J=7.8 Hz,1H),7.34(dd,J1=8.4 Hz,J2=2.4 Hz,1H),6.97(s,1H),3.89(s,3H)；13C NMR(d6-DMSO,150 MHz)δ:187.35,166.57(q,2JCF=33.0 Hz),166.35,164.97,155.78,155.69,147.12,146.80,142.92,131.82,128.44,128.30,125.47,124.65,124.62,118.11,116.24(q,1JCF=282.0 Hz),114.81,94.99,56.03；HRMS(ESI):C21H16F3N2O3Pd[M]+計(jì)算值為507.015 1,實(shí)測(cè)值為507.014 7.化合物C21H16N2F9O3PPd元素分析理論值為C,38.64；H,2.47；N,4.29.實(shí)測(cè)值為C,38.76；H,2.41；N,4.14.

3f:黃色固體,產(chǎn)率:95%；IR(KBr,cm-1):3 095,2 946,1 567,1 506,1 274,840,771,557；1H NMR(d6-DMSO,600 MHz)δ:8.65(br s,2H),8.59(br s,1H),8.49(d,J=7.2 Hz,2H),8.31(br s,1H),7.97(br s,2H),7.92(dd,J1=8.4 Hz,J2=1.8 Hz,1H),7.58(d,J=1.8 Hz,1H),7.07(d,J=8.4 Hz,1H),6.93(s,1H),3.91(s,3H),3.90(s,3H)；13C NMR(d6-DMSO,150 MHz)δ:185.63,166.75(q,2JCF=33.0 Hz),156.05,155.25,149.12,147.10,143.17,143.12,128.54,125.84,124.92,124.71,121.42,121.32,118.51,117.48(q,1JCF=280.5 Hz),114.54,111.86,111.16,95.48,56.39,56.13；HRMS(ESI):C22H18F3N2O4Pd[M]+計(jì)算值為537.025 7,實(shí)測(cè)值為537.026 0.化合物C22H18N2F9O4PPd·0.5CH3CN元素分析理論值為C,39.28；H,2.79；N,4.98.實(shí)測(cè)值為C,39.13；H,2.67；N,4.95.

3g:黃色固體,產(chǎn)率:98%；IR(KBr,cm-1):3 095,2 946,1 565,1 498,1 328,1 286,1 218,1 126,844,771,557；1H NMR(d6-DMSO,600 MHz)δ:8.67(d,J=7.2 Hz,2H),8.59(br s,1H),8.50(br s,2H),8.35(br s,1H),7.99(d,J=6.0 Hz,2H),7.39(s,2H),7.01(s,1H),3.94(s,6H),3.81(s,3H)；13C NMR(d6-DMSO,150 MHz)δ:186.34,167.75(q,2JCF=33.0 Hz),156.23,153.26,147.24,147.07,143.89,143.21,128.82,128.60,128.48,124.97,124.94,117.42(q,1JCF=280.5 Hz),106.75,96.23,60.76,56.73；HRMS(ESI):C23H20F3N2O5Pd[M]+計(jì)算值為567.036 3,實(shí)測(cè)值為567.036 1.化合物C23H20N2F9O5PPd·0.5H2O元素分析理論值為C,38.27；H,2.93；N,3.88.實(shí)測(cè)值為C,37.96；H,2.62；N,3.66.

2.2 配合物3g的晶體結(jié)構(gòu)

X線晶體結(jié)構(gòu)分析證實(shí)了配合物3g的分子結(jié)構(gòu).該晶體屬于三斜晶系,P-1空間群.如圖1所示，配合物3g是一個(gè)以鈀(Ⅱ)為中心的離散單核物質(zhì).聯(lián)吡啶和β-二酮配體都是以二齒形式與鈀(Ⅱ)配位.Pd—O鍵長(zhǎng)在0.198 0(2)到 0.200 2(2)nm之間，Pd—N鍵長(zhǎng)在0.199 3(2)到0.199 9(3)nm(表2).N(1)-Pd(1)-N(2)和O(1)-Pd(1)-O(2)2個(gè)平面的角度為2.378(105)°，這表明Pd(1)-O(1)-O(2)-N(1)-N(2)有輕微扭曲.同時(shí)，晶體結(jié)構(gòu)中六氟磷酸根陰離子的出現(xiàn)為配合物存在形式提供了有力證據(jù).

圖1 配合物3g的晶體結(jié)構(gòu)Fig.1 ORTEP type view of the molecular structure of complex 3g with labeled non-H atoms

2.3 體外細(xì)胞毒性

以HeLa、A549和MCF-7為模型,采用MTT法測(cè)定化合物3a-3g以及對(duì)照物順鉑的IC50值，結(jié)果見表3.結(jié)果表明，制得的大部分配合物(3a,3b,3c,3d 和3e)對(duì)MCF-7和Hela細(xì)胞的毒性比對(duì)A549要好一些.對(duì)MCF-7細(xì)胞，配合物3a的細(xì)胞毒性(11.74 μmol/L)與順鉑(11.06 μmol/L)相當(dāng).

新的β-二酮Pd(Ⅱ)配合物構(gòu)效關(guān)系如下：1)對(duì)MCF-7細(xì)胞，苯環(huán)上取代基(甲基、甲氧基和乙氧基)的引入在一定程度上降低了其細(xì)胞毒性.例如，配合物3b-3g的細(xì)胞毒性明顯低于3a.2)對(duì)Hela細(xì)胞，苯環(huán)上的取代基也同樣影響了配合物的細(xì)胞毒性.甲基的引入增強(qiáng)細(xì)胞毒性，而甲氧基的引入反而減小細(xì)胞毒性.例如，3b比3a細(xì)胞毒性更好，而3c-3g的細(xì)胞毒性比3a小.3)對(duì)A549細(xì)胞，配合物3g相對(duì)于3a表現(xiàn)出更好的細(xì)胞毒性.這可能因?yàn)?個(gè)甲基的引入增加了3g的脂溶性，從而導(dǎo)致細(xì)胞攝取增加.該結(jié)果可能對(duì)未來(lái)設(shè)計(jì)新的抗癌藥物具有一定的借鑒意義.

表2 配合物3g的鍵長(zhǎng)(nm)和鍵角(°)

表3 配合物對(duì)MCF-7,Hela 和A549的細(xì)胞毒性

3 結(jié)論

在三氟甲基修飾β-二酮類化合物制備的基礎(chǔ)上，經(jīng)螯合反應(yīng)合成了7種新穎的以2,2’-聯(lián)吡啶與三氟甲基修飾β-二酮為配體的單核Pd(Ⅱ)配合物，采用MTT法對(duì)其體外細(xì)胞毒性進(jìn)行了評(píng)價(jià).配合物3a-3g對(duì)MCF-7,Hela 和A549 3種細(xì)胞系有比較明顯的細(xì)胞毒性.其中，配合物3a對(duì)MCF-7的細(xì)胞毒性與順鉑相當(dāng).三氟甲基的引入賦予金屬鈀配合物優(yōu)良的脂溶性、代謝穩(wěn)定性和較高的細(xì)胞毒性.有關(guān)這些金屬鈀(Ⅱ)配合物的作用機(jī)制尚待進(jìn)一步的研究.研究結(jié)果對(duì)將來(lái)新的金屬抗腫瘤試劑的設(shè)計(jì)、合成具有一定的借鑒意義.

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(責(zé)任編輯：梁俊紅)

Synthesis,characterization and cytotoxicity of palladium(Ⅱ)complexes withβ-diketonate ligands functionalized with trifluoromethyl group and 2,2’-bipyridine

YANG Yaxing,DUAN Xiaobo,DUAN Fei,LI Shenghui,WANG Shuxiang,ZHANG Jinchao

(College of Chemistry and Environment Science,Hebei University,Baoding 071002,China)

A novel series of palladium(Ⅱ)complexes withβ-diketonate ligands functionalized with trifluoromethyl group and 2,2’-bipyridine(bipy)have been synthesized through a directed self-assembly approach that involves spontaneous deprotonation of theβ-diketone ligands in H2O/acetone solution.These complexes have been characterized by elemental analysis,IR,1H NMR,and HRMS.Crystal structure of 3g has been determined by X-ray diffraction analysis.The cytotoxicity was tested by MTT assay.The preliminary results showed that most of the obtained complexes were more toxic against MCF-7 and Hela than A549 cells.The cytotoxicity of complexes 3a is almost equal to that of cisplatin against MCF-7.

palladium(Ⅱ)complexes；β-diketone；trifluoromethyl；bipyridine；cytotoxicity

10.3969/j.issn.1000-1565.2017.02.005

2016-08-23

河北省自然科學(xué)基金資助項(xiàng)目(B2015201213)；河北省應(yīng)用基礎(chǔ)研究計(jì)劃重點(diǎn)基礎(chǔ)研究項(xiàng)目(15962602D)

楊亞星(1990—)，女，河北保定人，河北大學(xué)在讀碩士研究生.E-mail:yangyaxingo@163.com

李勝輝(1972—)，男，河北元氏人，河北大學(xué)教授，主要從事抗腫瘤藥物研究.E-mail:lish@hbu.edu.cn 張金超(1969—)，男，河北衡水人，河北大學(xué)教授，主要從事納米醫(yī)學(xué)研究.E-mail:jczhang6970@163.com

O621

A

1000-1565(2017)02-0134-07