CN107226828B - 一种水溶性羰基铬Fischer卡宾氨基酸钠盐及其制备方法 - Google Patents
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Abstract
本发明公开了一种水溶性羰基铬Fischer卡宾氨基酸钠盐及其制备方法,该化合物的结构式为其中R1代表H或C1~C4烷基,其是由羰基铬的Fischer卡宾和常见氨基酸在三乙胺催化条件下‑10℃反应所得产物经盐酸酸洗、氢氧化钠中和制备而成,制备方法简单,可突破性地改善Fischer卡宾的水溶性、生物相容性、降低分子的毒性,当以水为递质时,在没有光刺激的条件下,也可以自发缓释CO,且半衰其较长,因此在一氧化碳治疗药物领域具有非常广泛的应用前景。
Description
技术领域
本发明属于医药合成技术领域,具体涉及一种离子型水溶性一氧化碳释放分子及其制备方法。
背景技术
一氧化碳(CO)由于其对人体血红蛋白的强结和力,降低了血红蛋白运输氧气的能力,造成机体缺氧窒息死亡,因此,普遍认为是一种高毒致命的气体分子。随着现代生物医学研究技术的发展,临床研究发现CO可以在生物体内通过人体血红素的分解以及其它一系列代谢活动产生,并发挥着重要的生理或病理作用,是一种重要的信使分子。通过CO载体及一氧化碳释放分子(CORMs)可作为解决生理环境下传输CO的新方法。然而,现有大部分CORMs先导结构水溶性较差,需有机溶剂溶解后进行释放CO研究,难以用于以水为介质的生物体系。
天然氨基酸以多种形式存在于生物体内,它是含有酸性的羧基(-COOH)和碱性的氨基(-NH2)的双功能团小分子生物配体,是构成生物体蛋白质、酶类、DAN等生物大分子的基础小分子。采用氨基酸作为过渡金属羰基化合物的配位体,在不同的化学环境中可以采用多种配位模式,可在一定程度上改善此类化合物的水溶性、生物相容性。研究氨基酸配位的金属羰基化合物的性质,将为探索氨基酸和金属离子在生物体内的代谢、吸收、分布及相关生物效应提供依据,研究发现氨基酸在配位化学、生物化学方面也具有非常重要和深远的意义。
Mann小组采用一氧化碳释放分子[Ru(CO)3Cl2]2(CORM-2)与甘氨酸在甲醇溶剂和强碱乙醇钠的作用下制备了三羰基甘氨酸氯化钌(II)配合物(CORM-3),该配合物由天然氨基酸螯合羰基钌构成,具有较好的稳定性和水溶性,并且可以缓释一氧化碳,促进了CO生物医学研究的进展。但CORM-3在纯水中释放半衰期约4d,在生理环境下半衰期降低为20.4min,而在人体血浆中仅为3.6min,CO的生理功能不仅取决于CO释放总量,还与CO动态平衡浓度相关,释放太快会降低其生理作用。另外,Motterlini对CORM-3的一系列生理治疗作用进行了测试,包括抗缺血再灌注再损伤、减轻心血管炎症、抑制同种异体移植排斥反应等生理作用,展现出了过渡金属羰基化合物作为CORM的诱人应用前景。
发明内容
本发明所要解决的技术问题在于克服现有羰基金属存在的水溶性较差的缺点,提供一种稳定较好、毒性较低且具有较好的水溶性和生物相容性、能够实现缓释一氧化碳的水溶性羰基铬Fischer卡宾氨基酸钠盐,以及该化合物的制备方法。
解决上述技术问题所采用的技术方案是该水溶性羰基铬Fischer卡宾氨基酸钠盐的结构式如下所示:
结构式中R1代表H或C1~C4烷基,优选R1代表H、(CH3)2CHCH2、(CH3)2CH、CH3中的任意一种。
上述水溶性羰基铬Fischer卡宾氨基酸钠盐的制备方法为:在无水无氧和惰性气体保护下,以乙醇为溶剂,将式I所示的羰基铬的Fischer卡宾和式II所示的氨基酸、三乙胺按摩尔比为1:(1.1~1.5):(1.5~2.5),-10℃反应5~6小时,反应结束后,旋转蒸发除去乙醇,浓缩产物溶于二氯甲烷后再依次经1mol/L HCl水溶液洗涤、1mol/L NaOH水溶液中和、无水MgSO4干燥,抽滤,滤液经旋转蒸发,得到离子型水溶性Fisher卡宾氨基酸羰基铬化合物,具体反应方程式如下:
本发明的有益效果如下:
1、本发明通过把水溶性较差的羰基铬的化合物制备成钠盐,不仅增加了Fischer卡宾稳定性、生物相容性,降低了分子的毒性,并且极大地增加了分子的水溶性。
2、本发明制备方法简单,所得水溶性羰基铬Fischer卡宾氨基酸钠盐能在水相中缓慢释放CO分子,较好的水溶解性是该化合物在药物应用领域方面的敲门砖。
3、本发明水溶性羰基铬Fischer卡宾氨基酸钠盐在马心肌红蛋白模拟的生理环境下的半衰期均在340s~1600s之间。
附图说明
图1是实施1~4制备的水溶性羰基铬Fischer卡宾氨基酸钠盐的logP柱状图。
图2是施1~4制备的水溶性羰基铬Fischer卡宾氨基酸钠盐在马心肌红蛋白模拟的生理环境中(37℃)水解条件下碳氧肌红蛋白浓度的柱状图。
图3是实施例1~4制备的水溶性羰基铬Fischer卡宾氨基酸钠盐半衰期的柱状图。
具体实施方式
下面结合附图和实施例对本发明进一步详细说明,但本发明的保护范围不仅限于这些实施例。
实施例1
制备结构式如下的水溶性羰基铬Fischer卡宾氨基酸钠盐化合物:
向100mL史莱克管中加入羰基铬的Fischer卡宾(0.2500g,1mmol)和L-亮氨酸(0.1582g,1.2mmol),在氮气保护下,加入无水无氧的3mL乙醇作为溶剂,然后加入三乙胺(296μL,2mmol),-10℃条件下反应6小时,亮橙红色的溶液变为淡黄色,反应结束后,旋转蒸发除去乙醇,浓缩产物溶于二氯甲烷,用1mol/L HCl水溶液洗涤后,再用1mol/L NaOH水溶液中和至中性,用无水MgSO4干燥,用砂芯漏斗进行抽滤,滤液经减压旋转蒸发,得到亮黄色固体粉末,即水溶性羰基铬Fischer卡宾氨基酸钠盐,其产率为82%。
所得产物的结构表征数据为:IR(KBr,cm-1):ν(CO)=2055cm-1,1909cm-1,ν(R-CO)=1660cm-1;1H NMR(400MHz,MeOH)δ:9.93(s,1H,NH),4.29(s,1H,CH),2.55(s,3H,CH3),3.25(s,1H,CH),1.67-1.64(m,2H,CH2),0.9-0.86(s,6H,CH3);13C NMR(400MHz,MeOD)δ:273.02(Cr=CO),224.52(CO),219.47(CO),213.01(CO),177(COONa),62.65(CH),48.83(CH),36.06(=CCH3),26.22(CH3),23.29(CH3),22.81(CH3);理论值[(CO)5Cr=C(CH3)(NHCH(CH2CH(CH3)2)COONa](371):C 40.06,H 3.93,N 3.77,元素分析:C 39.28,H 4.02,N 3.48;LC-MS:m/z=348。
实施例2
制备结构式如下的水溶性羰基铬Fischer卡宾氨基酸钠盐:
在实施例1中,所用的L-亮氨酸用等摩尔甘氨酸替换,其它步骤与实施例1相同,得到亮黄色粉末状固体产物277mg,其产率为88%。
所得产物的结构表征数据为:IR(KBr,cm-1):ν(CO)=2068cm-1,1942cm-1,ν(R-CO)=1629cm-1;1H NMR(400MHz,MeOD)δ:10.19(s,1H,NH),2.62(s,3H,CH3),3.99(d,2H,CH2);13CNMR(400MHz,MeOD)δ:224.55(CO),219.46(CO),173.96(COONa),51.46(CH2),36.82(=CCH3);理论值[(CO)5Cr=C(CH3)(NHCH2)COONa](315.1):C 34.30,H 1.92,N 4.44,元素分析:C 34.42,H 2.17,N 4.17;LC-MS:m/z=291.05。
实施例3
制备结构式如下的水溶性羰基铬Fischer卡宾氨基酸钠盐:
在实施例1中,所用的L-亮氨酸用等摩尔丙氨酸替换,其它步骤与实施例1相同,得到亮黄色粉末状固体产物273mg,其产率为83%。
所得产物的结构表征数据为:IR(KBr,cm-1):ν(CO)=2057cm-1,1907cm-1,ν(R-CO)=1607cm-1;1H NMR(400MHz,MeOD)δ:10.15(s,1H,NH),4.24(d,1H,CH),2.57(s,3H,CH3),1.35(s,3H,CH3);13C NMR(400MHz,MeOD)δ:273.31(Cr=C),224.51(CO),219.50(CO),213(CO),177.21(COONa),49.03(CH),35.94(=CCH3),19.58(CH3);理论值[(CO)5Cr=C(CH3)(NHCH(CH3))COONa](329.2):C 36.49.H 2.45,N 4.26,元素分析:C 34.68,H 2.50,N 4.37;LC-MS:m/z=305.95。
实施例4
制备结构式如下的水溶性羰基铬Fischer卡宾氨基酸钠盐:
在实施例1中,所用L-亮氨酸用等摩尔缬氨酸替换,其它步骤与实施例1相同,得到亮黄色粉末状固体产物278mg,其产率为78%。
所得产物的结构表征数据为:IR(KBr,cm-1):ν(CO)=2056cm-1,1907cm-1,ν(R-CO)=1637cm-1;1H NMR(400MHz,MeOD)δ:9.79(s,1H,NH),4.11(s,1H,CH),2.09(d,1H,CH),2.55(s,3H,CH3),0.92(s,6H,CH3);13C NMR(400MHz,MeOD)δ:219.47(CO),219.45(CO),213.01(CO),176.26(COOH),69.17(CH),35.93(CH),33.44(=CCH3),19.45(CH3),18.98(CH3);理论值:[(CO)5Cr=C(CH3)(NHCHCH(CH3)2COONa](357.2):C 40.35,H 3.39,N 3.92,元素分析:C42.99,H 38.76,N 3.39;LC-MS:m/z=333.95。
为了证明本发明的有益效果,发明人对实施例1~4制备的水溶性羰基铬Fischer卡宾氨基酸钠盐(以下简称待测物)进行了各种性能测试,具体测试情况如下:
1、水溶性测试
采用油水分配系数测定法测试待测物的水溶性,结果见图1和表1。
表1水溶性测试结果
由表1和图1可见,本发明水溶性羰基铬Fischer卡宾氨基酸钠盐水溶性均较好。
2、CO释放性能测试
称取5mg肌红蛋白加入到5mL容量瓶中,然后用5mL pH=7.4的磷酸缓冲溶液充分溶解,配制成肌红蛋白溶液。用移液枪吸取1mL肌红蛋白溶液加入比色皿中,然后加入25mgNa2S2O4,在室温条件下,采用紫外-可见分光光度计测试被还原的肌红蛋白在波长为500~600nm范围内的紫外吸收光谱,然后向被还原的肌红蛋白溶液中通入CO气体直至溶液颜色变红,测试其在波长为500~600nm范围内的紫外吸收光谱。
将1.1mg待测物溶解于110μL H2O中,得到母液,然后将母液用H2O稀释,配制成60μmol/L的待测物标准溶液。
将5μL 60μmo1/L待测物标准溶液和1mL肌红蛋白溶液加入到比色皿中,并加入25mg Na2S2O4混合均匀,比色皿上方加入1滴石蜡油密封,然后采用紫外-可见分光光度计测试在波长为500~600nm范围内的紫外吸收光谱,待测物不释放CO后停止测试,其中降解释放2小时后的碳氧肌红蛋白浓度如图2所示。由图2可见,本发明实施例1~4制备的水溶性羰基铬Fischer卡宾氨基酸钠盐在水相中均能释放较多的CO,在水相中较慢的释放一氧化碳。由图3可见,本发明水溶性羰基铬Fischer卡宾氨基酸钠盐的半衰期最大能达到1595s,最小也能达到340s。
Claims (3)
1.一种水溶性羰基铬Fischer卡宾氨基酸钠盐,其特征在于该化合物的结构式为:
结构式中R1代表H或C1~C4烷基。
2.根据权利要求1所述的水溶性羰基铬Fischer卡宾氨基酸钠盐,其特征在于:所述的R1代表H、(CH3)2CHCH2、(CH3)2CH、CH3中的任意一种。
3.一种权利要求1所述的水溶性羰基铬Fischer卡宾氨基酸钠盐的制备方法,其特征在于:在无水无氧和惰性气体保护下,以乙醇为溶剂,将式I所示的羰基铬的Fischer卡宾和式II所示的氨基酸、三乙胺按摩尔比为1:(1.1~1.5):(1.5~2.5),-10℃反应5~6小时,反应结束后,旋转蒸发除去乙醇,浓缩产物溶于二氯甲烷后再依次经1mol/L HCl水溶液洗涤、1mol/L NaOH水溶液中和、无水MgSO4干燥,抽滤,滤液经旋转蒸发,得到水溶性羰基铬Fischer卡宾氨基酸钠盐;
式II中R1代表H或C1~C4烷基。
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