CN115850137A - 一种截短侧耳素衍生化合物及其制备方法与应用 - Google Patents

一种截短侧耳素衍生化合物及其制备方法与应用 Download PDF

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CN115850137A
CN115850137A CN202211415953.5A CN202211415953A CN115850137A CN 115850137 A CN115850137 A CN 115850137A CN 202211415953 A CN202211415953 A CN 202211415953A CN 115850137 A CN115850137 A CN 115850137A
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李剑勇
李准
秦哲
刘亚娴
刘希望
杨亚军
白莉霞
李世宏
葛闻博
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Lanzhou Institute of Animal Husbandry and Veterinary Medicine CAAS
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Abstract

本发明公开了一种截短侧耳素衍生化合物及其制备方法与应用。本发明通过将将截短侧耳素与对甲苯磺酰氯反应,得到中间1,将中间体1作为原料,通过与R1基团供体在特定条件下反应得到中间体2,再将中间体2与R2基团供体进行酰胺化反应,得到带有Boc保护基的目标化合物,最后将该带有Boc保护基的目标化合物在酸性条件下进行脱保护,得到截短侧耳素衍生化合物。本发明制备工艺简单,产率高,所得截短侧耳素衍生化合物适合作为新型抗菌药物用于防治人或动物由细菌引起的感染性疾病,抗菌活性优于已上市的泰妙菌素和沃尼妙林,并且对耐药菌也具有很好的抗菌活性。

Description

一种截短侧耳素衍生化合物及其制备方法与应用
技术领域
本发明属于药物化学领域,尤其涉及一种具有氨基和肽键侧链的截短侧耳素衍生化合物及其制备方法与应用。
背景技术
抗菌药物在兽医临床上大量使用及滥用,导致兽医临床上的动物源耐药菌愈来愈严重,动物源耐药菌可以通过食物链传递给人类,使人医临床上出现无药可用的境况。近年来,我国畜牧业集约化和规模化养殖程度有了很大的提高,伴随着抗菌药物使用的大量增加,导致动物源细菌耐药性越来越严重。动物源耐药细菌及其耐药性可以通过食物链等途径传递给人类,影响着人类的生命健康。耐药菌尤其是金黄色葡萄球菌、肺炎链球菌等,每年引起数百万人死亡,严重威胁了人类的健康。因此,研制新的抗耐药菌类药物尤为重要。
截短侧耳素由高等真菌pleurotusmutiliz(Fr.)Sacc.和pleurotusPasseckeranius Pilat中分离出来的具有抗菌活性的一种双萜类化合物,具有骈合(5-6-8)三环的一种三环二萜化合物,其分子结构式如下所示:
Figure BDA0003939948630000011
研究表明,该类化合物是在核糖体水平上抑制细菌蛋白质的合成,作用于细菌核糖体50S亚基的23SRNA上,结合位点在肽基转移酶(PTC)的V结构域。其三元母核结合于A位点的活性口袋中,而侧链部分覆盖了tRNA与核糖体结合的P位点,通过抑制细菌蛋白质的合成而达到抑菌目的。截短侧耳素类化合物具有异于临床常见抗菌母核结构,与其它结构类抗菌药之间不易产生交叉耐药性。
截短侧耳素C14的酯基结构侧链是进行化学修饰的主要位点,对C14侧链的结构修饰研究大多都是在保留酯基结构的前提下,对C22位进行改造,这样能够大大提高其抑菌活性合生物利用度。构效关系表明,C14位侧链连接一个碱性中心的硫醚基侧链,其衍生物活性就会发生决定性的改进。
发明内容
为解决现有技术所存在的不足之处,本发明的首要目的在于提供一种具有氨基和肽键侧链的截短侧耳素衍生化合物或其药学上可接受的盐。
本发明的再一目的在于提供上述截短侧耳素衍生化合物的制备方法。
本发明的另一目的在于提供上述截短侧耳素衍生化合物的应用。
本发明是这样实现的,一种截短侧耳素衍生化合物,该化合物的分子结构式如下式(I)所示:
Figure BDA0003939948630000021
其中,R1选自以下基团中的任意一种:
Figure BDA0003939948630000022
R2选自以下基团中的任意一种:
Figure BDA0003939948630000031
上述述优选结构的化合物的具体基团归纳如表1所示:
表1化合物编号及具体基团
Figure BDA0003939948630000032
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Figure BDA0003939948630000041
本发明进一步公开了上述截短侧耳素衍生化合物的药学上可接受的盐,所述盐为式(I)所示化合物与盐酸、硫酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、谷氨酸、天冬氨酸、琥珀酸、柠檬酸或苹果酸形成的盐。
所述的药学上可接受的盐优选具体有如下结构式:
Figure BDA0003939948630000051
本发明进一步公开了上述截短侧耳素衍生化合物的制备方法,该方法包括以下步骤:
(1)将截短侧耳素、对甲苯磺酰氯加入溶剂1中混合,搅拌下滴加10mol/L氢氧化钠溶液,55~60℃回流反应1~2h,将反应产物经过冷析、洗涤、干燥,得到如式(II)所示结构的中间体1;
Figure BDA0003939948630000052
(2)中间体2的合成包括以下两种途径:
途径一:
将中间体1与R1基团供体1加入溶剂2中,在35~36℃下搅拌滴加催化剂苄基三丁基氯化铵、20wt%氢氧化钠溶液,50~55℃搅拌反应4~5h,将反应产物浓缩、萃取、干燥、纯化,得到如下式(Ⅲ)所示结构的中间体2;其中,所述R1基团供体1选自二甲基半胱胺盐酸盐、半胱胺盐酸盐中的任意一种;
或,途径二:
将中间体1、碘化钾加入溶剂3中,70~75℃搅拌反应1h,往该反应液中加入R1基团供体2和碳酸钾,或者,往该反应液中加入含有R1基团供体2的20wt%氢氧化钠溶液;添加完成后搅拌反应4~5h,将反应产物洗涤、干燥,纯化,得到如下式(Ⅲ)所示结构的中间体2:
Figure BDA0003939948630000061
其中,所述R1基团供体2选自3-氨基-5-巯基-1,2,4-三氮唑、3-氨基苯硫酚、4-氨基苯硫酚或2-氨基苯硫酚中的任意一种;
具体的,中间体2优选为以下分子结构式化合物:
Figure BDA0003939948630000062
(3)将中间体2与R2基团供体、催化剂添加到溶剂4中,在室温、搅拌进行酰胺化反应6h~12h,反应淬灭后,将反应产物经过萃取、干燥、纯化,得到如下式(Ⅳ)所示分子结构的带有Boc保护基的目标化合物:
Figure BDA0003939948630000063
其中,所述R2基团供体选自Boc-L-苯丙氨酸、Boc-L-苏氨酸、Boc-L-色氨酸、Boc-L-谷氨酰胺、Boc-L-精氨酸或Boc-L-组氨酸中的任意一种;
所述催化剂为Pyaop或由EDCI、HOBT、DIPEA构成的混合物;
(4)将所述带有Boc保护基的目标化合物添加到溶剂5中,室温下搅拌反应1~2h,将反应产物旋蒸除掉溶剂、烘干,得到式(I)所示截短侧耳素衍生物。
优选地,在步骤(1)中,所述对截短侧耳素、对甲苯磺酰氯、溶剂1、氢氧化钠溶液的摩尔体积比为10~15mmol:13~17mmol:12~15mL:2.0~2.5mL;
所述溶剂1为甲基叔丁基醚;
所述冷析、洗涤、干燥具体为:将反应产物冷却至0℃,过滤,将所得白色固体用甲基叔丁基醚冲洗三次,再用去离子水冲洗三次,在45℃下真空干燥。
优选地,在步骤(2)的途径一中,所述中间体1、R1基团供体1、溶剂2、苄基三丁基氯化铵、氢氧化钠溶液的摩尔体积比为7.1~20.8mmol:14.2~41.6mmol:28~80mL:0.7~2.1mmol:5~15mL;
所述溶剂2为四氢呋喃;
所述浓缩、萃取、干燥、纯化为:反应液浓缩后用二氯甲烷萃取,用无水硫酸钠干燥,柱层析按乙酸乙酯/1%二乙胺进行纯化。
优选地,在步骤(2)的途径二中,往反应液中添加R1基团供体2和碳酸钾时,所述中间体1、碘化钾、溶剂3、R1基团供体2和碳酸钾的摩尔体积比为18~19mmol:20~21mmol:95~105mL:20~21mmol:37~38mmol;
往该反应液中加入含有R1基团供体2的20wt%氢氧化钠溶液时,所述中间体1、碘化钾、溶剂3、R1基团供体2和氢氧化钠溶液的摩尔体积比为18~19mmol:20~21mmol:95~105mL:24~25mmol:40~50mL;
所述溶剂3为乙酸乙酯;
所述洗涤、干燥,纯化具体为:将反应产物用去离子水洗3次,用无水硫酸钠干燥,柱层析按石油醚:乙酸乙酯=1:2。
优选地,在步骤(3)中,所述中间体2、R2基团供体、催化剂、溶剂4的摩尔体积比为1.2~1.3mmol:1.4~1.6mmol:5.3~5.8mmol:20~25mL;
所述催化剂中EDCI、HOBT、DIPEA的摩尔比为1.4~1.6mmol:1.4~1.6mmol:2.5~2.6mmol;
所述中间体2、R2基团供体、催化剂、溶剂4的摩尔体积比为1.0~1.1mmol:1.2~1.3mmol:1.5~1.7mmol:20~25mL;
所述溶剂4为二氯甲烷;
所述淬灭通过饱和碳酸氢钠溶液进行淬灭,所述萃取通过二氯甲烷萃取,所述干燥通过无水硫酸钠,所述纯化通过柱层析进行纯化。
优选地,在步骤(4)中,目标化合物与溶剂5的摩尔体积比为0.5~1mmol:2~4mL;
所述溶剂5为按体积比为1:1混合的三氟乙酸与二氯甲烷。
本发明进一步公开了上述截短侧耳素衍生化合物、或上述截短侧耳素衍生化合物的药学上可接受的盐在制备治疗感染性疾病的抗菌药物中的应用。
本发明进一步公开了一种抗菌药物,该药物包括上述截短侧耳素衍生化合物以及一种或多种该截短侧耳素衍生化合物在药学上可接受的载体、赋形剂或稀释剂;或,该药物包括上述截短侧耳素衍生化合物的药学上可接受的盐以及该盐在药学上可接受的载体、赋形剂或稀释剂。
相比于现有技术的缺点和不足,本发明具有以下有益效果:
(1)本发明合成了大量全新结构的具有氨基和肽键侧链的截短侧耳素衍生化合物,并进行了广泛的抗菌活性筛选,首次发现该类化合物具有较好的体外抗菌活性,特别适合作为新型抗菌药物用于防治人或动物由细菌引起的感染性疾病,尤其对革兰氏阳性菌,如:金黄色葡萄球菌、链球菌,抗菌活性优于已上市的泰妙菌素和沃尼妙林,并且对耐药菌(MRSA、MRSE)也具有很好的抗菌活性;
(2)本发明截短侧耳素衍生化合物的制备工艺简单,产率高。
附图说明
图1是本发明实施例中截短侧耳素衍生物5的核磁图谱图;
图2是本发明实施例中截短侧耳素衍生物9的核磁图谱图;
图3是本发明实施例中截短侧耳素衍生物13的核磁图谱图;
图4是本发明实施例中截短侧耳素衍生物20的核磁图谱图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1中间体1制备
将5.0g(13.2mmol)截短侧耳素和对甲苯磺酰氯2.8g(14.5mmol)加入到13.2mL甲基叔丁基醚中,搅拌下滴加2.2mL的10mol/L氢氧化钠溶液,滴加完毕后加热至55℃,回流1h,出现大量白色沉淀,反应结束后冷却至0℃,过滤的白色固体用甲基叔丁基醚冲洗三次,然后再用去离子水冲洗三次,将白色固体在45℃下真空干燥,得到如式(II)所示结构的中间体1,产率92.9%。无须纯化可以下一步中直接使用。
Figure BDA0003939948630000091
实施例2中间体2的制备
1、中间体2-1制备
取3.9g(7.1mmol)实施例1制得的中间体1和1.6g(14.2mmol)半胱胺盐酸盐加入到28mL四氢呋喃中,然后在35℃下,搅拌加入0.22g(0.7mmol)催化剂苄基三丁基氯化铵和5mL的20%氢氧化钠溶液,滴加完毕后升温至50℃,搅拌4h,浓缩后用二氯甲烷萃取,用无水硫酸钠干燥,柱层析进行纯化(乙酸乙酯/1%二乙胺)得到如式(Ⅲ-1)所示结构的中间体2-1,产95.0%。
1H NMR(400MHz,CDCl3)δ6.48(dd,J=17.4,11.0Hz,1H),5.75(d,J=8.5Hz,1H),5.35(d,J=10.9Hz,1H),5.21(d,J=17.4Hz,1H),3.36(d,J=6.5Hz,1H),3.14(s,2H),2.88(t,J=6.2Hz,2H),2.70(t,J=6.3Hz,2H),2.41–2.05(m,5H),1.77(d,J=14.7Hz,1H),1.65(q,J=11.5Hz,3),1.47(d,J=14.8Hz,9H),1.22–1.09(m,4H),0.88(d,J=6.9Hz,3H),0.74(d,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ217.30,169.24,139.38,117.49,74.92,69.60,58.50,45.75,45.13,44.22,42.06,40.96,37.14,37.07,36.31,34.76,34.33,30.73,27.15,26.64,25.14,17.13,15.20,11.80.Chemical Formula:C24H39NO4S,Exact Mass:437.2600,HRMS(+TOF MS):438.2656(M+H+).
Figure BDA0003939948630000101
2、中间体2-2的制备
取11.1g(20.8mmol)实施例1制得的中间体1和9.0g(41.6mmol)二甲基半胱胺盐酸盐加入到80mL四氢呋喃中,然后在35℃下,搅拌加入0.65g(2.1mmol)催化剂苄基三丁基氯化铵和15mL的20%氢氧化钠溶液,滴加完毕后升温至50℃,搅拌4h,浓缩后用二氯甲烷萃取,用无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=1:1)得到如式(Ⅲ-2)所示结构的中间体2-2,产率88.0%。
1H NMR(400MHz,CDCl3)δ6.47(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.5Hz,1H),5.33(dd,J=11.0,1.5Hz,1H),5.19(dd,J=17.4,1.6Hz,1H),3.34(d,J=6.5Hz,1H),3.12(d,J=1.6Hz,2H),2.59(s,2H),2.39–2.26(m,1H),2.27–2.15(m,2H),2.13–2.01(m,2H),1.76(dd,J=14.4,3.1Hz,1H),1.68–1.62(m,2H),1.57–1.48(m,4H),1.45(s,3H),1.43–1.37(m,1H),1.31(d,J=16.1Hz,1H),1.23(s,6H),1.16(s,3H),1.10(dd,J=13.9,4.4Hz,1H),0.86(d,J=7.0Hz,3H),0.72(d,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ217.30,169.68,139.29,117.49,74.86,69.58,58.47,51.93,48.80,45.72,44.99,44.18,42.05,37.04,36.27,34.73,31.51,30.71,29.95,27.11,26.59,26.49,25.11,17.12,15.19,11.78.Chemical Formula:C26H43NO4S,Exact Mass:465.2913,HRMS(+TOF MS):466.3026(M+H+).
Figure BDA0003939948630000111
3、中间体2-3的制备
取10g(18.8mmol)实施例1制得的中间体1与3.4g(20.7mmol)碘化钾加入100mL乙酸乙酯中,加热至70℃,搅拌反应1h后加入2.4g(20.7mmol)3-氨基-5-巯基-1,2,4-三氮唑和5.2g(37.6mmol)碳酸钾,继续搅拌4h,反应完毕后,去离子水洗3次,用无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=1:2)得到如式(Ⅲ-3)所示结构的中间体2-3,产率82.3%。
1H NMR(400MHz,CDCl3)δ11.74(s,1H),6.34(dd,J=17.4,11.0Hz,1H),5.69(d,J=8.4Hz,1H),5.23–5.01(m,4H),3.82–3.62(m,2H),3.35(s,1H),2.33–2.14(m,3H),2.09(d,J=2.6Hz,1H),1.78–1.54(m,4H),1.53–1.40(m,5H),1.36–1.23(m,3H),1.11(s,4H),0.86(d,J=6.9Hz,3H),0.67(d,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ217.35,169.06,146.95,146.60,139.25,117.39,74.86,70.74,58.39,45.71,44.78,44.29,42.15,36.93,36.28,35.20,34.74,30.64,27.14,26.90,25.09,16.89,15.11,11.78.Chemical Formula:C24H36N4O4S,Exact Mass:476.2457,HRMS(+TOF MS):477.2542(M+H+).
Figure BDA0003939948630000121
4、中间体2-4的制备
取10g(18.8mmol)实施例1制得的中间体1与3.4g(20.7mmol)碘化钾加入100mL乙酸乙酯中,加热至70℃,搅拌反应1h后加入50mL含有3.1g(24.8mmol)3-氨基苯硫酚的20wt%氢氧化钠溶液,搅拌4h,反应完毕后,去离子水洗3次,用无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=1:1)得到如式(Ⅲ-4)所示结构的中间体2-4,产率91.6%。
1H NMR(400MHz,CDCl3)δ7.02(t,J=7.9Hz,1H),6.72(dd,J=1.7,0.9Hz,1H),6.66(t,J=2.0Hz,1H),6.51–6.47(m,1H),6.41(dd,J=17.4,11.0Hz,1H),5.71(d,J=8.5Hz,1H),5.30(dd,J=11.0,1.6Hz,1H),5.14(dd,J=17.4,1.6Hz,1H),3.66(s,2H),3.53(s,2H),3.32(dd,J=10.2,6.5Hz,1H),2.34–2.26(m,1H),2.25–2.11(m,2H),2.06(d,J=2.7Hz,1H),1.98(dd,J=16.1,8.5Hz,1H),1.78–1.70(m,1H),1.67–1.56(m,2H),1.55–1.42(m,2H),1.40(s,3H),1.37–1.28(m,1H),1.21–1.04(m,5H),0.85(d,J=7.0Hz,3H),0.68(d,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ217.28,168.57,147.17,139.25,136.02,130.01,119.71,117.35,115.98,113.86,74.85,69.77,58.41,45.67,44.91,44.11,42.01,37.20,37.00,36.23,34.70,30.65,27.07,26.62,25.07,16.96,15.11,11.73.Chemical Formula:C28H39NO4S,Exact Mass:485.2600,HRMS(+TOF MS):486.2689(M+H+).
Figure BDA0003939948630000122
5、中间体2-5的制备
取10g(18.8mmol)实施例1制得的中间体1与3.4g(20.7mmol)碘化钾加入100mL乙酸乙酯中,加热至70℃,搅拌反应1h后加入50mL含有3.1g(24.8mmol)4-氨基苯硫酚的20%氢氧化钠溶液,搅拌4h,反应完毕后,去离子水洗3次,用无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=1:1)得到如式(Ⅲ-5)所示结构的中间体2-5,产率87.2%。
1H NMR(400MHz,CDCl3)δ7.24(d,J=2.0Hz,1H),6.58–6.55(m,2H),6.46(dd,J=17.4,11.0Hz,1H),5.71(d,J=8.5Hz,1H),5.34(dd,J=10.9,1.6Hz,1H),5.19(dd,J=17.4,1.6Hz,1H),3.73(s,2H),3.44–3.30(m,3H),2.37–2.28(m,1H),2.26–2.12(m,2H),2.09–2.06(m,1H),1.98(dd,J=16.1,8.6Hz,1H),1.75(dq,J=14.5,3.1Hz,1H),1.66–1.57(m,3H),1.55–1.44(m,2H),1.39(s,3H),1.33(dd,J=14.1,3.6Hz,1H),1.21–1.06(m,5H),0.86(d,J=7.0Hz,3H),0.66(d,J=6.8Hz,3H).13C NMR(101MHz,CDCl3)δ217.40,168.99,146.92,139.38,134.85,122.04,117.40,115.77,74.91,69.37,58.49,45.73,44.93,44.17,42.02,39.85,37.09,36.28,34.77,30.73,27.12,26.54,25.14,17.01,15.18,11.79.
Chemical Formula:C28H39NO4S,Exact Mass:485.2600,HRMS(+TOF MS):486.2682(M+H+).
Figure BDA0003939948630000131
6、中间体2-6的制备
取10g(18.8mmol)实施例1制得的中间体1与3.4g(20.7mmol)碘化钾加入100mL乙酸乙酯中,加热至70℃,搅拌反应1h后加入50mL含有3.1g(24.8mmol)2-氨基苯硫酚的20%氢氧化钠溶液,搅拌4h,反应完毕后,去离子水洗3次,用无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=2:1)得到如式(Ⅲ-6)所示结构的中间体2-6,产率89.4%。
1H NMR(400MHz,CDCl3)δ7.36(dd,J=7.7,1.6Hz,1H),7.15–7.07(m,1H),6.72–6.59(m,2H),6.46(dd,J=17.4,11.0Hz,1H),5.70(d,J=8.5Hz,1H),5.34(dd,J=11.0,1.6Hz,1H),5.19(dd,J=17.4,1.6Hz,1H),4.38(s,2H),3.50–3.25(m,3H),2.35–2.26(m,1H),2.26–2.11(m,2H),2.05(d,J=2.7Hz,1H),1.96(dd,J=16.0,8.6Hz,1H),1.74(dd,J=14.5,3.1Hz,1H),1.68–1.49(m,3H),1.52–1.41(m,2H),1.37(s,3H),1.35–1.29(m,1H),1.22–1.04(m,5H),0.86(d,J=7.0Hz,3H),0.63(d,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ217.31,169.10,148.69,139.43,136.60,130.78,118.85,117.36,116.52,115.40,74.86,69.63,58.40,45.69,44.81,44.18,42.00,37.78,37.01,36.26,34.73,30.68,27.09,26.51,25.10,16.91,15.11,11.76.Chemical Formula:C28H39NO4S,Exact Mass:485.2600,HRMS(+TOF MS):486.2679(M+H+).
Figure BDA0003939948630000141
实施例3
1、截短侧耳素衍生物1~6的制备
(1)取0.54g(1.24mmol)实施例2制得的中间体2-1溶于20mL二氯甲烷,加入1.49mmol的R2基团供体、0.28g(1.49mmol)的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、0.2g(1.49mmol)1-羟基苯并三唑(HOBT)和0.45mL(2.48mmol)的N,N-二异丙基乙胺(DIPEA),加料完毕后,室温搅拌6h,饱和碳酸氢钠溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=2:1→二氯甲烷:甲醇=10:1),浓缩后得到带有Boc保护基的目标化合物;其中,
上述反应过程中,R2基团供体分别为Boc-L-苯丙氨酸、Boc-L-苏氨酸、Boc-L-色氨酸、Boc-L-谷氨酰胺、Boc-L-精氨酸、Boc-L-组氨酸,相应得到目标化合物1~6;
(2)将带有Boc保护基的目标化合物1~6分别加入1:1的三氟乙酸和二氯甲烷溶液,室温搅拌1h,反应结束后旋蒸除掉溶剂,相应获得截短侧耳素衍生物1~6。
合成路线如下式所示:
Figure BDA0003939948630000151
截短侧耳素衍生物1
1H NMR(400MHz,CDCl3)δ7.55(t,J=6.0Hz,1H),7.28–7.23(m,2H),7.22–7.11(m,3H),6.40(dd,J=17.4,11.0Hz,1H),5.68(d,J=8.4Hz,1H),5.26(dd,J=11.0,1.6Hz,1H),5.13(dd,J=17.5,1.6Hz,1H),3.56(dd,J=9.3,4.2Hz,1H),3.46–3.33(m,2H),3.30(d,J=6.5Hz,1H),3.19(dd,J=13.7,4.2Hz,1H),3.08(d,J=1.3Hz,2H),2.70–2.59(m,3H),2.32–2.24(m,1H),2.23–2.09(m,2H),2.08–1.98(m,2H),1.74–1.68(m,1H),1.64–1.57(m,2H),1.56–1.41(m,3H),1.38(s,3H),1.37–1.28(m,1H),1.25(d,J=16.1Hz,1H),1.11(s,3H),1.05(dd,J=13.9,4.4Hz,1H),0.81(d,J=7.0Hz,3H),0.67(d,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ217.24,174.46,169.12,139.32,138.04,129.56,128.97,127.10,117.47,74.87,69.72,58.43,56.72,45.71,45.11,44.20,42.02,41.21,37.83,37.01,36.27,34.71,34.13,32.79,30.68,27.11,26.67,25.10,17.13,15.16,11.78.ChemicalFormula:C33H48N2O5S,Exact Mass:584.3284,HRMS(+TOF MS):585.3315(M+H+).
截短侧耳素衍生物2
1H NMR(400MHz,CDCl3)δ7.77(t,J=6.2Hz,1H),6.44(dd,J=17.4,11.0Hz,1H),5.72(d,J=8.4Hz,1H),5.31(d,J=11.1Hz,1H),5.18(d,J=17.3Hz,1H),4.25(dd,J=6.7,3.2Hz,1H),3.49–3.44(m,2H),3.34(d,J=6.5Hz,1H),3.24–3.10(m,3H),2.81–2.68(m,2H),2.34–2.03(m,8H),1.75(dd,J=14.6,3.3Hz,1H),1.68–1.58(m,2H),1.56–1.28(m,8H),1.22–1.14(m,6H),1.09(dd,J=14.0,4.4Hz,1H),0.86(d,J=6.9Hz,3H),0.71(d,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ217.26,174.22,169.14,139.35,117.40,74.86,69.80,68.08,59.92,58.41,45.69,45.09,44.18,42.00,37.84,36.98,36.25,34.69,34.10,32.76,30.65,27.09,26.67,25.08,19.23,17.08,15.12,11.74.Chemical Formula:C28H46N2O6S,Exact Mass:538.3077,HRMS(+TOF MS):539.3118(M+H+).
截短侧耳素衍生物3
1H NMR(400MHz,CDCl3)δ8.37(s,1H),7.66(d,J=7.8Hz,1H),7.58(t,J=6.1Hz,1H),7.36(d,J=8.1Hz,1H),7.23–7.14(m,1H),7.15–7.03(m,2H),6.46(dd,J=17.4,11.0Hz,1H),5.73(d,J=8.4Hz,1H),5.31(dd,J=11.0,1.6Hz,1H),5.18(dd,J=17.4,1.6Hz,1H),3.71(dd,J=8.6,4.3Hz,1H),3.52–3.39(m,2H),3.40–3.30(m,2H),3.10(d,J=1.6Hz,2H),2.95(dd,J=14.5,8.7Hz,1H),2.67(t,J=6.4Hz,2H),2.39–2.04(m,6H),1.82–1.50(m,7H),1.44(s,3H),1.42–1.31(m,2H),1.16(s,3H),1.10(dd,J=13.9,4.5Hz,1H),0.87(d,J=7.0Hz,3H),0.73(d,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ217.31,175.23,169.14,139.32,136.66,127.78,123.39,122.48,119.84,119.21,117.48,111.90,111.52,74.87,69.72,58.44,55.88,45.71,45.10,44.20,42.02,37.80,37.02,36.27,34.72,34.11,32.80,31.06,30.68,27.11,26.67,25.10,17.12,15.16,11.77.Chemical Formula:C35H49N3O5S,Exact Mass:623.3393,HRMS(+TOF MS):624.3430(M+H+).
截短侧耳素衍生物4
1H NMR(400MHz,CDCl3)δ7.55(s,1H),6.44(dd,J=17.3,11.1Hz,1H),5.73(d,J=8.3Hz,1H),5.32(d,J=11.1Hz,1H),5.19(d,J=17.4Hz,1H),4.19(dd,J=8.5,4.7Hz,1H),3.53–3.33(m,2H),3.16(s,1H),2.85–2.69(m,2H),2.53–1.96(m,8H),1.76(d,J=13.9Hz,1H),1.71–1.56(m,2H),1.58–1.34(m,6H),1.25(d,J=4.1Hz,2H),1.16(s,3H),1.10(dd,J=13.9,4.4Hz,1H),0.88(d,J=6.9Hz,3H),0.72(d,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ217.28,179.79,172.16,169.38,139.40,117.40,74.91,69.91,58.45,57.46,45.73,45.12,44.24,42.05,38.32,37.02,36.29,34.73,34.23,32.54,30.70,29.83,27.13,26.68,25.58,25.11,17.09,15.14,11.77.Chemical Formula:C29H47N3O6S,Exact Mass:565.3186,HRMS(+TOF MS):566.3242(M+H+).
截短侧耳素衍生物5
1H NMR(400MHz,DMSO-d6)δ8.68(t,J=5.7Hz,1H),8.22(s,2H),7.95(t,J=5.9Hz,1H),6.15(dd,J=17.7,11.2Hz,1H),5.56(d,J=8.2Hz,1H),5.11–5.01(m,2H),3.73(s,2H),3.49–3.20(m,6H),3.10(q,J=6.7Hz,2H),2.74–2.60(m,2H),2.41(s,1H),2.23–2.03(m,4H),1.76–1.57(m,4H),1.56–1.39(m,4H),1.37(s,3H),1.33–1.23(m,3H),1.06(s,3H),0.99(dd,J=13.6,4.1Hz,1H),0.82(d,J=6.8Hz,3H),0.64(d,J=6.7Hz,3H).13C NMR(101MHz,DMSO)δ217.31,168.54,168.43,157.01,141.02,115.22,72.69,69.61,57.40,52.00,48.70,45.09,44.15,43.86,41.58,38.05,36.57,36.50,34.12,33.30,31.18,30.25,28.68,28.41,26.68,24.60,24.23,16.23,14.67,11.67.Chemical Formula:C30H51N5O5S,Exact Mass:593.3611,HRMS(+TOF MS):594.3716(M+H+).
截短侧耳素衍生物6
1H NMR(400MHz,CDCl3)δ8.52(s,2H),7.72–7.33(m,2H),6.40(dd,J=17.1,11.3Hz,1H),5.68(d,J=6.9Hz,1H),5.24(d,J=11.1Hz,1H),5.14(d,J=17.2Hz,1H),4.47(d,J=29.1Hz,1H),3.51–3.06(m,8H),2.69(s,2H),2.33–2.04(m,5H),1.83–1.57(m,4H),1.44–1.25(m,7H),1.13(s,3H),1.00(t,J=7.3Hz,1H),0.86(d,J=6.1Hz,3H),0.68(d,J=6.4Hz,3H).13C NMR(101MHz,CDCl3)δ216.55,168.23,167.17,138.49,126.46,117.16,116.24,114.25,73.92,68.86,57.43,44.72,44.04,43.19,41.02,36.01,35.26,33.74,32.98,30.76,29.68,26.09,25.72,24.10,23.24,18.84,15.99,14.09,12.76,10.77.Chemical Formula:C30H46N4O5S,Exact Mass:574.3189,HRMS(+TOF MS):575.3276(M+H+).
2、截短侧耳素衍生物7~12的制备
(1)取0.58g(1.24mmol)实施例2制得的中间体2-2溶于20ml二氯甲烷,加入1.49mmol的R2基团供体、0.28g(1.49mmol)的EDCI、0.2g(1.49mmol)HOBT和0.45ml(2.48mmol)的DIPEA,加料完毕后,室温搅拌6h,饱和碳酸氢钠溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=2:1→二氯甲烷:甲醇=10:1),浓缩后带有Boc保护基的目标化合物;
上述反应过程中,R2基团供体分别为Boc-L-苯丙氨酸、Boc-L-苏氨酸、Boc-L-色氨酸、Boc-L-谷氨酰胺、Boc-L-精氨酸、Boc-L-组氨酸,相应得到目标化合物7~12;
(2)将带有Boc保护基的目标化合物7~12分别加入1:1的三氟乙酸和二氯甲烷溶液,室温搅拌1h,反应结束后旋蒸除掉溶剂,相应获得截短侧耳素衍生物7~12。
合成路线如下式所示:
Figure BDA0003939948630000181
截短侧耳素衍生物7
1H NMR(400MHz,CDCl3)δ7.73(q,J=6.8Hz,1H),7.30–7.21(m,2H),7.22–7.14(m,3H),6.39(dd,J=17.4,11.0Hz,1H),5.66(d,J=8.4Hz,1H),5.27–5.18(m,2H),5.11(dd,J=17.5,1.7Hz,1H),3.59(dd,J=9.0,3.6Hz,1H),3.29(d,J=6.5Hz,1H),3.24–3.17(m,2H),3.17–3.08(m,2H),2.65(dd,J=13.7,9.3Hz,1H),2.26(q,J=6.9Hz,1H),2.24–2.05(m,2H),2.06–1.95(m,2H),1.75–1.65(m,1H),1.65–1.49(m,3H),1.54–1.38(m,2H),1.39(s,3H),1.38–1.25(m,1H),1.24(d,J=16.0Hz,1H),1.22–1.11(m,6H),1.09(d,J=2.0Hz,3H),1.04(dd,J=13.9,4.3Hz,1H),0.80(d,J=7.0Hz,3H),0.65(d,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ217.21,174.47,169.71,139.20,138.12,129.56,128.94,127.04,117.46,74.80,69.83,58.38,56.90,53.69,47.57,47.09,45.67,44.98,44.17,42.02,41.34,36.96,36.24,34.69,31.75,30.64,27.09,26.72,26.63,25.07,17.15,15.14,11.77.Chemical Formula:C35H52N2O5S,Exact Mass:612.3597,HRMS(+TOF MS):613.3720(M+H+).
截短侧耳素衍生物8
1H NMR(400MHz,CDCl3)δ7.89(t,J=6.3Hz,1H),6.45(dd,J=17.4,11.0Hz,1H),5.72(d,J=8.4Hz,1H),5.31(d,J=11.0Hz,1H),5.18(d,J=17.4Hz,1H),4.29–4.20(m,1H),3.39–3.29(m,2H),3.29–3.14(m,4H),2.35–2.03(m,7H),1.76(d,J=14.1Hz,2H),1.68–1.60(m,3H),1.52(dd,J=13.8,3.2Hz,2H),1.44(s,3H),1.38–1.32(m,2H),1.29–1.21(m,8H),1.15(s,3H),1.13–1.07(m,1H),0.87(d,J=6.9Hz,3H),0.71(d,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ217.27,174.18,169.84,139.26,117.47,74.85,69.96,68.27,60.07,58.41,47.44,47.33,45.70,45.00,44.21,42.05,36.98,36.25,34.72,31.93,30.67,27.11,26.79,26.68,26.62,25.09,19.26,17.16,15.16,11.77.ChemicalFormula:C30H50N2O6S,Exact Mass:566.3390,HRMS(+TOF MS):567.3473(M+H+).
截短侧耳素衍生物9
1H NMR(400MHz,CDCl3)δ8.52(s,1H),7.79(t,J=6.2Hz,1H),7.69(t,J=6.6Hz,1H),7.36(d,J=7.8Hz,1H),7.24–7.05(m,3H),6.51–6.39(m,1H),5.73(d,J=8.1Hz,1H),5.28(d,J=10.9Hz,1H),5.17(d,J=17.4Hz,1H),4.12(q,J=7.2Hz,1H),3.81–3.72(m,1H),3.44–3.23(m,4H),3.13(d,J=3.2Hz,2H),2.94(dd,J=14.1,9.2Hz,1H),2.38–2.02(m,6H),1.80–1.49(m,8H),1.44(s,3H),1.40–1.25(m,3H),1.22(s,3H),1.15(s,3H),1.10(d,J=13.8Hz,1H),0.86(d,J=6.8Hz,3H),0.72(d,J=6.2Hz,3H).13C NMR(101MHz,CDCl3)δ217.34,175.25,169.68,139.21,136.70,127.75,123.45,122.42,119.78,119.23,117.49,111.92,111.52,74.83,69.82,58.42,56.02,47.53,47.10,45.69,44.99,44.18,42.04,37.00,36.25,34.72,31.72,31.24,30.66,27.10,26.71,26.68,25.09,17.15,15.16,14.45,11.78.Chemical Formula:C37H53N3O5S,Exact Mass:651.3706,HRMS(+TOFMS):652.3800(M+H+).
截短侧耳素衍生物10
1H NMR(400MHz,CDCl3)δ7.48(s,1H),6.42(dd,J=17.5,11.0Hz,1H),5.70(d,J=8.3Hz,1H),5.27(d,J=9.8Hz,1H),5.16(d,J=17.5Hz,1H),4.30–4.06(m,1H),3.35(d,J=6.0Hz,1H),3.22(d,J=6.1Hz,1H),3.21–3.12(m,2H),2.65–2.41(m,2H),2.35–2.26(m,2H),2.24–2.16(m,2H),2.15–2.01(m,3H),1.99(s,1H),1.75(d,J=14.1Hz,1H),1.63(q,J=11.3,10.2Hz,2H),1.55–1.33(m,5H),1.26–1.18(m,8H),1.12(d,J=12.8Hz,7H),0.86(d,J=5.2Hz,3H),0.69(d,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ217.29,179.67,172.27,172.03,139.34,117.33,74.82,70.20,70.05,62.71,58.39,57.43,55.77,47.29,45.68,45.04,44.19,42.03,36.93,36.25,34.68,31.83,30.63,29.84,27.09,26.57,25.94,25.05,17.08,15.09,11.75.Chemical Formula:C31H51N3O6S,Exact Mass:593.3499,HRMS(+TOF MS):594.3589(M+H+).
截短侧耳素衍生物11
1H NMR(400MHz,CDCl3)δ8.21(d,J=64.7Hz,3H),7.62(s,1H),7.16(d,J=7.8Hz,1H),6.38(s,1H),5.68(s,1H),5.26–5.08(m,2H),4.11(s,1H),3.45(s,1H),3.41–2.97(m,6H),2.85–2.63(m,3H),2.43–1.95(m,7H),1.68(d,J=51.0Hz,4H),1.47–1.37(m,4H),1.35–1.21(m,4H),1.19–1.01(m,8H),0.86(d,J=8.0Hz,3H),0.67(d,3H).13C NMR(101MHz,CDCl3)δ217.65,170.27,169.35,157.58,141.00,115.34,74.91,70.03,58.49,50.98,46.98,45.72,45.04,44.18,42.05,40.90,36.99,36.28,34.75,31.79,30.62,26.78,26.50,26.32,25.08,24.15,22.90,21.60,17.07,15.14,11.79.Chemical Formula:C32H55N5O5S,Exact Mass:621.3924,HRMS(+TOF MS):622.3989(M+H+).
截短侧耳素衍生物12
1H NMR(400MHz,DMSO-d6)δ8.48(t,J=6.2Hz,1H),7.64(s,1H),6.93(s,1H),6.13(dd,J=17.7,11.2Hz,1H),5.54(d,J=8.2Hz,1H),5.12–4.98(m,2H),4.55(d,J=15.6Hz,1H),3.99(t,J=6.5Hz,1H),3.43(d,J=5.8Hz,1H),3.37–3.26(m,3H),3.20(d,J=28.2Hz,1H),3.11–2.96(m,2H),2.86(dd,J=15.0,7.7Hz,1H),2.41(s,1H),2.26–1.94(m,4H),1.69–1.41(m,3H),1.37(s,3H),1.32–1.21(m,4H),1.11(d,J=5.4Hz,5H),1.05(s,3H),0.99(dd,J=15.0,5.4Hz,1H),0.81(d,J=6.9Hz,3H),0.63(d,J=6.8Hz,3H).13C NMR(101MHz,DMSO-d6)δ217.31,169.40,168.76,140.93,135.28,133.77,115.90,115.32,72.70,69.59,57.39,53.05,47.78,46.43,45.08,44.09,43.78,41.58,36.49,34.12,31.09,30.23,29.71,28.59,26.70,26.17,26.08,24.59,16.35,14.70,11.66.ChemicalFormula:C32H50N4O5S,Exact Mass:602.3502,HRMS(+TOF MS):603.3550(M+H+).
3、截短侧耳素衍生物13、14的制备
(1)取0.5g(1.05mmol)实施例2制得的中间体2-3溶于20ml二氯甲烷,加入1.26mmol的R2基团供体、0.82g(1.58mmol)(7-氮杂苯并三唑-1-氧)三吡咯磷六氟磷酸盐(PYAOP)、0.38ml(2.1mmol)的DIPEA,加料完毕后,室温搅拌12h,饱和碳酸氢钠溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=1:1→二氯甲烷:甲醇=20:1),浓缩后带有Boc保护基的目标化合物;
上述反应过程中,R2基团供体分别为Boc-L-苯丙氨酸、Boc-L-色氨酸,相应得到目标化合物13~14;
(2)将带有Boc保护基的目标化合物13~14分别加入1:1的三氟乙酸和二氯甲烷溶液,室温搅拌1h,反应结束后旋蒸除掉溶剂,相应得到截短侧耳素衍生物13、14。
合成路线如下式所示:
Figure BDA0003939948630000211
截短侧耳素衍生物13
1H NMR(400MHz,CDCl3)δ7.38–7.18(m,4H),6.44(dd,J=16.6,11.3Hz,1H),5.75(d,J=9.4Hz,1H),5.33–5.10(m,2H),3.84–3.74(m,2H),3.39–3.26(m,2H),2.89–2.78(m,1H),2.35–2.16(m,3H),2.16–1.97(m,3H),1.76(d,J=14.1Hz,1H),1.71–1.22(m,12H),1.14(s,3H),0.87(d,J=6.1Hz,3H),0.72(d,J=6.6Hz,3H).13C NMR(101MHz,CDCl3)δ217.36,174.72,168.00,157.31,149.79,139.32,136.76,129.48,129.25,127.57,117.37,74.86,70.18,58.44,56.35,45.71,44.77,44.19,42.12,40.51,37.02,36.27,34.87,34.74,30.68,27.11,26.73,25.09,16.97,15.10,11.75.Chemical Formula:C33H45N5O5S,Exact Mass:623.3141,
HRMS(+TOF MS):624.3225(M+H+).
截短侧耳素衍生物14
1H NMR(400MHz,CDCl3)δ8.45(s,1H),7.62(d,J=7.9Hz,1H),7.36(d,J=8.0Hz,1H),7.20(t,J=7.5Hz,1H),7.12(t,J=7.5Hz,1H),7.03(d,J=2.3Hz,1H),6.44(dd,J=16.5,11.9Hz,1H),5.73(d,J=8.2Hz,1H),5.28(d,J=11.0Hz,2H),5.16(d,J=17.4Hz,1H),3.92(dd,J=8.0,4.4Hz,1H),3.80(d,J=2.7Hz,2H),3.44–3.30(m,2H),3.20–3.04(m,1H),2.34–2.16(m,3H),2.08(s,1H),2.00(dd,J=16.1,8.5Hz,1H),1.75(dd,J=14.6,3.1Hz,1H),1.67–1.30(m,12H),1.16–1.08(m,4H),0.86(d,J=7.0Hz,3H),0.69(t,J=6.7Hz,3H).13C NMR(101MHz,CDCl3)δ217.63,175.39,168.07,157.46,149.68,139.31,136.65,127.60,123.58,122.69,120.08,118.75,117.39,111.74,110.44,74.86,70.12,58.48,55.55,45.74,44.76,44.18,42.11,37.08,36.26,34.80,34.75,30.69,30.34,27.11,26.67,25.09,16.96,15.07,11.75.Chemical Formula:C35H46N6O5S,Exact Mass:662.3250,HRMS(+TOF MS):663.3345(M+H+).
4、截短侧耳素衍生物15~17的制备
(1)取0.5g(1.03mmol)实施例2制得的中间体2-4溶于20ml二氯甲烷,加入1.24mmol的R2基团供体、0.8g(1.55mmol)(7-氮杂苯并三唑-1-氧)三吡咯磷六氟磷酸盐(PYAOP)、0.37ml(2.1mmol)的DIPEA,加料完毕后,室温搅拌12h,饱和碳酸氢钠溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=2:1→二氯甲烷:甲醇=20:1),浓缩后得到带有Boc保护基的目标化合物;
上述反应过程中,R2基团供体分别为Boc-L-苯丙氨酸、Boc-L-色氨酸、Boc-L-组氨酸,相应得到目标化合物15~17;
(2)将带有Boc保护基的目标化合物15~17分别加入1:1的三氟乙酸和二氯甲烷溶液,室温搅拌1h,反应结束后旋蒸除掉溶剂,相应获得截短侧耳素衍生物15~17。
合成路线如下式所示:
Figure BDA0003939948630000231
截短侧耳素衍生物15
1H NMR(400MHz,CDCl3)δ9.45(s,1H),7.63(q,J=2.1Hz,1H),7.51–7.43(m,1H),7.38–7.25(m,2H),7.28–7.17(m,3H),7.12–7.04(m,1H),6.39(dd,J=17.4,11.0Hz,1H),5.71(d,J=8.4Hz,1H),5.32–5.20(m,1H),5.13(dd,J=17.4,1.6Hz,1H),3.71(dd,J=9.6,3.9Hz,1H),3.59(d,J=2.5Hz,2H),3.41–3.27(m,2H),2.76(ddd,J=13.8,9.6,2.1Hz,1H),2.34–2.26(m,1H),2.26–2.11(m,2H),2.05(d,J=2.7Hz,1H),1.98(dd,J=16.1,8.5Hz,1H),1.80–1.69(m,1H),1.69–1.54(m,3H),1.56–1.40(m,4H),1.39(s,3H),1.38–1.27(m,1H),1.21–1.03(m,5H),0.85(d,J=7.0Hz,3H),0.68(d,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ217.29,172.65,168.35,139.18,138.56,137.85,136.11,129.75,129.54,129.12,127.25,125.25,120.25,118.02,117.41,74.87,69.89,58.43,57.04,45.69,44.98,44.13,42.03,40.89,37.01,36.25,34.72,30.67,27.08,26.65,25.09,17.00,15.13,14.46,11.75.Chemical Formula:C37H48N2O5S,Exact Mass:632.3284,HRMS(+TOF MS):633.3367(M+H+).
截短侧耳素衍生物16
1H NMR(400MHz,CDCl3)δ9.47(s,1H),8.38(s,1H),7.69(d,J=7.9Hz,1H),7.68–7.59(m,1H),7.52–7.41(m,1H),7.38(d,J=8.0Hz,1H),7.25–7.04(m,4H),6.39(dd,J=17.4,11.0Hz,1H),5.70(d,J=8.0Hz,1H),5.31–5.22(m,1H),5.13(dd,J=17.4,1.8Hz,1H),3.88–3.79(m,1H),3.60(d,J=3.5Hz,2H),3.44(dd,J=14.5,4.2Hz,1H),3.31(d,J=6.4Hz,1H),3.06(dd,J=14.5,8.5Hz,1H),2.34–2.25(m,1H),2.27–2.13(m,2H),2.05(d,J=2.7Hz,1H),1.95(dd,J=15.9,8.6Hz,1H),1.80–1.70(m,1H),1.72–1.55(m,5H),1.56–1.47(m,1H),1.50–1.40(m,1H),1.37(s,2H),1.38–1.28(m,1H),1.21–1.04(m,5H),0.86(d,J=7.0Hz,3H),0.68(d,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ217.51,173.25,168.42,139.16,138.68,136.67,136.03,129.72,127.83,125.19,123.51,122.58,120.26,119.99,119.04,118.03,117.44,111.62,111.51,74.88,69.92,58.46,56.22,45.71,44.95,44.14,42.04,37.04,36.25,34.77,30.68,30.58,27.09,26.65,25.09,17.02,15.14,14.47,11.75.Chemical Formula:C39H49N3O5S,Exact Mass:671.3393,HRMS(+TOF MS):672.3475(M+H+).
截短侧耳素衍生物17
1H NMR(400MHz,CDCl3)δ9.73(s,1H),7.64(d,J=5.4Hz,1H),7.56(s,1H),7.44–7.35(m,1H),7.18(t,J=7.9Hz,1H),7.05(d,J=7.8Hz,1H),6.84(s,1H),6.42–6.28(m,1H),5.67(d,J=8.4Hz,1H),5.28–5.19(m,1H),5.10(d,J=17.3Hz,1H),3.77–3.69(m,1H),3.57(d,J=3.3Hz,2H),3.32(d,J=6.4Hz,1H),3.12–2.99(m,2H),2.93(q,J=7.3Hz,3H),2.34–2.09(m,3H),2.05(s,1H),1.99–1.90(m,1H),1.75–1.70(m,1H),1.67–1.54(m,2H),1.52–1.40(m,2H),1.35(d,J=4.1Hz,3H),1.17–1.03(m,5H),0.85(d,J=6.9Hz,3H),0.67–0.63(m,3H).13C NMR(101MHz,CDCl3)δ217.59,173.37,168.39,139.23,138.57,136.05,135.57,129.72,125.24,120.40,118.13,117.32,74.83,70.00,58.45,55.75,45.70,44.97,44.14,42.83,42.02,37.01,36.25,34.75,32.02,30.65,27.08,26.75,25.07,16.97,15.10,12.21,11.75.Chemical Formula:C34H46N4O5S,Exact Mass:622.3189,HRMS(+TOF MS):623.3283(M+H+).
5、截短侧耳素衍生物18~20的制备
(1)取0.5g(1.03mmol)实施例2制得的中间体2-5溶于20ml二氯甲烷,加入1.24mmol的R2基团供体、0.8g(1.55mmol)(7-氮杂苯并三唑-1-氧)三吡咯磷六氟磷酸盐(PYAOP)、0.37ml(2.1mmol)的DIPEA,加料完毕后,室温搅拌12h,饱和碳酸氢钠溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=2:1→二氯甲烷:甲醇=20:1),浓缩后得到带有Boc保护基的目标化合物;
上述反应过程中,R2基团供体分别为Boc-L-苯丙氨酸、Boc-L-色氨酸、Boc-L-组氨酸,相应得到目标化合物18~20;
(2)将带有Boc保护基的目标化合物18~20分别加入1:1的三氟乙酸和二氯甲烷溶液,室温搅拌1h,反应结束后旋蒸除掉溶剂,相应获得截短侧耳素衍生物18~20。
合成路线如下式所示:
Figure BDA0003939948630000251
截短侧耳素衍生物18
1H NMR(400MHz,CDCl3)δ8.90(d,J=19.2Hz,1H),7.28–7.09(m,9H),6.35(dd,J=17.4,11.0Hz,1H),5.66(d,J=6.0Hz,1H),5.25(d,J=11.1Hz,1H),5.11(d,J=17.3Hz,1H),4.52–4.38(m,1H),3.47(d,J=4.0Hz,2H),3.33(d,J=4.9Hz,1H),3.27–3.09(m,2H),2.32–1.87(m,6H),1.72(d,J=14.2Hz,1H),1.66–1.22(m,10H),1.07(t,J=4.1Hz,5H),0.82(d,J=6.0Hz,3H),0.63(d,J=6.7Hz,3H).13C NMR(101MHz,CDCl3)δ218.22,168.60,167.01,139.02,135.61,133.59,131.77,131.42,129.60,129.49,128.42,121.55,117.57,75.02,69.93,58.47,55.76,45.72,44.94,44.01,41.99,37.90,37.60,37.06,36.16,34.76,30.64,27.05,26.45,25.07,16.96,15.07,11.78.Chemical Formula:C37H48N2O5S,Exact Mass:632.3284,HRMS(+TOF MS):633.3364(M+H+).
截短侧耳素衍生物19
1H NMR(400MHz,CDCl3)δ9.50(s,1H),8.40(s,1H),7.68(d,J=7.9Hz,1H),7.54(d,J=8.5Hz,2H),7.42–7.33(m,3H),7.21(t,J=7.6Hz,1H),7.13(t,J=7.4Hz,1H),7.07(d,J=2.6Hz,1H),6.42(dd,J=17.4,11.0Hz,1H),5.70(d,J=8.3Hz,1H),5.31(t,1H),5.18(d,J=17.2Hz,1H),3.83(dd,J=8.4,4.2Hz,1H),3.57–3.25(m,5H),3.08(dd,J=14.5,8.4Hz,1H),2.33–2.17(m,3H),2.11–1.89(m,3H),1.78–1.72(m,1H),1.62–1.44(m,6H),1.33(s,3H),1.20–1.08(m,5H),0.86(d,J=7.0Hz,3H),0.66(t,J=6.5Hz,3H).13C NMR(101MHz,CDCl3)δ217.64,173.29,168.64,139.18,137.57,136.65,132.29,129.40,127.87,123.45,122.56,120.07,119.97,119.02,117.52,111.62,111.45,74.86,69.72,58.48,56.21,45.73,44.99,44.15,42.00,38.38,37.08,36.24,34.79,30.69,30.57,27.09,26.57,25.10,17.02,15.10,11.77.Chemical Formula:C39H49N3O5S,Exact Mass:671.3393,HRMS(+TOF MS):672.3466(M+H+).
截短侧耳素衍生物20
1H NMR(400MHz,CDCl3)δ9.82(s,1H),7.58–7.47(m,3H),7.32(d,J=8.3Hz,2H),6.82(s,1H),6.37(dd,J=17.4,11.0Hz,1H),5.68(d,J=8.3Hz,1H),5.27(d,J=11.1Hz,1H),5.13(d,J=17.4Hz,1H),3.80(t,J=5.9Hz,2H),3.48(d,J=8.3Hz,2H),3.33(d,J=6.3Hz,1H),3.06(h,J=10.7,8.9Hz,2H),2.34–2.14(m,3H),2.06(s,1H),1.96(dd,J=15.7,7.9Hz,1H),1.74(d,J=13.7Hz,1H),1.67–1.29(m,10H),1.13(d,J=18.3Hz,5H),0.86(d,J=6.8Hz,3H),0.65(t,J=5.8Hz,3H).13C NMR(101MHz,CDCl3)δ217.80,172.99,168.59,139.24,137.39,135.40,133.82,132.06,132.00,129.73,120.28,117.36,74.84,69.81,58.49,55.68,45.71,44.99,44.13,41.98,38.17,37.06,36.23,34.78,31.98,30.65,27.06,26.69,25.08,16.97,15.09,11.78.Chemical Formula:C34H46N4O5S,ExactMass:622.3189,
HRMS(+TOF MS):623.3270(M+H+).
6、截短侧耳素衍生物21~22的制备
(1)取0.5g(1.03mmol)实施例2制得的中间体2-6溶于20ml二氯甲烷,加入1.24mmol的R2基团供体、0.8g(1.55mmol)(7-氮杂苯并三唑-1-氧)三吡咯磷六氟磷酸盐(PYAOP)、0.37ml(2.1mmol)的DIPEA,加料完毕后,室温搅拌12h,饱和碳酸氢钠溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥,柱层析进行纯化(石油醚:乙酸乙酯=2:1→二氯甲烷:甲醇=20:1),浓缩后得到带有Boc保护基的目标化合物;
上述反应过程中,R2基团供体分别为Boc-L-苯丙氨酸、Boc-L-色氨酸,相应得到目标化合物21~22;
(2)将带有Boc保护基的目标化合物21~22分别加入1:1的三氟乙酸和二氯甲烷溶液,室温搅拌1h,反应结束后旋蒸除掉溶剂,相应获得截短侧耳素衍生物21~22。
合成路线如下式所示:
Figure BDA0003939948630000271
截短侧耳素衍生物21
1H NMR(400MHz,CDCl3)δ10.52(d,J=6.8Hz,1H),8.47(dd,J=7.3,3.5Hz,1H),7.55–7.47(m,1H),7.39–7.25(m,5H),7.25(d,J=7.1Hz,1H),7.07–6.97(m,1H),6.39(dd,J=17.4,11.0Hz,1H),5.66(d,J=8.5Hz,1H),5.31–5.22(m,1H),5.13(dd,J=17.6,8.1Hz,1H),3.85–3.76(m,1H),3.46–3.26(m,4H),2.84(dd,J=21.0,9.5Hz,1H),2.30–2.14(m,3H),2.04(s,2H),2.01–1.87(m,1H),1.73(d,J=14.5Hz,1H),1.65–1.35(m,10H),1.16–1.02(m,5H),0.85(d,J=6.9Hz,3H),0.58(d,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ217.17,172.95,168.28,139.71,139.16,137.99,135.50,130.49,129.58,129.06,127.19,124.45,122.24,120.66,117.43,74.79,70.01,58.31,57.74,45.65,44.86,44.15,41.97,41.18,38.76,36.90,36.23,34.68,30.62,27.07,26.56,25.06,16.87,15.08,11.74.Chemical Formula:C37H48N2O5S,Exact Mass:632.3284,HRMS(+TOF MS):633.3358(M+H+).
截短侧耳素衍生物22
1H NMR(400MHz,CDCl3)δ9.67(d,J=29.5Hz,1H),8.88(d,J=16.6Hz,1H),7.87(dd,J=12.5,8.2Hz,1H),7.61–7.52(m,1H),7.45(t,J=8.3Hz,1H),7.23–7.04(m,3H),7.04–6.90(m,2H),6.23(dd,J=16.8,11.1Hz,1H),5.62(dd,J=12.9,8.3Hz,1H),5.16–4.94(m,2H),4.44(d,J=7.0Hz,1H),3.71–3.40(m,2H),3.23(d,J=7.9Hz,2H),2.22–2.09(m,2H),2.01–1.89(m,2H),1.65–1.48(m,3H),1.45–1.13(m,10H),1.09–0.93(m,5H),0.64(dd,J=24.9,6.7Hz,3H),0.46(dd,J=37.5,6.9Hz,3H).13C NMR(101MHz,CDCl3)δ217.39,171.46,169.87,167.34,138.75,136.84,135.95,130.61,127.10,125.80,125.52,123.99,122.33,119.83,118.64,117.42,112.00,107.11,106.76,74.75,70.96,58.20,54.54,45.55,44.86,44.10,41.94,40.22,39.81,36.69,36.09,34.65,30.43,27.08,26.53,24.95,16.66,14.97,11.39.Chemical Formula:C39H49N3O5S,Exact Mass:671.3393,HRMS(+TOF MS):672.3467(M+H+).
图1~4是截短侧耳素衍生物5、9、13和20的核磁谱图。
上述截短侧耳素衍生物的制备产率归纳如下表2所示:
表2截短侧耳素衍生物编号及产率
Figure BDA0003939948630000281
效果实施例1抑菌试验
本发明所制得的截短侧耳素衍生物(截短侧耳素衍生物1~22)采用二倍稀释法测定其对耐甲氧西林金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus)、耐甲氧西林的表皮葡萄球菌(Methicillin-resistant Staphylococcus epidermidis)、金黄色葡萄球菌(Staphylococcus aureus)(S.aureus-1、S.aureus-29213和S.aureus-25923)、大肠杆菌(Escherichia coli)、无乳链球菌(S.agalactiae)和停乳链球菌(S.dysgalactiae equisimilis)(S.dysgalactiae-1、S.dysgalactiae-2、S.dysgalactiae-3)的最少抑菌浓度(MIC),结果见表3和表4,标准菌株购自ATCC,临床菌株是中国农业科学院兰州畜牧与兽药研究所保存。
表3截短侧耳素类衍生物的体外最少抑菌浓度
Figure BDA0003939948630000291
Figure BDA0003939948630000301
表4截短侧耳素类衍生物的体外最少抑菌浓度
Figure BDA0003939948630000302
从表3和表4可以看,此类截短侧耳素衍生物抑菌活性较好,其中截短侧耳素衍生物7、9、15、16、19和20的对MRSA、MRSE、S.aureus-1、S.aureus-29213、S.aureus-25923、S.agalactiae-1、S.dysgalactiae-1、S.dysgalactiae-2和S.dysgalactiae-3的抑制效果优于泰妙菌素、瑞他莫林和沃尼妙林,其中截短侧耳素衍生物9的MIC值是泰妙菌素的128倍以上、瑞他莫林32倍以上和沃尼妙林的16倍以上;截短侧耳素衍生物5、11、17和20对E.coli-25922的抑制效果优于泰妙菌素、瑞他莫林和沃尼妙林。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。

Claims (10)

1.一种截短侧耳素衍生化合物,其特征在于,该化合物的分子结构式如下式(I)所示:
Figure FDA0003939948620000011
其中,R1选自以下基团中的任意一种:
Figure FDA0003939948620000012
R2选自以下基团中的任意一种:
Figure FDA0003939948620000013
2.权利要求1所述截短侧耳素衍生化合物的药学上可接受的盐,其特征在于,所述盐为式(I)所示化合物与盐酸、硫酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、谷氨酸、天冬氨酸、琥珀酸、柠檬酸或苹果酸形成的盐。
3.权利要求1所述截短侧耳素衍生化合物的制备方法,其特征在于,该方法包括以下步骤:
(1)将截短侧耳素、对甲苯磺酰氯加入溶剂1中混合,搅拌下滴加10mol/L氢氧化钠溶液,55~60℃回流反应1~2h,将反应产物经过冷析、洗涤、干燥,得到如式(II)所示结构的中间体1;
Figure FDA0003939948620000021
(2)中间体2的合成包括以下两种途径:
途径一:
将中间体1与R1基团供体1加入溶剂2中,在35~36℃下搅拌滴加催化剂苄基三丁基氯化铵、20wt%氢氧化钠溶液,50~55℃搅拌反应4~5h,将反应产物浓缩、萃取、干燥、纯化,得到如下式(Ⅲ)所示结构的中间体2;其中,所述R1基团供体1选自二甲基半胱胺盐酸盐、半胱胺盐酸盐中的任意一种;
或,途径二:
将中间体1、碘化钾加入溶剂3中,70~75℃搅拌反应1h,往该反应液中加入R1基团供体2和碳酸钾,或者,往该反应液中加入含有R1基团供体2的20wt%氢氧化钠溶液;添加完成后搅拌反应4~5h,将反应产物洗涤、干燥,纯化,得到如下式(Ⅲ)所示结构的中间体2:
Figure FDA0003939948620000022
其中,所述R1基团供体2选自3-氨基-5-巯基-1,2,4-三氮唑、3-氨基苯硫酚、4-氨基苯硫酚或2-氨基苯硫酚中的任意一种;
(3)将中间体2与R2基团供体、催化剂添加到溶剂4中,在室温、搅拌进行酰胺化反应6h~12h,反应淬灭后,将反应产物经过萃取、干燥、纯化,得到如下式(Ⅳ)所示分子结构的带有Boc保护基的目标化合物:
Figure FDA0003939948620000031
其中,所述R2基团供体选自Boc-L-苯丙氨酸、Boc-L-苏氨酸、Boc-L-色氨酸、Boc-L-谷氨酰胺、Boc-L-精氨酸或Boc-L-组氨酸中的任意一种;
所述催化剂为Pyaop或由EDCI、HOBT、DIPEA构成的混合物;
(4)将所述带有Boc保护基的目标化合物添加到溶剂5中,室温下搅拌反应1~2h,将反应产物旋蒸除掉溶剂、烘干,得到式(I)所示截短侧耳素衍生物。
4.如权利要求3所述的制备方法,其特征在于,在步骤(1)中,所述对截短侧耳素、对甲苯磺酰氯、溶剂1、氢氧化钠溶液的摩尔体积比为10~15mmol:13~17mmol:12~15mL:2.0~2.5mL;
所述溶剂1为甲基叔丁基醚;
所述冷析、洗涤、干燥具体为:将反应产物冷却至0℃,过滤,将所得白色固体用甲基叔丁基醚冲洗三次,再用去离子水冲洗三次,在45℃下真空干燥。
5.如权利要求3所述的制备方法,其特征在于,在步骤(2)的途径一中,所述中间体1、R1基团供体1、溶剂2、苄基三丁基氯化铵、氢氧化钠溶液的摩尔体积比为7.1~20.8mmol:14.2~41.6mmol:28~80mL:0.7~2.1mmol:5~15mL;
所述溶剂2为四氢呋喃;
所述浓缩、萃取、干燥、纯化为:反应液浓缩后用二氯甲烷萃取,用无水硫酸钠干燥,柱层析按乙酸乙酯/1%二乙胺进行纯化。
6.如权利要求3所述的制备方法,其特征在于,在步骤(2)的途径二中,往反应液中添加R1基团供体2和碳酸钾时,所述中间体1、碘化钾、溶剂3、R1基团供体2和碳酸钾的摩尔体积比为18~19mmol:20~21mmol:95~105mL:20~21mmol:37~38mmol;
往该反应液中加入含有R1基团供体2的20wt%氢氧化钠溶液时,所述中间体1、碘化钾、溶剂3、R1基团供体2和氢氧化钠溶液的摩尔体积比为18~19mmol:20~21mmol:95~105mL:24~25mmol:40~50mL;
所述溶剂3为乙酸乙酯;
所述洗涤、干燥,纯化具体为:将反应产物用去离子水洗3次,用无水硫酸钠干燥,柱层析按石油醚:乙酸乙酯=1:2。
7.如权利要求3所述的制备方法,其特征在于,在步骤(3)中,所述中间体2、R2基团供体、催化剂、溶剂4的摩尔体积比为1.2~1.3mmol:1.4~1.6mmol:5.3~5.8mmol:20~25mL;
所述催化剂中EDCI、HOBT、DIPEA的摩尔比为1.4~1.6mmol:1.4~1.6mmol:2.5~2.6mmol;
所述中间体2、R2基团供体、催化剂、溶剂4的摩尔体积比为1.0~1.1mmol:1.2~1.3mmol:1.5~1.7mmol:20~25mL;
所述溶剂4为二氯甲烷;
所述淬灭通过饱和碳酸氢钠溶液进行淬灭,所述萃取通过二氯甲烷萃取,所述干燥通过无水硫酸钠,所述纯化通过柱层析进行纯化。
8.如权利要求3所述的制备方法,其特征在于,在步骤(4)中,目标化合物与溶剂5的摩尔体积比为0.5~1mmol:2~4mL;
所述溶剂5为按体积比为1:1混合的三氟乙酸与二氯甲烷。
9.权利要求1所述的截短侧耳素衍生化合物、权利要求2或权利要求3所述截短侧耳素衍生化合物的药学上可接受的盐在制备治疗感染性疾病的抗菌药物中的应用。
10.一种抗菌药物,其特征在于,该药物包括权利要求1所述截短侧耳素衍生化合物以及一种或多种该截短侧耳素衍生化合物在药学上可接受的载体、赋形剂或稀释剂;
或,该药物包括权利要求2或权利要求2所述的药学上可接受的盐以及该盐在药学上可接受的载体、赋形剂或稀释剂。
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CN114716384A (zh) * 2022-03-10 2022-07-08 中国农业科学院兰州畜牧与兽药研究所 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用
CN114634498A (zh) * 2022-03-29 2022-06-17 陕西科技大学 一种含噻唑-吡啶苄基季铵盐侧链的截短侧耳素衍生物及其制备方法与应用
CN114940671A (zh) * 2022-05-10 2022-08-26 华南农业大学 一种具有4-氨基苯硫醇侧链的截短侧耳素衍生物及其制备方法和应用

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