CN105111219B - 亲水性长波长二氢卟吩类光、声敏剂及其制备方法与应用 - Google Patents
亲水性长波长二氢卟吩类光、声敏剂及其制备方法与应用 Download PDFInfo
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- CN105111219B CN105111219B CN201510455477.3A CN201510455477A CN105111219B CN 105111219 B CN105111219 B CN 105111219B CN 201510455477 A CN201510455477 A CN 201510455477A CN 105111219 B CN105111219 B CN 105111219B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一类亲水性长波长二氢卟吩类光、声敏剂及其制备方法与应用,属于化学医药领域。所述化合物具有如下通式:
Description
技术领域
本发明涉及一类亲水性长波长二氢卟吩类光、声敏剂及其制备方法与应用,属于化学医药领域。
背景技术
光动力学治疗(Photodynamic therapy,PDT)与声动力学治疗(Sonodynamictherapy,SDT),分别是通过光敏剂(photosensitizer)或光敏剂(sonosensitizer) 在光或超声激发下发生化学反应杀死肿瘤细胞从而达到治疗目的的一种医疗技术。其中光动力学治疗(Photodynamic therapy,PDT)是利用光敏剂和可见光在有氧气存在的环境中,通过反应产生的单线态氧(1O2)和自由基对肿瘤细胞有很大的杀伤力。与外科手术、化学治疗、放射治疗等传统的治疗方法相比,PDT 有对靶组织选择性高、副作用小、对内脏器官无损伤等优点;声动力学治疗 (Sonodynamic therapy,SDT),则是在光动力学治疗(Photodynamictherapy,PDT) 的基础上发展起来的一种可用于恶性、深度肿瘤临床治疗的新方法。利用声敏剂分子可在肿瘤细胞内富集,采用超声激发取代光动力学治疗的光激发,产生具有细胞毒性的单线态氧和形成超声空化等作用,导致肿瘤细胞凋亡或死亡。与光动力学疗法相比,还具有穿透力强,无创等优点。很多光敏型化合物也具有声敏作用,光敏剂可以作为声敏剂而使用。目前光、声敏剂还存在对肿瘤细胞选择性不高,最大照射波长较短,治疗窗口窄,生理条件下溶解性较差以及在体内清除速率较慢等缺点。因此,需要开发一类具有较长的照射波长且水溶性良好的光、声敏剂来推动光动力学治疗与声动力学治疗的发展。
发明内容
本发明通过合成一类亲水性长照射波长二氢卟吩类光、声敏剂,找到了具有较长的最大吸收波长且良好的水溶性,可用于光、声动力学治疗的抗肿瘤化合物。
本发明所述的二氢卟吩类光、声敏剂,具有如下通式I、II、III和IV:
其中:R1为羟基、甲氧基、
R2为中任一;
R3为H、Boc基团、甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、脯氨酸、色氨酸、酪氨酸、丝氨酸、半胱氨酸、蛋氨酸、天冬酰胺、谷氨酰胺、赖氨酸或组氨酸等20种常见氨基酸;
R4为OH、甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、脯氨酸、色氨酸、酪氨酸、丝氨酸、半胱氨酸、蛋氨酸、天冬酰胺、谷氨酰胺、赖氨酸或组氨酸等20种常见氨基酸;
n为1~5中任一整数。
M选自Cu2+,Fe2+,Zn2+,Mg2+,Ni2+,Co2+,Sn4+,Pt2+,Ti4+,Rh2+,Ru4+, Ir3+。
所述的二氢卟吩类光、声敏剂的制备方法,包括如下步骤:
①以化合物1为原料,溶于体积比为4~5:1的DCM与DMF的混合溶液,得到 0.1M化合物1的混合溶液;再依次加入EDCI、N-Boc-ethylenediamine和TEA,化合物1:EDCI:N-Boc-ethylenediamine:TEA的摩尔比为1:1~2:1~2:0.1~ 0.5,酰胺化反应0.5~4小时,再加入碘甲烷和无水碳酸钾反应1~4小时;其中,化合物1:碘甲烷:无水碳酸钾的摩尔比为1:2~10:2~10,反应结束后,加入二氯甲烷,水洗多次,干燥,浓缩有机相,硅胶柱层析,得到化合物2a。
将化合物2a溶于体积比为乙醚/二氯甲烷=1:1的混合溶液即为溶液A,冷却至零下90℃;配制0.1M Br2的体积比为乙醚/二氯甲烷=1:1的混合溶液即为溶液 B,溶液B加入恒压漏斗中;将溶液B缓慢滴加至溶液A中,40min滴加完毕,保持零下90℃反应2h;将反应液转移至分液漏斗中,冰水洗2次,有机相无水硫酸钠干燥,过滤,浓缩得固体残渣;将固体残渣80℃条件下反应2h,用二氯甲烷溶解转移至分液漏斗中,有机相水洗2次、饱和碳酸氢钠洗1次,收集有机层,加入无水硫酸钠干燥,过滤,旋干;硅胶柱层析分离,得到化合物3a。
将化合物3a溶于1,4-二氧六环中,浓度为0.1M。依次加入苯硼酸、三苯基膦、三(二亚苄基丙酮)二钯和碳酸铯,化合物3a:苯硼酸:三苯基膦:三(二亚苄基丙酮)二钯:碳酸铯摩尔比为1:2~5:05~1:0.1~0.5:1~5,N2保护,80℃搅拌反应4h。TLC监测反应终点,旋蒸除去1,4-二氧六环;二氯甲烷溶解,有机相用去离子水洗,收集有机相,无水硫酸钠干燥,过滤,旋蒸,硅胶柱层析分离得到化合物4a。
将化合物4a溶于二氯甲烷,在0℃下加入TFA,化合物4a的浓度为0.1M,反应结束后,加入饱和碳酸氢钠溶液,调节pH为8~9,二氯甲烷萃取,干燥浓缩,得到化合物5a。
将化合物5a溶于DMF,化合物5a的浓度为0.1M,依次加入EDCI、HOBt、 TEA和N-Boc-氨基酸,投料比化合物5a:EDCI:HOBt:TEA:N-Boc-氨基酸的摩尔比为1:2~5:2~5:0.1:2~5常温下反应1~6小时,浓缩,硅胶柱层析分离得到化合物6a。
将化合物6a溶于二氯甲烷,在0℃下加入TFA,化合物6a的浓度为0.1M,反应结束后,加入饱和碳酸氢钠溶液,调节pH为8~9,二氯甲烷萃取,干燥浓缩,得到化合物7a。
将化合物7a溶于0.1M NaOH水溶液,加入甲醇使化合物7a溶解,化合物 7a的浓度为0.1M,室温反应2~8小时,反应结束后,反相硅胶柱层析分离,得到化合物8a。
②以化合物1为原料,溶于体积比为4~5:1的DCM与DMF的混合溶液,得到 0.1M化合物1的混合溶液;再依次加入EDCI、氨基乙酸叔丁酯和TEA,化合物1:EDCI:氨基乙酸叔丁酯:TEA的摩尔比为1:1~2:1~2:0.1~0.5,酰胺化反应0.5~4小时,再加入碘甲烷和无水碳酸钾反应1~4小时;其中,化合物1:碘甲烷:无水碳酸钾的摩尔比为1:2~10:2~10,反应结束后,加入二氯甲烷,水洗多次,干燥,浓缩有机相,硅胶柱层析,得到化合物2b。
化合物3b~化合物6b的合成方法与上述化合物3a~化合物6a的合成方法相同,化合物7b的合成方法与化合物8a的合成方法相同。
③将化合物1溶于二氯甲烷,浓度为0.1M,加入碘甲烷和无水碳酸钾反应1~4 小时,化合物1:碘甲烷:无水碳酸钾的摩尔比为1:2~10:2~10,反应结束后,加入二氯甲烷,水洗多次,干燥,浓缩有机相,硅胶柱层析,得到化合物 2c。
化合物3c~化合物5c的合成方法与化合物3a~化合物5a的合成方法相同。
④分别以上述制得的化合物4a、6a、4b、6b和4c为原料,溶于甲醇,浓度为 0.1M,加入金属氯化物或乙酸根络合物,其中化合物4a、6a、4b、6b和4c与金属氯化物或乙酸根络合物的摩尔比为1:1~6,甲醇溶解,加热回流,反应2~ 8小时,依次得到相应的金属络合物4a(M)、6a(M)、4b(M)、6b(M)和4c(M)。
⑤分别以化合物4a(M)、6a(M)、4b(M)、6b(M)和4c(M)为原料,按照化合物5a、 8a、5b、7b和5c的合成方法,合成5a(M)、8a(M)、5b(M)、7b(M)和5c(M)。
上述制备的二氢卟吩类光、声敏剂用于制备抗肿瘤药物或作为活性部分制备靶向性抗肿瘤药物。
本发明所述的二氢卟吩类光、声敏剂在体外抗肿瘤活性评价中对人肝癌细胞HepG2增殖具有较强的抑制作用。光活性与暗活性的比值以及声活性与暗活性的比值均高于作为阳性对照的血卟啉单甲醚。可用于肿瘤治疗的光动力学治疗、声动力学治疗方法中光敏剂和声敏剂的制备。
具体实施方式
下述非限制性实施例可以使本领域的普通技术人员更全面地理解本发明,但不以任何方式限制本发明。
实施例1
化合物8a-TEL的合成
(1)将53.2mg市售化合物1溶于10mL甲醇,滴加200μL浓硫酸,0~50℃温度下搅拌,氮气球保护,TLC监测,反应4h后停止,向反应液中加入20mL去离子水,并转移至125mL分液漏斗,用二氯甲烷萃取(30ml×3),合并二氯甲烷层,加入无水硫酸钠干燥,抽滤,浓缩得到粗产物。将粗产物通过硅胶柱层析(石油醚:乙酸乙酯=1:4)纯化,得到44.2mg墨绿色固体,即二氢卟吩15, 17-二甲酯,产率77%。ESI-MS m/z:625.4[M+H]+.1H NMR(400MHz,CDCl3)δ9.64(1H,s),9.50(1H,s),8.72(1H,s),8.01(1H,dd,J=17.8,11.5Hz),6.32(1H,dd, J=17.8,1.2Hz),6.12(1H,dd,J=11.5,1.2Hz),5.51(1H,d,J=18.7Hz),5.26(1H, d,J=18.7Hz),4.46(1H,q,J=7.56Hz),4.12(1H,d,J=7.1Hz),3.82(3H,s), 3.74(2H,m),3.72(3H,s),3.70(3H,s),3.62(3H,s),3.25(3H,s),2.55(1H,m),2.19 (1H,m),2.16(1H,m),1.87(1H,m),1.79(3H,d,J=7.1Hz),1.68(3H,t,J=7.6 Hz),-1.29(1H,s).
(2)将725mg,二氢卟吩15,17二甲酯,溶于体积比为4:1的DCM与 DMF的混合溶液,得到0.1M的混合溶液;再依次加入24.4mg EDCI,27.2mg N-Boc-ethylenediamine,0.1mlTEA化合物,反应0.5~4小时经酰胺化反应,TLC 监测,原料反应完全后,反应液用50mL二氯甲烷稀释,置于250mL分液漏斗中,用去离子水(50mL×3)水洗,二氯甲烷层用无水硫酸钠干燥,浓缩得到粗产物,硅胶柱层析分离(展开体系丙酮:石油醚=1:3),湿法上样,得418mg产物2a-TEL,收率为47%。
ESI-MS m/z for C43H54N607[M+H]+calcd 766.4054,found 767.4143.
1H NMR(400MHz,CD3COCD3)δ9.59(1H,s,H-10),9.57(1H,s,H-5),9.07 (1H,s,H-20),8.14(1H,t,J=5.3Hz,H-13N1),8.05(1H,dd,J=11.6,17.8Hz, H-31),6.35(1H,s,H-13N2),6.25(1H,dd,J=1.32,17.8Hz,H-32),6.98(1H,dd,J= 1.32,17.8Hz,H-32),5.65(1H,d,J=19.1Hz,H-151),5.38(1H,d,J=19.1Hz, H-151),4.65(1H,q,J=7.2Hz,H-18),4.50(1H,m,H-17),3.91(1H,m,H-132), 3.78(1H,m,H-132),3.75(3H,s,H-121),3.60(3H,s,H-174),3.56(2H,m,H-133), 3.54(2H,q,J=7.6Hz,H-81),3.47(3H,s,H-21),3.42(3H,s,H-153),3.14(3H,s, H-71),2.69(1H,m,H-172),2.34(1H,m,H-171),2.26(1H,m,H-172),1.79(1H,m, H-171),1.70(3H,d,J=7.2Hz,H-181),1.59(3H,t,J=7.6Hz,H-82),1.44(9H,s, H-Boc),-1.66,-1.95(2H,s,s,H-N-21,23).
(3)用乙醚/二氯甲烷=1:1溶液20ml将124mg的2a-TEL溶解转移至管式反应器内,-76℃,配制0.1M Br2的乙醚/二氯甲烷=1:1溶液,取3307μl(2.05equ)于恒压漏斗中。缓慢滴加,40min滴加完毕,之后保持低温反应2h。将反应液转移至100ml分液漏斗中,冰水洗30ml×2次,有机相无水硫酸钠干燥,过滤,浓缩得固体残渣后80℃加热反应2h。二氯甲烷将反应物溶解转移至100ml分液漏斗中,有机相用去离子水洗50ml×2次、饱和碳酸氢钠洗50ml×1次,收集有机层,加入无水硫酸钠干燥,过滤,旋干。硅胶柱层析分离(展开体系丙酮:石油醚=1:4),湿法上样,得39mg产物3a-TEL,收率29%。
ESI-MS m/z for C43H5379BrN607[M+H]+calcd 844.3159,found 845.3256,C43H5381BrN607[M+H]+calcd 846.3139,found 847.3242.
1H NMR(400MHz,CD3COCD3)δ9.27(1H,s,H-10),9.04(1H,s,H-5), 8.93(1H,s,H-20),7.99(1H,t,J=5.2Hz,H-13N1),7.94(1H,d,J=14.1Hz,H-31), 6.96(1H,d,J=14.0Hz,H-32),6.31(1H,t,J=5.2Hz,H-13N2),5.63(1H,d,J= 19.0Hz,H-151),5.36(1H,d,J=19.0Hz,H-151),4.61(1H,q,J=7.2Hz,H-18), 4.48(1H,m,H-17),3.83(1H,m,H-132),3.78(1H,m,H-132),3.74(3H,s,H-121), 3.60(3H,s,H-174),3.53(2H,m,H-133),3.31(3H,s,H-21),3.20(2H,q,J=7.6Hz, H-81),3.05(3H,s,H-153),2.81(3H,s,H-71),2.70(1H,m,H-172),2.34(1H,m, H-171),2.27(1H,m,H-172),1.82(1H,m,H-171),1.66(3H,d,J=7.2Hz,H-181), 1.44(9H,s,H-Boc),1.43(3H,m,H-82),-1.95,-2.13(2H,s,s,H-N21,23).
称取39mg的3a-TEL,11mg的2-噻吩硼酸(2.0equ),9mg三苯基膦 (0.8equ),4mg三(二亚苄基丙酮)二钯(0.1equ),28mg碳酸铯(2.0equ)于100ml 单口瓶内,10ml 1,4-二氧六环溶解,N2气球保护,80℃搅拌反应4h。TLC(丙酮:石油醚=1:2)监测反应终点,停止反应,旋蒸除去1,4-二氧六环。二氯甲烷将浓缩液转移至100ml分液漏斗中,有机相用去离子水洗50ml×3次,收集有机相,无水硫酸钠干燥,过滤,旋蒸。硅胶柱层析分离(展开体系丙酮:石油醚=1:4),湿法上样,得到21mg的产物4a-TEL,收率53%。
ESI-MS m/z for C47H56N607S[M+H]+calcd 848.3931,found 849.4022.
1H NMR(400MHz,CD3COCD3)δ9.54(1H,s,H-10),9.50(1H,s,H-5), 9.02(1H,s,H-20),8.13(1H,d,J=16.3Hz,H-31),8.07(1H,t,J=5.3Hz,H-13N1), 7.70(1H,d,J=16.3Hz,H-32),7.51(1H,d,J=5.0Hz,H-32-thienyl),7.32(1H,d,J =3.4Hz,H-32-thienyl),7.14(1H,dd,J=3.5,5.0Hz,H-32-thienyl),6.35(1H,s, H-13N2),5.61(1H,d,J=19.5Hz,H-151),5.37(1H,d,J=19.1Hz,H-151),4.64 (1H,q,J=7.2Hz,H-18),4.49(1H,m,H-17),3.87(1H,m,H-132),3.76(1H,m, H-132),3.75(3H,s,H-121),3.61(3H,s,H-174),3.57(2H,m,H-133),3.54(2H,q,J =7.6Hz,H-81),3.42(3H,s,H-21),3.38(3H,s,H-153),3.10(3H,s,H-71),2.72 (1H,m,H-172),2.37(1H,m,H-171),2.27(1H,m,H-172),1.82(1H,m,H-171), 1.69(3H,d,J=7.2Hz,H-181),1.59(3H,t,J=7.6Hz,H-82),1.44(9H,s,H-Boc), -1.62,-1.88(2H,s,s,H-N21,23).
称取38mg的4a-TEL于25ml单口烧瓶中,加入三氟甲酸:二氯甲烷=1:10 溶液5.5ml,N2气置换后连接尾气吸收装置,室温搅拌反应。反应完成后,将反应液转移至100ml分液漏斗中,用去离子水洗50ml×2次,饱和碳酸氢钠洗 50ml×1次,有机相无水硫酸钠干燥,过滤旋蒸,得30mg产物5a-TEL,收率为88%。
ESI-MS m/z for C42H48N605S[M+H]+calcd 748.3407,found 749.3494.1H NMR(400MHz,CD3COCD3)δ9.60(1H,s,H-10),9.49(1H,s,H-5),9.02(1H,s, H-20),8.08(1H,d,J=16.3Hz,H-31),7.92(1H,s,H-13N1),7.67(1H,d,J=16.3 Hz,H-32),7.49(1H,d,J=5.0Hz,H-32-thienyl),7.29(1H,d,J=3.2Hz, H-32-thienyl),7.12(1H,dd,J=3.5,5.0Hz,H-32-thienyl),5.64(1H,d,J=19.1Hz, H-151),4.63(1H,q,J=7.2Hz,H-18),4.48(1H,m,H-17),3.96(1H,m,H-132), 3.80(1H,m,H-132),3.73(3H,s,H-121),3.62(2H,m,H-133),3.60(3H,s,H-174), 3.57(2H,q,J=7.6Hz,H-81),3.44(3H,s,H-21),3.37(3H,s,H-153),3.11(3H,s, H-71),2.71(1H,m,H-172),2.35(1H,m,H-171),2.23(1H,m,H-172),1.79(1H,m, H-171),1.69(3H,d,J=7.2Hz,H-181),1.61(3H,t,J=7.6Hz,H-82),-1.64,-1.89(2H,s,s,H-N21,23).
5a-TEL称取30mg 32-噻吩-131-乙二胺-CHCDME,5ml DMF溶解于25ml 单口烧瓶内,加入32mg N,N-叔丁氧羰基-L-赖氨酸(2.0equ),53mg HBTU(3.5 equ),20ml Et3N(5.0equ),N2保护下30℃搅拌反应3h。停止反应,用乙酸乙酯稀释反应液并转移至100ml分液漏斗中,去离子水洗50ml×3次,再饱和食盐水洗50ml×1次,无水硫酸钠干燥,过滤,旋蒸。硅胶柱层析分离(展开体系丙酮:石油醚=1:2),湿法上样,得36.8mg产物6a-TEL,收率86%。
ESI-MS m/z for C58H76N8010S[M+H]+calcd 1076.5405,found 1077.5507.
1H NMR(400MHz,CD3COCD3)δ9.53(1H,s,H-10),9.51(1H,s,H-5), 9.02(1H,s,H-20),8.11(1H,d,J=16.3Hz,H-31),7.93(1H,s,H-13N1),7.71(1H, m,H-N),7.66(1H,d,J=16.3Hz,H-32),7.52(1H,d,J=5.0Hz,H-32-thienyl), 7.30(1H,d,J=3.1Hz,H-32-thienyl),7.14(1H,dd,J=3.6,4.8Hz,H-32-thienyl), 6.10(1H,d,J=7.5Hz,H-13N2),5.85(1H,s,H-N),5.55(1H,d,J=19.0Hz,H-151), 5.35(1H,d,J=18.9Hz,H-151),4.65(1H,q,J=7.2Hz,H-18),4.49(1H,m,H-17), 4.13(1H,m,H-Lys),3.75(2H,m,H-132),3.73(3H,s,H-121),3.62(3H,s,H-174), 3.61(2H,m,H-133),3.60(2H,m,H-81),3.36(3H,s,H-21),3.32(3H,s,H-153), 3.13(3H,s,H-71),2.74(1H,m,H-172),2.38(1H,m,H-171),2.30(1H,m,H-172), 1.84(2H,m,H-Lys),1.74(1H,m,H-171),1.70(3H,d,J=7.2Hz,H-181),1.62(3H, t,J=7.6Hz,H-82),1.41(6H,m,H-Lys),1.36(9H,s,H-Boc),1.33(9H,s,H-Boc),-1.62,-1.89(2H,s,s,H-N21,23).
称取29mg 6a-TEL于25ml单口瓶中,加入三氟乙酸:二氯甲烷=1:10溶液5.5ml,N2保护后连接尾气吸收装置室温下搅拌反应3h,用二氯甲烷将反应液转移至100ml分液漏斗中,先用去离子水洗50ml×2次,再用饱和碳酸氢钠洗50ml×1次,收集有机相。无水硫酸钠干燥,过滤,旋蒸除去溶剂,得到 7a-TEL,收率88%。
ESI-MS m/z for C48H60N806S[M+H]+calcd 876.4357,found 877.4524.
1H NMR(400MHz,CD3COCD3)δ9.72(1H,s,H-10),9.66(1H,s,H-5), 9.07(1H,s,H-20),8.28(1H,d,J=16.3Hz,H-31),8.22(1H,m,H-13N1),7.86(1H, d,J=16.3Hz,H-32),7.55(1H,d,J=5.1Hz,H-32-thienyl),7.44(1H,d,J=3.3Hz, H-32-thienyl),7.19(1H,dd,J=3.2,5.1Hz,H-32-thienyl),5.61(1H,d,J=19.0Hz, H-151),5.39(1H,d,J=19.1Hz,H-151),4.66(1H,q,J=7.2Hz,H-18),4.51(1H,m, H-17),3.93(1H,m,H-Lys),3.86(1H,m,H-132),3.77(1H,m,H-132),3.74(3H,s, H-121),3.72(2H,m,H-133),3.69(2H,m,H-81),3.61(3H,s,H-174),3.55(1H,s, H-Lys),3.49(3H,s,H-21),3.48(3H,s,H-153),3.24(3H,s,H-71),2.97(1H,m, H-172),2.85(4H,s,H-Lys),2.72(1H,m,H-171),2.36(1H,m,H-172),2.32(1H,m, H-171),2.26(1H,m,H-172),1.80(6H,m,H-Lys),1.71(3H,d,J=7.2Hz,H-181), 1.67(3H,t,J=7.6Hz,H-82),-1.55,-1.83(2H,s,s,H-N21,23).
称取20mg 7a-TEL于25ml单口瓶中,加入5ml(最终浓度1M)NaOH溶液和甲醇(1:1),N2保护,室温下搅拌反应6h,反应结束后,反相硅胶柱层析,得到8a-TEL,收率88%。
ESI-MS m/z for C48H60N806S[M+H]+calcd 876.4357,found 877.4524.
1H NMR(400MHz,CD3COCD3)δ9.72(1H,s,H-10),9.66(1H,s,H-5), 9.07(1H,s,H-20),8.28(1H,d,J=16.3Hz,H-31),8.22(1H,m,H-13N1),7.86(1H, d,J=16.3Hz,H-32),7.55(1H,d,J=5.1Hz,H-32-thienyl),7.44(1H,d,J=3.3Hz, H-32-thienyl),7.19(1H,dd,J=3.2,5.1Hz,H-32-thienyl),5.61(1H,d,J=19.0Hz, H-151),5.39(1H,d,J=19.1Hz,H-151),4.66(1H,q,J=7.2Hz,H-18),4.51(1H,m, H-17),3.93(1H,m,H-Lys),3.86(1H,m,H-132),3.77(1H,m,H-132),3.74(3H,s, H-121),3.72(2H,m,H-133),3.69(2H,m,H-81),3.61(3H,s,H-174),3.55(1H,s, H-Lys),3.49(3H,s,H-21),3.48(3H,s,H-153),3.24(3H,s,H-71),2.97(1H,m, H-172),2.85(4H,s,H-Lys),2.72(1H,m,H-171),2.36(1H,m,H-172),2.32(1H,m, H-171),2.26(1H,m,H-172),1.80(6H,m,H-Lys),1.71(3H,d,J=7.2Hz,H-181), 1.67(3H,t,J=7.6Hz,H-82),-1.55,-1.83(2H,s,s,H-N21,23).
应用例1
本发明部分中间产物与目标化合物(如下式 )的体外抗癌活性评价:
部分测试化合物为:5c-1:(R=Phenyl),5c-2:(4-biphenyl),5c-3:(2-naphthyl), 5c-4:(2-thienyl)和8a-TEL
光动力活性:
将化合物5c-1,5c-2,5c-3,5c-4,8a-TEL、阳性对照药血卟啉单甲醚用DMSO 溶解,-4℃保存;使用时,用细胞培养液稀释至DMSO的最终浓度<0.1%。
将处于对数生长期的HepG2肝癌细胞,以5×103个/空接种于96孔板中,每孔加入细胞悬液100μL,培养24h后,加入100μL药液,终浓度分别为100μmol/L、 30μmol/L、10μmol/L、1μmol/L、0.1μmol/L、0.01μmol/L的待测化合物,设置空白组(含培养液,无细胞)、对照组(培养细胞不加药),细胞在37℃培养箱(5% CO2)中孵育24h后,进行光毒性实验。培养板距离光源高度为20cm,光强 1.7J/cm2,波长660nmLED,时间2min,再放入37℃培养箱(5%CO2)中孵育 24h后,每孔加入浓度为5mg/mL的MTT溶液20μL,继续培养4h,吸走上清液,加入100μLDMSO。酶标仪测定570nm波长下各孔的吸光度(OD值),计算 IC50。结果见表1
声动力活性:
同光活性评价操作的区别在于:将加入药液的96孔板置于底部发超声的装置上,加入脱气水,使悬浮于水面上,距超声发声探头2cm,超声激发(2MHz, 2W)2min,再放入37℃培养箱(5%CO2)中孵育24h后,每孔加入浓度为5mg/mL 的MTT溶液20μL,继续培养4h,吸走上清液,加入100μLDMSO。酶标仪测定570nm波长下各孔的吸光度(OD值),计算IC50。结果见表2。
暗毒性活性:
同光活性评价操作的区别在于:将加入药液的96孔板置于暗室中2min,再放入37℃培养箱(5%CO2)中孵育24h后,每孔加入浓度为5mg/mL的MTT溶液20μL,继续培养4h,吸走上清液,加入100μLDMSO。酶标仪测定570nm,波长下各孔的吸光度(OD值),计算IC50。
表1目标化合物对HepG2肝癌细胞的体外光活性与暗毒性
表2目标化合物对HepG2肝癌细胞的体外声动力活性与暗毒性
上述实验结果显示:
(1)见表1,设计合成的系列两亲型二氢卟吩类化合物及其中间产物在很小的能量的光照射下(光强1.7J/cm2),都显示较强的光活性,其中8a-TEL 的光活性最强,远远高于已上市的对照品血卟啉单甲醚,同时所有化合物的暗毒性均很弱,说明化合物本身在非光照条件下,对细胞的毒性很小。
(2)见表2,设计合成的系列化合物及其中间产物也具有较强的声动力活性,要优于对照品血卟啉单甲醚。
综上所述,本发明所述的化合物对人肝癌细胞HepG2显示很好的光活性和声活性,同时毒性弱。具有高效,低毒,治疗波长红移等优点。本发明的化合物可以作为性能优异的光敏剂和声敏剂用于肿瘤的光动力学和声动力学治疗。
Claims (3)
1.一种亲水性长波长二氢卟吩类光、声敏剂,其特征在于,具有如下通式II和IV:
其中:R1为羟基或
R2为中任一;
R3为甘氨酸基、丙氨酸基、缬氨酸基、亮氨酸基、异亮氨酸基、苯丙氨酸基、脯氨酸基、色氨酸基、酪氨酸基、丝氨酸基、半胱氨酸基、蛋氨酸基、天冬酰胺基、谷氨酰胺基或组氨酸基;
n为1~5中任一整数;
M选自Cu2+,Fe2+,Zn2+,Mg2+,Ni2+,Co2+,Sn4+,Pt2+,Ti4+,Rh2+,Ru4+,Ir3+。
2.一种亲水性长波长二氢卟吩类光、声敏剂8a、5c和8a(M)的制备方法,其特征在于,为如下步骤:
①以化合物1为原料,溶于体积比为4~5:1的DCM与DMF的混合溶液,得到0.1M化合物1的混合溶液;再依次加入EDCI、和TEA,化合物1:EDCI:TEA的摩尔比为1:1~2:1~2:0.1~0.5,酰胺化反应0.5~4小时,再加入碘甲烷和无水碳酸钾反应1~4小时;其中,化合物1:碘甲烷:无水碳酸钾的摩尔比为1:2~10:2~10,反应结束后,加入二氯甲烷,水洗多次,干燥,浓缩有机相,硅胶柱层析,得到化合物2a;
将化合物2a溶于体积比为乙醚/二氯甲烷=1:1的混合溶液即为溶液A,冷却至零下90℃;配制0.1M Br2的体积比为乙醚/二氯甲烷=1:1的混合溶液即为溶液B,溶液B加入恒压漏斗中;将溶液B缓慢滴加至溶液A中,40min滴加完毕,保持零下90℃反应2h;将反应液转移至分液漏斗中,冰水洗2次,有机相无水硫酸钠干燥,过滤,浓缩得固体残渣;将固体残渣80℃条件下反应2h,用二氯甲烷溶解转移至分液漏斗中,有机相水洗2次、饱和碳酸氢钠洗1次,收集有机层,加入无水硫酸钠干燥,过滤,旋干;硅胶柱层析分离,得到化合物3a;
将化合物3a溶于1,4-二氧六环中,浓度为0.1M;依次加入2-噻吩硼酸、三苯基膦、三(二亚苄基丙酮)二钯和碳酸铯,化合物3a:2-噻吩硼酸:三苯基膦:三(二亚苄基丙酮)二钯:碳酸铯摩尔比为1:2~5:05~1:0.1~0.5:1~5,N2保护,80℃搅拌反应4h;TLC监测反应终点,旋蒸除去1,4-二氧六环;二氯甲烷溶解,有机相用去离子水洗,收集有机相,无水硫酸钠干燥,过滤,旋蒸,硅胶柱层析分离得到化合物4a;
将化合物4a溶于二氯甲烷,在0℃下加入TFA,化合物4a的浓度为0.1M,反应结束后,加入饱和碳酸氢钠溶液,调节pH为8~9,二氯甲烷萃取,干燥浓缩,得到化合物5a;
将化合物5a溶于DMF,化合物5a的浓度为0.1M,依次加入EDCI、HOBt、TEA和HOOCCH2NHBoc,投料比化合物5a:EDCI:HOBt:TEA:HOOCCH2NHBoc的摩尔比为1:2~5:2~5:0.1:2~5,常温下反应1~6小时,浓缩,硅胶柱层析分离得到化合物6a;
将化合物6a溶于二氯甲烷,在0℃下加入TFA,化合物6a的浓度为0.1M,反应结束后,加入饱和碳酸氢钠溶液,调节pH为8~9,二氯甲烷萃取,干燥浓缩,得到化合物7a;
将化合物7a溶于0.1M NaOH水溶液,加入甲醇使化合物7a溶解,化合物7a的浓度为0.1M,室温反应2~8小时,反应结束后,反相硅胶柱层析分离,得到化合物8a;
R2如权利要求1中所述,硼酸试剂为R2B(OH)2;
②将化合物1溶于二氯甲烷,浓度为0.1M,加入碘甲烷和无水碳酸钾反应1~4小时,化合物1:碘甲烷:无水碳酸钾的摩尔比为1:2~10:2~10,反应结束后,加入二氯甲烷,水洗多次,干燥,浓缩有机相,硅胶柱层析,得到化合物2c;
化合物3c~化合物5c的合成方法与化合物3a~化合物5a的合成方法相同;
③以上述制得的化合物6a为原料,溶于甲醇,浓度为0.1M,加入金属氯化物或乙酸根络合物,其中化合物6a与金属氯化物或乙酸根络合物的摩尔比为1:1~6,甲醇溶解,加热回流,反应2~8小时,依次得到相应的金属络合物6a(M);
再以化合物6a(M)为原料,按照化合物8a的合成方法,合成8a(M),金属氯化物或乙酸根络合物中的金属和M选自Cu2+,Fe2+,Zn2+,Mg2+,Ni2+,Co2+,Sn4+,Pt2+,Ti4+,Rh2+,Ru4+,Ir3+。
3.权利要求1所述的亲水性长波长二氢卟吩类光、声敏剂用于制备靶向性抗肿瘤药物或作为活性部分制备靶向性抗肿瘤药物的用途。
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