CN115368347A - 一类具有ptt和pdt效应的近红外分子及其用途 - Google Patents
一类具有ptt和pdt效应的近红外分子及其用途 Download PDFInfo
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- CN115368347A CN115368347A CN202211065844.5A CN202211065844A CN115368347A CN 115368347 A CN115368347 A CN 115368347A CN 202211065844 A CN202211065844 A CN 202211065844A CN 115368347 A CN115368347 A CN 115368347A
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
Description
技术领域
本发明属于药物化学生物学技术领域,具体涉及一类具有光热治疗(PTT,Photothermal Therapy)和光动力治疗(PDT,Photodynamic Therapy)效应的近红外分子、其制备方法,以及其治疗肿瘤方面的应用。
背景技术
肿瘤一直是当今世界难以攻克的难题,其对人类的健康具有严重的影响。目前对于肿瘤的临床治疗主要包括手术、放疗及化疗,但对患者的创伤较大并且难以根除肿瘤。因此,光疗的出现为肿瘤治疗提供了一种新兴的方法,研究者寄希望于光疗达到更好的治疗效果来提高恶性肿瘤的治愈率。细菌感染常见于人们的日常生活中,但是随着抗生素的滥用,产生许多耐药菌,其难以清除和治疗,而光疗同样提供了一种非侵入式的抗菌方法。因此,寻找安全、高效、低毒的抗肿瘤和抗菌药物,在目前临床治疗方面显得尤为重要。
近些年,光疗包括光热治疗(PTT)和光动力治疗(PDT)由于其组织创伤低,副作用小,治疗可控性强等特点,在肿瘤治疗方面展现出了独特的优势。其治疗过程主要包括,药物在病变部位的富集之后,利用如近红外激光等特定波长的激光来照射病变部位,光敏剂分子吸收光子产生大量热能或者活性氧(Reactive Oxygen Species,ROS)来杀死病变部位细胞,最终治愈病变。
现如今,已经开发出不同种类的光敏剂,例如有机小分子,金属配合物,纳米材料等等。但是大多数光敏剂仍存在许多缺陷限制其临床应用发展,例如紫外吸收较小,组织穿透能力较弱,稳定性和水溶性较差等。因此,开发诸多优点,包括低成本、易获取、近红外信号、可自身降解以降低副作用、可经由肿瘤标志物激活来进行“off-on”调控的光敏剂或前体的设计合成及应用研究,对于PDT和PTT的发展具有重要意义。
发明内容
本发明提供了一类具有PTT和PDT效应的近红外分子,其具有有价值的药理性质,特别是提高对肿瘤细胞的杀伤力,有效减少荷瘤小鼠的肿瘤体积。
本发明还进一步提供了所述近红外分子的制备方法。
具有式I结构的化合物,或者其立体异构体、药物可接受的盐或多晶型:
其中:
R1独立的选自氢、羟基、卤素、1-10个碳原子的烷基、1-10个碳原子的烷氧基、1-10个碳原子的卤代烷烃、1-10个碳原子的伯胺基、1-10个碳原子取代的仲胺基、1-10个碳原子取代的叔胺基或1-10个碳原子的烷苯基等;
R2独立的选自氢、羟基、卤素、1-10个碳原子的烷基、1-10个碳原子的烷氧基、1-10个碳原子的卤代烷烃、1-10个碳原子的伯胺基、1-10个碳原子取代的仲胺基、1-10个碳原子取代的叔胺基、1-10个碳原子的烷苯基、未取代或取代的苯基、萘基、蒽基、菲基,其中的取代基包括羧基、卤素、1-10个碳原子的烷基、1-10个碳原子的烷氧基、1-10个碳原子的卤代烷烃或1-10个碳原子的烷苯基中的一个或更多个基团;
R3独立的选自未取代的或取代的包含氧氮硫的饱和或不饱和五元六元杂环化合物,其中的取代基包括1-10个碳原子的烷基、1-10个碳原子的烷氧基、苯基、萘基、蒽基、菲基、烯烃和被一个或多个乙腈基取代的烯烃、氮取代的1-10个碳原子的烷基、氮取代的1-10个碳原子的烷氧基、氮取代的1-10个碳原子的硫氧基中一个或更多个基团。
优选,R1选自羟基、1-10个碳原子的烷氧基、1-10个碳原子取代的仲胺基或1-10个碳原子取代的叔胺基;
优选,R2选自羟基、未取代或取代的苯基、萘基、蒽基、菲基,其中的取代基包括羧基、卤素、1-10个碳原子的烷基、1-10个碳原子的烷氧基、1-10个碳原子的卤代烷烃或1-10个碳原子的烷苯基中的一个或更多个基团;
优选,R3选自取代的包含氧氮硫的饱和或不饱和苯并五元六元杂环化合物,其中的取代基包括1-10个碳原子的烷基、苯基、萘基、烯烃和被一个或多个乙腈基取代的烯烃、氮取代的1-10个碳原子的烷基、氮取代的1-10个碳原子的硫氧基中一个或更多个基团。
本发明提供了上述具化合物Rh1-Rh10的制备路线,主要包括以下步骤:
(1)合成化合物Rh1,Rh2
(a)0℃下,将4.5mL三溴化磷加入到1:10的N,N-二甲基甲酰胺和二氯甲烷溶液中,加入2mL环己酮溶液,室温下反应18小时。反应完全后倒入碎冰中,调节pH为中性。二氯甲烷萃取,浓缩有机相得橙红色油状物化合物2。
(b)将4-甲氧基水杨醛与上述橙红色油状物按1比1的当量溶解于N,N-二甲基甲酰胺中,加入3当量的碳酸铯,在50℃下反应6小时,过滤除去碳酸铯,浓缩反应液,乙酸乙酯和饱和食盐水萃取,浓缩有机相,柱层析法纯化得化合物4。
(c)将化合物4溶解于二氯甲烷中,在-70℃条件下,加入三溴化硼的二氯甲烷溶液,搅拌10分钟后移至室温,反应12小时。监测反应完全后加水淬灭,浓缩反应液,柱层析法纯化得到化合物5。
(d)将化合物4或化合物5与碳酸钾按1比1.5的当量溶解于适量乙酸酐中,加入1.2当量的化合物6后,在80℃条件下搅拌5小时。浓缩反应液,柱层析法纯化得化合物Rh1和Rh2为深绿色固体。
(2)合成化合物Rh3-Rh10
(e)将6.6mL环己酮滴加到70mL浓硫酸中,分别加入化合物7,化合物8,化合物9为32mmol,90℃下搅拌3h。冷却后缓慢倒入碎冰中,加入7mL高氯酸,充分搅拌,4℃下静置24h,析出固体,过滤分别得化合物10,化合物11,化合物12,为橙色或黄色固体。
(f)分别将化合物10,化合物11,化合物12溶于DMF中,0℃下滴加三氯氧磷10mL,室温下监测反应完成后倒入碎冰中淬灭,二氯甲烷萃取水相,减压浓缩有机相后,用少量甲醇溶解,滴加到氢氧化钠溶液中,加入盐酸调节至中性,二氯甲烷萃取,干燥,石油醚/乙酸乙酯柱层析纯化,得化合物13-15为均为橙红色固体。
(g)将分别将化合物13,化合物14,化合物15与碳酸钾按1比2的当量溶解于适量乙酸酐中,分别加入1.2当量的化合物6,化合物16,化合物17,化合物18,化合物19,化合物20后回流3小时。监测反应完全后,浓缩反应液,柱层析法纯化得到Rh3,Rh4,Rh5和Rh6为红棕色固体,Rh7,Rh8,Rh9和R10为深绿色固体。
本发明还提供一种药物组合物,其包含本发明的式I结构化合物或其溶剂化物作为活性成分,任选地还含有一种或多种药学上可接受的载体。所述药学上可接受的载体是制药领域中常用或已知的各种辅料,包括但不限于:稀释剂、粘合剂、抗氧化剂、pH调节剂、防腐剂、润滑剂、崩解剂等。
在本发明的一种实施方式中,所述药物组合物应用于肿瘤光疗领域,有效减少荷瘤小鼠肿瘤体积,这些肿瘤包括但不限于乳腺癌,肺癌,结肠癌,胃癌,黑色素瘤或脑胶质瘤等。
所述药物组合物的施用途径包括但不限于:口服的;含服的;舌下的;透皮的;肺的;直肠的;肠胃外的,例如,通过注射,包括皮下的、真皮内的、肌内的、静脉内的;通过植入储库或储液器。
本发明提供了一类具有PTT和PDT效应的近红外分子,其具有以下优势:
(1)通过药物化学生物学的思维进行结构修饰,使该类分子相较于传统光敏剂拥有更高的结构稳定性和光稳定性,有利于储存和使用。
(2)该分子在近红外区有紫外吸收,因此可以用近红外光来激发和发射,从而拥有更好的组织穿透能力,利于深层组织的治疗。
(3)该分子对正常细胞的毒性较低,因而拥有更高的生物稳定性,有利于针对性治疗。
(4)该分子同时具有PTT和PDT效果,因而有利于进行协同治疗,治疗效果相互促进。
(5)该分子为之后的新型光敏剂的开发提供了思路。
附图说明
图1化合物Rh4的紫外吸收光谱图。
图2化合物Rh4在溶液中的PTT升温效果图。
图3化合物Rh4处理后肿瘤细胞的细胞存活率图。
图4不同样品处理后小鼠肿瘤体积生长曲线。
具体实施方式
下述实施方式为优选实施方式,有必要指出,本发明所保护的范围包括但不限于此。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
实施例一
(1)该类光疗小分子Rh1和Rh2的合成路线:
(a)0℃下,将4.5mL三溴化磷加入到1:10的N,N-二甲基甲酰胺和二氯甲烷溶液中,加入2mL环己酮溶液,室温下反应18小时。反应完全后倒入碎冰中,调节pH为中性。二氯甲烷萃取,浓缩有机相得橙红色油状物化合物2。
(b)将4-甲氧基水杨醛与上述橙红色油状物按1比1的当量溶解于N,N-二甲基甲酰胺中,加入3当量的碳酸铯,在50℃下反应6小时,过滤除去碳酸铯,浓缩反应液,乙酸乙酯和饱和食盐水萃取,浓缩有机相,柱层析法纯化得化合物4。
(c)将化合物4溶解于二氯甲烷中,在-70℃条件下,加入三溴化硼的二氯甲烷溶液,搅拌10分钟后移至室温,反应12小时。监测反应完全后加水淬灭,浓缩反应液,柱层析法纯化得到化合物5。
(d)将化合物4或化合物5与碳酸钾按1比1.5的当量溶解于适量乙酸酐中,加入1.2当量的化合物6后,在80℃条件下搅拌5小时。浓缩反应液,柱层析法纯化得化合物Rh1和Rh2为深绿色固体。
Rh1:1H NMR(400MHz,DMSO-d6)δ8.93(d,J=14.5Hz,1H),8.68(d,J=7.4Hz,1H),8.37(d,J=8.1Hz,1H),8.08(t,J=7.7Hz,1H),7.91(d,J=8.2Hz,1H),7.81(d,J=7.3Hz,1H),7.73(t,J=7.8Hz,1H),7.67(s,1H),7.59(d,J=8.7Hz,1H),7.34(d,J=2.4Hz,1H),7.04(dd,J=8.6,2.5Hz,1H),6.81(d,J=14.5Hz,1H),4.51(q,J=7.2Hz,2H),3.97(s,3H),2.76(t,J=6.2Hz,4H),1.86(p,J=6.3Hz,2H),1.41(t,J=7.1Hz,3H).
13C NMR(100MHz,DMSO-d6)δ162.45,161.10,155.90,153.73,142.65,139.08,135.01,132.42,130.18,130.08,129.06,128.64,128.53,127.97,126.72,124.60,123.35,116.61,115.35,113.31,112.34,106.78,100.67,47.96,28.36,27.72,23.35,19.28,13.60
Rh2:1H NMR(400MHz,DMSO-d6)δ8.92(d,J=14.3Hz,1H),8.63(d,J=7.5Hz,1H),8.36(d,J=8.1Hz,1H),8.03(t,J=7.7Hz,1H),7.88(d,J=7.8Hz,1H),7.76-7.69(m,3H),7.55(d,J=8.6Hz,1H),7.17(d,J=2.2Hz,1H),6.94(dd,J=8.5,2.3Hz,1H),6.77(d,J=14.3Hz,1H),4.47(q,J=7.1Hz,2H),2.79-2.75(m,4H),1.86(p,J=6.2Hz,2H),1.40(t,J=7.1Hz,3H).
13C NMR(100MHz,DMSO-d6+CD3OD)δ162.95,162.80,156.31,155.22,143.27,140.34,137.57,133.04,130.86,130.27,130.12,130.05,129.82,129.35,126.83,124.97,124.62,117.94,116.04,115.65,112.50,107.04,102.89,29.47,28.68,24.43,20.46,14.51.
(2)该类光疗小分子Rh4的合成路线:
将3g化合物9与6mL环己酮加入到适量浓硫酸中,90℃下搅拌3小时。冷却后缓慢倒入碎冰中,加入少量高氯酸,充分搅拌,析出固体,趁冷过滤,得化合物12为橙黄色固体。
(a)将化合物12溶于DMF中,0℃下滴加三氯氧磷10mL,室温下监测反应完成后倒入碎冰中淬灭,二氯甲烷萃取水相,减压浓缩有机相后,用少量甲醇溶解,滴加到氢氧化钠溶液中,加入盐酸调节至中性,二氯甲烷萃取,干燥,石油醚/乙酸乙酯柱层析纯化,得化合物15为橙红色固体。
(b)将化合物15与碳酸钾按1比2的当量溶解于适量乙酸酐中,加入1.2当量的化合物6后回流3小时。监测反应完全后,浓缩反应液,柱层析法纯化得到Rh4为红棕色固体。
如图2所示,实施例一(2)得到的氧杂蒽环核的有机光热小分子Rh4的1H NMR谱图和13C NMR谱图。
1H NMR(400MHz,DMSO-d6)δ8.54(d,J=13.7Hz,1H),8.24(d,J=7.2Hz,1H),8.03(d,J=7.9Hz,1H),7.80(t,J=7.7Hz,1H),7.69-7.63(m,3H),7.51-7.45(m,2H),7.39(t,J=6.2Hz,3H),7.05-6.96(m,2H),6.74(s,1H),6.48(d,J=13.8Hz,1H),4.26(q,J=7.1Hz,2H),3.62(q,J=7.1Hz,4H),2.67(t,J=6.1Hz,2H),2.42(t,J=5.9Hz,2H),1.73(p,J=6.1Hz,2H),1.34(t,J=6.8Hz,3H),1.27(t,J=6.9Hz,6H).
13C NMR(100MHz,DMSO-d6)δ162.64,156.32,152.81,152.81,152.42,141.07,138.66,138.63,133.88,130.64,130.04,130.00,129.89,129.89,129.37,129.37,129.15,129.01,129.01,127.61,125.31,121.78,121.73,120.01,114.42,114.09,108.70,104.55,96.28,45.31,38.80,26.88,24.26,20.69,14.12,13.02.
(3)使用实例一(2)的合成方法,更换中间体化合物,其余试剂制备方法不变,制备得到化合物Rh3:
1H NMR(400MHz,DMSO-d6)δ8.63(d,J=13.8Hz,1H),8.36(d,J=7.4Hz,1H),8.10(d,J=8.1Hz,1H),7.93-7.83(m,2H),7.61-7.48(m,3H),7.37(d,J=6.9,Hz,1H),6.94(dd,J=9.0,2.4Hz,1H),6.77(s,1H),6.47(d,J=13.7Hz,1H),4.24(q,J=7.1Hz,2H),3.17(s,6H),2.77-2.71(m,4H),1.85(p,J=6.1Hz,2H),1.32(t,J=7.1Hz,3H).
13C NMR(100MHz,DMSO-d6)δ163.13,156.44,155.03,152.54,141.43,141.07,138.46,130.76,130.54,130.20,130.15,129.94,129.91,127.79,125.27,123.96,122.08,119.50,114.81,114.30,108.88,104.52,96.46,55.38,38.70,28.30,24.62,20.70,14.08.
(4)使用实例一(2)的合成方法,更换中间体化合物,其余试剂制备方法不变,制备得到化合物Rh4:
1H NMR(400MHz,DMSO-d6)δ8.54(d,J=13.7Hz,1H),8.24(d,J=7.2Hz,1H),8.03(d,J=7.9Hz,1H),7.80(t,J=7.7Hz,1H),7.69-7.63(m,3H),7.51-7.45(m,2H),7.39(t,J=6.2Hz,3H),7.05-6.96(m,2H),6.74(s,1H),6.48(d,J=13.8Hz,1H),4.26(q,J=7.1Hz,2H),3.62(q,J=7.1Hz,4H),2.67(t,J=6.1Hz,2H),2.42(t,J=5.9Hz,2H),1.73(p,J=6.1Hz,2H),1.34(t,J=6.8Hz,3H),1.27(t,J=6.9Hz,6H).
13C NMR(100MHz,DMSO-d6)δ162.64,156.32,152.81,152.81,152.42,141.07,138.66,138.63,133.88,130.64,130.04,130.00,129.89,129.89,129.37,129.37,129.15,129.01,129.01,127.61,125.31,121.78,121.73,120.01,114.42,114.09,108.70,104.55,96.28,45.31,38.80,26.88,24.26,20.69,14.12,13.02.
(5)使用实例一(2)的合成方法,更换中间体化合物,其余试剂制备方法不变,制备得到化合物Rh5:
1H NMR(400MHz,DMSO-d6)δ8.57(d,J=12Hz,1H),8.29(d,J=7.3Hz,1H),8.04(d,J=8.1Hz,1H),7.84(s,1H),7.78(t,J=7.7Hz,1H),7.55-7.51(m,3H),7.36-7.30(m,1H),7.01-7.03(m,1H),6.75(s,1H),6.45(d,J=12Hz,1H),4.22(q,J=7.0Hz,2H),3.59(q,J=7.1Hz,4H),2.71(t,J=5.3Hz,4H),1.84(p,J=6.2Hz,2H),1.32(t,J=7.1Hz,3H),1.25(t,J=7.0Hz,6H).
13C NMR(100MHz,DMSO-d6)δ162.90,156.72,153.19,152.12,141.47,141.05,138.05,130.60,130.60,130.48,130.06,129.94,129.86,127.39,125.29,123.56,121.72,119.49,114.82,114.35,108.48,104.20,95.96,45.29,38.64,28.14,24.44,20.67,14.06,13.00.
(6)使用实例一(2)的合成方法,更换中间体化合物,其余试剂制备方法不变,制备得到化合物Rh6:
1H NMR(400MHz,DMSO-d6)δ8.66(d,J=13.7Hz,1H),8.35(d,J=7.5Hz,1H),8.09(d,J=8.1Hz,1H),7.84-7.78(m,2H),7.60-7.52(m,3H),7.39(d,J=6.8Hz,1H),6.99(dd,J=9.1,2.4Hz,1H),6.81(s,1H),6.56(d,J=13.8Hz,1H),4.21(t,J=7.3Hz,2H),3.57(q,J=7.0Hz,4H),2.73(p,J=4.9Hz,4H),2.48-2.46(m,2H),1.83(t,J=6.5Hz,4H),1.74-1.68(m,2H),1.22(t,J=7.0Hz,6H).
13C NMR(100MHz,DMSO-d6)δ163.19,156.91,155.15,153.22,152.89,150.34,141.75,141.35,138.71,130.65,130.23,130.14,130.11,129.99,125.25,123.79,121.88,119.78,114.80,114.28,109.08,104.91,96.28,51.26,49.07,45.25,31.75,29.47,28.24,27.81,23.07,22.55,14.40,12.96.
(7)使用实例一(2)的合成方法,更换中间体化合物,其余试剂制备方法不变,制备得到化合物Rh7:
1H NMR(400MHz,DMSO-d6)δ8.56(d,J=14.4Hz,1H),8.35-8.30(m,1H),8.16-8.10(m,2H),7.84(d,J=8.8Hz,1H),7.71(t,J=7.5Hz,1H),7.63(s,1H),7.57(t,J=7.5Hz,1H),7.50(d,J=9.0Hz,1H),6.92(dd,J=9.0,2.4Hz,1H),6.65(d,J=2.4Hz,1H),6.35(d,J=14.4Hz,1H),4.44(q,J=7.1Hz,2H),3.57(q,J=7.0Hz,4H),2.75-2.69(m,4H),1.99(s,6H),1.86-1.83(m,2H),1.41(t,J=7.1Hz,3H),1.22(t,J=6.9Hz,6H).
13C NMR(100MHz,DMSO-d6)δ175.39,162.40,156.04,151.94,141.75,139.66,137.56,134.44,132.11,131.01,130.43,130.01,128.30,127.90,125.67,123.35,122.77,114.41,112.77,112.37,112.18,100.49,96.07,55.42,51.52,44.86,28.55,27.74,24.37,20.73,12.97,12.89.
(8)使用实例一(2)的合成方法,更换中间体化合物,其余试剂制备方法不变,制备得到化合物Rh8:
1H NMR(400MHz,CDCl3)δ8.79(d,J=8.2Hz,1H),8.06(d,J=15.2Hz,1H),7.64(t,J=7.5Hz,1H),7.47(d,J=8.3Hz,1H),7.32(t,J=7.7Hz,1H),6.92(d,J=8.5Hz,1H),6.63(s,1H),6.45-6.29(m,3H),5.90(d,J=15.3Hz,1H),3.41(q,J=7.1Hz,4H),2.49(t,J=6.2Hz,2H),2.40(t,J=6.1Hz,2H),1.79(p,J=6.1Hz,2H),1.24(t,J=7.0Hz,6H).
13C NMR(100MHz,CDCl3)δ160.12,154.76,154.51,152.47,152.00,149.55,134.46,133.56,127.34,127.34,126.44,125.64,125.21,124.11,118.27,118.25,117.15,111.18,110.99,109.61,107.87,104.57,97.13,44.64,29.54,24.68,20.92,12.73.
(9)使用实例一(2)的合成方法,更换中间体化合物,其余试剂制备方法不变,制备得到化合物Rh9:
1H NMR(400MHz,CDCl3)δ8.14(d,J=13.9Hz,1H),8.09(d,J=7.8Hz,1H),7.52(d,J=8.3Hz,1H),7.43(t,J=7.8Hz,1H),7.30(t,J=7.6Hz,1H),7.18(d,J=8.5Hz,1H),7.05(s,1H),6.57-6.55(m,2H),6.31(d,J=13.8Hz,1H),4.58(q,J=7.2Hz,2H),3.46(q,J=7.1Hz,4H),2.60-2.55(m,4H),1.80(p,J=6.1Hz,2H),1.45(t,J=7.1Hz,3H),1.24(t,J=7.1Hz,6H).
13C NMR(100MHz,CDCl3)δ166.61,160.98,155.68,151.26,141.98,140.92,134.76,128.80,128.44,126.40,126.06,123.83,123.00,113.46,112.61,112.01,110.68,100.14,96.54,45.14,43.40,28.95,25.34,20.63,13.29,12.84.
(10)使用实例一(2)的合成方法,更换中间体化合物,其余试剂制备方法不变,制备得到化合物Rh10:
1H NMR(400MHz,DMSO-d6)δ8.85(d,J=6.8Hz,1H),8.74(d,J=8.5Hz,1H),8.52(d,J=13.6Hz,1H),8.25(dd,J=13.6,7.8Hz,2H),8.08(t,J=7.7Hz,1H),7.82(t,J=7.7Hz,1H),7.23-7.14(m,2H),6.92(s,1H),6.73(d,J=2.4Hz,1H),6.58(dd,J=8.7,2.5Hz,1H),4.78(q,J=7.1Hz,2H),3.46(q,J=7.0Hz,4H),2.70(t,J=6.1Hz,2H),2.57(t,J=6.1Hz,2H),1.82-1.78(m,2H),1.52(t,J=7.1Hz,3H),1.18(t,J=7.0Hz,6H).
13C NMR(100MHz,DMSO-d6)δ156.78,155.10,152.16,150.32,144.74,138.22,138.06,134.57,129.71,128.45,128.23,126.50,126.02,123.83,118.74,118.74,113.52,112.35,112.06,111.20,109.26,97.18,51.02,44.43,29.48,29.08,20.99,15.37,13.01.
实施例二
紫外吸收光谱测定:配制10μM化合物Rh4的二甲基亚砜溶液,于紫外分光光度计进行扫描。
结果如图1所示,该化合物紫外吸收位于近红外区,从而可以使用近红外激光器进行激发,实现更高的组织穿透效率。
实施例三
PTT升温测定:配制10μM化合物Rh4的水溶液,使用NIR激光器照射该溶液并计时,记录不同时间的升温情况并绘制升温曲线,评估该化合物的PTT效率。
结果如图2所示,在10μM浓度下该化合物可以实现较高的升温效果,同时在多次激光照射后仍能保持较高升温,说明其光稳定性良好,可以实现单次给药多次照射。
实施例四
MTT法测定细胞杀伤效率:
(1)将MCF-7肿瘤细胞按每孔8000个接种于96孔板中,继续培养24h。
(2)将实施例一中的化合物配制为终浓度10μM,每孔加入100μL,于培养箱继续培养6h,后于NIR激光器照射下照射5min,置于培养箱继续培养6h。
(3)向每孔加入20μL MTT溶液,培养4h后弃掉,加150μL DMSO溶液充分溶解甲瓒结晶。最后于酶标仪检测每孔在562nm处的吸光度。最后计算细胞存活率。
结果如图3所示,在无激光照射情况下,其对细胞杀伤效率较低,这也验证了该化合物的体内安全性。在近红外光照射下,其在2.5μM左右便可杀伤50%左右肿瘤细胞,相较于常见光敏剂具有更高的光疗效率。
实施例五
将4T1肿瘤细胞皮下注射至小鼠体内构建乳腺癌肿瘤消暑模型,将实施例一得到化合物原位注射到荷瘤小鼠体内,于24h后给予其NIR激光照射,共重复三次,在治疗过程中监测小鼠肿瘤体积生长情况。
结果如图4所示,在给予荷瘤小鼠化合物治疗之后,其肿瘤体积能够实现较大程度的抑制,抗肿瘤效果较为显著。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一类具有光热治疗(PTT,Photothermal Therapy)和光动力治疗(PDT,PhotodynamicTherapy)效应的近红外分子,其结构如式(I)所示:
其中:
R1独立的选自氢、羟基、卤素、1-10个碳原子的烷基、1-10个碳原子的烷氧基、1-10个碳原子的卤代烷烃、1-10个碳原子的伯胺基、1-10个碳原子取代的仲胺基、1-10个碳原子取代的叔胺基或1-10个碳原子的烷苯基等;
R2独立的选自氢、羟基、卤素、1-10个碳原子的烷基、1-10个碳原子的烷氧基、1-10个碳原子的卤代烷烃、1-10个碳原子的伯胺基、1-10个碳原子取代的仲胺基、1-10个碳原子取代的叔胺基、1-10个碳原子的烷苯基、未取代或取代的苯基、萘基、蒽基、菲基,其中的取代基包括羧基、卤素、1-10个碳原子的烷基、1-10个碳原子的烷氧基、1-10个碳原子的卤代烷烃或1-10个碳原子的烷苯基中的一个或更多个基团;
R3独立的选自未取代的或取代的包含氧氮硫的饱和或不饱和五元六元杂环化合物,其中的取代基包括1-10个碳原子的烷基、1-10个碳原子的烷氧基、苯基、萘基、蒽基、菲基、烯烃和被一个或多个乙腈基取代的烯烃、氮取代的1-10个碳原子的烷基、氮取代的1-10个碳原子的烷氧基、氮取代的1-10个碳原子的硫氧基中一个或更多个基团。
优选,R1选自羟基、1-10个碳原子的烷氧基、1-10个碳原子取代的仲胺基或1-10个碳原子取代的叔胺基;
优选,R2选自羟基、未取代或取代的苯基、萘基、蒽基、菲基,其中的取代基包括羧基、卤素、1-10个碳原子的烷基、1-10个碳原子的烷氧基、1-10个碳原子的卤代烷烃或1-10个碳原子的烷苯基中的一个或更多个基团;
优选,R3选自取代的包含氧氮硫的饱和或不饱和五元六元杂环化合物,其中的取代基包括1-10个碳原子的烷基、苯基、萘基、烯烃和被一个或多个乙腈基取代的烯烃、氮取代的1-10个碳原子的烷基、氮取代的1-10个碳原子的硫氧基中一个或更多个基团。
4.根据权利要求3所述的化合物或者其药物可接受的盐或其溶剂合物的合成方法。
5.根据权利要求3所述的化合物,其特征在于,具有近红外区的紫外吸收,具有不同的PTT和PDT效率。
6.一种药物组合物,其含有权利要求1-5所述的化合物、其药物可接受的盐或其溶剂合物,应用于联合治疗和纳米药物的构建。
7.权利要求1-5所述的化合物或其溶剂合物在制备药物中的应用;优选在制备抗肿瘤和抗菌光疗药物方面的应用。所述药物用于治疗或预防癌症,抑制肿瘤生长、加速细胞凋亡和抑制细胞活力。
8.权利要求1-5所述的近红外分子的不同给药途径,包括但不限于静脉注射,皮下注射,肌肉注射等。
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