CN118027129A - 一种可电离脂质化合物及其应用 - Google Patents
一种可电离脂质化合物及其应用 Download PDFInfo
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- CN118027129A CN118027129A CN202410013830.1A CN202410013830A CN118027129A CN 118027129 A CN118027129 A CN 118027129A CN 202410013830 A CN202410013830 A CN 202410013830A CN 118027129 A CN118027129 A CN 118027129A
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- optionally substituted
- alkyl
- ionizable lipid
- lipid compound
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- 108090000623 proteins and genes Proteins 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 229920001184 polypeptide Polymers 0.000 claims abstract description 7
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 7
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 7
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- 125000000217 alkyl group Chemical group 0.000 claims description 42
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 9
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- 239000002105 nanoparticle Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
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Abstract
本发明公开了一种可电离脂质化合物及其应用,所述可电离脂质化合物包括其药学上可接受的盐,其结构式如下式(1)所示,本发明丰富了可电离脂质化合物的种类,为核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物等生物分子的有效递送提供更多的选择,对生物分子作为预防剂及治疗剂的发展和应用具有重要的意义。
Description
技术领域
本发明涉及一类可电离脂质化合物及其应用。
背景技术
目前正在开发许多不同类型的核酸,作为治疗许多疾病的疗法。这些核酸包括用于基因治疗的DNA、RNA、以及用于RNA干扰(RNAi)的小干扰核酸,包括siRNA、miRNA、反义分子、核酶和适体。随着这些基于核酸疗法的发展,核酸分子的设计及其递送方法的研究提出了更高的要求。核酸药物的生产应用仍面临若干挑战,包括低细胞渗透性和核酸分子的高降解性。因此,需要研究开发出能够递送核酸分子的脂质化合物,及用于递送核酸分子的脂质组合物及相关方法,以促进各类核酸分子能够成功递送到胞外或胞内,从而达到治疗和/或预防的目的。
典型的可电离脂质结构包含三个基础的部分:(1)可电离氨基头;(2)疏水尾;(3)连接两个部分的功能键。可电离的氨基头在中性调价下为负电,可电离脂质通过疏水作用力插入细胞膜中,维持细胞膜的稳定;在酸性调价下,氨基电离转变为正电,与细胞膜中的带负电的磷脂强烈吸引,破坏细胞膜的稳定,在酸性的溶酶体中,将破坏溶酶体,促进所携带基因的逃逸(Nat,Mater.,2021,20,701–710)。当可电离脂质的疏水尾巴比较大时,更容易撬动细胞膜,使得溶酶体逃逸效率更高。
传统市售的可电离脂质,其疏水尾部分都是脂肪烃链组成的,比如D-Lin-MC3-DMA有两条长碳链疏水尾,SM-102有三条长碳链做疏水尾,而ALC-0315具有四条长碳链疏水尾,而本专利的所有可电离脂质在长碳尾的基础上,配有胆固醇类结构做疏水尾,胆固醇类结构独特的刚性、生物降解性及膜融合能力使复合物有更好的稳定性,在真核细胞中表达出更好的转染效率。同时,由于胆固醇的空间构型特性,与市售长碳链可电离脂质相比,更易导致不稳定的非双层、六边形(HII)结构的形成,易诱导膜融合和溶酶体破坏,提高了溶酶体逃逸的成功率。
发明内容
本发明提供一类新的用于递送核酸分子等生物活性分子的可电离脂质化合物及其脂质组合物,丰富可电离脂质化合物的种类,为核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物等生物分子的有效递送提供更多的选择,对生物分子作为预防剂及治疗剂的发展和应用具有重要的意义。
本发明提供一种通式(I)所示的可电离脂质化合物,包括其药学上可接受的盐,为:
其中,R1为C6-12烷基,-Rh-C(=O)-Ri、-Rj-C(=O)OH、C4-8不饱和内脂环,或R1和R3及与其连接的C构成任选地取代的C6-12含氧螺杂环;其中,Rh为不存在或C1-3亚烷基;Ri为H或C1-3烷基;Rj为C3-11亚烷基;
R2为H或OH;
R3为H,C1-3烷基,或R1和R3及与其连接的C构成任选地取代的C4-8含氧螺杂环;
G为N或C;
L1为任选地取代的C1-6亚烷基或C1-6亚烯基;
L2和L3分别独立地为H、或任选地取代的C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、C3-8环烯基、C3-8环炔基、4元至8元杂环基、C6-10芳基或5元至10元杂芳基;或者L2和L3和它们所接的氮连接成环;
L4为Ra、-RbMRc、-(C6-10亚芳基)-Rd或-(6元至10元杂亚芳基)-Re;
其中,Ra为任选地取代的C8-24烷基或任选地取代的C8-24烯基;
Rb为任选地取代的亚烷基或任选地取代的亚烯基,Rc分别独立地为任选地取代的烷基或任选地取代的烯基,M为-OC(=O)-、-C(=O)O-、-OC(=O)O-、-C(=O)-、-O-、-S-S-、-SC(=S)-、-C(=O)S-、-SC(=O)-、-C(=S)S-、-C(=S)-;且Rb、M和Rc的总C数是8-24;
Rd或Re为任选地取代的C8-18烷基或任选地取代的C8-18烯基。
所述任选地取代的C6-12含氧螺杂环,优选C6-12含氧螺杂环被一个、二个或三个甲基、乙基、丙基或异丙基取代。
进一步的Ra为任选地取代的C12-16烷基或任选地取代的C12-16烯基,且Ra为直链或具有1、2或3条支链。
作为优选,Ra为C12-16直链烷基。
优选地,Ra为
进一步的,Rb为C1-6亚烷基。
进一步的,Rc分别独立地为任选地取代的C10-18烷基或任选地取代的C10-18烯基,且Rc为直链或具有1、2或3条支链。
优选地,-RbMRc为
作为优选,L1为未取代的C1-6亚烷基或C1-6亚烯基,或为被羧基、羟基或氨基取代的C1-6亚烷基或C1-6亚烯基。
进一步的,L2和L3分别独立地为未取代的C1-8直链烷基,或被羧基、羟基或氨基取代的C1-8直链烷基或L2和L3和它们所接的氮连接成C3-6环。
作为优选,L2和L3分别独立地为C1-3直链烷基,或L2和L3和它们所接的氮连接成C3-6环。
进一步的,L2和L3分别独立地为甲基、乙基、丙基。
进一步的,R1为C7-10烷基。
在可选的实施方案中,R1为以下结构的任意一种:
在可选的实施方案中,所述的可电离脂质化合物为以下结构式的任意一种:
本发明第二方面提供一种药物组合物,所述组合物包括治疗或预防剂和用于递送所述治疗或预防剂的载体,所述载体包括可电离脂质化合物,所述可电离脂质包括上述通式(I)所示的可电离脂质化合物、或其药物可用的盐中的一种或多种。
具体地,治疗或预防剂被包封在载体内或与载体缔合。
具体地,所述治疗或预防剂包括核酸分子、小分子化合物、多肽或蛋白质中的一种或多种。
具体地,所述核酸包括任何形式的核酸分子,包括但不限于单链DNA、双链DNA、短异构体、agomir、antagomir、反义分子、小干扰RNA(siRNA)、不对称干扰RNA(aiRNA)、microRNA(miRNA)、Dicer-substrate RNA(dsRNA)、小发夹RNA(shRNA)、转移RNA(tRNA)、信使RNA(mRNA)和本领域已知的其他形式的RNA分子,或锁核酸(LNA)、肽核酸(PNA)和吗啉环寡聚核苷酸等核酸模拟物。
所述治疗或预防剂包含至少一种编码抗原的mRNA或其片段或表位。更具体地,所述mRNA是单顺反子mRNA或多顺反子mRNA。更具体地,所述抗原是病原性抗原。更具体地,所述mRNA包含一种或多种功能性核苷酸类似物,所述功能性核苷酸类似物包括但不限于假尿嘧啶核苷、1-甲基-假尿嘧啶核苷和5-甲基胞嘧啶中的一种或多种。
具体地,所述小分子化合物包括但不限于治疗和/或预防剂的有效成分,所述治疗和/或预防剂为现有已知的药物,例如抗肿瘤药、抗感染药、局部麻醉药、抗抑郁药、抗惊厥药、抗生素/抗菌剂、抗真菌药、抗寄生虫药、激素、激素拮抗剂、免疫调节剂、神经递质拮抗剂、抗青光眼剂、麻醉剂、或成像剂。
优选地,所述载体与所述有治疗或预防剂的质量比为5:1~50:1,进一步优选为5:1~35:1,更优选为10:1~30:1。
优选地,所述药物组合物为纳米颗粒制剂,所述纳米颗粒制剂的平均尺寸为10nm~150nm,优选为40nm~140nm,进一步优选为50nm~130nm。
进一步优选地,所述纳米颗粒制剂的多分散指数≤0.5,进一步优选≤0.45,更优选≤0.4。
根据一些具体实施方式,所述载体还包括中性脂质,所述可电离脂质与所述中性脂质的摩尔比为1~10:1,进一步优选为2~8:1,更优选为3~6:1。
具体地,所述中性脂质化合物为已公开的或未公开的在选定的有用的pH值或范围内以不带电荷形式或中性两性离子形式存在的任何脂质分子。选定的有用的pH值或范围对应于脂质的预期使用的环境的pH条件,例如生理pH。
更具体地,所述中性脂质包括磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂、神经酰胺、甾醇及其衍生物中的一种或多种。
更具体地,所述中性脂质包括但不限于1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)、1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱(DPPC)、1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱(DMPC)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)、11,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)、1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、2-(((2,3-双(油酰氧基)丙基))磷酸二甲基铵)乙基氢(DOCP)、鞘磷脂(SM)、神经酰胺、甾醇及其衍生物。
根据一些具体实施方式,所述载体还包括结构脂质,所述可电离脂质与所述结构脂质的摩尔比为1~5:1,进一步优选为1~3:1,更优选为1~2:1。
根据一些具体实施方式,所述载体还包括结构脂质,所述可电离脂质与所述结构脂质的摩尔比为1~5:1,进一步优选为1~3:1,更优选为1~2:1。
结构脂质可以稳定载体的两亲结构。具体地,所述结构脂质包括但不限于胆固醇、非甾醇、谷固醇、麦角固醇、菜油甾醇、豆甾醇、芸苔甾醇、番茄碱、番茄碱、熊果酸、α-生育酚、皮质类固醇中的一种或多种。
根据一些具体实施方式,所述载体还包括聚合物共轭脂质,所述可电离脂质与所述聚合物共轭脂质的摩尔比为20~100:1,进一步优选为20~60:1,再进一步优选为20~40:1,更优选为25~35:1。
具体地,所述聚合物共轭脂质主要包括已公开的或未公开的PEG修饰的脂质化合物,可以改善脂质体的稳定性并减少脂质体的蛋白质吸收,例如PEG修饰的磷脂酰乙醇胺、PEG修饰的磷脂酸、PEG修饰的神经酰胺、PEG修饰的二烷基胺、PEG修饰的二酰基甘油、PEG修饰的二烷基甘油中的一种或多种。
更具体地,所述聚合物共轭脂质可以是PEG-c-DOMG、PEG-DMG、PEG-DLPE、PEGDMPE、PEG-DPPC、PEG-DSPE、神经酰胺-PEG2000、Chol-PEG2000、1-(单甲氧基-聚乙二醇)-2,3-二肉豆蔻基甘油(PEG-DMG)、聚乙二醇化磷脂酰乙醇胺(PEG-PE)、4-O-(2',3'-二(十四烷酰氧基)丙基-1-O-(ω-甲氧基(聚乙氧基)乙基)丁二酸酯(PEG-S-DMG)、聚乙二醇化神经酰胺(PEG-cer)、ω-甲氧基(聚乙氧基)乙基-N-(2,3-二(十四烷氧基)丙基)氨基甲酸酯、或2,3-二(四癸氧基)丙基-N-(ω-甲氧基)(聚乙氧基)乙基)氨基甲酸酯。
根据一些具体且优选地实施方式,所述聚合物共轭脂质为DMG-PEG2000或者DMPE-PEG2000。
优选地,所述载体还包括中性脂质、结构脂质以及聚合物共轭脂质,所述阳离子脂质、所述中性脂质、所述结构脂质、以及所述聚合物共轭脂质的摩尔比为(15~45):(1~10):(15~35):1,进一步优选为(25~35):(1~10):(20~35):1,更优选为(30~35):(5~8):(20~30):1。
优选地,所述组合物还包括药物可用的赋形剂或稀释剂中的一种或多种。
本发明第三方面提供一种所述的通式(I)所示的可电离脂质化合物,或其药物可用的盐、或所述的组合物在制备核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物中的应用。其制成纳米颗粒制剂,平均尺寸为10nm~150nm。
本发明与现有技术相比具有如下优势:
本发明提供了一种新的可电离脂质化合物,其具有良好的细胞安全性,高效的转染效果,且体内蛋白表达多样。本发明所述可电离脂质化合物丰富了可电离脂质化合物种类,为核酸药物、基因疫苗、小分子药物、多肽及蛋白质药物等生物分子的递送提供更多的安全高效的选择,尤其对核酸预防剂及治疗剂的发展和应用具有重要的意义。
附图说明
图1:各实施例在HEK-293T细胞中的细胞毒性。
图2:SM-102LNPs与S-1LNPs荧光表达。
图3:SM-102LNPs与S-1LNPs在小鼠体内表达情况。
术语解释
“烷基”是指饱和脂肪烃,包括直链、支链和环烷基,烷基可以是取代的或未取代的。优选地,除非有相反的明确说明,烷基具有1至24个(1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个、21个、22个、23个、24个)碳原子(C1-24烷基);优选地,烷基具有一到十二个碳原子(C1-12烷基)、一到八个碳原子(C1-8烷基)、一到六个碳原子(C1-6烷基)、一到三个碳原子(C1-3烷基)、六到十二个碳原子(C6-12烷基)、三到十二个碳原子(C3-12烷基)、七到十个碳原子(C7-10烷基)、八到十八个碳原子(C8-18烷基)、八到二十四个碳原子(C8-24烷基)、十一到十六个碳原子(C11-16烷基)。
“亚烷基”是指将分子的其余部分连接到基团的直链或支链二价烃链,仅由碳和氢组成,优选地,其具有例如1到24个碳原子(C1-24亚烷基)、1到15个碳原子(C1-15亚烷基)、1到12个碳原子(C1-12亚烷基)、1到8个碳原子(C1-8亚烷基)、1到6个碳原子(C1-6亚烷基)、1到3个碳原子(C1-3亚烷基),例如亚甲基、亚乙基、亚丙基、亚正丁基、亚乙烯基、亚丙烯基、亚正烯基、亚丙炔基、亚正丁炔基等。除非在说明书中另有特别说明,否则亚烷基可以任选地被取代。
所述“含氧螺杂环”可以为6-12元含氧螺环基、7-11元含氧螺环基等;含氧螺杂环可以含有1个或多个(1个、2个、3个、4个、5个等)氧原子;其实例包括但不限于: 本申请中“被甲基取代的含氧螺杂环”包括但不限于:/>
所述的“任选地取代”指可以被取代或可以不被取代,例如任选地取代的烷基包括取代的烷基和未取代的烷基。
所述的基团被“取代”时,它们可以被任何合适的一个或多个取代基取代。
所述的基团被“取代”时,指被羧基、羟基或氨基、烷氧基、卤素、烷基、烯基、环烷基中的一种或多种全部取代或部分取代。
所述“其药物可用的盐”是指酸加成盐或碱加成盐。
所述酸包括但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸,柠檬酸、环酰胺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘酸、萘-1,5二甲酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、棕榈酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、以及十一碳烯酸。
所述碱加成盐指通过将无机碱或有机碱加成至游离碱化合物而制备的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐,锌盐、铜盐、锰盐、铝盐等;所述有机碱包括但不限于氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、脱醇、2-二甲基氨基乙醇、2-二乙基氨基乙醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、肼苯胺、胆碱、甜菜碱、苯那敏(benethamine)、苄星青霉素(benzathine)、乙二胺、葡糖胺、甲基葡糖胺、可可碱、三乙醇胺、嘌呤、哌嗪、哌啶、N-乙基哌啶、以及聚胺树脂。
具体实施方式
以下所列实施例有助于本领域技术人员更好地理解本发明,但不以任何方式限制本发明。
实施例1
将1-溴十六烷烃(1eq)与超过量的N,N-二甲基乙二胺在ACN中室温搅拌。将反应后的混合物真空浓缩,残留物用DCM(100ml)溶解并用水(3×100ml)。合并有机相,经无水MgSO4干燥后,减压浓缩除溶剂。粗产物通过快速柱色谱法纯化,得到化合物1-1。
1H-NMR(400MHz,Chloroform-d)δ2.69(t,J=6.2Hz,2H),2.63–2.61(m,2H),2.41(t,J=6.2Hz,2H),2.22(s,6H),1.72(s,1H),1.49(t,J=7.2Hz,2H),1.25(s,26H),0.88(t,J=6.7Hz,3H)。
步骤2:
将化合物1-1(1.0eq)、三乙胺(1.2eq)溶于DCM中反应5min后,将溶于DCM的胆固醇氯甲酸酯(1.0eq)溶液逐滴滴加到上述体系中,室温搅拌反应5h。将反应混合物倒入水中,并用DCM萃取。有机层用MgSO4干燥,过滤,减压浓缩,得到粗品。粗品通过快速柱色谱法纯化,得到化合物1-2。
1H NMR(400MHz,Chloroform-d)δ5.40–5.35(m,1H),4.51(tt,J=11.4,4.7Hz,1H),3.40–3.14(m,4H),2.51(t,2H),2.31(m,2H),2.28(s,6H),2.07–0.81(m,69H),0.69(s,3H)。
实施例2:
步骤1:
将1-溴十六烷烃(1eq)与超过量的N,N-二乙基乙二胺在ACN中室温搅拌。将反应后的混合物真空浓缩,残留物用DCM(100ml)溶解并用水(3×100ml)。合并有机相,经无水MgSO4干燥后,减压浓缩除溶剂。粗产物通过快速柱色谱法纯化,得到化合物2-1。
1H-NMR(400MHz,Chloroform-d)δ2.69(t,J=6.2Hz,2H),2.63–2.61(m,2H),2.46(s,4H),2.39(t,J=6.2Hz,2H),1.72(s,1H),1.49(t,J=7.2Hz,2H),1.25(s,26H),0.93(s,6H),0.88(t,J=6.7Hz,3H)。
步骤2:
将化合物2-1(1.0eq)、三乙胺(1.2eq)溶于DCM中反应5min后,将溶于DCM的胆固醇氯甲酸酯(1.0eq)溶液逐滴滴加到上述体系中,室温搅拌反应5h。将反应混合物倒入水中,并用DCM萃取。有机层用MgSO4干燥,过滤,减压浓缩,得到粗品。粗品通过快速柱色谱法纯化,得到化合物2-2。
1H NMR(400MHz,Chloroform-d)δ5.40–5.35(m,1H),4.51(tt,J=11.4,4.7Hz,1H),3.40–3.14(m,4H),2.51(t,2H),2.46(s,4H),2.31(m,2H),2.07–0.81(m,75H),0.69(s,3H)。
实施例3:
步骤1:
将1-溴十六烷烃(1eq)与超过量的N,N-二丙基乙二胺在ACN中室温搅拌。将反应后的混合物真空浓缩,残留物用DCM(100ml)溶解并用水(3×100ml)。合并有机相,经无水MgSO4干燥后,减压浓缩除溶剂。粗产物通过快速柱色谱法纯化,得到化合物3-1。
1H-NMR(400MHz,Chloroform-d)δ2.69(t,J=6.2Hz,2H),2.63–2.61(m,2H),2.46(s,4H),2.39(t,J=6.2Hz,2H),1.72(s,1H),1.44(s,4H),1.38(t,J=7.2Hz,2H),1.25(s,26H),0.88(t,J=6.7Hz,3H),0.87(s,6H)。
步骤2:
将化合物3-1(1.0eq)、三乙胺(1.2eq)溶于DCM中反应5min后,将溶于DCM的胆固醇氯甲酸酯(1.0eq)溶液逐滴滴加到上述体系中,室温搅拌反应5h。将反应混合物倒入水中,并用DCM萃取。有机层用MgSO4干燥,过滤,减压浓缩,得到粗品。粗品通过快速柱色谱法纯化,得到化合物3-2。
1H NMR(400MHz,Chloroform-d)δ5.40–5.35(m,1H),4.51(tt,J=11.4,4.7Hz,1H),3.40–3.14(m,4H),2.51(t,2H),2.46(s,4H),2.31(m,2H),2.07–0.81(m,79H),0.69(s,3H)。
实施例4:
步骤1:
将1-溴十六烷烃(1eq)与超过量的1-吡咯烷乙胺在ACN中室温搅拌。将反应后的混合物真空浓缩,残留物用DCM(100ml)溶解并用水(3×100ml)。合并有机相,经无水MgSO4干燥后,减压浓缩除溶剂。粗产物通过快速柱色谱法纯化,得到化合物4-1。
1H-NMR(400MHz,Chloroform-d)δ2.69(t,J=6.2Hz,2H),2.63–2.61(m,2H),2.52(s,4H),2.39(t,J=6.2Hz,2H),1.72(s,1H),1.68(s,4H),1.38(t,J=7.2Hz,2H),1.25(s,26H),0.88(t,J=6.7Hz,3H)。
步骤2:
将化合物4-1(1.0eq)、三乙胺(1.2eq)溶于DCM中反应5min后,将溶于DCM的胆固醇氯甲酸酯(1.0eq)溶液逐滴滴加到上述体系中,室温搅拌反应5h。将反应混合物倒入水中,并用DCM萃取。有机层用MgSO4干燥,过滤,减压浓缩,得到粗品。粗品通过快速柱色谱法纯化,得到化合物4-2。
1H NMR(400MHz,Chloroform-d)δ5.40–5.35(m,1H),4.51(tt,J=11.4,4.7Hz,1H),3.40–3.14(m,4H),2.51(t,2H),2.49(s,4H),2.31(m,2H),2.07–0.81(m,73H),0.69(s,3H)。
实施例5:
步骤1:
将1-溴十二烷烃(1eq)与超过量的N,N-二甲基乙二胺在ACN中室温搅拌过夜。将反应后的混合物真空浓缩,残留物用DCM(100ml)溶解并用水(3×100ml)。合并有机相,经无水MgSO4干燥后,减压浓缩除溶剂。粗产物通过快速柱色谱法纯化,得到化合物5-1。
1H-NMR(400MHz,Chloroform-d)δ2.69(t,J=6.2Hz,2H),2.63–2.61(m,2H),2.41(t,J=6.2Hz,2H),2.22(s,6H),1.72(s,1H),1.49(t,J=7.2Hz,2H),1.29(s,2H),1.26(s,16H),0.88(t,J=6.7Hz,3H)。
步骤2:
将化合物5-1(1.0eq)、三乙胺(1.2eq)溶于DCM中反应5min后,将溶于DCM的胆固醇氯甲酸酯(1.0eq)溶液逐滴滴加到上述体系中,室温搅拌反应5h。将反应混合物倒入水中,并用DCM萃取。有机层用MgSO4干燥,过滤,减压浓缩,得到粗品。粗品通过快速柱色谱法纯化,得到化合物5-2。
1H NMR(400MHz,Chloroform-d)δ5.40–5.35(m,1H),4.51(tt,J=11.4,4.7Hz,1H),3.40–3.14(m,4H),2.51(t,2H),2.31(m,2H),2.28(s,6H),2.07–0.81(m,57H),0.69(s,3H)。
实施例6:
步骤1:
将N,N-二乙基乙二胺(20mmol)、溴乙酸叔丁酯(20mmol)、无水K2CO3(40mmol)到28mLACN(适当加热),反应2h。反应混合物旋转蒸发至干,所得残余物用水处理并用DCM萃取。有机相用无水MgSO4干燥、过滤、旋转蒸发除去DCM。粗品通过快速柱色谱法纯化,得到化合物6-1。(跑板比例为DCM:MC=5:1,过柱出产物在EA:MC=10:1);化合物6-1(9mmol)加入20ml DCM,20mL TFA在室温下搅拌3h,旋转蒸发至干,定量得到的酸化合物6-2,可直接用于下一步反应。
化合物6-1:
1H NMR(400MHz,Chloroform-d)δ4.95(q,J=7.1Hz,1H),3.44(d,2H),2.89–2.81(m,4H),2.74(q,J=6.9Hz,4H),1.40(s,9H),0.96(t,J=7.1Hz,6H)。
步骤2:
将化合物6-2(1eq)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺(EDC 1.3eq)、HOBT(1.3eq)溶于DCM中,在0℃条件下,活化1h。将醇(1eq)、DMAP(1.2eq)溶于DCM中,加入到上述体系内,室温反应12h;用水猝灭反应物,分离有机层。用DDCM洗涤水层,合并有机相,用无水MgSO4干燥,减压浓缩除去DCM。将所得粗品用饱和NaHCO3溶液洗涤,EA萃取三次,减压浓缩得粗产物。粗产物通过快速柱色谱法纯化,得到化合物6-3。
1H NMR(400MHz,Chloroform-d)δ4.97(tt,1H),4.49(p,J=6.3Hz,1H),3.51(d,J=6.3Hz,2H),2.79–2.47(m,8H),1.75–1.55(m,4H),1.41–1.21(m,22H),1.04(t,J=6.9Hz,6H),0.94–0.81(m,6H)。
步骤3:
将化合物6-3(1eq)、三乙胺(1.5eq)溶于DCM中反应5min,将胆固醇氯甲酸酯溶于DCM中,并逐滴加入上述体系内,室温搅拌反应3h。直接加水萃取,有机相用无水MgSO4干燥、过滤、旋转蒸发得粗品。粗品通过快速柱色谱法纯化,得到终产物6-4;
1H NMR(400MHz,Chloroform-d)δ5.37(tdt,J=4.7,1.9,1.0Hz,1H),4.61–4.58(m,2H),3.99(s,2H),3.29(t,J=5.4Hz,2H),2.80–2.28(m,8H),1.91–0.74(m,78H),0.68(s,3H)。
实施例7:
步骤1:
将2-己基癸醇(1.0eq)和6-溴己酸(1.2eq)溶于DCM中,加入DIEA(0.25eq)、DMAP(0.2eq)。室温搅拌反应5min后,加入EDCI(1.8eq);该体系室温搅拌过夜,TLC显示起始醇完全消失。将反应液用DCM(300mL)稀释,并用饱和NaHCO3(100mL),水(100mL)和饱和食盐水(100mL)洗涤。合并有机层经无水Na2SO4干燥,旋蒸除去溶剂,得到粗产物。将粗产柱色谱纯化(硅胶柱,洗脱液为含1%EA(体积百分比)的石油醚溶液)并将纯产物馏分蒸发,得到无色油状化合物7-1(58%收率)。
1H NMR(400MHz,Chloroform-d)δ4.03(dd,J=6.0,0.9Hz,2H),3.49(t,J=4.6Hz,2H),2.32(t,J=8.5Hz,2H),1.90–1.56(m,5H),1.48–1.22(m,26H),0.95–0.83(m,6H)。
步骤2:
将化合物7-1(1.2eq)、N,N-二甲基丙二胺(1.0eq)、K2CO3(3eq)、Cs2CO3(0.27eq)溶于ACN溶液中,加入催化量的NaI(0.27eq),反应混合物常温搅拌12h。TLC显示反应结束,将反应液过滤,滤液减压浓缩的粗品。粗品通过快速柱色谱法纯化,得到化合物产物7-2。
1H NMR(400MHz,Chloroform-d)δ4.03(dd,J=6.0,0.9Hz,2H),2.79–2.48(m,7H),2.28(d,J=25.3Hz,8H),1.72–1.20(m,33H),0.93–0.83(m,6H).
步骤3:
将化合物7-2(1eq)、三乙胺(1.5eq)溶于DCM中反应5min,将胆固醇氯甲酸酯溶于DCM中,并逐滴加入上述体系内,室温搅拌反应3h,TLC监测反应进程。直接加水萃取,有机相用无水MgSO4干燥、过滤、旋转蒸发得粗品。粗品通过快速柱色谱法纯化,得到化合物7-3;
1H NMR(400MHz,Chloroform-d)δ5.36(tdt,J=4.7,1.9,1.0Hz,1H),4.75(tt,J=6.4,4.0Hz,1H),4.03(dd,J=6.0,0.9Hz,2H),3.32–3.07(m,4H),2.63(td,J=6.5,0.6Hz,2H),2.41–2.18(m,10H),1.91–0.64(m,81H)。
实施例8
步骤1:
将3β-羟基-Δ5-胆烯(1.0eq)和3-{[2-(二甲胺基)乙基]氨基}丙酸(1.5eq)溶于DCM中,加入DIEA(0.5eq)、DMAP(0.4eq)。室温搅拌反应5min后,加入EDCI(4eq);该体系室温搅拌过夜,TLC显示起始醇完全消失。将反应液用DCM(300mL)稀释,并用饱和NaHCO3(100mL),水(100mL)和饱和食盐水(100mL)洗涤。合并有机层经无水Na2SO4干燥,旋蒸除溶剂,得到粗产物。将粗产物柱色谱纯化(硅胶柱,洗脱液为含5%EA(体积百分比)的石油醚溶液)并将纯产物馏分蒸发,得化合物8-1(47%收率)。
1H NMR(400MHz,Chloroform-d)δ5.36(tdt,J=4.7,1.9,1.0Hz,1H),4.96(t,J=4.8Hz,1H),4.42(dddd,J=6.3,5.7,4.3,3.6Hz,1H),3.32–3.24(m,2H),2.74–2.56(m,2H),2.37–2.20(m,10H),1.91–1.25(m,21H),1.19–1.10(m,1H),1.03–0.87(m,7H),0.70(s,2H).
步骤2:
将化合物8-1(2eq)与1-溴十五烷(0.5eq)在ACN中室温搅拌过夜。将反应后的混合物真空浓缩,残留物用DCM(100ml)溶解并用水(3×100ml)萃取。合并有机相,经无水MgSO4干燥后,减压浓缩除溶剂。粗产物通过快速柱色谱法纯化,得到化合物8-2。
1H NMR(400MHz,Chloroform-d)δ5.36(dddt,J=4.7,3.8,1.9,1.0Hz,1H),4.73(tt,J=6.5,4.1Hz,1H),3.38–3.26(m,4H),2.80(qt,J=11.4,6.1Hz,2H),2.43–2.20(m,10H),1.90–1.22(m,46H),1.16(dddd,J=9.7,4.7,2.6,0.7Hz,1H),1.03–0.84(m,10H),0.70(s,3H).
实施例9
步骤1:
将薯蓣皂素(1.0eq)和3-{[2-(二甲胺基)乙基]氨基}丙酸(1.5eq)溶于DCM中,加入DIEA(0.5eq)、DMAP(0.4eq)。室温搅拌反应5min后,加入EDCI(4eq);该体系室温搅拌过夜,TLC显示起始醇完全消失。将反应液用DCM(300mL)稀释,饱和食盐水(3×100mL)洗涤萃取。合并有机层经无水MgSO4干燥,旋蒸除溶剂,得到粗产物。将粗产物柱色谱纯化(硅胶柱,洗脱液为含5%EA(体积百分比)的石油醚溶液)并将纯产物馏分蒸发,得化合物9-1(39%收率)。
1H NMR(400MHz,Chloroform-d)δ5.36(tdt,J=4.7,1.9,1.0Hz,1H),4.96(t,J=4.8Hz,1H),4.48–4.39(m,2H),3.42(dd,J=4.3,1.2Hz,2H),3.34–3.24(m,2H),2.73–2.55(m,2H),2.46–1.16(m,28H),1.05–0.90(m,11H),0.83(s,3H).
步骤2:
将化合物9-1(2eq)与1-溴十五烷(0.5eq)在ACN中室温搅拌过夜。将反应后的混合物真空浓缩,残留物用DCM(100ml)溶解并用水(3×100ml)萃取。合并有机相,经无水MgSO4干燥后,减压浓缩除溶剂。粗产物通过快速柱色谱法纯化,得到化合物9-2。
1H NMR(400MHz,Chloroform-d)δ5.36(tdt,J=4.7,1.9,1.0Hz,1H),4.75(p,J=5.5Hz,1H),4.48–4.41(m,1H),3.45–3.24(m,6H),2.80(qt,J=11.4,6.1Hz,2H),2.51–2.30(m,8H),2.22–1.16(m,48H),1.04–0.80(m,17H).
实施例10
步骤1:
将洋地黄毒苷配基(1.0eq)和3-{[2-(二甲胺基)乙基]氨基}丙酸(1.5eq)溶于DCM中,加入DIEA(0.5eq)、DMAP(0.4eq)。室温搅拌反应5min后,加入EDCI(4eq);该体系室温搅拌过夜,TLC显示起始醇完全消失。将反应液用DCM(300mL)稀释,饱和食盐水(3×100mL)洗涤萃取。合并有机层经无水MgSO4干燥,旋蒸除溶剂,得到粗产物。将粗产物柱色谱纯化(硅胶柱,洗脱液为含5%EA(体积百分比)的石油醚溶液)并将纯产物馏分蒸发,得化合物10-1(41%收率)。
1H NMR(400MHz,Chloroform-d)δ5.93(dt,J=1.9,1.0Hz,1H),5.00–4.70(m,4H),3.43(s,1H),3.32–3.24(m,2H),2.78–2.55(m,3H),2.26(s,6H),2.11–1.18(m,21H),0.90(d,J=1.9Hz,6H).
步骤2:
将化合物10-1(2eq)与1-溴十五烷(0.5eq)在ACN中室温搅拌过夜。将反应后的混合物真空浓缩,残留物用DCM(100ml)溶解并用水(3×100ml)萃取。合并有机相,经无水MgSO4干燥后,减压浓缩除溶剂。粗产物通过快速柱色谱法纯化,得到化合物10-2。
1H NMR(400MHz,Chloroform-d)δ4.93–4.74(m,3H),3.45–3.25(m,5H),2.88–2.71(m,3H),2.35(s,6H),2.11–1.18(m,46H),0.94–0.83(m,9H).
实施例11
步骤1:
将17α-羟孕烯醇酮(1.0eq)和3-{[2-(二甲胺基)乙基]氨基}丙酸(1.5eq)溶于DCM中,加入DIEA(0.5eq)、DMAP(0.4eq)。室温搅拌反应5min后,加入EDCI(4eq);该体系室温搅拌过夜,TLC显示起始醇完全消失。将反应液用DCM(300mL)稀释,饱和食盐水(3×100mL)洗涤萃取。合并有机层经无水MgSO4干燥,旋蒸除溶剂,得到粗产物。将粗产物柱色谱纯化(硅胶柱,洗脱液为含5%EA(体积百分比)的石油醚溶液)并将纯产物馏分蒸发,得化合物11-1。
1H NMR(400MHz,DMSO-d6)δ5.98(t,J=4.9Hz,1H),5.35(tdt,J=4.5,1.8,1.0Hz,1H),5.10(s,1H),4.42(p,J=5.3Hz,1H),3.25(tdd,J=6.2,4.8,1.4Hz,2H),2.66–2.52(m,2H),2.45–2.08(m,11H),1.96–1.23(m,16H),1.15–0.97(m,4H),0.70(s,3H).
步骤2:
将化合物9-1(2eq)与1-溴十二烷(0.5eq)在ACN中室温搅拌过夜。将反应后的混合物真空浓缩,残留物用DCM(100ml)溶解并用水(3×100ml)萃取。合并有机相,经无水MgSO4干燥后,减压浓缩除溶剂。粗产物通过快速柱色谱法纯化,得到化合物11-2。
1H NMR(400MHz,DMSO-d6)δ5.35(tdt,J=4.5,1.8,1.0Hz,1H),5.10(s,1H),4.61(p,J=5.5Hz,1H),3.36–3.23(m,4H),2.70–2.55(m,2H),2.49–2.30(m,8H),2.13(s,3H),2.00–1.20(m,36H),1.13–0.98(m,4H),0.92–0.84(m,3H),0.70(s,3H).
测试例
脂质体的制备
将实施例1-实施例11的可电离脂质化合物分别与DSPC、胆固醇和DMG-PEG2000以50:10:38.5:1.5的摩尔比溶于乙醇制备乙醇脂质溶液,并将Luc mRNA在10mM柠檬酸盐缓冲液(pH=4)中稀释得到mRNA水溶液。通过使用微流控装置以1:3的体积比混合乙醇脂质溶液和mRNA水溶液,以总脂质与mRNA的重量比为约40:1制备脂质体。经静置透析6h除去乙醇并使用DPBS代替。最后,脂质纳米颗粒通过0.2μm无菌过滤器过滤,得到使用可电离脂质/DSPC/胆固醇/DMG-PEG2000(50/10/38.5/1.5mol%)包封Luc mRNA的LNP制剂S-1LNPs至S-11LNPs。
对比测试例SM-102:以CN 113271926 A【0950】段,可电离脂质1,与DSPC、胆固醇和DMG-PEG2000以50:10:38.5:1.5的摩尔比溶于乙醇制备乙醇脂质溶液,并将Luc mRNA在10mM柠檬酸盐缓冲液(pH=4)中稀释得到mRNA水溶液。通过使用微流控装置以1:3的体积比混合乙醇脂质溶液和mRNA水溶液,以总脂质与mRNA的重量比为约40:1制备脂质体。经静置透析6h除去乙醇并使用DPBS代替。最后,脂质纳米颗粒通过0.2μm无菌过滤器过滤,得到使用可电离脂质/DSPC/胆固醇/DMG-PEG2000(50/10/38.5/1.5mol%)包封Luc mRNA的LNP制剂获得SM-102LNPs。
可电离脂质1(SM-102)
测试例1粒径表征
使用Malvern ZetasizerNano ZS(Malvern UK),以173°反向散射检测模式通过动态光散射测定脂质纳米颗粒的大小及多分散指数,测试结果见表1:
表1各实施例纳米粒的大小及多分散指数
测试例2细胞毒性测试
以巨噬细胞、293T细胞为模型细胞,采用MTT法考察所得新型可电离脂质形成的脂质体的安全性。记录吸光度值,计算细胞存活率,结果见图1,可见本专利提供的新型可电离脂质具有良好的细胞安全性。
测试例3细胞转染情况
以RAW264.7细胞为模型细胞,通过倒置荧光显微镜观察由实施例1所得可电离脂质参与形成的脂质体在RAW264.7细胞中的转染情况。调整RAW264.7细胞接种在96孔板中,DMEM培养基培养细胞使其数量达到培养板面积的70%左右。随后,用含Luc mRNA-LNP的新鲜培养基对细胞进行转染24h。24小时后,将每孔细胞用PBS洗两遍,吸净,每孔加入80μl 1×细胞裂解液,置于37℃、5%CO2培养箱中10分钟,显微镜下观察细胞全部裂解后,每孔吸取40μl裂解液上清,避光条件下加入20μl荧光素酶底物,快速混匀,置于倒置荧光显微镜观察,通过生物发光仪定量检测表达量。
结果见图2,可见本专利提供的新型可电离脂质可以在RAW264.7细胞中成功转染,具有良好的转染效果。
利用电化学发光仪ECL intensity(a.u.),定量荧光蛋白b表达量,具体数据如表2所示。
表2各实施例在RAW264.7细胞系中表达Fluc-mRNA荧光蛋白定量结果
说明以上实施例中可电离脂质所构建的LNPs均能够在细胞内成功表达。
测试例5体内表达的主要脏器分布情况
以20g ICR小鼠为模型动物,通过尾静脉注射由实施例1所得可电离脂质制备的Luc mRNA-LNP考察该递送系统在小鼠各器官的Luc mRNA表达及分布情况。按注射剂量为每kg小鼠体重注射0.5mg的Luc RNA,尾静脉注射。6小时后,注射底物荧光素,反应10分钟左右,处死小鼠,分离、心脏、肝脏、脾脏、肺、肾脏等主要器官,在IVIS动力学成像系统(PerkinElmer)中使用生物发光方法对小鼠进行成像,检测各主要器官的荧光强度,结果见图3。
测试例6体内表达定量情况
以20g ICR小鼠为模型动物,通过尾静脉注射由可电离脂质制备的Luc mRNA-LNP;检测该递送系统在小鼠主要脏器的Luc mRNA表达量情况。按注射剂量为每kg小鼠体重注射0.5mg的Luc RNA,尾静脉注射。8小时后,处死小鼠,分离心脏、肝脏、脾脏、肺、肾脏等主要器官,裂解脏器细胞,通过萤火虫荧光素酶报告基因检测试剂盒,利用生物发光仪定量测定luc表达量,表3为肝脏器官的定量情况。
表3各实施例mRNA-LNPs在肝脏器官中的荧光蛋白定量结果
对应实施例 | 测试样品编号 | 肝脏化学/生物发光强度(a.u.) |
实施例1 | S1 mRNA-LNPs | 1190 |
实施例2 | S2 mRNA-LNPs | 1102 |
实施例3 | S3 mRNA-LNPs | 1176 |
实施例4 | S4 mRNA-LNPs | 1090 |
实施例5 | S5 mRNA-LNPs | 1110 |
实施例6 | S6 mRNA-LNPs | 1320 |
实施例7 | S7 mRNA-LNPs | 1240 |
实施例8 | S8 mRNA-LNPs | 1100 |
实施例9 | S9 mRNA-LNPs | 1080 |
实施例10 | S10 mRNA-LNPs | 1089 |
实施例11 | S11 mRNA-LNPs | 1100 |
对比例1 | SM102 mRNA-LNPs | 1080 |
Claims (14)
1.一种可电离脂质化合物,其特征在于,其为下述式(I)所示化合物或其药学上可接受的盐:
其中,R1为C6-12烷基,-Rh-C(=O)-Ri、-Rj-C(=O)OH、C4-8不饱和内脂环,或R1和R3及与其连接的C构成任选地取代的C6-12含氧螺杂环;其中,Rh为不存在或C1-3亚烷基;Ri为H或C1-3烷基;Rj为C3-11亚烷基;
R2为H或OH;
R3为H,C1-3烷基,或R1和R3及与其连接的C构成任选地取代的C4-8含氧螺杂环;
G为N或C;
L1为任选地取代的C1-6亚烷基或C1-6亚烯基;
L2和L3分别独立地为H、或任选地取代的C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、C3-8环烯基、C3-8环炔基、4元至8元杂环基、C6-10芳基或5元至10元杂芳基;或者L2和L3和它们所接的氮连接成环;
L4为Ra、-RbMRc、-(C6-10亚芳基)-Rd或-(6元至10元杂亚芳基)-Re;
其中,Ra为任选地取代的C8-24烷基或任选地取代的C8-24烯基;
Rb为任选地取代的亚烷基或任选地取代的亚烯基,Rc分别独立地为任选地取代的烷基或任选地取代的烯基,M为-OC(=O)-、-C(=O)O-、-OC(=O)O-、-C(=O)-、-O-、-S-S-、-SC(=S)-、-C(=O)S-、-SC(=O)-、-C(=S)S-、-C(=S)-;且Rb、M和Rc的总C数是8-24;
Rd或Re为任选地取代的C8-18烷基或任选地取代的C8-18烯基。
2.根据权利要求1所述的可电离脂质化合物,其特征在于,Ra为任选地取代的C12-16烷基或任选地取代的C12-16烯基,且Ra为直链或具有1、2或3条支链。
3.根据权利要求2所述的可电离脂质化合物,其特征在于,Ra为C12-16直链烷基。
4.根据权利要求1所述的可电离脂质化合物,其特征在于,Rb为C1-6亚烷基。
5.根据权利要求1所述的可电离脂质化合物,其特征在于,Rc分别独立地为任选地取代的C10-18烷基或任选地取代的C10-18烯基,且Rc为直链或具有1、2或3条支链。
6.根据权利要求1所述的可电离脂质化合物,其特征在于,L1为未取代的C1-6亚烷基或C1-6亚烯基,或为被羧基、羟基或氨基取代的C1-6亚烷基或C1-6亚烯基。
7.根据权利要求1所述的可电离脂质化合物,其特征在于,L2和L3分别独立地为未取代的C1-8直链烷基,或被羧基、羟基或氨基取代的C1-8直链烷基或L2和L3和它们所接的氮连接成C3-6环。
8.根据权利要求7所述的可电离脂质化合物,其特征在于,L2和L3分别独立地为C1-3直链烷基,或L2和L3和它们所接的氮连接成C3-6环。
9.根据权利要求8所述的可电离脂质化合物,其特征在于,L2和L3分别独立地为甲基、乙基、丙基。
10.根据权利要求1所述的可电离脂质化合物,其特征在于,R1为C7-10烷基。
11.根据权利要求1-10中的任一项所述的可电离脂质化合物,其特征在于,其为以下结构式的任意一种:
12.一种递送所述治疗或预防剂的载体,其特征在于,包含权利要求1-11中的任一项所述的可电离脂质化合物,所述治疗或预防剂被包封在载体内或与载体缔合。
13.根据权利要求12所述的递送所述治疗或预防剂的载体,其特征在于,所述治疗或预防剂包括核酸分子、基因疫苗、小分子化合物、多肽或蛋白质中的一种或多种。
14.权利要求1-11的任一项所述的可电离脂质化合物的应用,其特征在于,制备核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物的纳米颗粒制剂,所述纳米颗粒制剂的平均尺寸为10nm~150nm。
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