WO2020252648A1 - 一种果胶-阿霉素轭合物及其制备方法和用途 - Google Patents

一种果胶-阿霉素轭合物及其制备方法和用途 Download PDF

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WO2020252648A1
WO2020252648A1 PCT/CN2019/091627 CN2019091627W WO2020252648A1 WO 2020252648 A1 WO2020252648 A1 WO 2020252648A1 CN 2019091627 W CN2019091627 W CN 2019091627W WO 2020252648 A1 WO2020252648 A1 WO 2020252648A1
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compound
formula
pectin
doxorubicin conjugate
preparing
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PCT/CN2019/091627
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French (fr)
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唐小海
曾诚
黄源芳
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四川瀛瑞医药科技有限公司
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Priority to US16/636,343 priority Critical patent/US11596643B2/en
Priority to PCT/CN2019/091627 priority patent/WO2020252648A1/zh
Priority to CN201980001356.8A priority patent/CN110418653B/zh
Priority to JP2019564079A priority patent/JP7051906B2/ja
Publication of WO2020252648A1 publication Critical patent/WO2020252648A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0045—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Galacturonans, e.g. methyl ester of (alpha-1,4)-linked D-galacturonic acid units, i.e. pectin, or hydrolysis product of methyl ester of alpha-1,4-linked D-galacturonic acid units, i.e. pectinic acid; Derivatives thereof

Definitions

  • the invention relates to the field of pharmacy, in particular to a pectin-doxorubicin conjugate and its preparation method and application.
  • Pectin-Adriamycin Conjugate Targeted Drug Delivery System
  • PAC Targeted Drug Delivery System
  • PAC is a polymer conjugate with a particle size of about 200nm. Part of the drugs that enter the circulatory system after injection can take advantage of the enhanced permeability and retention (EPR) effect of tumor tissue on macromolecular substances and accumulate in tumor tissue to achieve passive The purpose of targeting. PAC is gradually engulfed by tumor cells in tumor tissues, and is hydrolyzed in lysosomes to release adriamycin to play a role in killing tumors.
  • EPR enhanced permeability and retention
  • the existing pectin-doxorubicin conjugates are all pectin and adriamycin directly bonded by amide bond or acylhydrazone bond, which is hard to dissolve in water and must be made into nano suspension or freeze-dried powder injection , It can only be used locally; if it is used systemically, it is easy to be swallowed by the reticuloendothelial system, has limited targeting, and cannot accumulate in malignant tumor tissues in high concentrations for a long time, resulting in poor anti-tumor efficacy.
  • the purpose of the present invention is to provide a pectin-doxorubicin conjugate that can be accumulated in malignant tumor tissues for a long time in a targeted high concentration against the deficiencies of the prior art, which can achieve the purpose of increasing efficiency and reducing toxicity.
  • the invention also provides a method for preparing the above-mentioned pectin-doxorubicin conjugate.
  • a is pectin or modified pectin
  • b is PEGn
  • c is an enzymatic cleavage group
  • polypeptide or polypeptide derivative
  • d is a self-degrading group
  • e is adriamycin.
  • the pectin is a polygalacturonic acid ester-free pectin
  • the modified pectin is a C 2 -C 4 alkylamine substituted with a carbonyl group and a hydroxyl group of the polygalacturonic acid ester-free pectin Generate amides, and then be further activated into pectin carbonate; preferably, a is modified pectin; more preferably, the molecular weight of a is 1-4KD; even more preferably, the polygalacturonic acid is ester-free
  • the galacturonic acid content of pectin is more than 95%.
  • n is an integer of 1-20
  • c is a dipeptide, dipeptide derivative, tripeptide, tripeptide derivative, tetrapeptide, tetrapeptide derivative; preferably, n is 6
  • d is p-aminobenzyloxycarbonyl (PABC).
  • the pectin is a pectin in which a carbonyl group is connected to a C 2 -C 4 alkyl amine group substituted with a hydroxyl group; preferably, the molecular weight of the pectin is 1-4 KD.
  • the present invention also discloses a method for preparing the pectin-doxorubicin conjugate as described above, by reacting the compound of formula (13) with the compound of formula (9) in the presence of an alkaline reagent;
  • a is an integer selected from 2-4, m is 1-60KD; the compound of formula (9) is bcd-ADM, ADM is adriamycin, b is PEGn, and c is a polypeptide; preferably, c Is dipeptide, dipeptide derivative, tripeptide, tripeptide derivative, tetrapeptide, tetrapeptide derivative; preferably, n is an integer of 6-12; preferably, c is val-ala; preferably, d is PABC; PEGn is polyethylene glycol and n is the degree of polymerization.
  • the preparation method of the compound of formula (13) is as follows: pectin carboxyl group is condensed with alcohol to obtain esterified pectin, and then with hydroxyl substituted C 2 -C 4 alkyl amine to form amide and then react with bis(4-nitro group).
  • the compound of formula (13) can be obtained by reaction of phenyl) carbonate.
  • the preparation method of the compound of formula (9) is: the compound of formula (5) is reacted with adriamycin in the presence of a basic reagent to obtain the compound of formula (6), and the compound of formula (6) is in the presence of piperidine
  • the compound of formula (7) is obtained by deprotection, and then the compound of formula (8) is obtained by reaction with R 1 -b-COOH.
  • the compound of formula (8) is deprotected in the presence of piperidine to obtain compound (9); compound of formula (5) Is R 1 -c-PABC, the compound of formula (6) is R 1 -c-PABC-e, the compound of formula (7) is c-PABC-e, and the compound of formula (8) is R 1 -bc-PABC-e, R 1 is a protecting group; preferably, R 1 is fluorenylmethyloxycarbonyl (Fmoc).
  • the preparation method of the compound of formula (5) is: the compound of formula (3) reacts with p-aminobenzol in the presence of an acid binding agent to obtain the compound of formula (4), and the compound of formula (4) is in the presence of a basic reagent
  • the compound of formula (3) is R 1 -c-OH
  • the compound of formula (4) is R 1 -c-PABOH
  • PABOH is 4- (Hydroxymethyl)phenylamino.
  • the preparation method of the compound of formula (3) is: the compound of formula (1) is reacted in the presence of NHS and DCC to obtain the compound of formula (2), and the compound of formula (2) is reacted with amino acid in the presence of a basic reagent to obtain the formula (3)
  • the compound; the compound of formula (1) is R 1 -c 1 -OH, the compound of formula (2) is R 1 -c 1 -OSu, and c 1 is an amino acid; preferably, c 1 is val.
  • the invention also discloses the use of the pectin-doxorubicin conjugate as described above for preparing medicines for treating cancer.
  • the pectin-doxorubicin conjugate of the present invention has a brand-new chemical structure and can be accumulated in malignant tumor tissues in a targeted high concentration for a long time to achieve the purpose of increasing efficiency and reducing toxicity.
  • the indication is the chemotherapy of various solid malignant tumors .
  • Figure 1 is the 1 H NMR spectrum of compound 6
  • Figure 2 is the 1 H NMR spectrum of compound 7;
  • Figure 3 is a 1 H NMR spectrum of compound 8.
  • Figure 4 is a 13 C NMR spectrum of compound 8.
  • Figure 5 is a 1 H NMR spectrum of compound 9
  • Figure 6 is a 1 H NMR spectrum of compound 13;
  • Figure 7 is the 1 H NMR spectrum of the final product doxorubicin-pectin conjugate
  • Figure 8 shows the inhibitory effect of the final product doxorubicin-pectin conjugate and the control compound (pectin and doxorubicin are directly bonded via an amide bond) on the H22 liver cancer mouse tumor model;
  • Figure 9 shows the inhibitory effect of the final product doxorubicin-pectin conjugate and the control compound (pectin and doxorubicin are directly bonded via an amide bond) on the 4T1 breast cancer mouse tumor model.
  • MALDI-TOPMS m/z 1531.2103[(M+Na+H)+,C77H97N5O26].
  • the pectin-doxorubicin conjugate (which can be prepared through Examples 1-13) has the following structure:
  • In vitro cytotoxicity test Collect HT-29 colon cancer cells, HepG-2 liver cancer cells, SMMC7721 liver cancer cells, SKOV3 ovarian cancer cells and MCF-7 breast cancer cells growing in log phase, adjust the cell suspension concentration, and add 100 ⁇ L to each well , Pave the plate so that the cell density to be tested is 4000 cells/well (the edge holes are filled with sterile PBS).
  • the pectin-doxorubicin conjugate prepared in the present invention (which can be prepared in Examples 1-13) is accumulated in tumor tissue through the EPR effect in vivo to achieve the purpose of passive targeting, the preparation of the present invention is investigated The result of the obtained pectin-doxorubicin conjugate in vivo pharmacodynamics on tumor-bearing mice.
  • In vivo efficacy test Collect H22 liver cancer cells, 4T1 breast cancer cells, EMT6 breast cancer cells and HT-29 colon cancer cells in logarithmic growth phase, adjust the cell suspension concentration to 3 ⁇ 10 7 cells/mL, and inoculate the cells In Balb/c mice or nude mice, 0.1 mL/mouse (containing approximately 3 ⁇ 10 6 cells) subcutaneously in the right upper limb of Balb/c mice or nude mice.
  • the tumor-bearing mice When the tumor volume of the mice to be inoculated reaches 100 mm 3 on average, the tumor-bearing mice will be randomly divided into groups: Negative control group (0.9% sodium chloride injection), adriamycin control group (5mg/kg), pectin adriamycin experimental group (adriamycin equivalent 5mg/kg), 8 mice in each group, intravenous
  • Negative control group (0.9% sodium chloride injection
  • adriamycin control group 5mg/kg
  • pectin adriamycin experimental group adriamycin equivalent 5mg/kg
  • the pectin-doxorubicin conjugate prepared by the present invention has better curative effect on H22 liver cancer, 4T1 breast cancer, EMT-6 breast cancer and HT-29 colon cancer than the adriamycin control.
  • the pectin-doxorubicin conjugate prepared by the present invention can obviously inhibit the tumor growth of H22 liver cancer, 4T1 breast cancer, EMT-6 breast cancer tumor-bearing mice, and the inhibition rate is relatively high, 72.98%, 78.1%, respectively.
  • the inhibition rate of H22 liver cancer, 4T1 breast cancer, EMT-6 breast cancer tumor-bearing mice is lower than that of the pectin-doxorubicin conjugate prepared by the present invention , Respectively: 53.42%, 50.61%, 56.95%.
  • the weight of the mice in the pectin-doxorubicin conjugate group prepared by the present invention did not significantly decrease, and no mice died; while the weight of the mice in the doxorubicin group decreased significantly, with a weight loss of more than 15%, and A few mice died.
  • the results of in vivo pharmacodynamics show that, compared with adriamycin, the pectin-adriamycin conjugate prepared by the present invention has the effect of increasing efficacy and reducing toxicity.
  • the tumor tissue was taken and the doxorubicin imaging intensity in the tissue was observed with a small animal in vivo fluorescence imaging system. It was found that mice in the pectin-doxorubicin conjugate administration group prepared by the present invention The tumor exhibits strong fluorescence of doxorubicin, indicating that the pectin-doxorubicin conjugate prepared by the present invention can accumulate in tumor tissues for a long time and at high concentration.
  • the pectin-doxorubicin conjugate prepared by the present invention has a higher inhibitory rate on H22 liver cancer and 4T1 breast cancer mouse tumor models than the existing control compound (pectin and adriamycin directly pass through the amide bond Bonding), the inhibition rates were 70.83% and 76.20%, respectively, while the inhibition rates of the existing control compounds (pectin and adriamycin were directly bonded via amide bonds) were only 48.64% and 47.00%.
  • the inventors also found in experiments that the pectin-doxorubicin conjugate prepared by the present invention not only has a high tumor inhibition rate, but also can maintain a high inhibition rate for a long time. That is, given the same dose, the pectin-doxorubicin conjugate maintains the inhibitory effect longer.

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Abstract

一种果胶-阿霉素轭合物，所述轭合物的制备方法及用途。该果胶-阿霉素轭合物能够靶向性高浓度长时间蓄积于恶性肿瘤组织内，达到增效减毒的目的，适应症为各种实体恶性肿瘤的化疗。

Description

一种果胶-阿霉素轭合物及其制备方法和用途 技术领域
本发明涉及药学领域，特别是涉及一种果胶-阿霉素轭合物及其制备方法和用途。
背景技术
“果胶-阿霉素轭合物”靶向药物递送系统(PAC)是在大量前期工作和文献研究的基础上，选定果胶作为高分子抗癌前药的载体，并通过对果胶的结构进行修饰，使其可以与多肽-阿霉素共价结合形成水溶性的具有高载药量的果胶-阿霉素轭合物。
PAC是高分子轭合物，粒径在200nm左右，注射后进入循环系统的部分药物可以利用肿瘤组织对大分子物质具有的增强通透和潴留效应(EPR)而蓄积于肿瘤组织中，达到被动靶向的目的。PAC在肿瘤组织中逐渐被肿瘤细胞吞噬，在溶酶体中水解释放出阿霉素，发挥杀伤肿瘤的作用。现有的果胶-阿霉素轭合物均为果胶和阿霉素直接通过酰胺键键合或酰腙键键合，难溶于水，必须做成纳米混悬剂或冻干粉针，只能局部用药；若是全身用药，易被网状内皮系统吞噬，靶向性有限、无法高浓度长时间蓄积于恶性肿瘤组织内，抗肿瘤疗效不佳。
发明内容
本发明的目的在于针对现有技术的不足，提供一种能够靶向性高浓度长时间蓄积于恶性肿瘤组织内的果胶-阿霉素轭合物，可达到增效减毒的目的，本发明还提供了上述果胶-阿霉素轭合物的制备方法。
本发明为实现上述目的采用的技术方案是：一种果胶-阿霉素轭合物，具有如式(I)结构：
a-b-c-d-e  (I)
其中a为果胶或修饰果胶，b为PEGn，c为为酶促裂解基团，多肽或多肽衍生物，d为自降解基团，e为阿霉素。
进一步地，所述果胶为多聚半乳糖醛酸无酯果胶，所述修饰果胶为多聚半乳糖醛酸无酯果胶的羰基与羟基取代的C 2-C 4的烷基胺生成酰胺、再进一步被活化为果胶碳酸酯；优选的，a为修饰果胶；再优选的，所述a的分子量为1-4KD；再优选的，所述多聚半乳糖醛酸无酯果胶的半乳糖醛酸含量为95％以上。
进一步地，式(I)中，n为1-20的整数，c为二肽、二肽衍生物、三肽、三肽衍生物、四肽、四肽衍生物；优选的，n为6-12的整数；优选的，c为val-ala。
进一步地，d为对氨基苄氧羰基(PABC)。
进一步地，所述果胶为羰基与羟基取代的C 2-C 4的烷基胺基相连的果胶；优选的，所述果胶分子量为1-4KD。
本发明还公开了如上所述的果胶-阿霉素轭合物的制备方法，将式(13)化合物与式(9)化合物在碱性试剂存在的条件下反应；
Figure PCTCN2019091627-appb-000001
式(13)中，a为选自2-4的整数，m为1-60KD；式(9)化合物为b-c-d-ADM，ADM为阿霉素，b为PEGn，c为多肽；优选的，c为二肽、二肽衍生物、三肽、三肽衍生物、四肽、四肽衍生物；优选的，n为6-12的整数；优选的，c为val-ala；优选的，d为PABC；PEGn为聚乙二醇、n表示聚合度。
进一步地，式(13)化合物的制备方法为：果胶羧基与醇缩合后得到酯化果胶，再与羟基取代的C 2-C 4的烷基胺生成酰胺后与二(4-硝基苯基)碳酸酯反应即得式(13)化合物。
进一步地，式(9)化合物的制备方法为：式(5)化合物与阿霉素在碱性试剂存在的条件下反应得式(6)化合物，式(6)化合物在哌啶存在的条件下脱保护得式(7)化合物、再与R 1-b-COOH反应得式(8)化合物，式(8)化合物在哌啶存在的条件下脱保护得化合物(9)；式(5)化合物为R 1-c-PABC，式(6)化合物为R 1-c-PABC-e，式(7)化合物为c-PABC-e，式(8)化合物为R 1-b-c-PABC-e，R 1为保护基团；优选的，R 1为芴甲氧羰基(Fmoc)。
进一步地，式(5)化合物的制备方法为：式(3)化合物在缚酸剂存在下与对氨基卞醇反应得到式(4)化合物，式(4)化合物在碱性试剂存在的条件下与二(4-硝基苯基)碳酸酯反应得到式(5)化合物；式(3)化合物为R 1-c-OH，式(4)化合物为R 1-c-PABOH，PABOH为4-(羟甲基)苯基氨基。
进一步地，所述式(3)化合物的制备方法为：式(1)化合物在NHS和DCC存在下反应得到式(2)化合物，式(2)化合物在碱性试剂存在下与氨基酸反应得到式(3)化合物；式(1)化合物为R 1-c 1-OH，式(2)化合物为R 1-c 1-OSu，c 1为氨基酸；优选的，c 1为val。
本发明还公开了如上所述的果胶-阿霉素轭合物用于制备治疗癌症的药物的用途。
本发明的优点和效果：
本发明的果胶-阿霉素轭合物具有全新化学结构，能够靶向性高浓度长时间蓄积于恶性肿瘤组织内，达到增效减毒的目的，适应症为各种实体恶性肿瘤的化疗。
附图说明
图1为化合物6的 1H NMR谱图；
图2为化合物7的 1H NMR谱图；
图3为化合物8的 1H NMR谱图；
图4为化合物8的 13C NMR谱图；
图5为化合物9的 1H NMR谱图；
图6为化合物13的 1H NMR谱图；
图7为最终产物阿霉素-果胶轭合物的 1H NMR谱图；
图8为最终产物阿霉素-果胶轭合物与对照化合物(果胶与阿霉素直接通过酰胺键键合)对H22肝癌小鼠肿瘤模型的抑制作用；
图9为最终产物阿霉素-果胶轭合物与对照化合物(果胶与阿霉素直接通过酰胺键键合)对4T1乳腺癌小鼠肿瘤模型的抑制作用。
具体实施方式
以下通过实施例，对本发明作进一步的具体说明，但这些实施例不对本发明有任何限制。
实施例1
150g化合物1(0.44mol)溶于1.5LTHF，依次加入NHS(56g,0.49mol)、DCC(137g,0.66mol)，室温搅拌过夜，过滤，固体二氯甲烷洗两遍，滤液浓缩至干，并重结晶一次，即可得到化合物2纯产品。
实施例2
Figure PCTCN2019091627-appb-000002
147g化合物2(0.34mol)溶于1.5LTHF，依次加入L-丙氨酸(32g,0.35mol)，NaHCO 3(30g,0.35mol)，再加入500mL水。调节THF和水的比例使反应液成单相(较难)。室温搅拌过夜，反应完毕，浓缩除去THF，加水稀释，HCl调节PH至3-4，析出固体，固体水洗，真空干燥，乙酸乙酯洗涤，得130g产物3(含有少许杂质)，结晶纯化。
实施例3
Figure PCTCN2019091627-appb-000003
30g化合物3(73mmol)悬浮于二氯甲烷500mL，依次加入4-氨基苄醇(11g,90mmol)，EEDQ(27g,113mmol)，最后加入甲醇直到溶液澄清，室温搅拌过夜，过滤，固体二氯甲烷洗，滤液浓缩至干得到粗品化合物4，再用甲基叔丁基醚洗涤得到纯品20g。
实施例4
Figure PCTCN2019091627-appb-000004
21g化合物4(41mmol)悬浮于500mL二氯甲烷中，依次加入DIPEA(16g,126mmol)，二(对硝基苯)碳酸酯(18.5g,69mmol)，最后加入DMF直到溶液澄清，室温搅拌过夜。减压蒸馏除去DMF，粘稠状固体先用少量甲醇洗，再用石油醚和乙酸乙酯(或甲基叔丁基醚)重结晶数次，得7g纯化合物5。
实施例5
Figure PCTCN2019091627-appb-000005
称取690mg阿霉素盐酸盐、1.036g化合物5于圆底烧瓶中，加毕，加入10mLDMF。搅拌下加入DIPEA 0.21mL,室温反应5h。反应完毕，将反应液缓慢滴入甲基叔丁基醚中，离心，得粗品。再用少量DMF溶解，进行第二次重结晶。得产品1.076g，产率＝78％。
实施例6
Figure PCTCN2019091627-appb-000006
称取400mg化合物6于圆底烧瓶中，加毕，加入10mLDMF。室温搅拌下快速加入哌啶1.8mL,室温反应70s。反应完毕，快速将反应液倒入冰浴中的甲基叔丁基醚中，离心，得粗品。再用少量DMF溶解，缓慢滴入室温下的甲基叔丁基醚中进行第二次重结晶。得产品210mg，产率＝66％。
实施例7
Figure PCTCN2019091627-appb-000007
称取565mgPEG8于圆底烧瓶中，加入5mLDMF。加毕,室温搅拌下加入HATU 440mg、DIPEA 0.13mL。用少量DMF将化合物7溶解，滴管加入反应瓶中(共用溶剂5mL)。室温搅拌反应1.5h。反应完毕，将反应液缓慢加入甲基叔丁基醚中，离心，得粗品。再用少量DMF溶解，再次滴入甲基叔丁基醚中进行第二次重结晶。柱层析纯化：Ea:MeOH＝20:1。产率55％。
化合物8的确认：
1H NMR(400MHz,DMSO-d 6)ppm:14.03(s,1H),13.27(s,1H),9.88(s,1H),8.16(d,j＝6.8Hz,1H),7.91-7.87(m,5H),7,85-7.63(m,3H),7,54(d,j＝8.4Hz,2H),7.51(t,j＝7.6Hz,3H),7.32(t,j＝7.6Hz,2H),7.24(d,j＝8.4Hz,2H),6.19(s,1H),5.45(s,1H),5.22(d,j＝2.4Hz,1h),4.9(m,4H),4.57(s,2H),4.38-4.15(m,8H),4.0(s,3H),3.6(t,j＝6.8Hz,2H),3.5-3.3(m,32H),3.12(m,2H),2.96(m,2H),2.42(m,2H),2.2(m,2H),1.9(m,2H),1.43(m,1H),1.22(m,4H),0.86 (d,j＝4Hz,3H),0.82(dj＝4Hz,3H)
13C NMR(100MHz,DMSO-d 6)ppm:171.11,170.91,170.40,160.78,156.21,156.13,155.36,154.54,143.93,140.76,128.56,127.64,127.09,125.19,120.13,118.92,110.60,74.98,69.80,69.72,69.61,69.51,69.12,66.94,65.37,63.76,57.49,56.58,49.05,46.75,35.91,10.61,19.18,18.14,17.93,17.07.
MALDI-TOPMS:m/z 1531.2103[(M+Na+H)+,C77H97N5O26].
RP-HPLC(Agilent 1260)20.641min,峰面积：92.4038％.
实施例8
Figure PCTCN2019091627-appb-000008
称取200mg化合物8于圆底烧瓶中，加毕，加入6mLDMF。室温搅拌下快速加入哌啶660uL,室温反应140s。反应完毕，快速将反应液倒入冰浴中的甲基叔丁基醚中，离心，得粗品。再用少量DMF溶解，缓慢滴入室温下的甲基叔丁基醚中进行第二次重结晶。
实施例9
取柑橘果胶(购买的原料)2g溶于200mL(0.2mol/L)稀硝酸溶液中，升温至85度(内温83度，外温90度)，升温到85度(内温实际83度)开始计时，反应约2h后停止加热，降温至室温后，将反应液滴加入800mL的无水乙醇中，膜过滤，洗涤，真空干燥得化合物10。
化合物10的确认：
Figure PCTCN2019091627-appb-000009
IR(KBr,v,cm -1):3421(O-H)，2925(C-H)，1740(COOH)，1632(COOH)，1414，1384,1334,1234,1146(C-O-C),1102(C-O-C,C-OH)，1018(C-OH)， 952，885,831(α-D-GalA),742,634.
1H NMR(400MHz,D 2O)δppm:5.10(s,1H,H-1),5.07(s,1H,H-5))4.50(s,1H,H-4),4.05(d,J＝10.4,1H,H-3),3.78(d,J＝10.4,H-2).
13C NMR(100MHz,D 2O)δppm:172.56(COOH),99.86(C-1，α型),78.30(C-5),70.34(C-4),68.10(C-3),67.91(C-2).
1H NMR(400MHz，DMSO-d 6)δppm:12.52(COOH，1H)，5.04-4.85(m，3H)，4.16(s，1H)，3.67-3.59(m，3H).
13C NMR(100MHz，DMSO-d6)δppm:170.44(COOH),98.69(C-1,α型)，76.71(C-5)，69.55(C-4)，68.24(C-3)，67.90(C-2).
实施例10
Figure PCTCN2019091627-appb-000010
取2g化合物10于单口瓶中，加入20mL的甲醇与2mL的浓HCl，内温升温至55度开始计时，反应7h后停止搅拌，降温，将反应液滴加至无水乙醇中，搅拌，过滤，洗涤，真空干燥得化合物11。
实施例11
向圆底烧瓶中加入600mg的化合物11，再加入3.16g的3-氨基-1-丙醇(粘稠状液体)，搅拌2天，反应时间超过48h，将澄清的粘稠状反应液缓慢滴加入无水乙醇中，搅拌，过滤，洗涤，真空干燥得化合物12。
实施例12
Figure PCTCN2019091627-appb-000011
取1g的化合物12溶于15mL的DMSO中使其完全溶解，再加入1.29g的二(对硝基苯基)碳酸酯，再加入0.7mL的DIEA，过夜反应(反应超过12h)，最后将反应液缓慢滴加入EA溶液中(200mL)，快速过滤，洗涤，真空干燥得化合物13。
化合物13的确认：
1H NMR(400MHz，DMSO-d 6)δppm:8.305(s，2H)，7.56(d，2H)，4.88-4.79(m)，4.26-4.02(m)，3.64-3.20(m)，1.98(s，2H)，1.58(s，1H)，1.19-1.16(m).
实施例13
称取化合物13将其完全溶于DMF与DMSO的混合溶液中，加入化合物9，搅拌均匀后加入DIEA，室温反应24h，然后将溶液直接用DMSO-水梯度透析，HPLC检测至无阿霉素及其衍生物，透析完成后冻干得果胶-阿霉素轭合物。
果胶-阿霉素轭合物的确认：
1H NMR(400MHz，DMSO-d 6)δppm:14.03(s，1H)，13.26(s，1H)，9.89(s，1H)，8.31-6.82(m,10H)，5.47-3.38(m)，1.95-0.84(m).
实施例14
本实施例中果胶-阿霉素轭合物(可通过实施例1-13制备得到)具有如下结构：
Figure PCTCN2019091627-appb-000012
体外细胞毒性试验：收集对数期生长的HT-29结肠癌细胞、HepG-2肝癌细胞、SMMC7721肝癌细胞、SKOV3卵巢癌细胞及MCF-7乳腺癌细胞，调整细胞悬液浓度，每孔加入100μL，铺板使待测细胞密度为4000个/孔(边缘孔用无菌PBS填充)。5％CO 2，37℃孵育24h，弃去培养基，加入浓度梯度(含阿霉 素为0.125、0.25、0.5、1.0、2.0、4.0、8.0和16.0μg/mL)的果胶阿霉素或阿霉素，每个浓度设3个复孔。然后在5％CO 2，37℃的孵箱中孵育48h。每孔加入10μl CCK-8溶液后继续培养2h。用酶标仪测定在450nm处各孔的吸光度，计算果胶阿霉素和阿霉素对各种癌细胞的IC 50值。
表1体外细胞毒性试验
Figure PCTCN2019091627-appb-000013
表1所示的体外细胞毒性试验结果表明，本发明制备得到的果胶-阿霉素轭合物对各种癌细胞的抑制率与阳性对照药阿霉素无明显区别，具有较好的体外细胞毒作用。
实施例15
由于本发明制备得到的果胶-阿霉素轭合物(可通过实施例1-13制备得到)在体内是通过EPR效应蓄积于肿瘤组织内，达到被动靶向的目的，因此考察本发明制备得到的果胶-阿霉素轭合物对荷瘤小鼠的体内药效结果。
体内药效试验：收集对数生长期的H22肝癌细胞、4T1乳腺癌细胞、EMT6乳腺癌细胞及HT-29结肠癌细胞，调整细胞悬液浓度为3×10 7个细胞/mL，将细胞接种于Balb/c小鼠或裸鼠右上肢皮下0.1mL/只(约含细胞数3×10 6个)，待接种好的小鼠瘤体积平均达100mm 3时将荷瘤鼠随机分组，分别为阴性对照组(0.9％氯化钠注射液)、阿霉素对照组(5mg/kg)、果胶阿霉素实验组(阿霉素当量为5mg/kg)，每组8只小鼠，静脉注射上述各种药物，共给药4次。记录肿瘤体积变化和体重，体积计算公式为：体积＝(长度×宽度 2)/2。
在体内药效实验中，本发明制备得到的果胶-阿霉素轭合物对H22肝癌、4T1乳腺癌、EMT-6乳腺癌及HT-29结肠癌的疗效均优于阿霉素对照。本发明制备得到的果胶-阿霉素轭合物可以明显抑制H22肝癌、4T1乳腺癌、EMT-6乳腺癌荷瘤小鼠的肿瘤生长，抑制率较高，分别为72.98％、78.1％、71.68％；而作为 对照的阿霉素，对H22肝癌、4T1乳腺癌、EMT-6乳腺癌荷瘤小鼠的抑制率低于本发明制备得到的果胶-阿霉素轭合物的抑制率，分别为：53.42％、50.61％、56.95％。在试验中，本发明制备得到的果胶-阿霉素轭合物组小鼠的体重无明显下降，无小鼠死亡；而阿霉素组小鼠体重下降明显，体重下降超过15％，并且有个别小鼠出现死亡。体内药效结果表明，与阿霉素相比，本发明制备得到的果胶-阿霉素轭合物具有增效减毒的作用。将H22肝癌荷瘤小鼠处死后取肿瘤组织用小动物活体荧光成像系统观察组织内的阿霉素成像强度，发现本发明制备得到的果胶-阿霉素轭合物给药组的小鼠肿瘤呈现出阿霉素强荧光，说明本发明制备得到的果胶-阿霉素轭合物可长时间、高浓度的蓄积于肿瘤组织。
实施例16
为了比较本发明制备得到的果胶-阿霉素轭合物(可通过实施例1-13制备得到)与现有的对照化合物(果胶与阿霉素直接通过酰胺键键合)的疗效，我们选用H22肝癌和4T1乳腺癌小鼠模型进行比较。
表2本发明制备得到的果胶-阿霉素轭合物与对照化合物(果胶与阿霉素通过酰胺键键合)的性质差异比对
Figure PCTCN2019091627-appb-000014
结果表明，本发明制备得到的果胶-阿霉素轭合物对H22肝癌和4T1乳腺癌小鼠肿瘤模型的抑制率均高于现有的对照化合物(果胶与阿霉素直接通过酰胺键键合)，抑制率分别为70.83％、76.20％，而现有的对照化合物(果胶与阿霉素直接通过酰胺键键合)的抑制率只有48.64％、47.00％。如图8及图9所示，发明人在实验中还发现，本发明制备得到的果胶-阿霉素轭合物不仅对肿瘤的抑制率高，还可以长时间维持较高的抑制率，即给与相同的剂量，果胶-阿霉素轭合物维持的抑制作用时间更长。
上述实施例只是为了说明本发明的技术构思及特点，其目的是在于让本领域内的普通技术人员能够了解本发明的内容并据以实施，并不能以此限制本发明及合成路线优化的保护范围。凡是根据本发明内容的实质所作出的等效的变化或修饰，都应涵盖在本发明的保护范围内。

Claims (10)

  1. 一种果胶-阿霉素轭合物，其特征在于，具有如式(I)结构：
    a-b-c-d-e (I)
    其中a为果胶或修饰果胶，b为聚乙二醇PEGn，c为酶促裂解基团、多肽或多肽衍生物，d为自降解基团，e为阿霉素。
  2. 如权利要求1所述的果胶-阿霉素轭合物，其特征在于，所述果胶为多聚半乳糖醛酸含量为90％以上、分子量为1-60KD的无酯果胶，所述修饰果胶为多聚半乳糖醛酸无酯果胶的羰基与羟基取代的C 2-C 4的烷基胺生成酰胺、再进一步被活化为果胶碳酸酯式(13)；优选的，a为修饰果胶；再优选的，所述a的分子量为1-4KD；再优选的，所述多聚半乳糖醛酸无酯果胶的半乳糖醛酸含量为95％以上。
  3. 如权利要求1所述的果胶-阿霉素轭合物，其特征在于，式(I)中，n为1-20的整数，c为二肽、二肽衍生物、三肽、三肽衍生物、四肽或四肽衍生物中的任意一种；优选的，n为6-12的整数；优选的，c为val-ala。
  4. 如权利要求1所述的果胶-阿霉素轭合物，其特征在于，d为自降解基团氨基苄氧羰基；优选的，所述氨基苄氧羰基为对氨基苄氧羰基，即PABC。
  5. 一种如权利要求1-4任一项所述的果胶-阿霉素轭合物的制备方法，其特征在于，将式(13)化合物与式(9)化合物在碱性试剂存在的条件下反应，
    Figure PCTCN2019091627-appb-100001
    式(13)中，a为选自2-4的整数，m为1-60KD；式(9)化合物为b-c-d-ADM，b为PEGn；c为多肽，优选的，c为二肽、二肽衍生物、三肽、三肽衍生物、四肽或四肽衍生物中的任意一种；d为自降解基团，优选的，n为6-12的整数；优选的，c为val-ala；优选的，d为PABC。
  6. 如权利要求5所述的果胶-阿霉素轭合物的制备方法，其特征在于，式(13)化合物的制备方法为：果胶与醇反应后得到酯化果胶，再与氨基取代的C 2-C 4 的醇反应生成酰胺后再与二(4-硝基苯基)碳酸酯反应即得式(13)化合物。
  7. 如权利要求5所述的果胶-阿霉素轭合物的制备方法，其特征在于，式(9)化合物的制备方法为：式(5)化合物与阿霉素在碱性试剂存在的条件下反应得式(6)化合物，式(6)化合物在哌啶存在的条件下脱保护得式(7)化合物、(7)化合物再与R 1-b-COOH反应得式(8)化合物，式(8)化合物在哌啶存在的条件下脱保护得化合物(9)；式(5)化合物为R 1-c-PABC，式(6)化合物为R 1-c-PABC-e，式(7)化合物为c-PABC-e，式(8)化合物为R 1-b-c-PABC-e，R 1为保护基团；优选的，R 1为芴甲氧羰基Fmoc。
  8. 如权利要求7所述的果胶-阿霉素轭合物的制备方法，其特征在于，式(5)化合物的制备方法为：式(3)化合物在缚酸剂存在下与对氨基苄醇醇反应得到式(4)化合物，式(4)化合物在碱性试剂存在的条件下与二(4-硝基苯基)碳酸酯反应得到式(5)化合物；式(3)化合物为R 1-c-OH，式(4)化合物为R 1-c-PABOH，其中，PABOH为4-(羟甲基)苯基氨基；c为多肽，优选的，c为val-ala。
  9. 如权利要求8所述的果胶-阿霉素轭合物的制备方法，其特征在于，所述式(3)化合物的制备方法为：式(1)化合物在NHS和DCC存在下反应得到式(2)化合物，式(2)化合物在碱性试剂存在下与氨基酸反应得到式(3)化合物；式(1)化合物为R 1-c 1-OH，式(2)化合物为R 1-c 1-OSu，c 1为氨基酸；优选的，c 1为val。
  10. 一种如权利要求1-4任一项所述的果胶-阿霉素轭合物用于制备治疗癌症药物的用途。
PCT/CN2019/091627 2019-06-18 2019-06-18 一种果胶-阿霉素轭合物及其制备方法和用途 WO2020252648A1 (zh)

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