CN110028480A - 4,7- position split melphalan class nitrogen mustard derivatives of brefeldin A and its preparation method and application - Google Patents
4,7- position split melphalan class nitrogen mustard derivatives of brefeldin A and its preparation method and application Download PDFInfo
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- CN110028480A CN110028480A CN201810042469.XA CN201810042469A CN110028480A CN 110028480 A CN110028480 A CN 110028480A CN 201810042469 A CN201810042469 A CN 201810042469A CN 110028480 A CN110028480 A CN 110028480A
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- Prior art keywords
- brefeldin
- melphalan
- pharmaceutically acceptable
- preparation
- general formula
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- JUMGSHROWPPKFX-UHFFFAOYSA-N brefeldin-A Natural products CC1CCCC=CC2(C)CC(O)CC2(C)C(O)C=CC(=O)O1 JUMGSHROWPPKFX-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 melphalan class nitrogen mustard derivatives Chemical class 0.000 title claims description 17
- KQNZDYYTLMIZCT-KQPMLPITSA-N brefeldin A Chemical group O[C@@H]1\C=C\C(=O)O[C@@H](C)CCC\C=C\[C@@H]2C[C@H](O)C[C@H]21 KQNZDYYTLMIZCT-KQPMLPITSA-N 0.000 claims abstract description 38
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical class OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims abstract description 11
- 150000003839 salts Chemical group 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 8
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229960001924 melphalan Drugs 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical class OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
- GTDPSWPPOUPBNX-UHFFFAOYSA-N ac1mqpva Chemical compound CC12C(=O)OC(=O)C1(C)C1(C)C2(C)C(=O)OC1=O GTDPSWPPOUPBNX-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 208000032839 leukemia Diseases 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- YHYUQHQOUXSXQE-ZDUSSCGKSA-N methyl (2s)-2-amino-3-[4-[bis(2-chloroethyl)amino]phenyl]propanoate Chemical compound COC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 YHYUQHQOUXSXQE-ZDUSSCGKSA-N 0.000 claims 1
- 239000012624 DNA alkylating agent Substances 0.000 abstract description 3
- 229940126161 DNA alkylating agent Drugs 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000006667 mitochondrial pathway Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DZBCEUTUWOWUDY-ZETCQYMHSA-N Ascochitine Chemical compound OC1=C(C(O)=O)C(=O)C=C2C(C)=C([C@@H](C)CC)OC=C21 DZBCEUTUWOWUDY-ZETCQYMHSA-N 0.000 description 1
- 241000235349 Ascomycota Species 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000985535 Penicillium decumbens Species 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 241000235070 Saccharomyces Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000001679 anti-nematodal effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- DZBCEUTUWOWUDY-UHFFFAOYSA-N ascochitine Natural products OC1=C(C(O)=O)C(=O)C=C2C(C)=C(C(C)CC)OC=C21 DZBCEUTUWOWUDY-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及天然药物及药物化学领域，布雷菲德菌素A的4,7‑位拼合美法仑类氮芥衍生物的制备方法和用途。具体涉及这些在布雷菲德菌素A的4‑OH及7‑OH位点引入DNA烷化剂美法仑衍生物的制备方法及其在制备抗肿瘤药物中的应用。本发明所述的布雷菲德菌素A的4,7‑位拼合美法仑类氮芥衍生物及其药学上可接受的盐结构如通式I所示，其中，n如权利要求书和说明书中所述。 The invention relates to the field of natural medicine and medicinal chemistry, and relates to a preparation method and application of a melphalan-like nitrogen mustard derivative of 4,7-position of Brefeldin A. Specifically, it relates to a preparation method of introducing a DNA alkylating agent melphalan derivative into the 4-OH and 7-OH sites of Brefeldin A and its application in the preparation of antitumor drugs. The melphalan-like nitrogen mustard derivatives and their pharmaceutically acceptable salt structures at the 4,7-position of Brefeldin A of the present invention are shown in the general formula I, wherein, n is as claimed in the claims and described in the manual.
Description
Technical field
The invention belongs to natural drug and field of medicinal chemistry, are related to 4, the 7- position split melphalan of brefeldin A
Class nitrogen mustard derivatives and its preparation method and application, and in particular to the site 4-OH and 7-OH of brefeldin A is modified
Derivative, be related to these and spread out in the site 4-OH and 7-OH by the brefeldin A that DNA alkylating agent melphalan derivative replaces
Biology and preparation method thereof and application in preparation of anti-tumor drugs.
Background technique
Brefeldin A (brefeldin A, BFA) is that a kind of cometabolism of Saccharomyces (Ascomycetes) produces
Object belongs to macrolide type antibiotic, also referred to as decumbin or ascochitine.It in 1958, by Singleton et al. from
It is isolated in the fermentation liquid of Penicillium decumbens.Brefeldin A, crystal are in prismatic, and white does not dissolve in
Petroleum ether, chloroform, water are soluble in ethyl acetate, acetone and methanol.It is anti-swollen that pharmacological research shows that brefeldin A has
The pharmacological activity such as tumor, antiviral, antimycotic, anti-nematode and antimitotic, wherein anti-tumor activity is especially pronounced.NCI's grinds
Study carefully and shows that the brefeldin A property of can choose inhibits and kills human tumor cells.Macrolide antibiotic brefeldin A
The number of ways such as cell Proliferation can be inhibited to inhibit simultaneously with induced various types of tumors apoptosis as a kind of er stress agent
Tumour cell is killed, including human cervical carcinoma cell, prostate gland cancer cell, chronic lymphocytic leukemia cell and follicular lymphoma
Cell etc. has inhibiting effect to kinds of tumor cells.Research shows that brefeldin A by activation mitochondria and it is dead by
Body approach and the cell invasion for inhibiting focal adhesion kinase to adjust come apoptosis-induced.For example, brefeldin A can be by swashing
Apoptosis occurs for the mitochondrial pathways living and capase-8, Bid dependent form access induction ovarian cancer cell.Brefeldin A withers
Dying effect may be to be adjusted by the generation of active oxygen and the consumption of glutathione, and this adjusting will lead to apoptosis correlation
The activation of caspase approach.In addition, brefeldin A can inhibit sticking for the OVCAR-3 cell induced by fetal calf serum
And transfer.This effect is completed by the activation for the intracellular Related Component for inhibiting focal adhesion kinase to rely on.Mine-laying is luxuriant and rich with fragrance
Moral rhzomorph A leads to the apoptosis for activating induction er stress to adjust of caspase-3,6 by the mitochondrial pathways.With right
Brefeldin A pharmacological research gos deep into, and brefeldin A causes the great interest of domestic and international scientist, opens
The synthetic work to brefeldin A derivative is opened up.Purpose is that acquisition activity is more preferable, toxicity is lower, property is more stable
Antitumor candidate compound.It is separated, compared with the report in terms of mechanism of action with extracting, about brefeldin A structural modification
Report in terms of the pharmaceutical chemistry such as synthesizing with transformation, derivative is less.
Chlormethine series pharmaceuticals, also referred to as DNA alkylating agent, belong to cytotoxic drug, and mechanism of action is to be formed in vivo
The height reactive intermediate of electron deficient or other compounds with active electrophilic groups, and then occur with large biological molecule
Covalent Irreversible binding makes DNA molecular loss of activity or is broken.This kind of drug is clinically widely used, but it
Toxic side effect is bigger, lacks specificity to cytosis, and with the generation of tumor drug resistance in recent years, therapeutic effect is not
Therefore ideal is chemically modified chlormethine series pharmaceuticals, improving its curative effect has critically important value.
Summary of the invention
The technical problem to be solved by the present invention is to find anti-tumor activity, good brefeldin A split melphalan spreads out
Biology, i.e. 4, the 7- position split melphalan class nitrogen mustard derivatives of brefeldin A, and further provide for comprising the derivative
Pharmaceutical composition, 4,7- position split melphalan class nitrogen mustard derivatives of the brefeldin A or combinations thereof object have anti-
Tumor promotion.
In order to solve the above technical problems, the invention provides the following technical scheme:
General formula I is the 4,7- position split melphalan class nitrogen mustard derivatives of shown brefeldin A and its can pharmaceutically connect
The salt received:
Wherein, n is the integer of 1-12.
Preferably, n is the integer of 1-6.
It is highly preferred that n is 2.
The derivative of general formula I of the present invention can be prepared with following method:
Melphalan (2) and methanol are in SOCl2Under the conditions of existing, heating reflux reaction obtains melphalan methyl esters (3), then
(3) melphalan methyl esters carboxylic acid derivates (4) are obtained with diacid anhydride reactant under conditions of DMAP is catalyzed.
Brefeldin A (1) and 2 equivalent melphalan methyl esters carboxylic acid derivates (4) room temperatures under the conditions of EDCI/DMAP are anti-
It should obtain compound (5).
The present invention also provides a kind of pharmaceutical compositions, 4, the 7- position split comprising brefeldin A shown in general formula I
Melphalan class nitrogen mustard derivatives and its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.
4,7- position split melphalan class nitrogen mustard derivatives of brefeldin A of the invention and its pharmaceutically acceptable
Salt or its pharmaceutical composition can be prepared into clinically acceptable preparation with clinically acceptable carrier, and the preparation is
Tablet, granule, capsule etc..
The present invention, using principle of hybridization, selects the preferable melphalan of activity using brefeldin A as lead compound
It is connected on the position 4-OH and 7-OH of its molecular structure by derivative by linking group, and having designed and synthesized general formula is I's
Brefeldin A split melphalan derivative.Compound after split has preferable pharmaceutical active.
Specific embodiment
Embodiment 1
Brefeldin A 1 (32mg, 0.08mmol) is taken, is dissolved in methylene chloride (2.5ml), sequentially adds melphalan
Reaction, TCL prison is stirred at room temperature in the DMAP of methyl esters butyric acid (68mg, 0.16mmol), EDCI (29mg, 0.15mmol) and catalytic amount
Reaction process is surveyed, terminates reaction afterwards for 24 hours.Reaction solution is poured into 20ml mixture of ice and water, methylene chloride extracts (30ml × 3),
The washing of saturated common salt aqueous solution, anhydrous sodium sulfate is dry, recycles methylene chloride, through silicagel column (petroleum ether: ethyl acetate=2:
1) it, separates, obtains yellow oil 5-1, yield 24%.HR-MS(ESI,M+H)m/z:calcd for C43H51Cl2N5O7H:
1081.3661,found 1081.3552.1H NMR(400MHz,DMSO-d6): δ (ppm) 7.23 (1H, dd, J=15.8,
3.1Hz,C3- H), 7.03 (4H, d, J=8.5Hz, Ar-H), 6.64 (4H, d, J=8.4Hz, Ar-H), 5.75 (1H, m, C11-
), H 5.64 (1H, dd, J=15.8,1.5Hz, C2-H),5.17-5.24(2H,m,C4,C10-H),4.98(1H,m,C7-H),4.73
(1H,m,C15-H),4.33-4.40(2H,m,-NH),3.69(16H,m,-NCH2CH2Cl),3.57-3.58(6H,s,-OCH3),
0.74-2.89(29H,m,-COCH2CH2CO-,-ArCH2CHNCO-,C5,2C6,2C8,C9,2C12,2C13,2C14-H,CH3).13C
NMR(100MHz,DMSO-d6):δ(ppm)172.6,172.6,172.2,171.7,171.3,171.3,165.4,148.6,
145.4,145.4,136.4,131.1,130.6,130.6,130.6,130.6,125.6,125.6,117.7,112.1,
112.1,112.1,112.1,76.3,75.2,71.6,54.4,54.4,52.6,52.6,52.6,52.6,52.2,52.2,
49.6,43.0,41.6,41.6,41.6,41.6,41.6,41.6,37.8,36.4,36.4,33.9,31.8,30.0,30.0,
29.5,29.2,21.1.
Pharmacological testing
Experimental facilities and reagent
Experimental method
Cell inhibitory activity experimental method
Cell is in 37 DEG C, 5%CO2Routine culture in the incubator of saturated humidity.Culture solution is containing 10% heat inactivation tire ox
The RPMI1640 cell culture medium of serum, penicillin 100U/mL and streptomysin 100U/mL.48h replaces culture solution, and cell is adherent
Afterwards, it is passed on 0.25% trypsin digestion.Experiment is in logarithmic growth phase with cell, and trypan exclusion stain shows that cell is living
Power > 95%.
It takes in good condition one bottle of cell of logarithmic growth phase, digestive juice (0.125% trypsase+0.01% is added
EDTA it) digests, counts 2~4 × 104Cell suspension inoculation is made on 96 orifice plates in cell/mL, and constant temperature CO is set in 100 holes μ L/2Training
It supports and is cultivated 24 hours in case.Liquid is changed, test medicine is added, 100 holes μ L/ are cultivated 72 hours.CCK-8 is added in 96 orifice plates, 50
The hole μ L/ is incubated for 4 hours in incubator.Supernatant is sucked, adds DMSO, 200 holes μ L/ are shaken 10 minutes on plate shaker.It is tested
Object investigates 3 concentration (0.25 μM, 0.5 μM, 1 μM), with enzyme linked immunological monitor in the extinction that wavelength is the every hole of measurement at 450nm
Degree, calculates separately the cell inhibitory rate under each concentration.
Inhibiting rate calculation method:
Susceptibility hole is with respect to the absolute absolute OD value of OD value ﹣ blank control wells in OD value=susceptibility hole
Experimental result
IC of 1 embodiment of table to 5 kinds of human cancer cells strains and a kind of normal liver cell strain antiproliferative activity50It is worth (μM)
Pharmacological testing proves that brefeldin A derivative of the invention is much smaller than tumour to the toxicity of normal cell strain
Cell strain has selectivity, can be further used for preparing anti-tumor drug.
Claims (9)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103788053A (en) * | 2012-10-30 | 2014-05-14 | 浙江工业大学 | Brefeldin A ester derivatives and their preparation method and use |
| CN106928209A (en) * | 2017-03-10 | 2017-07-07 | 沈阳药科大学 | Brefeldin A derivative and its production and use |
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| CN103788053A (en) * | 2012-10-30 | 2014-05-14 | 浙江工业大学 | Brefeldin A ester derivatives and their preparation method and use |
| CN106928209A (en) * | 2017-03-10 | 2017-07-07 | 沈阳药科大学 | Brefeldin A derivative and its production and use |
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| CN116535380A (en) * | 2023-05-15 | 2023-08-04 | 沈阳药科大学 | Isothiocyanate derivative of brefeldin A, preparation method and application thereof |
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