CN113546085B - A kind of purposes of chiral bisphosphonamide compound - Google Patents
A kind of purposes of chiral bisphosphonamide compound Download PDFInfo
- Publication number
- CN113546085B CN113546085B CN202110814325.3A CN202110814325A CN113546085B CN 113546085 B CN113546085 B CN 113546085B CN 202110814325 A CN202110814325 A CN 202110814325A CN 113546085 B CN113546085 B CN 113546085B
- Authority
- CN
- China
- Prior art keywords
- compound
- chiral
- bisphosphonamide
- reaction
- purposes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 201000007270 liver cancer Diseases 0.000 claims abstract description 4
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- -1 diamide compound Chemical class 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 8
- 201000011510 cancer Diseases 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 230000001093 anti-cancer Effects 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- IJXJGQCXFSSHNL-MRVPVSSYSA-N (2s)-2-amino-2-phenylethanol Chemical compound OC[C@@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-MRVPVSSYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 2
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010019695 Hepatic neoplasm Diseases 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- IBDMRHDXAQZJAP-UHFFFAOYSA-N dichlorophosphorylbenzene Chemical compound ClP(Cl)(=O)C1=CC=CC=C1 IBDMRHDXAQZJAP-UHFFFAOYSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VXZORTQWVCTFFI-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=C(C#N)C=CC=C1.C(C=1C(N)=CC=CC1)#N VXZORTQWVCTFFI-UHFFFAOYSA-N 0.000 description 1
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical compound NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 238000006842 Henry reaction Methods 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 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
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 238000001394 phosphorus-31 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Images
Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
手性双膦酰二胺化合物(I)在制备抗癌试剂中的用途,是针对肝癌SMMC‑7721癌症细胞种类试验中均显示出抑制活性,其化学式如下：
The use of the chiral bisphosphonamide compound (I) in the preparation of anticancer reagents is aimed at liver cancer SMMC-7721 cancer cell type tests and shows inhibitory activity, and its chemical formula is as follows:
Description
一、技术领域1. Technical Field
本发明涉及一种手性化合物的用途，具体地说是一种含有手性噁唑啉基的膦酰胺化合物的医药用途。The present invention relates to the application of a chiral compound, in particular to the medical application of a phosphamide compound containing a chiral oxazoline group.
二、背景技术2. Background Technology
手性膦噁唑啉及金属的配合物在Didls-Alder(狄乐斯-艾而特)二烯环加成反应、Michael(米歇尔)缩合反应、Friedel-Crafts(傅瑞德-克拉佛兹)缩合反应、Aldol(醇醛)、亨利反应、腈硅化等反应等许多反应中表现出良好的不对称催化活性和高对映选择性，因而受到广泛的关注[1-4]。Chiral phosphinothiophene oxazolines and their metal complexes have shown good asymmetric catalytic activity and high enantioselectivity in many reactions such as Didls-Alder diene cycloaddition reaction, Michael condensation reaction, Friedel-Crafts condensation reaction, Aldol, Henry reaction, nitrile silylation, etc., and have therefore attracted widespread attention [1-4].
(1)(a)Glos，M.；Reiser，O.Org.Lett.2000，2(14)，2045.(b)Braga，A.L.Vargas，F.；Sehnem，J.A.；Braga，R.C.J.Org.Chem.2005，70(22)，9021.(c)Breit，B.；Schmidt，Y.；Chem.Rev.2008，108(8)，2928.(d)McManus，H.A.；Guiry，P.J.J.Org.Chem.2002，67(24)，8566.(1) (a) Glos, M.; Reiser, O. Org. Lett. 2000, 2(14), 2045. (b) Braga, A. L. Vargas, F.; Sehnem, J. A.; Braga, R. C. J. Org. Chem. 2005, 70(22), 9021. (c) Breit, B.; Schmidt, Y.; Chem.Rev.2008, 108(8), 2928. (d) McManus, H.A.; Guiry, P.J.J.Org.Chem.2002 , 67(24), 8566.
(2)Wang，W.B.；Fang，J.M.J.Org.Chem.1998，63，1356.(2) Wang, W.B.; Fang, J.M.J.Org.Chem.1998, 63, 1356.
(3)(a)Fu，G.C.Acc.Chem.Res.2006，39(11)，853.(b)Hargaden，G.C.；PatrickJ.Guiry，P.J.Chem.Rev.2009，109(6)，2505.(c)McManu，H.A.；Guiry，P.J.Chem.Rev.2004，104(9)，4151.(3) (a) Fu, G.C.Acc.Chem.Res.2006, 39(11), 853. (b) Hargaden, G.C.; Patrick J.Guiry, P.J.Chem.Rev.2009, 109(6), 2505.( c) McManu, H.A.; Guiry, P.J. Chem. Rev. 2004, 104(9), 4151.
(4)(a)Takamichi，Y.；Masatoshi，O.；Takahiro，K.；Dai，M.；Kiyoshi，S.；Motowo，Y.Tetrahedron：Asymmetry 2003，14，3275.(b)Cristina G.-Y.，
申请人长期从事不对称化合物的研制，并陆续申请了发明专利，ZL200610096004.X、CN101016311A、CN101099936A、200810020198.4、CN101279954A、200810022278.3、200910116614.5。The applicant has been engaged in the research and development of asymmetric compounds for a long time, and has successively applied for invention patents, including ZL200610096004.X, CN101016311A, CN101099936A, 200810020198.4, CN101279954A, 200810022278.3, and 200910116614.5.
三、发明内容III. Summary of the invention
本发明旨在为不对称合成领域特别是制备手性药物化合物提供一种高效手性抗癌试剂，所要解决的技术问题是遴选该手性化合物作为最佳的抗肝癌试剂。The present invention aims to provide a highly efficient chiral anticancer agent for the field of asymmetric synthesis, especially for the preparation of chiral drug compounds. The technical problem to be solved is to select the chiral compound as the best anti-liver cancer agent.
本发明所称的手性膦化合物是化学名称为双{N-2-[(4S)-4，5-二氢化-4-苯基-2-噁唑啉基]-二苯基-苯基膦酰二胺，有以下化学结构式：The chiral phosphine compound referred to in the present invention is a compound with the chemical name of bis{N-2-[(4S)-4,5-dihydro-4-phenyl-2-oxazolinyl]-diphenyl-phenylphosphine diamide, and has the following chemical structural formula:
式中R选自-Ph(苯基)。Wherein R is selected from -Ph (phenyl).
本手性膦化合物的合成方法为两步，第一步以2-氰基苯胺(2-氨基苯腈)和L-苯甘基醇反应制备中间体2-[(4S)-4，5-二氢化-4-苯基-2-噁唑啉基]苯胺，第二步上述中间体与苯基膦酰二氯[(Ph)POCl2]合成目标产物，流程示意如下：The synthesis method of the chiral phosphine compound is a two-step process. The first step is to react 2-cyanoaniline (2-aminobenzonitrile) with L-phenylglycol to prepare the intermediate 2-[(4S)-4,5-dihydro-4-phenyl-2-oxazolinyl]aniline. The second step is to react the intermediate with phenylphosphonic acid dichloride [(Ph)POCl 2 ] to synthesize the target product. The schematic process is as follows:
所述的L-氨基醇选自L-苯甘氨醇。L-苯甘氨醇与2-氰基苯胺反应时闭环形成噁唑啉基，其携带的R基是-Ph。The L-amino alcohol is selected from L-phenylglycinol. When L-phenylglycinol reacts with 2-cyanoaniline, a ring is closed to form an oxazoline group, and the R group carried by the oxazoline group is -Ph.
本手性膦化合物的合成方法是先制备中间体后合成目标产物，包括反应、分离和纯化，其特征是制备中间体的反应由2-氰基苯胺和L-苯甘氨醇在无水无氧条件下和催化剂无水ZnCl2存在时于氯苯溶剂中回流反应24小时，然后分离、纯化，即反应结束后脱去氯苯，加水溶解后用氯仿萃取，萃取相脱溶后用柱层析纯化；合成目标产物的反应是所制备的中间体与二苯基膦酰氯在无水无氧条件下于甲苯和三乙胺混合溶剂中回流反应24小时，然后分离、纯化，即反应结束后脱去溶剂，用柱层析纯化。The synthesis method of the chiral phosphine compound comprises the steps of first preparing an intermediate and then synthesizing a target product, including reaction, separation and purification. The method is characterized in that the reaction for preparing the intermediate comprises the steps of reflux reaction of 2-cyanoaniline and L-phenylglycinol in a chlorobenzene solvent for 24 hours under anhydrous and oxygen-free conditions and in the presence of anhydrous ZnCl2 as a catalyst, followed by separation and purification, namely, removing chlorobenzene after the reaction is completed, extracting with chloroform after dissolving in water, and purifying with column chromatography after the extract phase is desolvated; and the reaction for synthesizing the target product comprises the steps of reflux reaction of the prepared intermediate and diphenylphosphonyl chloride in a mixed solvent of toluene and triethylamine for 24 hours under anhydrous and oxygen-free conditions, followed by separation and purification, namely, removing the solvent after the reaction is completed, and purifying with column chromatography.
该化合物已在2010年申请目标化合物的合成及制备方法。申请号：201010238319.X。目前，发现该化合物在抗肿瘤肝癌中显示了一定的抑制作用，其指标IC50值达到10.26±0.24。The synthesis and preparation method of the target compound has been applied for in 2010. Application number: 201010238319.X. At present, it is found that the compound shows a certain inhibitory effect in anti-tumor liver cancer, and its index IC50 value reaches 10.26±0.24.
四、附图说明IV. Description of the drawings
1.图1是目标化合物1的1HNMR，1. Figure 1 is the 1 H NMR of the target compound 1.
2.图2是目标化合物1的13CNMR2. Figure 2 is the 13 CNMR of target compound 1
3.图3是目标化合物1的31PNMR图。3. Figure 3 is the 31 P NMR spectrum of target compound 1.
五、具体实施方式V. Specific implementation methods
(一)中间体1的制备(I) Preparation of intermediate 1
1、中间体1的制备1. Preparation of Intermediate 1
在100mL两口瓶中，无水
2.化合物双N-2-[(4S)-4，5-二氢化-4-(苯基)-2-噁唑啉基]二苯基-二苯基膦酰胺的合成：2. Synthesis of compound bis-N-2-[(4S)-4,5-dihydro-4-(phenyl)-2-oxazolinyl]diphenyl-diphenylphosphinamide:
在100mL两口瓶中，无水无氧条件下，加入40mL甲苯，2-[(4S)-4，5-二氢化-4-(苯基)-2-噁唑啉基]苯胺(中间体1a)1.4g(6.42mmol)，三乙胺20mL，苯基膦酰二氯0.6mL(3.00mmol)，将混合物加热回流24h，停止反应，减压以除去溶剂，将粗产品用石油醚/二氯甲烷(1∶9)柱层析，得淡黄色液体，产率45％；[a]5 D＝+172.3°(c＝0.85，CHCl3)；1HNMR(500MHz，CDCl3，27℃)δ(ppm)＝11.92(d，J＝12Hz，1H)，7.67～7.87(m，6H)，6.88～7.26(m，17H)，5.27(t，J＝0.5Hz，1H)，5.08(t，J＝0.5Hz，1H)，4.56～4.68(m，3H)，4.00～4.10(m，1H).13CNMR(125MHz，CDCl3，27℃)165.02(x2)，143.52，143.34，141.90，141.84，132.71(x2)，132.07(x2)，131.54，131.44,129.55(x2)，128.80(x2)，128.72(x2)，128.61(x2)，127.57，127.46，126.46，126.36，120.00(x2)，119.92(x2)，118.42，118.38，118.06，118.02，73.12，73.02，69.62，69.53.13PNMR(300MHz，CDCl3，27℃)，δ(ppm)＝5.474.IR(KBr)：3062，2957，2924，2853，1633，1602，1584，1499，1455，1437，1361，1301，1265，1218，1164，1136，1122，1065，1047，954，910，752，731，697，645，621，514，475；HRMS(EI)：m/z(％)：calcd for C36H31N4O3P：598.2134；found：598.2131。In a 100 mL two-necked flask, under anhydrous and oxygen-free conditions, 40 mL of toluene, 1.4 g (6.42 mmol) of 2-[(4S)-4,5-dihydro-4-(phenyl)-2-oxazolinyl]aniline (intermediate 1a), 20 mL of triethylamine, and 0.6 mL (3.00 mmol) of phenylphosphonyl dichloride were added. The mixture was heated to reflux for 24 h, the reaction was stopped, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using petroleum ether/dichloromethane (1:9) to obtain a light yellow liquid with a yield of 45%; [a] 5 D ＝+172.3°(c＝0.85, CHCl 3 ); 1 HNMR (500 MHz, CDCl 3 , 27℃) δ (ppm) = 11.92 (d, J = 12Hz, 1H), 7.67 ~ 7.87 (m, 6H), 6.88 ~ 7.26 (m, 17H), 5.27 (t, J = 0.5Hz, 1H), 5.08 (t, J = 0.5Hz, 1H), 4.56 ~ 4.68 (m, 3H), 4.00 ~ 4. 10(m, 1H). 13 CNMR (125MHz, CDCl 3 , 27℃)165.02(x2),143.52,143.34,141.90,141.84,132.71(x2),132.07(x2),131.54,131.44,129.55(x2),128.80(x2),128.72(x2),128.61(x 2), 127.57, 127.46, 126.46, 126.36, 120.00 (x2), 119.92 (x2), 118.42, 118.38, 118.06, 118.02, 73.12, 73.02, 69.62, 69.53. 13 PNMR (300MHz, CDCl 3 , 27℃), δ (ppm) = 5.474. IR (KBr): 3062, 2957, 2924, 2853, 1633, 1602, 1584, 1499, 1455, 1437, 1361, 1301, 1265, 1218, 1164, 1136, 1122, 1065, 1047, 95 4, 910, 752, 731, 697, 645, 621, 514, 475; HRMS (EI): m/z (%): calcd for C36H31N4O3P: 598.2134; found: 598.2131.
(三)本化合物在抗肿瘤肝癌中的用途(III) Use of the present compound in anti-tumor liver cancer
本发明依据目标设计合成的化合物(I)在肝癌细胞(SMMC-7721)试验中均显示出较强的抑制活性(ED50＜10.0μg/mL)。参照[J.Natl.Cancer Inst.1990，82(13)：1107-1112]中所述的方法进行本试验。简言之，将所用的人体癌细胞(DU145，PC-3，A549，KB，KB-VIn等)置于单一培养基(RPMI-1640含10％(v/v)小牛血清)中，用显微镜对细胞在培养液中的形态特征和生长状况进行检查。细胞置于2.5cm2的培养皿中，37℃，含5％CO 2潮湿空气中培养。细胞系贴壁生长。样品配制和稀释及将其接种于细胞液中的过程应为无菌操作。测试样品通常用DMSO溶解，-70℃保存。在96孔培养板中，每个孔置于不同浓度的测试样品和约5000-20000个细胞，放置72小时。抑制癌细胞生长的IC 50值由SRB(sulforhodamine B)方法确定。The compound (I) designed and synthesized according to the target of the present invention shows strong inhibitory activity (ED50 < 10.0 μg/mL) in the liver cancer cell (SMMC-7721) test. The test is carried out with reference to the method described in [J. Natl. Cancer Inst. 1990, 82 (13): 1107-1112]. In brief, the human cancer cells (DU145, PC-3, A549, KB, KB-VIn, etc.) used are placed in a single culture medium (RPMI-1640 containing 10% (v/v) calf serum), and the morphological characteristics and growth conditions of the cells in the culture medium are examined under a microscope. The cells are placed in a 2.5 cm2 culture dish and cultured at 37°C in a humidified air containing 5% CO2. The cell line grows adherently. The process of sample preparation and dilution and inoculation into the cell fluid should be sterile. The test sample is usually dissolved in DMSO and stored at -70°C. In a 96-well culture plate, each well is placed with different concentrations of test samples and about 5,000-20,000 cells for 72 hours. The IC 50 value for inhibiting cancer cell growth is determined by the SRB (sulforhodamine B) method.
本发明化合物的部分抗癌活性测试结果见表1。Some anticancer activity test results of the compounds of the present invention are shown in Table 1.
表1.(I)的抗癌活性数据(IC50值)Table 1. Anticancer activity data (IC50 values) of (I)
IC 50是抑制半数癌细胞生长的有效浓度，表示抗癌活性。NA：无抑制活性。本试验所用的上述人体癌细胞从美国ATCC购买。IC50 is the effective concentration that inhibits the growth of half of the cancer cells, indicating anticancer activity. NA: No inhibitory activity. The human cancer cells used in this test were purchased from ATCC in the United States.
Claims (1)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110814325.3A CN113546085B (en) | 2021-07-19 | 2021-07-19 | A kind of purposes of chiral bisphosphonamide compound |
| PCT/CN2022/106366 WO2023001124A1 (en) | 2021-07-19 | 2022-07-19 | Use of chiral bisphosphonate diamine compound |
| GB2316418.9A GB2620096B (en) | 2021-07-19 | 2022-07-19 | Use of chiral bisphosphonate diamine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110814325.3A CN113546085B (en) | 2021-07-19 | 2021-07-19 | A kind of purposes of chiral bisphosphonamide compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113546085A CN113546085A (en) | 2021-10-26 |
| CN113546085B true CN113546085B (en) | 2023-04-25 |
Family
ID=78132083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110814325.3A Active CN113546085B (en) | 2021-07-19 | 2021-07-19 | A kind of purposes of chiral bisphosphonamide compound |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN113546085B (en) |
| GB (1) | GB2620096B (en) |
| WO (1) | WO2023001124A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113546085B (en) * | 2021-07-19 | 2023-04-25 | 合肥工业大学 | A kind of purposes of chiral bisphosphonamide compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5227508A (en) * | 1992-01-24 | 1993-07-13 | Mayo Foundation For Medical Education And Research | 3-deoxy-3-substituted analogs of phosphatidylinositol |
| CN102382138A (en) * | 2011-07-28 | 2012-03-21 | 罗梅 | Chiral diphosphonic diamine compound and applications thereof |
| CN108003111A (en) * | 2017-12-14 | 2018-05-08 | 华东理工大学 | Double target spot inhibitor of a kind of HDAC1 and IDO1 and its preparation method and application |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201100441A (en) * | 2009-06-01 | 2011-01-01 | Osi Pharm Inc | Amino pyrimidine anticancer compounds |
| CN101607970A (en) * | 2009-07-24 | 2009-12-23 | 合肥工业大学 | A kind of chiral bisphosphonamide compound and its synthetic method |
| CN113546085B (en) * | 2021-07-19 | 2023-04-25 | 合肥工业大学 | A kind of purposes of chiral bisphosphonamide compound |
-
2021
- 2021-07-19 CN CN202110814325.3A patent/CN113546085B/en active Active
-
2022
- 2022-07-19 GB GB2316418.9A patent/GB2620096B/en active Active
- 2022-07-19 WO PCT/CN2022/106366 patent/WO2023001124A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5227508A (en) * | 1992-01-24 | 1993-07-13 | Mayo Foundation For Medical Education And Research | 3-deoxy-3-substituted analogs of phosphatidylinositol |
| CN102382138A (en) * | 2011-07-28 | 2012-03-21 | 罗梅 | Chiral diphosphonic diamine compound and applications thereof |
| CN108003111A (en) * | 2017-12-14 | 2018-05-08 | 华东理工大学 | Double target spot inhibitor of a kind of HDAC1 and IDO1 and its preparation method and application |
Non-Patent Citations (3)
| Title |
|---|
| Wafaa M. Abdou et al.，.Carbodiimides in the Synthesis of Enamino- and a-Aminophosphonates as Peptidomimetics of Analgesic/Antiinflammatory and Anticancer Agents.《Arch. Pharm. Chem. Life Sci.》.2012,第345卷第884-895页. * |
| 卓仁禧,范昌烈,吴滨.聚5-氟尿嘧啶-1-乙酰天冬氨酰二胺的合成及其抗肿瘤活性.功能高分子学报.1988,(第01期),第9-14页. * |
| 马晓霖等.松香及其衍生物的应用研究进展.《广州化工》.2019,第47卷(第24期),第37-40页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB202316418D0 (en) | 2023-12-13 |
| GB2620096B (en) | 2025-02-12 |
| WO2023001124A1 (en) | 2023-01-26 |
| GB2620096A (en) | 2023-12-27 |
| CN113546085A (en) | 2021-10-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101885742B (en) | Chiral diphosphorodiamidate compound and synthesis method thereof | |
| Sakurai et al. | Cu-Catalyzed O-alkylation of phenol derivatives with alkylsilyl peroxides | |
| CN109704926B (en) | Anticancer active molecular skeleton 1, 4-eneyne compound and preparation method and application thereof | |
| CN113546085B (en) | A kind of purposes of chiral bisphosphonamide compound | |
| CN101671312A (en) | Chiral oxazolines derivative and synthesis method thereof | |
| CN104892682A (en) | Synthesis and Catalytic Activity of Metal Coordination Polymers Containing 4-Sulphonic Acid | |
| CN101591356A (en) | A kind of chiral phosphonamide compound and its synthetic method | |
| CN105688987B (en) | A kind of chiral phosphoric acid catalyst and its synthetic method and application | |
| CN105949118B (en) | A kind of preparation method of 2-arylquinoline derivatives | |
| CN102382138B (en) | Chiral diphosphonic diamine compound and applications thereof | |
| CN109535120B (en) | Preparation method of 7-substituted-3, 4,4, 7-tetrahydrocyclobutane coumarin-5-ketone | |
| CN106478487B (en) | Pyrrolidine compounds and synthesis method thereof | |
| CN114656417B (en) | Synthesis method and application of chiral oxazoline | |
| CN111468183A (en) | Polyfluorinated triaryl chiral spirophosphoric acid catalyst and preparation method and use thereof | |
| CN103467390B (en) | Method for preparing 2-amino-4(3H)-quinazolinones | |
| CN110256478B (en) | Alkene 1, 2-bifunctional reaction method | |
| Sun et al. | Isocyanate diinsertion into the N–H bond of the 2-pyridylamino ligand of organolanthanides | |
| CN102070669A (en) | Chiral phosphamide compound | |
| CN109867699B (en) | A kind of bipyridyl bridged bistriazine ruthenium complex and its preparation and application | |
| CN101538280A (en) | Chiral phosphine compound and synthesis method thereof | |
| CN105001164A (en) | Synthesis of p-toluenesulfonic acid containing metal coordination polymers and catalytic activity thereof | |
| CN105777773B (en) | Thiophene [2,3 b] quinoline and its synthetic method and application | |
| CN112844472A (en) | Preparation method and application of chiral imidazole urea catalyst | |
| CN115490730B (en) | Method for synthesizing selenium/sulfur ligand based on chiral BIDIME | |
| CN109096330B (en) | A kind of trifluoromethyl alkenyl phosphonate and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |