CN114315842A - Novel carbonic anhydrase IX targeted photosensitizer and application thereof in medical field - Google Patents
Novel carbonic anhydrase IX targeted photosensitizer and application thereof in medical field Download PDFInfo
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- 102100024423 Carbonic anhydrase 9 Human genes 0.000 title abstract description 16
- 239000003504 photosensitizing agent Substances 0.000 title description 18
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- -1 5-sulfamoyl-1, 3, 4-thiadiazol-2-yl Chemical group 0.000 claims description 69
- ANWUQYTXRXCEMZ-NYABAGMLSA-L chlorophyllide a Chemical compound C1([C@H](C2=O)C(=O)OC)=C(N3[Mg]N45)C2=C(C)\C3=C\C(=N2)C(CC)=C(C)\C2=C\C4=C(C=C)C(C)=C5\C=C/2[C@@H](C)[C@H](CCC(O)=O)C1=N\2 ANWUQYTXRXCEMZ-NYABAGMLSA-L 0.000 claims description 59
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- CKRVBMUJCFKRND-UHFFFAOYSA-N 2,4-difluoro-N-methyl-3-[10,15,20-tris[2,6-difluoro-3-(methylsulfamoyl)phenyl]-2,3,12,13,22,24-hexahydroporphyrin-5-yl]benzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(F)C(C=2C3=CC=C(N3)C(C=3C(=C(C=CC=3F)S(=O)(=O)NC)F)=C3CCC(=N3)C(=C3C=CC(N3)=C(C=3C(=C(C=CC=3F)S(=O)(=O)NC)F)C=3CCC=2N=3)C=2C(=C(C=CC=2F)S(=O)(=O)NC)F)=C1F CKRVBMUJCFKRND-UHFFFAOYSA-N 0.000 description 1
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- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a novel pyropheophorbide derivative (I, II, III) of targeting carbonic anhydrase IX and application thereof in the field of medicine, wherein the compound has the following structure:
Description
Technical Field
The invention belongs to the technical field of chemical medicine, relates to a photosensitizer medicine and photodynamic therapy, and particularly relates to a novel Carbonic Anhydrase IX (CAIX) targeted photosensitizer and application thereof in the field of medicine.
Background
Photodynamic Therapy (PDT) is a light-activated photosensitizer-based treatment that has been identified as a safe mode of ablation for a variety of tumors (NatRev Clin Oncol, 2020, 17, 657-674). Effective illumination turn-on enables highly controllable and minimally invasive treatment in space and time. Currently in clinical PDT, photo-excited photosensitizers generate cytotoxic free radicals by interacting with bioactive molecules (type I mechanism), or in type II mechanism, ground-state oxygen (x3O2) Direct conversion to highly reactive cytotoxic excited singlet oxygen: (1O2). PDT can not only kill tumor cells directly, but also cause tumor neovascularization damage and block oxygen supply for tumors.
Photosensitizers are key components of PDT. First generation photosensitizers
Is a mixture of oligomeric hematoporphyrin derivatives (HpD) approved in 1993 in Canada for treatment of bladder cancer with red light (630nm), which is the most widely used photosensitizer despite the problems of poor cancer selectivity, low red light absorption and long-term photosensitivity. 5-aminolevulinic acid
Is a key precursor of protoporphyrin IX biosynthesis, and derivative aminolevulinic acid methyl ester thereof
It is easy to synthesize in high purity and is approved by FDA as a second generation photosensitizer. Reduction of the peripheral double backbone of the porphyrin photosensitizer can red shift and enhance its absorbance at maximum wavelength. Therefore, chlorin derivatives Foscan, Radachlorin and Laserphyrin have been approved for clinical PDT in red light (around 660nm), whereas bacteriochlorin derivative Redaporfin is activated with infrared light (749nm) in clinical phase II. Hematoporphyrin monomethyl ether (journal of Chinese medical industry, 1989,20 (2): 60-63), also called as HMME (Hemoporfin), was developed in early times by Schenham, Zhanghao and the like in the team, has the obvious advantages of definite compound components, short photophobic period after administration and the like, becomes the first nationwide photosensitive drug for treating port wine stains (journal of Chinese laser medicine, 2018,27 (1): 01-05), but the hematoporphyrin monomethyl ether still has the defects of a pair of isomers as well as unstable structure and the like.
Most current PDT drugs act primarily through an oxygen-dependent type II mechanism, which leads to severe hypoxia within the tumor. This in turn can limit the therapeutic efficacy of photodynamic therapy. PDT-induced hypoxia may be due to direct consumption of oxygen by the photosensitizer or indirectly through degradation of the vasculature. One inference that PDT induces hypoxia is that it triggers a Hypoxia Inducible Factor (HIF) -mediated signaling cascade. Transcriptional activation by angiogenic factors leads to upregulation of many of the relevant regulatory genes responsible for tumor progression. The gene encoding Carbonic Anhydrase IX (CAIX) belongs to the gene upregulated by the HIF pathway. CAIX regulates intracellular and extracellular pH and promotes tumor survival and invasion in hypoxic environments. Indeed, CAIX is a marker of low survival and distant metastasis of invasive breast cancer (e.g., MDA-MB-231 tumor cells). The fact that CAIX is affected by tumor-specific overexpression and expression is highly restricted in normal tissues makes it a potentially attractive therapeutic target. Recently, Lou et al reported that inhibition of CAIX activity significantly controls the growth and metastasis of breast tumors in vivo (Cancer res.,2011,71, 3364-. Enhanced therapeutic effects were also observed in mouse tumor models following CAIX gene level knockdown and bevacizumab treatment (clin. cancer res.,2012,18, 3100-. Kim et al reported that acetazolamide-coupled BODIPY photosensitizer (AZ-BPS) reduces the effects of hypoxia caused by PDT by combining anti-angiogenic therapy with PDT (j.am.chem. soc.2017,139, 7595-7602).
Thus, in the present invention we used thiadiazole sulfonamide and benzenesulfonamide (AZ) as targeted Carbonic Anhydrase Ix (CAIX) groups in combination with PDT, i.e. the CAIX acceptor small molecule inhibitors thiadiazole sulfonamide and benzenesulfonamide were introduced at the carboxyl group of the photosensitizer pyropheophorbide-a synthesized in this group, to prepare a series of pyropheophorbide derivatives:
disclosure of Invention
The efficacy of PDT is related to the ROS generating capacity of the photosensitizer, which is intrinsically oxygen dependent. Depletion of oxygen in the tumor microenvironment exacerbates tumor hypoxia and triggers hypoxia-inducible factor (HIF) -mediated signaling cascades that in turn activate a series of target genes responsible for cancer cells (such as glucose transporters and vascular endothelial growth factors) for survival, tumorigenesis and distant metastasis. To solve this problem, there is an urgent need to eliminate the side effect of PDT exacerbating hypoxia to improve its therapeutic effect. The invention designs and synthesizes a novel pyropheophorbide derivative. Researches show that introduction of thiadiazole sulfonamide and benzene sulfonamide series compounds can improve the fluorescence quantum yield and the singlet oxygen yield of the compounds and enhance the phototoxicity effect of the compounds. The new compound has stable structure and simple and easy preparation process.
The invention relates to pyropheophorbide derivatives and application thereof.
The invention is summarized as follows:
the pyropheophorbide derivatives have the following structures (formula I), (formula II) and (formula III):
wherein n is 1,2,3,4,5,6,7, 8; m is an integer of 0 to 8.
The pyropheophorbide derivatives (formula I) and (formula II) comprise:
n- (5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) pyropheophorbide (I);
n- [2- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -2-oxoethyl]Pyrophorbide-magnesian chlorophyllide (II)1)；
N- [3- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -3-oxopropyl]Pyrophorbide-magnesian chlorophyllide (II)2)；
N- [4- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -4-oxobutyl]Pyrophorbide-magnesian chlorophyllide (II)3)；
N- [5- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -5-oxopentyl]Pyrophorbide-magnesian chlorophyllide (II)4)；
N- [6- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -6-oxohexyl]Pyrophorbide-magnesian chlorophyllide (II)5)；
N- [7- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -7-oxoheptyl]Pyrophorbide-magnesian chlorophyllide (II)6)；
N- [8- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -8-oxooctyl]Pyrophorbide-magnesian chlorophyllide (II)7)。
The pyropheophorbide derivative (formula III) provided by the invention comprises the following compounds:
n- ((4-sulfamoyl) phenyl) pyropheophorbide (III)1)；
N- ((4-sulfamoyl) phenylmethyl) pyropheophorbide (III)2)；
N- (2- ((4-sulfamoyl) phenyl) ethyl) pyropheophorbide (III)3)；
N- (3- ((4-sulfamoyl) phenyl) propyl) pyropheophorbide (III)4)；
N- (4- ((4-sulfamoyl) phenyl) butyl) pyropheophorbide (III)5)；
N- (5- ((4-sulfamoyl) phenyl) pentyl) pyropheophorbide (III)6)；
N- (6- ((4-sulfamoyl) phenyl) hexyl) pyropheophorbide (III)7)；
N- (7- ((4-sulfamoyl) phenyl) heptyl) pyropheophorbide (III)8)；
N- (8- ((4-sulfamoyl) phenyl) octyl) pyropheophorbide (III)9)。
According to the invention, the carbonic anhydrase IX micromolecule inhibitor compounds are introduced into the pyropheophorbide a side chain for the first time, so that the novel pyropheophorbide derivatives (formula I, formula II and formula III) are prepared, and the photosensitizer has obvious targeting and remarkable photodynamic activity, can be used as a photodynamic treatment medicament for diseases such as tumors, macular degeneration of retina, actinic keratosis, nevus rubra, condyloma acuminatum and the like, and has practicability.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
[ example 1]
Preparation of N- (5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) pyropheophorbide (I):
pyrophorbide-a (107mg, 200. mu. mol) and anhydrous acetonitrile (40 mL) were added to a round-bottom flask, followed by 1,3, 4-thiadiazole-2-sulfonamide (52mg, 240. mu. mol) and triethylamine (0.1mL, 800. mu. mol) and stirred at room temperature for 30 min. Finally HATU (56mg, 240. mu. mol) was added, the reaction was stirred at room temperature for 16h, and after completion of the TLC monitoring, 200mL of saturated sodium chloride solution was added, followed by 2M HCl solutionThe pH is adjusted to acidity. Then, ethyl acetate was added for extraction (100 mL. times.3), and the mixture was washed with water. Collecting organic phase, and adding anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. The obtained residue was subjected to column chromatography for separation and purification to give compound I (74mg, 53%) as a green solid powder.1H NMR(600MHz, DMSO-d6)δ：9.68(s,1H),9.40(s,1H),8.90(s,1H),8.20(dd,J＝17.7,11.6Hz,1H),7.24(s,2H), 6.38(d,J＝17.8Hz,1H),6.20(d,J＝11.6Hz,1H),5.24–5.08(m,2H),4.55(dd,J＝7.4,2.2Hz, 1H),4.33–4.25(m,1H),3.68(d,J＝7.7Hz,2H),3.61(s,3H),3.44(s,3H),3.19(s,3H),2.63– 2.57(m,1H),2.48–2.33(m,2H),2.21–2.13(m,1H),1.98–1.90(m,1H),1.74(d,J＝7.4Hz, 3H),1.61(t,J＝7.6Hz,3H),0.22(s,1H),-1.98(s,1H).13C NMR(151MHz,DMSO-d6)δ：195.26, 172.24,171.07,161.98,153.55,149.47,147.81,144.06,140.52,136.80,135.31,134.89,134.51, 131.45,128.85,127.35,122.37,105.72,103.43,95.93,93.60,51.40,49.36,47.61,36.01,30.57, 22.93,18.32,17.29,11.89,11.49,10.49.HRMS(MALDI-TOF)m/z：calcd for C35H37N8O4S2[M]+ 697.23737,found 697.23609.
[ example 2]
N- [2- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -2-oxoethyl]Pyrophorbide-magnesian chlorophyllide (II)1) The preparation of (1):
compound II is prepared by the synthetic method of compound I1。1H NMR(400MHz,DMSO-d6)δ：13.10(s,1H), 9.74(s,1H),9.46(s,1H),8.92(s,1H),8.38(s,1H),8.30(s,2H),8.29–8.17(m,1H),6.40(d,J＝ 17.8Hz,1H),6.22(d,J＝11.6Hz,1H),5.25(d,J＝20.2Hz,1H),5.13(d,J＝20.1Hz,1H),4.61(d, J＝7.6Hz,1H),4.35(s,1H),4.06(s,2H),3.80–3.66(m,2H),3.63(s,3H),3.45(s,3H),3.23(s, 3H),2.67(s,1H),2.33(s,1H),2.20(s,2H),1.80(d,J＝7.3Hz,3H),1.64(d,J＝7.5Hz,3H),0.28 (s,1H),-1.94(s,1H).13C NMR(151MHz,DMSO-d6)δ：195.28,172.76,172.13,170.01,164.03, 161.43,153.69,149.61,147.81,144.24,140.57,136.88,135.49,134.96,134.66,131.50,128.91, 127.50,122.52,105.87,103.63,96.11,93.61,51.23,49.38,47.55,42.50,32.29,30.21,22.90,18.38, 17.33,11.93,11.52,10.59.HRMS(MALDI-TOF)m/z：calcd for C37H40N9O5S2[M]+754.25883, found 754.25598.
[ example 3]
N- [3- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -3-oxopropyl]Pyrophorbide-magnesian chlorophyllide (II)2) The preparation of (1):
compound II is prepared by the synthetic method of compound I2。1H NMR(600MHz,DMSO-d6)δ：13.00(s,1H), 9.65(s,1H),9.38(s,1H),8.88(s,1H),8.27(s,2H),8.18(dd,J＝17.8,11.6Hz,1H),8.07(s,1H), 6.36(d,J＝17.9Hz,1H),6.19(d,J＝11.6Hz,1H),5.21(s,1H),5.13(s,1H),4.53(d,J＝7.7Hz, 1H),4.25(d,J＝8.9Hz,1H),3.64(d,J＝8.1Hz,2H),3.59(s,3H),3.42(s,3H),3.41(s,1H),3.17 (s,3H),2.68(d,J＝7.2Hz,2H),2.61(q,J＝5.5,4.9Hz,1H),2.38(s,2H),2.12-2.08(m,2H),1.74 (d,J＝7.4Hz,3H),1.59(s,3H),0.18(s,1H),-2.03(s,1H).13C NMR(151MHz,DMSO-d6)δ： 195.30,172.07,170.73,164.29,161.46,161.12,147.82,144.34,140.57,136.95,135.59,134.71, 131.52,128.92,122.57,105.89,103.76,96.20,93.63,51.19,49.40,47.52,35.26,34.54,32.32, 30.21,22.83,18.40,17.34,11.92,11.52,10.61.HRMS(MALDI-TOF)m/z：calcd for C38H42N9O5S2 [M]+768.27448,found 768.27272.
[ example 4]
N- [4- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -4-oxobutyl]Pyrophorbide-magnesian chlorophyllide (II)3) The preparation of (1):
compound II is prepared by the synthetic method of compound I3。1H NMR(600MHz,DMSO-d6)δ：12.94(s,1H), 9.64(s,1H),9.37(s,1H),8.89(s,1H),8.31(s,2H),8.18(dd,J＝17.8,11.6Hz,1H),7.86(s,1H), 6.36(dd,J＝17.8,1.3Hz,1H),6.19(dd,J＝11.5,1.2Hz,1H),5.23(d,J＝19.4Hz,1H),5.11(d,J ＝19.4Hz,1H),4.55(dd,J＝7.4,2.3Hz,1H),4.30-4.27(m,1H),3.64(dd,J＝7.7,4.0Hz,2H), 3.58(s,3H),3.42(s,3H),3.16(s,3H),3.08–2.99(m,2H),2.63–2.58(m,1H),2.46–2.42(m, 2H),2.37–2.31(m,1H),2.16(d,J＝8.9Hz,1H),2.08-2.04(m,1H),1.79(d,J＝7.3Hz,3H),1.64 (t,J＝7.2Hz,2H),1.59(t,J＝7.6Hz,3H),0.17(s,1H),-2.04(s,1H).13C NMR(151MHz, DMSO-d6)δ：195.26,172.09,171.94,171.81,164.30,161.40,161.06,153.76,149.69,147.81, 144.34,140.57,136.93,135.60,134.99,134.72,131.52,129.90,128.93,127.60,122.57,105.92, 103.75,96.21,93.61,51.29,49.41,47.53,37.79,32.39,32.27,30.16,24.45,22.88,18.41,17.35, 11.93,11.52,10.63.HRMS(MALDI-TOF)m/z：calcd for C39H44N9O5S2[M]+782.29013,found 782.28722.
[ example 5]
N- [5- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -5-oxopentyl]Pyrophorbide-magnesian chlorophyllide (II)4) The preparation of (1):
compound II is prepared by the synthetic method of compound I4。1H NMR(600MHz,DMSO-d6)δ：9.17(s,1H), 8.90(s,1H),8.23(d,J＝10.2Hz,2H),7.68(dd,J＝16.8,10.0Hz,1H),7.55(t,J＝6.7Hz,1H), 6.50(d,J＝0.9Hz,1H),5.96(dd,J＝10.0,2.1Hz,1H),5.55(dd,J＝16.8,2.1Hz,1H),4.38(pd,J ＝6.8,1.0Hz,1H),4.31(q,J＝6.9Hz,1H),3.60(dq,J＝16.2,8.0Hz,1H),3.41(d,J＝15.7Hz, 1H),3.32(dq,J＝16.1,8.0Hz,1H),3.07(q,J＝6.9Hz,2H),2.48–2.37(m,4H),2.32(s,2H), 2.27(s,2H),2.12(s,2H),2.01(q,J＝7.1Hz,2H),1.66–1.50(m,4H),1.38(t,J＝8.0Hz,3H), 1.08(d,J＝6.7Hz,3H).13C NMR(151MHz,DMSO-d6)δ：197.41,173.72,172.07,170.88,169.58, 168.66,154.28,153.88,153.12,151.01,144.85,141.23,136.53,136.46,136.22,136.04,135.92, 131.17,129.58,129.06,121.72,106.03,100.08,99.03,94.02,50.26,49.40,43.18,38.47,37.65, 34.35,28.82,28.14,24.53,20.21,19.47,17.42,12.22,11.92,11.55.HRMS(MALDI-TOF)m/z： calcd for C39H44N8O4S2[M]+795.2985,found 795.2960。
[ example 6]
N- [6- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -6-oxohexyl]Pyrophorbide-magnesian chlorophyllide (II)5) The preparation of (1):
compound II is prepared by the synthetic method of compound I5。1H NMR(600MHz,DMSO-d6)δ：9.17(s,1H), 8.90(s,1H),8.23(d,J＝10.3Hz,3H),7.68(dd,J＝16.8,10.0Hz,1H),7.42(t,J＝6.7Hz,1H), 6.50(d,J＝0.9Hz,1H),5.96(dd,J＝10.0,2.1Hz,1H),5.55(dd,J＝16.8,2.1Hz,1H),4.38(pd,J ＝6.8,1.1Hz,1H),4.31(q,J＝6.9Hz,1H),3.60(dq,J＝16.2,8.0Hz,1H),3.41(d,J＝15.8Hz, 2H),3.38–3.26(m,1H),3.07(q,J＝7.0Hz,2H),2.42(td,J＝7.3,1.1Hz,4H),2.32(s,2H),2.27 (s,2H),2.12(s,2H),2.01(q,J＝7.1Hz,2H),1.61(p,J＝7.1Hz,2H),1.57-1.48(m,2H),1.43– 1.33(m,5H),1.09(d,J＝6.7Hz,3H).13C NMR(151MHz,DMSO-d6)δ：197.41,173.72,172.07, 170.88,169.58,168.66,154.28,153.88,153.12,151.01,144.85,141.23,136.22,135.92,131.17, 129.58,129.06,121.72,106.03,100.08,99.03,94.02,50.26,49.40,43.18,39.35,37.65,34.35, 28.99,28.14,25.59,25.13,20.21,19.47,17.42,12.22,11.92,11.55.HRMS(MALDI-TOF)m/z： calcd for C40H46N8O4S2[M]+809.3142,found 809.3117。
[ example 7]
N- [7- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -7-oxoheptyl]Pyrophorbide-magnesian chlorophyllide (II)6) The preparation of (1):
compound II is prepared by the synthetic method of compound I6。1H NMR(600MHz,DMSO-d6)δ：9.17(s,1H), 8.90(s,1H),8.23(d,J＝10.3Hz,2H),7.68(dd,J＝16.8,10.0Hz,1H),7.50(t,J＝6.7Hz,1H), 6.50(d,J＝0.9Hz,1H),5.96(dd,J＝10.0,2.1Hz,1H),5.55(dd,J＝16.8,2.1Hz,1H),4.43–4.28(m,2H),3.60(dq,J＝16.2,8.0Hz,1H),3.42(d,J＝16.3Hz,1H),3.32(dq,J＝16.1,8.0Hz, 1H),3.08(q,J＝6.9Hz,2H),2.42(td,J＝7.3,3.7Hz,4H),2.32(s,2H),2.27(s,2H),2.12(s,2H), 2.01(q,J＝7.1Hz,2H),1.63(p,J＝7.1Hz,2H),1.53–1.44(m,2H),1.41–1.28(m,7H),1.09(d, J＝6.7Hz,3H).13C NMR(151MHz,DMSO-d6)δ：197.41,173.79,172.05,170.88,169.58,168.66, 154.28,153.88,153.12,150.99,144.85,141.29,136.53,136.46,136.22,136.04,135.92,131.17, 129.51,129.06,121.77,106.03,100.08,99.03,94.02,50.26,49.40,43.18,39.35,37.65,34.35, 29.10,28.62,28.14,27.31,25.55,20.21,19.47,17.42,12.22,11.92,11.55.HRMS(MALDI-TOF) m/z：calcd for C41H48N8O4S2[M]+823.3293,found 823.3273。
[ example 8]
N- [8- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -8-oxooctyl]Pyrophorbide-magnesian chlorophyllide (II)7) The preparation of (1):
compound II is prepared by the synthetic method of compound I7。1H NMR(600MHz,DMSO-d6)δ：9.17(s,1H), 8.90(s,1H),8.23(d,J＝10.3Hz,2H),7.68(dd,J＝16.8,10.0Hz,1H),7.48(t,J＝6.7Hz,1H), 6.50(d,J＝0.9Hz,1H),5.96(dd,J＝10.0,2.1Hz,1H),5.55(dd,J＝16.8,2.1Hz,1H),4.38(pd,J ＝6.7,1.0Hz,1H),4.32(q,J＝6.9Hz,1H),3.60(dq,J＝16.2,8.0Hz,1H),3.42(d,J＝16.3Hz, 1H),3.38–3.26(m,1H),3.08(q,J＝7.0Hz,2H),2.42(td,J＝7.3,3.7Hz,4H),2.32(s,2H),2.27 (s,2H),2.12(s,2H),2.01(q,J＝7.1Hz,2H),1.62(p,J＝7.1Hz,2H),1.48–1.40(m,2H),1.44– 1.37(m,2H),1.38(s,2H),1.36(s,1H),1.35–1.22(m,4H),1.09(d,J＝6.7Hz,3H).13C NMR (151MHz,DMSO-d6)δ：197.41,173.89,172.05,170.88,169.83,168.66,154.28,153.88,153.12, 150.99,144.85,141.29,136.55,136.46,136.22,136.04,135.92,131.17,129.51,129.06,121.77, 106.03,100.08,98.86,94.02,49.62,49.40,43.18,39.36,37.65,34.35,29.39,29.21,28.62,28.14, 27.31,25.47,20.21,19.47,17.42,12.22,11.92,11.55.HRMS(MALDI-TOF)m/z：calcd for C42H50N8O4S2[M]+837.3755,found 837.3730。
[ example 9]
N- ((4-sulfamoyl) phenyl) pyropheophorbide (III)1) The preparation of (1):
compound III is prepared by the synthetic method of compound I1。1H NMR(600MHz,DMSO-d6)δ：9.64(s,1H),7.93 (s,1H),7.72(d,J＝17.9Hz,5H),7.34(s,1H),6.92(dd,J＝16.8,10.0Hz,1H),6.68(s,1H),6.00 (d,J＝0.9Hz,1H),5.68(dd,J＝13.7,10.1Hz,1H),5.37(dd,J＝16.9,13.7Hz,1H),4.55(s,2H), 3.89-3.65(m,1H),3.13(dd,J＝19.5,1.6Hz,1H),3.08–2.80(m,4H),2.41(s,3H),2.39–2.28(m, 1H),2.26(s,3H),2.10-2.01(m,1H),1.84(s,2H),1.70-1.53(m,1H),1.29(d,J＝6.8Hz,3H),1.12 (t,J＝8.0Hz,3H).13C NMR(151MHz,DMSO-d6)δ：196.73,172.86,170.78,169.06,155.74, 155.19,151.12,145.02,142.15,140.05,136.32,136.13,135.30,133.99,131.62,130.50, 129.80,128.35,121.41,119.39,103.44,100.74,99.51,93.81,50.69,49.82,47.10,33.90, 28.69,19.44,17.91,17.29,12.07,12.02,11.12.HRMS(MALDI-TOF)m/z：calcd for C39H40N6O4S[M]+688.2832,found 688.2865。
[ example 10]
N- ((4-sulfamoyl) phenylmethyl) pyropheophorbide (III)2) The preparation of (1):
compound III is prepared by the synthetic method of compound I2。1H NMR(600MHz,DMSO-d6)δ：9.41(s,1H), 7.85-7.79(m,2H),7.56(s,1H),7.52-7.43(m,3H),7.20(s,1H),6.90-6.80(m,2H),6.02-5.94 (m,2H),5.76(dd,J＝13.7,10.1Hz,1H),5.38(dd,J＝16.8,13.8Hz,1H),4.44(s,2H),4.10(dt,J ＝12.3,1.0Hz,1H),3.85(dt,J＝12.5,8.4Hz,1H),3.72-3.56(m,1H),3.15-3.05(m,1H),2.99(d, J＝1.5Hz,2H),2.74-2.63(m,1H),2.44(s,3H),2.40–2.28(m,1H),2.25(s,3H),2.10-2.03(m, 1H),1.94–1.81(m,2H),1.83(s,2H),1.46–1.37(m,1H),1.27(d,J＝6.8Hz,3H),1.15(t,J＝8.0 Hz,3H).13C NMR(151MHz,DMSO-d6)δ：196.73,173.51,170.78,169.06,155.74,155.19, 151.12,145.02,143.06,142.15,139.68,136.32,136.13,133.99,131.62,130.50,129.80, 127.74,126.30,121.41,103.44,100.74,99.51,93.81,50.69,49.82,47.10,43.62,34.27, 28.69,19.44,17.91,17.29,12.07,12.02,11.12.HRMS(MALDI-TOF)m/z：calcd for C40H42N6O4S[M]+702.2988,found 702.3022。
[ example 11]
N- (2- ((4-sulfamoyl) phenyl) ethyl) pyropheophorbide (III)3) The preparation of (1):
compound III is prepared by the synthetic method of compound I3。1H NMR(600MHz,DMSO-d6)δ：9.37(s,1H), 7.83–7.74(m,3H),7.38–7.32(m,2H),7.06(s,1H),6.86(dd,J＝16.8,10.1Hz,1H),6.72(s, 1H),5.92(d,J＝1.1Hz,1H),5.83–5.73(m,2H),5.37(dd,J＝16.9,13.7Hz,1H),4.56-4.32(m, 1H),4.38(s,2H),3.37(td,J＝12.3,3.9Hz,1H),3.24-3.15(m,1H),3.08(dd,J＝19.6,1.1Hz,1H), 3.04–2.84(m,4H),2.57(td,J＝12.3,2.7Hz,1H),2.45(s,3H),2.40–2.28(m,1H),2.28(s,3H), 1.81(d,J＝2.2Hz,1H),1.81(s,2H),1.76–1.64(m,2H),1.29(d,J＝6.8Hz,3H),1.10(t,J＝8.0 Hz,3H).13C NMR(151MHz,DMSO-d6)δ：196.73,174.04,170.78,169.06,155.74,155.19, 151.12,147.20,145.02,142.80,142.15,136.32,136.13,133.99,131.62,130.50,129.80, 129.63,126.03,121.41,103.44,100.74,99.51,93.81,50.69,49.82,47.10,41.12,35.24, 34.27,28.69,19.44,17.91,17.29,12.07,12.02,11.12.HRMS(MALDI-TOF)m/z：calcd for C41H44N6O4S[M]+716.3145,found 716.3178。
[ example 12]
N- (3- ((4-sulfamoyl) phenyl) propyl) pyropheophorbide (III)4) The preparation of (1):
compound III is prepared by the synthetic method of compound I4。1H NMR(600MHz,DMSO-d6)δ：9.23(s,1H), 7.89–7.83(m,2H),7.65(s,1H),7.47–7.41(m,2H),7.02(s,1H),6.89(dd,J＝16.8,10.0Hz, 1H),6.67(s,1H),6.15(d,J＝1.1Hz,1H),5.76(s,1H),5.39(dd,J＝16.8,13.8Hz,1H),4.48(s, 2H),3.74-3.62(m,1H),3.63-3.50(m,1H),3.24–3.09(m,3H),3.00–2.85(m,2H),2.78(pd,J＝ 6.8,1.0Hz,1H),2.73–2.65(m,1H),2.43(s,3H),2.39-2.35(m,1H),2.31(s,3H),2.21-2.15(m, 1H),2.08–1.97(m,1H),1.92-1.90(m,1H),1.85–1.75(m,5H),1.26(d,J＝6.8Hz,3H),1.10(t, J＝8.0Hz,3H).13C NMR(151MHz,DMSO-d6)δ：196.73,174.04,170.78,169.06,155.74, 155.19,151.12,145.02,143.61,142.15,136.13,133.99,131.62,130.50,129.80,128.39, 126.25,121.41,103.44,100.74,99.51,93.81,50.69,49.82,47.10,39.84,34.27,33.31, 30.67,28.69,19.44,17.91,17.29,12.07,12.02,11.12.HRMS(MALDI-TOF)m/z：calcd for C42H46N6O4S[M]+730.3301,found 730.3335。
[ example 13]
N- (4- ((4-sulfamoyl) phenyl) butyl) pyropheophorbide (III)5) The preparation of (1):
compound III is prepared by the synthetic method of compound I5。1H NMR(600MHz,DMSO-d6)δ：9.17(s,1H), 7.95-7.89(m,2H),7.75(s,1H),7.52–7.47(m,2H),7.12(s,1H),6.90(dd,J＝16.8,10.0Hz,1H), 6.72(s,1H),5.80(dd,J＝13.8,10.0Hz,1H),5.55–5.45(m,3H),4.41(s,2H),4.00(td,J＝12.3, 1.8Hz,1H),3.55–3.44(m,2H),3.31(dt,J＝12.4,2.9Hz,1H),3.23–3.06(m,3H),3.00(dd,J＝ 19.6,1.3Hz,1H),2.71–2.59(m,1H),2.46(s,3H),2.41–2.18(m,3H),2.04(s,3H),1.95–1.85 (m,1H),1.82(d,J＝1.2Hz,3H),1.80–1.55(m,3H),1.18(d,J＝6.9Hz,3H),1.11(t,J＝8.0Hz, 3H).13C NMR(151MHz,DMSO-d6)δ：196.73,174.04,170.78,169.06,155.74,155.19, 151.12,145.02,143.61,142.15,136.32,136.13,133.99,131.62,130.50,129.80,128.39, 126.25,121.41,103.44,100.74,99.51,93.81,50.69,49.82,47.10,39.55,35.73,34.27, 28.74,28.69,28.06,19.44,17.91,17.29,12.07,12.02,11.12.HRMS(MALDI-TOF)m/z： calcd for C43H48N6O4S[M]+744.3458,found 744.3491。
[ example 14]
N- (5- ((4-sulfamoyl) phenyl) pentyl) pyropheophorbide (III)6) The preparation of (1):
compound III is prepared by the synthetic method of compound I6。1H NMR(600MHz,DMSO-d6)δ：9.34(s,1H), 7.88–7.78(m,3H),7.46(dt,J＝7.5,1.2Hz,2H),7.01(s,1H),6.87(dd,J＝16.7,10.1Hz,1H), 6.72(s,1H),5.85(d,J＝0.9Hz,1H),5.82–5.70(m,2H),5.37(dd,J＝16.9,13.7Hz,1H),4.38(s, 2H),4.13-4.02(m,1H),3.90-3.73(m,1H),3.19–3.08(m,3H),3.04–2.90(m,2H),2.81(pd,J＝ 6.7,6.2,3.3Hz,1H),2.62–2.46(m,2H),2.45(s,3H),2.39–2.28(m,1H),2.27(s,3H),2.06– 1.94(m,2H),1.81(s,2H),1.92–1.56(m,6H),1.27(d,J＝6.8Hz,3H),1.11(t,J＝8.0Hz,3H). 13C NMR(151MHz,DMSO-d6)δ：196.73,174.04,170.78,169.06,155.74,155.19,151.12, 145.02,143.61,142.15,136.13,133.99,131.62,130.50,129.80,128.39,126.25,121.41, 103.44,100.74,99.51,93.81,50.69,49.82,47.10,39.94,35.53,34.27,30.26,29.84,28.69, 26.59,19.44,17.91,17.29,12.07,12.02,11.12.HRMS(MALDI-TOF)m/z：calcd for C44H50N6O4S[M]+758.3614,found 758.3648。
[ example 15]
N- (6- ((4-sulfamoyl) phenyl) hexyl) pyropheophorbide (III)7) The preparation of (1):
compound III is prepared by the synthetic method of compound I7。1H NMR(600MHz,DMSO-d6)δ：9.33(s,1H), 7.85(dd,J＝5.5,2.0Hz,3H),7.49–7.44(m,2H),6.89(s,1H),6.76(s,1H),5.89–5.81(m,2H), 5.71(dd,J＝13.7,10.1Hz,1H),5.35(dd,J＝16.7,13.8Hz,1H),4.36(s,2H),4.21–4.12(m,1H), 4.05(dd,J＝19.5,1.1Hz,1H),3.67(td,J＝12.3,2.9Hz,1H),3.12–2.97(m,3H),2.89-2.80(m, 1H),2.70–2.56(m,3H),2.46(s,3H),2.39–2.28(m,1H),2.25(s,3H),2.02–1.90(m,2H),1.85 –1.75(m,5H),1.71–1.53(m,2H),1.55–1.31(m,4H),1.19(d,J＝6.8Hz,3H),1.12(t,J＝8.0 Hz,3H).13C NMR(151MHz,DMSO-d6)δ：196.73,174.04,170.78,169.06,155.74,155.19, 151.12,145.02,143.61,142.15,136.32,136.13,133.99,131.62,130.50,129.80,128.39, 126.25,121.41,103.44,100.74,99.51,93.81,50.69,49.82,47.10,41.60,35.53,34.27, 33.54,31.12,29.06,28.71,28.69,19.44,17.91,17.29,12.07,12.02,11.12.HRMS (MALDI-TOF)m/z：calcd for C45H52N6O4S[M]+772.3771,found 772.3804。
[ example 16]
N- (7- ((4-sulfamoyl) phenyl) heptyl) pyropheophorbide (III)8) The preparation of (1):
compound III is prepared by the synthetic method of compound I8。1H NMR(600MHz,DMSO-d6)δ：9.34(s,1H), 7.88–7.82(m,2H),7.80(s,1H),7.47(dt,J＝7.4,1.1Hz,2H),6.97–6.86(m,2H),6.73(s,1H), 5.89(d,J＝1.1Hz,1H),5.76(s,1H),5.69(dd,J＝13.7,10.1Hz,1H),5.39(dd,J＝16.8,13.8Hz, 1H),4.36(s,2H),3.92–3.81(m,2H),3.18(dd,J＝19.6,1.1Hz,1H),3.07–2.93(m,3H),2.92–2.78(m,2H),2.67–2.52(m,2H),2.45(s,3H),2.26(s,3H),2.14–2.04(m,1H),1.82(s,3H),1.86 –1.73(m,2H),1.73–1.49(m,6H),1.46–1.31(m,2H),1.28(d,J＝6.9Hz,3H),1.15–0.99(m, 4H).13C NMR(151MHz,DMSO-d6)δ：196.73,174.04,170.78,169.06,155.74,155.19, 151.12,145.02,143.61,142.15,136.32,136.13,133.99,131.62,130.50,129.80,128.39, 126.25,121.41,103.44,100.74,99.51,93.81,50.69,49.82,47.10,41.60,35.53,34.27, 33.54,31.52,29.44,28.85,28.69,26.91,19.44,17.91,17.29,12.07,12.02,11.12.HRMS (MALDI-TOF)m/z：calcd for C46H54N6O4S[M]+786.3927,found 786.3961。
[ example 17]
N- (8- ((4-sulfamoyl) phenyl) octyl) pyropheophorbide (III)9) The preparation of (1):
synthesis with Compound IThe method prepares the compound III9。1H NMR(600MHz,DMSO-d6)δ：9.33(s,1H), 7.87–7.77(m,3H),7.46–7.40(m,2H),7.35(s,2H),6.94–6.81(m,3H),5.84(d,J＝0.9Hz,1H), 5.77–5.66(m,2H),5.35(dd,J＝16.8,13.7Hz,1H),4.62-4.49(m,1H),3.32-3.12(m,1H),3.09– 3.00(m,1H),2.81–2.67(m,4H),2.67–2.56(m,1H),2.49(s,3H),2.49-2.44(m,1H),2.41–2.29 (m,1H),2.24(s,3H),1.92–1.79(m,4H),1.82–1.45(m,8H),1.31–1.21(m,4H),1.12(t,J＝8.0 Hz,3H).13C NMR(151MHz,DMSO-d6)δ：196.73,174.04,170.78,169.06,155.74,155.19, 151.12,145.02,143.61,142.15,136.32,136.13,133.99,131.62,130.50,129.80,128.39, 126.25,121.41,103.44,100.74,99.51,93.81,50.69,49.82,47.10,41.60,35.53,34.27, 33.54,31.52,29.79,29.14,28.69,26.91,19.44,17.91,17.29,12.07,12.02,11.12.HRMS (MALDI-TOF)m/z：calcd for C46H54N6O4S[M]+800.4084,found 800.4117。
[ example 18]
Photodynamic antiproliferation experiment of photosensitizer on human breast cancer MDA-MB-231 cells
Test cells: human breast cancer MDA-MB-231 cells.
Light source: XD-635AB laser; model SD2490 laser power measuring instrument.
Test compounds:
n- (5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) pyropheophorbide (I);
n- [2- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -2-oxoethyl]Pyrophorbide-magnesian chlorophyllide (II)1)；
N- [3- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -3-oxopropyl]Pyrophorbide-magnesian chlorophyllide (II)2)；
N- [4- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -4-oxobutyl]Pyrophorbide-magnesian chlorophyllide (II)3)；
N- [5- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -5-oxopentyl]Pyrophorbide-magnesian chlorophyllide (II)4)；
N- [6- ((5-sulfamoyl-1, 3, 4-thiadiazole-2-yl)Amino) -6-oxohexyl radical]Pyrophorbide-magnesian chlorophyllide (II)5)；
N- [7- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -7-oxoheptyl]Pyrophorbide-magnesian chlorophyllide (II)6)；
N- [8- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -8-oxooctyl]Pyrophorbide-magnesian chlorophyllide (II)7)；
N- ((4-sulfamoyl) phenyl) pyropheophorbide (III)1)；
N- ((4-sulfamoyl) phenylmethyl) pyropheophorbide (III)2)；
N- (2- ((4-sulfamoyl) phenyl) ethyl) pyropheophorbide (III)3)；
N- (3- ((4-sulfamoyl) phenyl) propyl) pyropheophorbide (III)4)；
N- (4- ((4-sulfamoyl) phenyl) butyl) pyropheophorbide (III)5)；
N- (5- ((4-sulfamoyl) phenyl) pentyl) pyropheophorbide (III)6)；
N- (6- ((4-sulfamoyl) phenyl) hexyl) pyropheophorbide (III)7)；
N- (7- ((4-sulfamoyl) phenyl) heptyl) pyropheophorbide (III)8)；
N- (8- ((4-sulfamoyl) phenyl) octyl) pyropheophorbide (III)9)；
Acetazolamide-conjugate BODIPYphotosensitizer(AZ-BPS)；
Pyropheophorbide-a;
the positive control drug, Talaporfin (Talaporfin).
Experiment of photodynamic anti-tumor cell proliferation:
after trypsinizing the cells in logarithmic growth phase, the complete medium was resuspended to a cell suspension, which was then seeded into 96-well plates at 100. mu.L per well in 5% CO at 37 ℃2Culturing in incubator for 24 hr, adding photosensitizer (with concentration of 0,0.04, 0.12,0.37,1.11, and 3.33 μ M); after 3h, the medium was replaced with fresh medium and then irradiated with light (power 18 mW/cm)2Wavelength of 650nmLight dose 4J/cm2) (ii) a MTT detection was performed at 72 h. 20 mu L of 5mg/mL MTT is added 4h before the culture is terminated, the reaction is terminated by adding 150 mu L DMSO after the culture solution is discarded, and the OD value is detected by a microplate reader at 570 nm. The experiment was repeated three times. The results are shown in Table 1 and show that pyropheophorbide derivatives I and II1–II7And III1–III9Has obvious antiproliferative effect on human breast cancer cells, has stronger inhibition capability than that of a positive control medicament talaporfin, and has targeting compound II compared with pyropheophorbide a without a targeting ligand1Has good effect of inhibiting cell activity.
TABLE 1 antiproliferative effect of novel Compounds on human Breast cancer MDA-MB-231 cells
P <0.05 compared to the positive control drug Talaporfin
P <0.001 compared to the positive control drug Talaporfin.
Claims (4)
1. The pyropheophorbide derivatives have the following structures (formula I), (formula II) and (formula III):
wherein n is 1,2,3,4,5,6,7, 8; m is an integer of 0 to 8.
2. Pyropheophorbide derivatives (formula I) and (formula II) according to claim 1, comprising:
n- (5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) pyropheophorbide (I);
n- [2- ((5-sulfamoyl-1, 3, 4-thiadiazole-2-Yl) amino) -2-oxoethyl]Pyrophorbide-magnesian chlorophyllide (II)1)；
N- [3- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -3-oxopropyl]Pyrophorbide-magnesian chlorophyllide (II)2)；
N- [4- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -4-oxobutyl]Pyrophorbide-magnesian chlorophyllide (II)3)；
N- [5- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -5-oxopentyl]Pyrophorbide-magnesian chlorophyllide (II)4)；
N- [6- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -6-oxohexyl]Pyrophorbide-magnesian chlorophyllide (II)5)；
N- [7- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -7-oxoheptyl]Pyrophorbide-magnesian chlorophyllide (II)6)；
N- [8- ((5-sulfamoyl-1, 3, 4-thiadiazol-2-yl) amino) -8-oxooctyl]Pyrophorbide-magnesian chlorophyllide (II)7)。
3. Pyropheophorbide derivatives according to claim 1 (formula III), comprising:
n- ((4-sulfamoyl) phenyl) pyropheophorbide (III)1)；
N- ((4-sulfamoyl) phenylmethyl) pyropheophorbide (III)2)；
N- (2- ((4-sulfamoyl) phenyl) ethyl) pyropheophorbide (III)3)；
N- (3- ((4-sulfamoyl) phenyl) propyl) pyropheophorbide (III)4)；
N- (4- ((4-sulfamoyl) phenyl) butyl) pyropheophorbide (III)5)；
N- (5- ((4-sulfamoyl) phenyl) pentyl) pyropheophorbide (III)6)；
N- (6- ((4-sulfamoyl) phenyl) hexyl) pyropheophorbide (III)7)；
N- (7- ((4-sulfamoyl) phenyl) heptyl) pyropheophorbide (III)8)；
N- (8- ((4-sulfamoyl) phenyl) octyl) pyropheophorbide leafChloroamide (III)9)。
4. The compound of any one of claims 1-3 is useful as a photodynamic therapy for tumors, macular degeneration, actinic keratosis, port wine stains, condyloma acuminatum, and the like.
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| CN106867514A (en) * | 2015-12-11 | 2017-06-20 | 中国科学院大连化学物理研究所 | A kind of small-molecule fluorescent probe and its synthetic method and application for ratio identification people's carbonic anhydrase |
| CN107226817A (en) * | 2016-03-25 | 2017-10-03 | 陈志龙 | A kind of pyropheophorbide-a methyl ether compound and preparation method and application |
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