CN102391183A - C-19 modified geldanamycin(GDM) derivatives and preparation method thereof - Google Patents
C-19 modified geldanamycin(GDM) derivatives and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a group of C-19 modified geldanamycin(GDM) derivatives prepared by using spontaneous reaction, and a preparation method thereof. The derivative is a product prepared by carrying out reaction on GDM and a sulphydryl compound under room-temperature and light-tight or aerobic and oxygenated conditions by using appropriate solvents such as alcohols, buffer solutions and the like; and through carrying out antitumor activity, cytotoxicity and water-solubility tests on the derivative, the test results show that the compounds all have certain antitumor activities, the toxicity of the derivatives is lower than that of the GDM, and compared with the GDM, the water-solubility of most of the derivatives is increased by several times, thereby showing that the derivatives can be possibly developed into medicaments with prospects in clinical application.
Description
Technical field:
The present invention relates to utilize spontaneous reaction to obtain geldanamycin derivant of modifying a series of C-19 position and preparation method thereof.
Background technology:
(geldanamycin is one type of benzene AMSA microbiotic GDM) to NSC 122750, has protozoacide, and is antitumor, multiple biological activity [Sasaki K et al.J Antibiot (Tokyo) 1979,32 (8): 849-851] such as antiviral and immunomodulatory; [Tao Peizhen etc., Chinese patent ZL97100523; China's microbiotic magazine, 1997,22:368-372].Find that in the recent period GDM also has the epithelium nitrogen oxygenase activity of adjusting and anti-inflammatory action [Murphy P et al.Journal of Neuroscience Research, 2002,67 (4): 461-470].Its anti-tumor activity mechanism is to be targeted molecular with heat shock protein 90 (Hsp90); Through competitively combining with the terminal ATP/ADP structural domain of Hsp90, suppress the interaction of Hsp90 and kinds of tumors GAP-associated protein GAP specifically, reduce protein stability; Promote its degraded; Thereby suppress growth of tumour cell signal path [Whitesell L et al.Proc.Natl.Acad.Sci (USA), 1994,91:8324-8328].But GDM also exists toxicity to reach shortcomings such as poorly water-soluble greatly, because water is the basic medium of human body, medicine must have certain water solubility at absorption site, and medicine is in dissolved state and just can be absorbed.Water-soluble missionary society influences its bioavailability, and these defectives will limit its exploitation becomes active drug.Therefore, seek a kind of hypotoxicity, the verivate of good water solubility has become the major objective of further investigation.At present, substituted GDM verivate 17-AAG is carried out in existing 3 C-17 positions, 17-DMAG, and IPI-504 gets into clinical trial [Heath EI et al.Clin Prostate Cancer, 2005,4:138-141]; [Ramanathan RK, et al.J Clin Oncol, 2010,28 (9): 1520-1526]; [Oh WK, et al.Urology, 2011,78 (3): 626-630].
Find that in to the toxic side effect research of GDM the C-19 position of GDM can be connected with the sulfydryl of gsh is spontaneous, form mixture, the spontaneous connection can be carried out with some important proteic sulfydryl in the C-19 position of hint GDM, thereby influences these proteic normal functions.Therefore, the C-19 position of GDM is the critical sites of the toxic side effect of GDM [Cysyk RL et al.Chem Res Toxicol, 2006,19:376-381].In theory, the GDM verivate that the C-19 position is modified can reduce the antibiotic toxic side effect of GDM class.At present, through the method for chemosynthesis and bio-modification, obtained the GDM verivate of number of C-19 modification.People such as Schnur RC carry out chemically derived to GDM, obtained the substituted GDM verivate in a series of C-19 position, comprise 19-Br-GDM, 19-CH=N-N [(CH
2)
2]
2NCH
3-GDM, 19-cyclopropylamino-GDM, 19-azepine-GDM, 1-oxo-19-cyclized-N-methyl-tert-butylamine-GDM etc., but it is to the IC of human breast cancer cell SKBR-3
50>=1500nM, contrast GDM (IC
50Be 70nM), activity decrease [Schnur RC et al.J Med Chem, 1995,38:3806-3812].People such as Shan GZ are when the GDM verivate that synthetic C-17 modifies; Obtained a C-17; C-19 all introduces the verivate 17 of a group, 19-di-(R)-THFM-17-demethoxy-GDM, the anti-HCV virus activity of this compound than GDM and have only the verivate that C-17 modifies [17-(2 '-(R)-THFM)-17-demethoxy-GDM]; Lower significantly, but its cytotoxicity CC
50Several times [Shan GZ et al.JAntibiot, 2011,64:177-182] have also been reduced.Recent years has been found 19-SCH in this laboratory from Streptomyces hygroscopicus 17997 and gdmP change strain thereof
3-GDM, 4,5-dihydro-19-SCH
3-GDM, thiazino-GDM and 4,5-dihydro-thiazino-GDM, though the biological activity of these several compounds slightly is inferior to GDM, it is water-soluble than GDM be significantly improved [Liu X et al.J Antibiot, 2011,64:519-522]; [Ni S et al.J Microbiol Biotechnol, 2011,21 (6): 599-603]; [Lin L et al.Biosci Biotechnol Biochem, 2011,75 (10): 2042-2045].
The objective of the invention is to utilize GDM C-19 position and sulfydryl can spontaneous reaction to form the principle of verivate, on purpose select some precursors, in the hope of obtain to have activity, good water solubility, verivate that toxicity is low.
The present invention utilizes GDM C-19 position and sulfydryl spontaneous reaction to form said verivate and anticancer usage thereof, and not seeing as yet so far has relevant report.
Summary of the invention:
1. GDM novel derivative of 11 C-19 position modifications and preparation method thereof is provided, has adopted appropriate solvent such as alcohols, damping fluid etc. that GDM is being reacted under the room temperature lucifuge condition or under the condition of aerobic and adding oxygenant with the compound that contains sulfydryl.
2, the purifying of target compound
The compound that forms is concentrated, directly revolve steaming when being reaction solvent with the alcohols, with revolving steaming after the ethyl acetate extraction, be dissolved in methyl alcohol after concentrating when being reaction solvent with the damping fluid, HPLC obtains pure article through preparation.
3, the structure of target compound is identified
Content of halogen, molecular weight and the molecular formula differentiate through hanging down, high resolution mass spectrum confirmed target compound, through MS/MS,
1The structure of compound is confirmed in H-NMR and heavy water exchange.
4, adopt human liver cancer cell HepG
2Mtt assay is tested and monkey kidney (Vero) cell experiment, has estimated the anti-tumor activity and the toxicity of target compound.
5., adopt HPLC to measure the solubleness of these verivates in damping fluid.
The invention effect:
The present invention carries out spontaneous reaction through GDM C-19 potential energy and sulfydryl, has introduced 4 halogenous precursors and 2 precursors that do not have halogen, has synthesized 11 GDM verivates.Find through anti-tumor activity, cytotoxicity and water-soluble test; These compounds all have certain anti-tumor activity; Toxicity is lower than GDM, and the water-soluble of most of verivate improve several times than GDM, shows that it might be developed as the clinical medicine that application prospect is arranged.
Embodiment:
Below listed embodiment be for helping those skilled in the art to understand the present invention better, but do not limit the present invention in any way.
< embodiment 1>GCP-1, GCP-2, the preparation of GCP-X and structure elucidation
Take by weighing 50mg GDM (89 μ mol) in the single port flask, add 20mL methyl alcohol, stirring at room gets orange-yellow suspension liquid.Add 3-chloro-1-propylmercaptan (Chloro-1-propanethiol, 500 μ mol), lucifuge reaction under the room temperature.Question response liquid is orange red after 48 hours, and evaporated under reduced pressure is dissolved in methyl alcohol, with the further separation and purification of preparation liquid phase.Preparative hplc is with Tianjin, island LC-10A chromatographic system, and chromatographic column is ODS-C
18: 150 * 20mm, moving phase is 40-100% methyl alcohol, the 30min gradient elution, flow velocity 10mL/min, the detection wavelength is 254nm, 304nm.Obtain purity respectively at RT RT 16.2min, 19.9min and 18.4min and reach the about 3mg of GCP-1 more than 90%, the about 10mg of GCP-2, the about 15mg of GCP-X.Carry out ESI-MS, HRFAB-MS,
1H-NMR analyzes.
The molecular ion peak 693 [M+Na] of GCP-1 from ESI-MS
+And 709 [M+K]
+, infer that its molecular weight is 670; And isotopic peak 695 and 693 exists in 1: 3 ratio, confirms to contain 1 Cl atom among the GCP-1.Drawing accurate molecular mass through HRFAB-ESI-MS is 693.25780, infers that its molecular formula is C
32H
47O
9N
2ClNaS, theoretical value is 693.25830.With GCP-1's
1The H-NMR spectrum is compared with GDM, can find at δ 6.165 places 2 hydrogen signals are arranged, and can be by D
2O exchange back replaces, and confirms that GCP-1 is the hydroquinone type verivate; At δ 1.938,2.045,2.710,3.579 places have had more 6 hydrogen signals, are placed in-line 3 methylene radical; And do not detect Wasserstoffatoms in C-19 position, δ 7.2 left and right sides.Confirm that the chemical structure of GCP-1 is that 19-(3-chlorine rosickyite)-(19-'s quinhydrones GDM (3-Chloropropylthio)-hydroquinone-GDM) conforms to expection.
GCP-1's
1The H-NMR data:
1H-NMR (600,000,000, CDCl
3) δ (ppm): 0.743 (bro, 3H, CH
3); 1.142 (bro, 3H, CH
3); 1.259 (t, 1H, J=7.2Hz); 1.447 (bro, 1H); 1.572 (m, 1H); 1.725 (s, 3H, CH
3); 1.938 (m, 2H); 2.045 (s, 1H); 2.143 (s, 3H, CH
3); 2.612 (m, 1H); 2.710 (m, 1H); 2.777 (m, 1H); 2.859 (m, 1H); 3.161 (bro, 1H); 3.339 (s, 6H, 2OCH
3); 3.410 (bro, 1H); 3.579 (m, 2H); 3.835 (s, 3H, OCH
3); 4.127 (q, 1H, J=7.2Hz); 4.623 (bro, 2H, CONH
2); 4.953 (s, 1H); 5.418 (bro, 1H); 5.497 (d, 1H, J=8.4Hz); 6.165 (s, 2H, 2OH); 6.474 (t, 1H, J=11.4Hz); 8.454 (bro, 1H, NH).
The molecular ion peak 655 [M+Na] of GCP-X from ESI-MS
+And 671 [M+K]
+, infer that its molecular weight is 632; And do not detect the isotopic peak of Cl element.Drawing accurate molecular mass through HRFAB-ESI-MS is 655.26361, infers that its molecular formula is C
32H
44O
9N
2NaS, theoretical value is 655.26597.From
1Can find in the H-NMR spectrum,, also not find the signal of any one phenolic hydroxyl group, and not detect the NH of interior acyl ring, explain that the reactive hydrogen on the NH is attacked free Cl atom, form the cyclic structure except not detecting the H atom of C-19 position.And
1The data of H-NMR spectrum conform to this compound of prediction fully, and the chemical structure that proves GCP-X is 19, and 22-ring-rosickyite-GDM (19,22-cyclized-propylthio-GDM).
GCP-X's
1The H-NMR data:
1H-NMR (600,000,000, CDCl
3) δ (ppm): 0.633 (d, 3H, CH
3, J=6.6Hz); 1.046 (d, 3H, CH
3, J=6.6Hz); 1.241 (bro, 1H); 1.368 (m, 1H); 1.571 (s, 3H, CH
3); 1.612 (m, 1H); 1.965 (s, 3H, CH
3); 2.157 (m, 1H); 2.182 (m, 1H); 2.266 (m, 1H); 2.314 (s, 1H, OH); 2.450 (m, 1H); 2.463 (m, 1H); 2.626 (m, 1H); 2.836 (m, 1H); 2.870 (m, 1H); 3.120 (s, 3H, OCH
3); 3.289 (s, 3H, OCH
3); 3.392 (s, 3H, OCH
3); 3.511 (m, 1H); 3.544 (m, 2H); 3.992 (m, 1H); 4.534 (bro, 2H, CONH
2); 4.998 (d, 1H, J=10.2Hz); 5.161 (m, 1H); 5.178 (m, 1H); 6.290 (t, 1H, J=11.4Hz); 6.390 (d, 1H, J=12Hz).
The molecular ion peak 691 [M+Na] of GCP-2 from ESI-MS
+And 707 [M+K]
+, infer that its molecular weight is 668; And isotopic peak 693 and 691 exists in 1: 3 ratio, confirms to contain 1 Cl atom among the GCP-2.Drawing accurate molecular mass through HRFAB-ESI-MS is 691.24235, infers that its molecular formula is C
32H
45O
9N
2ClNaS, theoretical value is 691.24265.GCP-2 compares with GCP-1, has lacked 2 hydrogen, and GCP-2 is stable than GCP-1, infers that it is the quinoid verivate.According to
1The digital proof of H-NMR spectrum, the chemical structure of GCP-2 is 19-(3-chlorine rosickyite)-GDM (19-(3-Chloropropylthio)-GDM).
The data of the various chemical collection of illustrative plates of GCP-2 have below been listed.
GCP-2's
1The H-NMR data:
1H-NMR (600,000,000, CDCl
3) δ (ppm): 0.754 (d, 3H, CH
3, J=6.6Hz); 1.008 (d, 3H, CH
3, J=6.6Hz); 1.259 (t, 1H, J=7.2Hz); 1.521 (bro, 1H); 1.546 (s, 3H, CH
3); 1.629 (m, 1H); 2.024 (s, 3H, CH
3); 2.044 (s, 1H); 2.094 (m, 2H); 2.472 (m, 2H); 2.515 (bro, 1H, OH); 2.580 (m, 1H); 3.038 (m, 1H); 3.215 (s, 3H, OCH
3); 3.317 (m, 1H); 3.336 (s, 3H, OCH
3); 3.595 (t, 1H, J=6Hz); 3.670 (m, 2H); 4.059 (s, 3H, OCH
3); 4.127 (m, 1H); 4.610 (bro, 2H, CONH
2); 5.075 (d, 1H, J=6.6Hz); 5.434 (d, 1H, J=7.8Hz); 5.496 (bro, 1H); 6.423 (t, 1H, J=11.4Hz); 6.640 (bro, 1H); 7.432 (bro, 1H, NH).Wherein GCP-1 is a light orange, and GCP-2 and GCP-X are orange red.Its structure is suc as formula shown in (1).
< embodiment 2>GF-1, the preparation of GF-2 and structure elucidation
Take by weighing 50mg GDM (89 μ mol) in the single port flask, add 20mL methyl alcohol, stirring at room gets orange-yellow suspension liquid.Add 3-chloro-1-fluoro thiophenol (3-Fluorothiophenol, 500 μ mol), lucifuge reaction under the room temperature.Question response liquid is orange red after 48 hours, and evaporated under reduced pressure is dissolved in methyl alcohol, and with the further separation and purification of preparation liquid phase, RT RT 17.6min obtains purity and reaches the about 16mg of GF-1 more than 90%.Take by weighing 12mg GF-1 in 20% FeCl
3Carry out oxidation in the solution, oxidation is after 4 hours, ethyl acetate extraction, and evaporate to dryness is dissolved in methyl alcohol, further separates with the preparation liquid phase, and RT RT 23.8min purity reaches the about 8mg of GF-2 more than 90%.The pure article of GF-1 and GF-2 are carried out ESI-MS, HRFAB-MS,
1H-NMR analyzes.
The molecular ion peak 711 [M+Na] of GF-1 from ESI-MS
+And 727 [M+K]
+, infer that its molecular weight is 688.Drawing accurate molecular mass through HRFAB-ESI-MS is 711.27438, infers that its molecular formula is C
35H
45O
9N
2FNaS, theoretical value is 711.27220.With GF-1's
1The H-NMR spectrum is compared with GDM, can find at δ 6.054 places 2 hydrogen signals are arranged, and can be by D
2O exchange back replaces, and confirms that GF-1 is the hydroquinone type verivate; At δ 6.863,6.902,7.176,7.216 places have had more 4 hydrogen signals, are the benzene ring hydrogen; And do not detect Wasserstoffatoms in C-19 position, δ 7.2 left and right sides.Confirm that the chemical structure of GF-1 is that (19-'s 19-(3 fluorobenzene sulphur)-quinhydrones GDM (3-Fluorophenylthio)-hydroquinone-GDM) conforms to the expection supposition.
Below listed GF-1's
1The H-NMR data.
1H-NMR (600,000,000, CDCl
3) δ (ppm): 0.815 (bro, 3H, CH
3); 1.163 (bro, 3H, CH
3); 1.271 (t, 1H, J=7.8Hz); 1.509 (bro, 1H); 1.560 (bro, 3H, CH
3); 1.732 (bro, 1H); 1.849 (s, 3H, CH
3); 2.491 (m, 1H); 2.545 (m, 1H); 2.737 (m, 1H); 3.238 (bro, 1H); 3.520 (m, 1H); 3.356 (s, 3H, OCH
3); 3.364 (s, 3H, CH
3); 3.865 (s, 3H, OCH
3); 4.127 (q, 1H, J=6.6,7.8Hz); 4.643 (bro, 2H, CONH
2); 4.869 (s, 1H); 5.534 (bro, 1H); 5.621 (bro, 1H); 6.054 (s, 2H, OH); 6.357, (t, 1H, J=11.4Hz); 6.751 (bro, 1H); 6.863 (d, 1H, J=7.8Hz); 6.902 (dt, 1H, J=1.8,8.4Hz); 7.176 (d, 1H, J=7.8Hz); 7.216 (dq, 1H, J=1.8,7.8Hz); 8.061 (bro, 1H, NH).
The molecular ion peak 709 [M+Na] of GF-2 from ESI-MS
+And 725 [M+K]
+, infer that its molecular weight is 686.Drawing accurate molecular mass through HRFAB-ESI-MS is 709.25449, infers that its molecular formula is C
35H
43O
9N
2FNaS, theoretical value is 709.25655.With GF-2's
1The H-NMR spectrum is compared with GF-1, and GF-2 does not have 2 hydrogen signals of phenolic hydroxyl group.Explain that GF-2 is a quinoid GDM verivate, and the molecular weight of GF-2 is few 2 than GF-1, therefore, the chemical structure of inferring GF-2 be 19-(3-fluorobenzene sulphur)-GDM (19-(3-Fluorophenylthio)-GDM),
1The data of H-NMR also conform to this structure.
Below listed GF-2's
1The H-NMR data.
1H-NMR (600,000,000, CDCl
3) δ (ppm): 0.845 (bro, 3H, CH
3); 0.988 (d, 3H, J=6.6Hz, CH
3); 1.240 (bro, 1H); 1.527 (bro, 1H); 1.556 (s, 3H, CH
3); 1.673 (m, 1H); 1.948 (s, 3H, CH
3), 2.431-2.538 (m, 3H); 3.109 (bro, 1H); 3.202 (s, 3H, OCH
3); 3.320 (s, 3H, OCH
3); 3.520 (q, 1H, J=5.4,6.0Hz); 3.934 (s, 3H, OCH
3); 4.020 (bro, 1H); 4.635 (bro, 2H, CONH
2); (5.010 d, 1H, 4.8); 5.483 (bro, 1H); 5.552 (bro, 1H); 6.361 (t, 1H, J=11.4Hz); 6.586 (bro, 1H); 6.885 (t, 1H, J=7.2,7.8Hz); 7.012 (d, 1H, J=9.0Hz); 7.101 (d, 1H, J=7.2Hz); 7.210 (t, 1H, J=6.0,7.8Hz); 7.885 (bro, 1H, NH).GF-1 is a light orange, and GF-2 is orange red.Its structure is suc as formula shown in (2).
< embodiment 3>GBT-1, the preparation of GBT-2 and structure elucidation
Take by weighing 50mg GDM (89 μ mol) in the single port flask, add 20mL methyl alcohol, stirring at room gets orange-yellow suspension liquid.Add 4-bromo thiophenol (4-Bromothiophenol, 500 μ mol), lucifuge reaction under the room temperature.Question response liquid is orange red after 48 hours, and evaporated under reduced pressure is dissolved in methyl alcohol, with the further separation and purification of preparation liquid phase, RT RT 19.3min.Obtain purity and reach the about 22mg of GBT-1 more than 90%.Take by weighing 15mg GBT-1 in 20% FeCl
3Carry out oxidation in the solution, oxidation is after 4 hours, ethyl acetate extraction, and evaporate to dryness is dissolved in methyl alcohol, further separates with the preparation liquid phase, and RT RT 25.0min obtains purity and reaches the about 7mg of GBT-2 more than 90%.The pure article of GBT-1 and GBT-2 are carried out ESI-MS, HRFAB-MS,
1H-NMR analyzes.
The molecular ion peak 771 [M+Na] of GBT-1 from ESI-MS
+And 787 [M+K]
+, infer that its molecular weight is 748, and isotopic peak 773 and 771 exists in 1: 1 ratio, confirm to contain 1 Br atom among the GBT-1.Drawing accurate molecular mass through HRFAB-ESI-MS is 771.19118, infers that its molecular formula is C
35H
45O
9N
2BrNaS, theoretical value is 771.19214.With GBT-1's
1The H-NMR spectrum is compared with GDM, can find at δ 6.047 places 2 hydrogen signals are arranged, and can be by D
2O exchange back replaces, and confirms that GBT-1 is the hydroquinone type verivate; Have more 4 hydrogen signals at δ 6.959,7.354 places, be the benzene ring hydrogen; And do not detect Wasserstoffatoms in C-19 position, δ 7.2 left and right sides.The chemical structure that confirms GBT-1 is that (19-'s 19-(4-bromobenzene sulphur)-quinhydrones GDM (4-Bromophenylthio)-hydroquinone-GDM) conforms to the expection supposition.
Below listed GBT-1's
1The H-NMR data.
1H-NMR (600,000,000, CDCl
3) δ (ppm): 1.140 (bro, 3H, CH
3); 1.259 (t, 3H, J=7.2Hz, CH
3); 1.493-1.653 (bro, 2H); 1.732 (bro, 1H); 1.897 (s, 1H); 2.045 (s, 3H, CH
3); 2.692-2.727 (m, 2H); 2.735 (m, 1H); 3.197 (bro, 1H); 3.353 (s, 6H, 2OCH
3); 3.502 (bro, 1H); 3.853 (s, 3H, OCH
3); 4.127 (q, 1H, J=7.2Hz); 4.915 (s, 1H); 5.519 (bro, 1H); 6.047 (bro, 2H, 2OH); 6.385 (t, 1H, J=10.8,12Hz); 6.959 (d, 2H, J=8.4Hz); 7.354 (d, 2H, J=9.0Hz).
The molecular ion peak 769 [M+Na] of GBT-2 from ESI-MS
+And 785 [M+K]
+, infer that its molecular weight is 746, and isotopic peak 771 and 769 exists in 1: 1 ratio, confirm to contain 1 Br atom among the GBT-2.Drawing accurate molecular mass through HRFAB-ESI-MS is 769.17395, infers that its molecular formula is C
35H
43O
9N
2BrNaS, theoretical value: 769.17649.With GBT-2's
1The H-NMR spectrum is compared with GBT-1, does not find near the signal (δ 6.047) of 2 phenolic hydroxyl groups, explains that GBT-2 is a quinoid GDM verivate; And the molecular weight of GBT-2 is than GBT-1 few 2; Therefore, the chemical structure of supposition GBT-2 is 19-(4-bromobenzene sulphur)-GDM (19-4-Bromophenylthio-GDM)
1The data of H-NMR also conform to this structure.
Below listed GBT-2's
1The H-NMR data.
1H-NMR (600,000,000, CDCl
3) δ (ppm): 0.807 (bro, 3H, CH
3); 0.996 (d, 3H, J=6.6Hz, CH
3); 1.242 (bro, 1H); 1.489 (bro, 1H); 1.548 (s, 3H, CH
3); 1.665 (m, 1H); 1.949 (s, 3H, CH
3); 2.438-2.528 (m, 2H); 2.534 (bro, 1H); 3.099 (bro, 1H); 3.215 (s, 3H, OCH
3); 3.318 (s, 3H, OCH
3); 3.545 (m, 1H); 3.939 (s, 3H, OCH
3); 4.022 (bro, 1H); 4.660 (bro, 2H, CONH
2); 5.016 (d, 1H, J=4.8Hz); 5.484 (bro, 1H); 5.536 (bro, 1H); 6.368 (t, 1H, J=10.8); 6.565 (bro, 1H); 7.218 (d, 2H, J=7.8); 7.364 (d, 2H, J=3.6); 7.871 (bro, 1H, NH).GBT-1 is a light orange, and GBT-2 is orange red.Its structure is suc as formula shown in (3).
< embodiment 4>GDBT-1, the preparation of GDBT-2 and structure elucidation
Take by weighing 50mg GDM (89 μ mol) in the single port flask, add 20mL methyl alcohol, stirring at room gets orange-yellow suspension liquid.Add 2,5-dichlorobenzene mercaptan (2,5-Dichlorobenzenethiol, 500 μ mol), lucifuge reaction under the room temperature.Question response liquid is orange red after 48 hours, and evaporated under reduced pressure is dissolved in methyl alcohol, with the further separation and purification of preparation liquid phase, RT RT 19.7min.Obtain purity and reach the about 25mg of GDBT-1 more than 90%.Take by weighing 15mg GDBT-1 in 20% FeCl
3Carry out oxidation in the solution, oxidation is after 4 hours, ethyl acetate extraction, and evaporate to dryness is dissolved in methyl alcohol, further separates with the preparation liquid phase, and RT RT 31.0min obtains purity and reaches the about 5mg of GDBT-2 more than 90%.The pure article of GDBT-1 and GDBT-2 are carried out ESI-MS, HRFAB-MS,
1H-NMR analyzes.
The molecular ion peak 761 [M+Na] of GDBT-1 from ESI-MS
+And 777 [M+K]
+, infer that its molecular weight is 738, and have the significantly isotopic peak of [M+2] and [M+4] that wherein 761/763/765 exists by 9: 6: 1 ratio, contains 2 Cl atoms among the confirmation GDBT-1.Drawing accurate molecular mass through HRFAB-ESI-MS is 761.20239, infers that its molecular formula is C
35H
44O
9N
2Cl
2NaS, theoretical value is 761.20368.With GDBT-1's
1The H-NMR spectrum is compared with GDM, can find at δ 5.949 places 2 hydrogen signals are arranged, and can be by D
2O exchange back replaces, and confirms that GDBT-1 is the hydroquinone type verivate; Extra at δ 7.096,7.260,7.294 places have had more 3 hydrogen signals, are the benzene ring hydrogen; And do not detect Wasserstoffatoms in C-19 position, δ 7.2 left and right sides.The chemical structure that confirms GDBT-1 be 19-(2,5-dichlorobenzene sulphur)-quinhydrones GDM (19-(and 2,5-Dichlorophenylthio)-hydroquinone-GDM), infer with expection to conform to.
Below listed GDBT-1's
1The H-NMR data.
1H-NMR (600,000,000, CDCl
3) δ (ppm): 1.140 (bro, 3H, CH
3); 1.271 (m, 3H, CH
3); 1.534 (bro, 1H); 1.596 (m, 1H); 1.733 (bro, 1H); 1.911 (s, 3H, CH
3); 2.045 (s, 3H, CH
3); 2.742 (m, 3H); 3.237 (m, 1H); 3.375 (s, 6H, 2OCH
3); 3.555 (bro, 1H); 3.861 (s, 3H, OCH
3); 4.127 (q, 1H, J=7.2Hz); 4.625 (bro, 2H, CONH
2); 4.951 (s, 1H); 5.582 (bro, 1H); 5.949 (s, 2H, 2OH); 6.405 (t, 1H, J=11.4Hz); 6.661 (bro, 1H); 7.096 (dd, 1H, J=2.4,6.0Hz); 7.260 (overlap, 1H); 7.294 (d, 1H, J=6.0Hz).
The molecular ion peak 759 [M+Na] of GDBT-2 from ESI-MS
+And 775 [M+K]
+, infer that its molecular weight is 736, and have the significantly isotopic peak of [M+2] and [M+4] that wherein 759/761/763 exists by 9: 6: 1 ratio, contains 2 Cl atoms among the confirmation GDBT-2.Drawing accurate molecular mass through HRFAB-ESI-MS is 759.18591, infers that its molecular formula is C
35H
42O
9N
2Cl
2NaS, theoretical value is 759.18803.With GDBT-2's
1The H-NMR spectrum is compared with GDBT-1, does not find near the signal (δ 6.0) of 2 phenolic hydroxyl groups, explains that GDBT-2 is a quinoid GDM verivate; And the molecular weight of GDBT-2 is than GDBT-1 few 2; Therefore, the chemical structure of supposition GDBT-2 is that (2,5-dichlorobenzene sulphur)-(19-(2 for GDM for 19-; 5-Dichlorophenylthio)-GDM), and GDBT-2
1H-NMR spectrum data and this structure fit like a glove.
Below listed GDBT-2's
1The H-NMR data.
1H-NMR (600,000,000, CDCl
3) δ (ppm): 0.883 (bro, 3H, CH
3); 0.987 (d, 3H, J=6.6Hz, CH
3); 1.241 (bro, 1H); 1.519 (bro, 1H); 1.549 (s, 3H, CH
3); 1.683 (m, 1H); 2.004 (s, 3H, CH
3); 2.433-2.535 (m, 2H); 2.589 (bro, 1H); 3.158 (bro, 1H); 3.250 (s, 3H, OCH
3); 3.326 (s, 3H, OCH
3); 3.524 (q, 1H, J=5.4Hz); 4.172 (d, 1H, J=4.8Hz); 4.638 (bro, 2H, CONH
2); 5.050 (d, 1H, J=3.6Hz); 5.540 (bro, 1H); 5.644 (bro, 1H); 6.427 (t, 1H, J=10.8,11.4Hz); 6.804 (bro, 1H); 7.087 (dd, 1H, J=2.4,6.6Hz); 7.234 (d, 1H, J=8.4Hz); 7.264 (d, 1H, J=2.4Hz); 8.028 (bro, 1H, NH).GDBT-1 is a light orange, and GDBT-2 is orange red.Its structure is suc as formula shown in (4).
Preparation and the structure elucidation of < embodiment 5>thiazole GDM (thiazol-GDM)
Take by weighing 50mg GDM (89 μ mol) in the single port flask, add 1mL methyl alcohol, the dissolving back adds 20ml P-buffer, and (0.7mol/L, pH6.5), stirring at room gets orange-yellow suspension liquid.Add halfcystine (500 μ mol), lucifuge reaction under the room temperature.Afterreaction liquid was yellow in 48 hours, ethyl acetate extraction, and evaporated under reduced pressure is dissolved in methyl alcohol, with the further separation and purification of preparation liquid phase.RT RT 11.7min obtains purity and reaches the about 10mg of thiazol-GDM more than 90%.Pure article carry out ESI-MS, HRFAB-MS,
1H-NMR analyzes.
The molecular ion peak 626 [M+Na] of Thiazol-GDM from ESI-MS
+And 642 [M+K]
+, infer that its molecular weight is 603.Drawing accurate molecular mass through HRFAB-ESI-MS is 626.26327, infers that its molecular formula is C
30H
41O
8N
3NaS, theoretical value is 626.25121.It is similar that the chemical reaction of synthetic and rifamycin S and the halfcystine of Thiazol-GDM generates rifamycin P.With thiazol-GDM's
1The H-NMR spectrum is compared with GDM, can find at δ 8.735,8.169 places 1 hydrogen signal is arranged respectively, and wherein δ 8.169 can be by D
2O exchange back replaces, and is confirmed that it is the reactive hydrogen (NH) on the lactan, the hydrogen that δ 8.735 then for C-22 is.And the integration at δ 5.726 places is 3 Wasserstoffatomss, after the D2O exchange, is 2 Wasserstoffatomss, confirms wherein to have covered 21-OH.And do not detect Wasserstoffatoms in C-19 position, δ 7.2 left and right sides.Therefore, the structure of compound is thiazole GDM (thiazol-GDM), infers with expection to conform to.
Thiazol-GDM's
1The H-NMR data are:
1H-NMR (600,000,000, CDCl
3) δ (ppm): 0.951 (d, 3H, CH
3, J=6.6Hz); 0.984 (s, 3H, CH
3); 1.602 (s, 3H, CH
3); 1.652 (bro, 1H); 1.767 (bro, 1H); 1.857 (s, 3H, CH
3); 1.995 (bro, 1H); 2.776 (bro, 2H); 2.940 (bro, 1H); 3.244 (s, 3H, OCH
3); 3.485 (d, 1H, J=4.2Hz); 3.451 (s, 3H, OCH
3); 3.588 (bro, 1H); 4.205 (s, 3H, OCH
3); 4.322 (m, 1H); 5.046 (s, 1H); 5.726 (bro, 2H); 5.726 (over, 1H, OH); 6.446 (bro, 1H); 7.085 (bro, 1H), 8.169 (s, 1H, NH); 8.735 (s, 1H).Structure is suc as formula shown in (5).
Preparation and the structure elucidation of < embodiment 6>GM-1
Take by weighing 50mg GDM (89 μ mol) in the single port flask, add 1mL methyl alcohol, the dissolving back adds 20mlP-buffer, and (0.7mol/L, pH6.5), stirring at room gets orange-yellow suspension liquid.Add 2-mercaptoethylamine (2-Mercaptoacetamide, 500 μ mol), lucifuge reaction under the room temperature.Question response liquid is orange red after 48 hours, ethyl acetate extraction, and evaporated under reduced pressure is dissolved in methyl alcohol, with the further separation and purification of preparation liquid phase.RT RT14.0min obtains purity and reaches the about 22mg of GM-1 more than 90%.Pure article carry out ESI-MS, HRFAB-MS,
1H-NMR analyzes.
The molecular ion peak 672 [M+Na] of GM-1 from ESI-MS
+And 688 [M+K]
+, infer that its molecular weight is 649.Drawing accurate molecular mass through HRFAB-ESI-MS is 672.26219, infers that its molecular formula is C
30H
41O
8N
3NaS, theoretical value is 672.25668.With GM-1's
1The H-NMR spectrum is compared with GDM, can find at δ 5.766 places 2 hydrogen signals are arranged, and can be replaced by D2O exchange back, is the group NH2 that newly derives up.Each many 1 hydrogen signal is the methylene radical on the group of newly deriving up, and does not detect the Wasserstoffatoms in C-19 position, δ 7.2 left and right sides at δ 3.613,3.638 places.Therefore, the structure of compound is that (19-'s 19-(2-ethanamide sulphur)-GDM (2-acetamidethio)-GDM) conforms to the expection supposition.
GM-1's
1The H-NMR data are:
1H-NMR (600,000,000, CDCl
3) δ (ppm): 0.934 (d, 3H, CH
3, J=6.6Hz); 0.982 (bro, 3H, CH
3); 1.564 (bro, 1H); 1.589 (bro, 1H); 1.666 (s, 3H, CH
3); 1.732 (m, 1H); 2.033 (s, 3H, CH
3); 2.372 (m, 1H); 2.491 (m, 1H); 2.667 (bro, 1H); 3.143 (bro, 1H); 3.337 (s, 3H, OCH
3); 3.343 (s, 3H, OCH
3): 3.490 (s, 1H); 3.613 (s, 1H); 3.638 (s, 1H); 4.060 (s, 3H, OCH
3); 4.251 (d, 1H, J=6.6Hz); 5.074 (d, 1H, J=3Hz); 5.608 (bro, 1H); 5.790 (s, 2H, NH
2); 6.079 (bro, 1H); 6.484 (t, 1H, J=11.4Hz); 7.000 (bro, 1H); 8.421 (s, 1H, NH).GM-1 is orange red.Its structure is suc as formula shown in (6).
The test of < embodiment 7>anti-tumor activity
Trysinization logarithmic phase HepG2 cell, cell suspension is processed in centrifugal collection; Its concentration of cell counting adjustment is to 5-10 * 10
4/ mL.After cell suspension prepared, mixing added 100 μ L in the every hole of 96 orifice plates gently, and the density of cell to be measured is 5000-10000/ hole (marginal pore adds aseptic PBS); The Tissue Culture Plate that inoculation is good is put into incubator and is cultivated; At the bottom of being paved with the hole to cell monolayer (96 hole flat underside); Add GDM C19 position modified derivative (GCP-1, GCP-X, GCP-2, GF-1, GF-2, GBT-1, GBT-2, GDBT-1, GDBT-2, thiazol-GDM, GM-1),, generally establish 5-7 gradient with the concentration gradient dilution; Every hole 200 μ L establish 3 repeating holes.Control wells (blank substratum) is set simultaneously; 5%CO
2, to hatch 48 hours for 37 ℃, inverted microscope is observed the action effect of medicine down.Every hole adds 20 μ L MTT solution (5mg/mL), continues to cultivate 4 hours, and crystallization this moment can fully form, and supernatant is removed, and every hole adds 150 μ L DMSO 99.8MIN.s, puts low-speed oscillation 10min on the shaking table, and crystallisate is fully dissolved.At ELIASA OD
490The light absorption value in each hole is measured at the nm place.
Improvement Kou Shifa:
The Xm=log maximal dose; I=log (maximal dose/face mutually dosage); P=positive reaction rate sum; The maximum positive reaction rate of Pm=; The minimum positive reaction rate of Pn=.
GDM-C19 position modified derivative antitumor activity sees Table 1.
Antitumor (HepG2) activity of the GDM verivate that table 1 C-19 modifies
< embodiment 8>water-soluble mensuration
GDM and verivate thereof with the accurate weighing of dissolve with methanol are processed standardized solution, detect the peak area (UV under the different concns through HPLC
250Nm or UV
304Nm) drawing standard curve.With excessive GDM and verivate sample to be measured stirred overnight under 28 ℃ of lucifuge conditions in the 50mM of pH7.0 PBS solution, next day 100,000g high speed centrifugation 10min removes insoluble solid, processes saturated solution.Measure UV according to HPLC
250(GDM verivate) or UV
304(GDM) peak area is with typical curve calculating concentration result.GDM C-19 position modified derivative water-soluble sees table 2.
Show the water-soluble of 2.GDM C19 position modified derivative
< embodiment 9>CTA
Cell cultures: in covering with the culturing bottle of cell, add 0.25% pancreatin 0.1ml, 0.02%EDTA 5ml, 37 ℃ of digestion 20～25min; Discarded Digestive system adds nutrient solution piping and druming, goes down to posterity at 1: 3; Covered with in 3 days, and be mixed with every milliliter 20～300,000 cells, inoculate 96 porocyte culture plates; Every hole 0.1ml, 37 ℃, 5%CO
2Cultivated 24 hours, cell experimentizes after growing up to individual layer.
VERO cell toxicity test: GDM and GDM verivate are carried out gradient dilution in 0-1000 μ mol/L scope, every concentration 2 holes are established and are not added like cell contrast.With the observation of cell pathology is index, microscopically observation of cell pathology, and completely destroy is 4; 75% is 3; 50% is 2; 25% is 1; Anosisly become 0.Calculate each concentration sample average cytopathy degree.Press the Reed&Muench method and calculate the poisonous concentration (TD of half
50).
The cytotoxicity of GDM C-19 position modified derivative is seen table 3.
The cytotoxicity of table 3.GDM C19 position modified derivative
NT: do not detect
Claims (8)
1.C-19 the NSC 122750 GDM verivate that the position is modified is characterized in that, said verivate is to be initial with NSC 122750, and with the different precursors that contain sulfydryl, one group of new 19-of spontaneous formation contains sulfur derivatives in solvent, and concrete structure is as follows:
2. prepare the method for the said verivate of claim 1, it is characterized in that, 19-(3-chlorine rosickyite)-quinhydrones GDM, 19-(3-chlorine rosickyite)-GDM and 19; The preparation of 22-ring-rosickyite-GDM is to take by weighing GDM, adding methyl alcohol; Stirring at room adds 3-chloro-1-propylmercaptan, and the lucifuge reaction is 48 hours under the room temperature; Evaporated under reduced pressure is dissolved in methyl alcohol, with the further separation and purification of preparation liquid phase; RT 16,20 and 18 minutes obtains 19-(3-chlorine the rosickyite)-quinhydrones GDM of light orange, orange-red 19-(3-chlorine rosickyite)-GDM and 19 respectively, the pure article of 22-ring-rosickyite-GDM.
3. prepare the method for the said verivate of claim 1, it is characterized in that, (3-fluorobenzene sulphur)-preparation of quinhydrones GDM is to take by weighing GDM to 19-; Add methyl alcohol, stirring at room adds 3-chloro-1-fluoro thiophenol; The lucifuge reaction is 48 hours under the room temperature, and evaporated under reduced pressure is dissolved in methyl alcohol; With the further separation and purification of preparation liquid phase, RT obtained 19-(3-fluorobenzene the sulphur)-quinhydrones GDM of light orange in 18 minutes; With gained 19-(3-fluorobenzene sulphur)-quinhydrones GDM at FeCl
3Carry out oxidation in the solution, ethyl acetate extraction, evaporate to dryness is dissolved in methyl alcohol, and the preparation liquid phase is further separated, and RT 24 minutes obtains the pure article of orange red 19-(3-fluorobenzene sulphur)-GDM.
4. prepare the method for the said verivate of claim 1, it is characterized in that, the preparation of 19-(4-bromobenzene sulphur)-quinhydrones GDM is to take by weighing GDM; Add methyl alcohol, stirring at room adds the 4-bromo thiophenol; The lucifuge reaction is 48 hours under the room temperature, and evaporated under reduced pressure is dissolved in methyl alcohol; With the further separation and purification of preparation liquid phase, RT 19 minutes obtains orange-red 19-(4-bromobenzene sulphur)-quinhydrones GDM; With gained 19-(4-bromobenzene sulphur)-quinhydrones GDM at FeCl
3Carry out oxidation in the solution, ethyl acetate extraction, evaporate to dryness is dissolved in methyl alcohol, further separates with the preparation liquid phase, and RT 25 minutes obtains the pure article of orange red 19-(4-bromobenzene sulphur)-GDM.
5. prepare the method for the said verivate of claim 1, it is characterized in that, the preparation of 19-(2,5-dichlorobenzene sulphur)-quinhydrones GDM is; Take by weighing GDM, add methyl alcohol, stirring at room adds 2; 5-dichlorobenzene mercaptan, the lucifuge reaction is 48 hours under the room temperature, and evaporated under reduced pressure is dissolved in methyl alcohol; With the further separation and purification of preparation liquid phase, RT 20 minutes obtains 19-(2,5-dichlorobenzene sulphur)-quinhydrones GDM; With gained 19-(2,5-dichlorobenzene sulphur)-quinhydrones GDM at FeCl
3Carry out oxidation in the solution, ethyl acetate extraction, evaporate to dryness is dissolved in methyl alcohol, further separates RT 31 minutes, the pure article of acquisition 19-(2,5-dichlorobenzene sulphur)-GDM with the preparation liquid phase.
6. prepare the method for the said verivate of claim 1, it is characterized in that, the preparation of thiazole GDM is that GDM is dissolved in methyl alcohol; Add phosphoric acid buffer, stirring at room adds halfcystine, and the lucifuge reaction is 48 hours under the room temperature; Ethyl acetate extraction, evaporated under reduced pressure is dissolved in methyl alcohol; With the further separation and purification of preparation liquid phase, RT 12 minutes obtains thiazole GDM.
7. prepare the method for the said verivate of claim 1, it is characterized in that, the preparation of 19-(2-ethanamide sulphur)-GDM is that GDM is dissolved in methyl alcohol; Add phosphoric acid buffer, stirring at room adds the 2-mercaptoethylamine, and the lucifuge reaction is 48 hours under the room temperature; Ethyl acetate extraction, evaporated under reduced pressure is dissolved in methyl alcohol; With the further separation and purification of preparation liquid phase, RT 14 minutes obtains 19-(2-ethanamide sulphur)-GDM.
8. claim 1,2,3,4,5, the application of 6 or 7 said verivates in the preparation medicines resistant to liver cancer.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57163369A (en) * | 1981-03-31 | 1982-10-07 | Kaken Pharmaceut Co Ltd | Novel geldanamycin derivative, its preparation, and drug comprising it as active ingredient |
| CN101220068A (en) * | 2008-01-18 | 2008-07-16 | 中国医学科学院医药生物技术研究所 | A set of geldanamycin derivant and method for preparing the same |
-
2011
- 2011-10-26 CN CN2011103285502A patent/CN102391183A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57163369A (en) * | 1981-03-31 | 1982-10-07 | Kaken Pharmaceut Co Ltd | Novel geldanamycin derivative, its preparation, and drug comprising it as active ingredient |
| CN101220068A (en) * | 2008-01-18 | 2008-07-16 | 中国医学科学院医药生物技术研究所 | A set of geldanamycin derivant and method for preparing the same |
Non-Patent Citations (2)
| Title |
|---|
| KEDAR PATEL,ET AL.: "Engineered Biosynthesis of Geldanamycin Analogs for Hsp90 Inhibition", 《CHEMISTYR & BIOLOGY》, vol. 11, 31 December 2004 (2004-12-31), pages 1625 - 1633 * |
| XIN LIU,ET AL.: "A pair of sulfur-containing geldanamycin analogs 19-S-methylgeldanamycin and 4,5-dihydro-19-S-methylgeldanamycin, from Streptomyces hygroscopicus 17997", 《THE JOURNAL OF ANTIBIOTICS》, vol. 64, 11 May 2011 (2011-05-11), pages 519 - 522 * |
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