CN103483413B - A kind of polyoxy pregnane compound and purposes - Google Patents

A kind of polyoxy pregnane compound and purposes Download PDF

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CN103483413B
CN103483413B CN201210197100.9A CN201210197100A CN103483413B CN 103483413 B CN103483413 B CN 103483413B CN 201210197100 A CN201210197100 A CN 201210197100A CN 103483413 B CN103483413 B CN 103483413B
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叶阳
林鸽
姚胜
杜健华
马良
蔡若涓
唐春萍
柯昌强
王亚周
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Shanghai Institute of Materia Medica of CAS
Chinese University of Hong Kong CUHK
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Abstract

This application involves field of medicinal chemistry, and in particular, to a kind of polyoxy pregnane compound and medical usage, especially such compound are preparing the purposes in the drug for reversing or inhibiting tumour cell Multidrug resistance.

Description

A kind of polyoxy pregnane compound and purposes
Technical field
This application involves field of medicinal chemistry, and in particular, to a kind of polyoxy pregnane compound and its medical usage, especially It is that such compound is preparing the purposes in the drug for reversing or inhibiting tumour cell Multidrug resistance.
Background technique
Multidrug resistance (Mutidrug Resistance, MDR), refers to that a kind of anti-tumor drug occurs in tumour cell While drug resistance, the phenomenon that anti-tumor drugs different to other structures, that target site is different also develop drug resistance.MDR is swollen One main obstacle of tumor chemotherapy.Usual MDR is by the overexpression of abc transport body in tumour cell that anti-tumor drug is inverse Concentration gradient is transferred out of cell, drug is caused to cause in the decline that tumour cell accumulates.Abc transport body is one group big of film knot Hop protein, it is made of two nucleotide binding domains and two transmembrane regions, and drug substrate active transport, which is gone out cell, is It is mediated by transmembrane region.Identified abc transport body has 48 kinds in human genome at present, the similarity based on sequence, it Be divided into 7 subfamilies (A-G).3 kinds of main abc transport bodies relevant to MDR, are by ABCB1 (or MDR-1) respectively The P-gp of gene coding, the MRP1 encoded by ABCC1 (or MRP1) gene and the BCRP/ABCG2 encoded by ABCG2 gene. They have extensive substrate specificity, can transport a variety of drugs, poisonous substance, metabolin and endogenous material.Therefore, they It is overexpressed the tumor cell line and clinical resistance for being common in chemotherapeutics screening.
Be currently known P-gp can transport including anthracycline antibiotic (anthracyclines) Changchun amine (vincas), Each based chemotherapy including taxanes (taxanes), Etoposide (etoposide) and mitoxantrone (mitoxantrone) Drug.P-gp widely expresses different tissues in vivo, includes intestines, testis in the capillary endothelial cell of brain and other organs Ball and skin more have the high expression in significant ground.P-gp expression is common in kidney, colon cancer, adrenal and teratocarcinoma.P-gp substrate Drug can be by one or more binding site in conjunction with transporter, therefore the mechanism of its transhipment possesses certain adaptability. Verapamil (Verapamil) is first known P-gp inhibitor, research shows that it can be by combining simultaneously with P-gp The outside transhipment for inhibiting P-gp to be mediated, to increase concentration of the anti-tumor drug in multidrug resistance cell.This discovery makes The drug resistance of anti-tumor drug must be reversed to have lighted hope.In order to improve the chemotherapy applied on multidrug resistance tumor cells, section Scholars devise a series of P-gp inhibitor again, as cyclosporin A, Dai Sipiao reach (Valspodar, PSC833) He Bili It examines up to (Biricodar, VX-710) and saccharin derivative Tariquidar (XR9576) etc., while this has been carried out and has been permitted More clinical researches.However, all to there is toxic dose in vivo close with effective dose for these drugs, it is difficult to which reaching can reverse Effective concentration；Action target spot is single, selectivity is low；Reversal agent is administered simultaneously with anticarcinogen, change pharmacokinetic properties and The problems such as aggravating the toxic side effect of anticarcinogen, to limit clinical application.On the whole, at present by multidrug resistance transporter Trial as clinical target is also in progress.
And the not all multidrug resistance cell with reduction drug concentration all expresses P-gp, this understanding promotes us to seek Look for other drug transporters relevant to multidrug resistance and its inhibitor.Some abc transport body family members being newly found The antagonist for having made development be able to suppress one or more transporter that goes out of (such as MRP1 and ABCG2) becomes inevitable.At present Until, some inhibitor of MRP1 such as Leukotriene C4(LTC4) and the like MK571, Sulfinpyrazone, Benzbromarone and Probenecid；The specificity of ABCG2 inhibits Flutoxin C (FTC), curcumin (curcumin) etc. to be found or design in succession Out.
The inhibition of P-gp and ABCG2 is increasing oral life in addition to showing importance in terms of anti-tumor drug drug resistance The absorption aspects of object availability and intracerebral are also a specific research direction.It is previous research shows that by ABCG2 inhibitor according to Ke Lida (elacridar) and Hycamtin, which combine to take, increases the latter in the intracorporal oral administration biaavailability of mouse.Also Research shows that another ABCG2 inhibitor Gefitinib (gefitinib) increases Irinotecan in the intracorporal oral life of mouse Object availability and anti-tumor activity.Moreover, the two transporters is inhibited to also add Hycamtin in the absorption of intracerebral, again Highlight the necessity for developing effective P-gp and/or ABCG2 inhibitor.Natural products and its derivative are the new treatments of discovery The treasure-house of drug.Different types of natural organic-compound such as Coumarins, terpene and steroid are it has been found that adjust multiple medicine The activity of drug resistance.
Rajmahal creeper (Moon) is a kind of plant of Asclepiadaceae (Asclepiadaceae), is mainly distributed on the west of China's Mainland South, its drying rattan and root are used to treating cancer.Some isolated polyoxy pregnane class chemical combination from Rajmahal creeper Object is fastened in tumour cell and shows cytotoxicity [bibliography: Luo S Q, et al., Polyoxygenpregnanes from Marsdenia tenacissima.Phytochem.,1993,34:10615].In the prior art [Hu Y J, et al.,Tenacigenin B Derivatives Reverse P-Glycoprotein-Mediated Multidrug Resistance in HepG2/Dox Cells.J.Nat.Prod.2008,71,1049] in it has been proved that two be isolated from it is logical Scattered tenacigenin B (tenacigenin B) analog of light has increase drug quick in the human liver cancer cell that P-gp is overexpressed The effect of perception.During further finding antineoplastic component or multidrug resistance reversal agent, inventor is from Rajmahal creeper Isolated more than a series of 30 polyoxy pregnane class compounds, and comprehensive research has been carried out to them.
Currently, mainly collecting from research of the compound isolated in Chinese medicine on the multidrug resistance for reversing P-gp to mediate In in their validity.The present inventor is systematically having evaluated a series of this polyoxy pregnane class compound more The anti-tumor activity and potential reverse multidrug resistance that the tumour cell that kind ABC multidrug resistance transporter is overexpressed is fastened are living Property, and the decisive structure for inhibiting P-gp, ABCG2 or MRP1 is disclosed, the compound filtered out can effectively overcome existing Defect present in technology.
Summary of the invention
It is an object of the present invention to provide the polyoxy pregnane compounds that a class formation is shown below:
Wherein, S2ForS3For
Ra isRb is
Tig isMBu isBz isAc is
It is still another object of the present invention to provide a kind of methods for preparing polyoxy pregnane compound as described above, should Method includes the following steps:
1, after the dry rattan of Rajmahal creeper crushes, at room temperature, using 95% industrial alcohol to the drying rattan of Rajmahal creeper Stem extracts three times, three days every time, each ethanol extract is merged, after solvent is evaporated off, obtains ethanol extract.The extract is outstanding Float on distilled water, then in succession use ethyl acetate and extracting n-butyl alcohol, after boiling off solvent, respectively obtain ethyl acetate extract and N-butanol extract.
2, ethyl acetate extract is subjected to silica gel column chromatography, successively uses petroleum ether: ethyl acetate 10:3,2:1,4:3,1: 1(respectively corresponds component A, B, C, D), ethyl acetate (corresponds to component E), then ethyl acetate: methanol 20:1,20:3,20:1(point Component F, G, H are not corresponded to) elution, merge by the same spot of thin layer, obtains A-H totally 8 components.This 8 group lease making silica gel column chromatographies, Aperture resin column chromatography, preparative high performance liquid chromatography isolate and purify, and obtain above compound.
It is still another object of the present invention to provide polyoxy pregnane class reactive compound as described above in preparation for inverse Turn or inhibit the purposes in the drug of tumour cell Multidrug resistance, more specifically, the polyoxy pregnane class reactive compound exists Prepare the purposes in the drug for reversing or inhibiting tumour cell Multidrug resistance, which is characterized in that the polyoxy pregnane class The Multidrug resistance that polyoxy pregnane class reactive compound can reverse or at least one abc transport body is inhibited to be mediated, preferably can Enough Multidrug resistances reversed or inhibition is mediated selected from one of P-gp, MRP1 and ABCG2, two or three of transporter, more It is preferably able to the more drug resistances for reversing simultaneously or two or three of transporter in P-gp, MRP1 and ABCG2 being inhibited to be mediated Property.
Preferably, the tumour cell refer to colon cancer cell, breast cancer cell, liver cancer cells, lung carcinoma cell, stomach Cancer cell, colorectal cancer cells, osteosarcoma cell, cervical cancer cell.The more preferably described tumour cell refers to colon cancer cell cream Adenocarcinoma cell, cell line used are colon carcinoma cell line SW620, breast cancer cell line MCF-7.
In above-mentioned polyoxy pregnane compound, as a kind of and known cancer cell multidrug-resistance reversal agent chemical structure Different reversing agent for drug-fast during treating tumor with multiple medicines, can be with anti-tumor drug or other reversing agent for drug-fast during treating tumor with multiple medicines drugs It is used in conjunction with, improves antitumor curative effect.Preferably compound POP 52,86,87 and 88 can reverse selected from P-gp, MRP1 and The MDR that one or more abc transport bodies is mediated in ABCG2, it is highly preferred that compound POP 86 and 87 can be reversed simultaneously The MDR that tri- kinds of abc transport bodies of P-gp, MRP1 and ABCG2 are mediated.
The polyoxy pregnane class compound can be selected from alkylating agents, taxanes, antibiotics, anthracycline, ghost Mortar endotoxin, camptothecin, uses for one of Buddhist nun's class drug or multiple combinations vinca.More specifically, the polyoxy Pregnane class compound can with cis-platinum, docetaxel, adriamycin, mitoxantrone, Teniposide, vincristine, topotecan, Gefitinib etc. is used in combination.
Yet another object of the invention is that providing polyoxy pregnane compound known to a class formation, this kind of compound A kind of MDR that abc transport body is mediated can be at least reversed, it can be with anti-tumor drug or other tumor cell multidrug resistances Reversal agent drug is used in conjunction with, and improves antitumor curative effect.Preferably POP 53,55,63 and 65 can reverse simultaneously by two kinds or The MDR that a variety of abc transport body P-gp and MRP1 are mediated, more preferably POP 65 can reverse simultaneously by three kinds of transporter P-gp, The MDR that MRP1 and ABCG2 are mediated.
It is still another object of the present invention to provide test polyoxy pregnane class compound on a kind of cell model in vitro The method of reversing tumor cell Multidrug resistance.Preferably tumor cell multidrug resistance be in P-gp, MRP1 and ABCG2 One or more transporters are relevant.
Specific embodiment
The extraction of 1 polyoxy pregnane class compound of embodiment with separate
After the dry rattan 21.0Kg of Rajmahal creeper is crushed, at room temperature, using the industrial alcohol of 40L 95% to Rajmahal creeper Drying rattan extract three times, three day every time, each ethanol extract is merged, after solvent is evaporated off, obtains the dark color of 3.4kg Medicinal extract.By the distillation aqueous suspension of medicinal extract 10L, is then extracted three times, mentioned with 10L ethyl acetate and 10L n-butanol in succession It takes liquid to merge respectively, after boiling off solvent, respectively obtains ethyl acetate extract 460g, n-butanol extract 500g.By 270g second Acetoacetic ester extract is separated with silica gel column chromatography, through petroleum ether: ethyl acetate 10:3,2:1,4:3,1:1(respectively correspond component A, B, C, D), ethyl acetate (corresponds to component E), then ethyl acetate: methanol 20:1,20:3,20:1(respectively correspond component F, G, H) Obtain eight component A-H.Component C gained fraction preparative high-efficient liquid phase color after silica gel column chromatography (chloroform: petroleum ether 10:1) Spectrum purifying (acetonitrile: water 20% ~ 50%, 15 ml/mins, 0-192 minutes) obtains compound POP 52(11mg)；Component D is through too small Hole resin column chromatography (methanol/water 60%, 70%, 85%, 100%, then acetone), then using silica gel column chromatography (chloroform: methanol 100:1) obtain compound POP 81(28mg)；Component E first pass through aperture resin column chromatography (methanol: 60%, 70%, 85%, 100%, so Acetone afterwards), then using preparative high performance liquid chromatography purifying, (acetonitrile: water 25% ~ 55%, 15 ml/mins, 0-192 divide Clock) obtain compound POP 74(25mg) and POP 75(23mg)；Fraction F first passes through silica gel column chromatography (chloroform: methanol 50:1), so Preparative high performance liquid chromatography purifying (acetonitrile: water 23% ~ 52%, 15 ml/mins, 0-192 minutes) obtains compound POP again afterwards 73(56mg), POP86(14mg), POP 87(13mg) and POP 88(34mg)；Fraction G through small holes resin column chromatograph (methanol/ Water 50% ~ 70%), then (acetonitrile: water 30% ~ 60%, 15 ml/mins, 0-192 is purified using preparative high performance liquid chromatography Minute) obtain compound POP 76(46mg) and POP 77(14mg).
The extraction of 2 polyoxy pregnane class compound of embodiment with separate
After the dry rattan 21.0Kg of Rajmahal creeper is crushed, at room temperature, using the industrial alcohol of 40L 95% to Rajmahal creeper Drying rattan extract three times, three day every time, each ethanol extract is merged, after solvent is evaporated off, obtains the dark color of 3.4kg Medicinal extract.By the distillation aqueous suspension of medicinal extract 10L, is then extracted three times, mentioned with 10L ethyl acetate and 10L n-butanol in succession It takes liquid to merge respectively, after boiling off solvent, respectively obtains ethyl acetate extract 460g, n-butanol extract 500g.By 270g second Acetoacetic ester extract is separated with silica gel column chromatography, through petroleum ether: ethyl acetate 10:3,2:1,4:3,1:1, ethyl acetate, then Ethyl acetate: methanol 20:1,20:3,20:1) eight components (A-H) are obtained after gradient elution.Component B is handled by recrystallization Compound POP 62(2.5g).Component C chromatograph through aperture resin column (methanol: water 50%, 60%, 70%, 85%, 100%, then third Ketone), 70% fraction of gained is after silica gel column chromatography (chloroform: methanol=150:1) using preparative high performance liquid chromatography (second Nitrile: water 25% ~ 55%, 15 ml/mins, 0-192 minutes) obtain compound POP 56(82mg)；85% fraction of gained is using silica gel Column chromatography (chloroform: methanol=100:1) purifies to obtain compound POP53(203mg)；85% fraction of gained passes through silica gel column chromatography (chlorine It is imitative: methanol=100:1) then using preparative high performance liquid chromatography, (acetonitrile: water 35% ~ 55%, 15 ml/mins, 0-192 divide Clock) purify to obtain compound POP 55(28mg).Component D through aperture resin column chromatograph (methanol: water 65%, 70%, 75%, 80%, 90%, 100%, then acetone) afterwards 80% fraction of gained using silica gel column chromatography (chloroform: methanol 50:1) purify to obtain compound POP 63 (1.2g).Group lease making E aperture resin column chromatography (methanol: water 65%, 70%, 75%, 80%, 90%, 100%, then acetone) after, gained 80% fraction purifies to obtain chemical combination by preparative high performance liquid chromatography (acetonitrile: water 28% ~ 62%, 15 ml/mins, 0-192 minutes) Object POP 65(16mg).Component F obtained solid after recrystallization is handled passes through preparative high performance liquid chromatography (acetonitrile: water 20% ~ 50%, 15 ml/mins, 0-192 minutes) purifying obtains compound POP 66(38mg).
The Structural Identification of the new polyoxy pregnane class compound of embodiment 3 and reactive compound
Compound POP 52, white amorphous powder show yellow under sulfuric acid-vanillic aldehyde color developing agent effect on the tlc plate Spot.EI-MS shows that molecular weight is 488, according to the high-resolution EI-MS accurate molecular weight 488.2763 shown and combines it1H- NMR and13C-NMR determines that its molecular formula is C28H40O7.In the compound1H-NMR(, which is shown in Table in 4), shows proton signal δH2.20 (m), 1.42 (m) and 1.63 (m), 0.88 (t, J=7.5), 1.04 (d, J=7.0Hz) and corresponding13In C H NMR spectroscopy (being shown in Table 1) Carbon signal δC175.5 (s), 41.2 (d), 26.1 (t), 11.7 (q), 15.3 (q) signals prompt the compound to contain a 2- Methylbutyryl substituent group.And δH1.97 (s) and δCContain one in the signal prompt at 170.6 (s), 20.8 (q) the places compound Acetyl substituents.With known compound POP's 5313C H NMR spectroscopy data compare, and find to have lacked one in the signal of POP 52 A methine carbon being connect with oxygen atom, more ketone carbonyl carbon, and their number other than the carbon signal near C-3 According to almost the same.It is inferred that the compound is the tenacigenin that C-3 are ketone group.In its HMBC spectrum, H-11 is observed {δH5.40 (t, J=10.0Hz) } and δCBetween 175.5 (s), H-12 { δH5.0 (d, J=10.1Hz) } and δCBetween 170.6 (s) Coherent signal illustrates that substituent group 2- methylbutyryl is connected to C-11, and substituent group acetyl group is connected to C-12.According to existing Technical report [Luo S.Q., et al., Assigment of the Proton and Carbon-13 NMR spetra of C21steroids 12β-O-acetyl tenacigenin A and tenacigenin A by two dimensional NMR techniques and computer modeling.Magn.Reson.Chem., 1993,31,215.], when C-17 Acetyl group side chain when being α configuration, H-17 proton shows as after being split point by adjacent proton as the peak dd, and coupling constant is about 11.5 And 7.0Hz；When C-17 acetyl group side chains are beta comfiguration, H-17 proton shows as the wide peak d after being split point, coupling Constant is about 7.0Hz.H-17 { the δ of analysis of compounds POP 52H2.92 (d, J=7.6Hz) } proton split point mode and coupling is normal Number, and H-17 and Me-18 in ROESY spectrum is combined, the correlativity between H-12 and Me-21 infers the position C-17 of the compound For H-17 beta comfiguration.Therefore noval chemical compound POP 52 is determined and is named as: -12 β-O- of 11 α-O-2- methylbutyryl Acetyl group -3- ketone tenacigenin B.
The Structural Identification of remaining compound can be analyzed by similar methods1H-NMR、13C-NMR、EI-MS、HR- EIMS, 2D-NMR and compared with the spectral data of known compound, to confirm its structure.
The physics and spectroscopy data of polyoxy pregnane class compound.
POP 52, C28H40O7, white amorphous powder, EI-MS:488 ([M]+,10),386(24),344(78),327 (16),283(100),230(57),156(46).HR-EIMS:488.2763[M]+(C28H40O7;Calc.288.2774) carbon is composed Data are shown in Table 1.Hydrogen modal data is shown in Table 4.
POP 73, C37H85O13;It is colourless, amorphous powder,IR(KBr): νmax 3425,2929,1705,1628,1735,1163,1082cm-1.HR-ESI-MS:m/z733.3817[M+Na]+ (C37H58O13Na;Calc.733.3775) carbon modal data is shown in Tables 1 and 2.Hydrogen modal data is shown in Table 3 and table 5.
POP 74, C40H62O13；It is colourless, unformed powder,IR(KBr): νmax 3448,2933,1700,1648,1450,1269,1163,1082cm-1.HR-ESI-MS:m/z 773.4056[M+Na]+ (C40H62O13Na;calc.773.4088).13C-NMR data are shown in Table 1 and 2.1H-NMR data are shown in Table 3 and 5.
POP 75, C42H60O13；It is colourless, unformed powder,IR(KBr): νmax 3434,2933,1714,1627,1452,1276,1068cm-1.HR-ESI-MS:m/z795.3943[M+Na]+ (C42H60O13Na;calc.795.3932).13C-NMR data are shown in Table 1 and 2.1H-NMR data are shown in Table 3 and 5.
POP 76, C41H66O17；It is colourless, unformed powder,IR(KBr): νmax 3423,2931,1691,1637,1452,1383,1163,1078,617cm-1.HR-ESI-MS:m/z 853.4233[M+ Na]+(C41H66O17Na;calc.853.4198).13C-NMR data are shown in Table 1 and 2.1H-NMR data are shown in Table 3 and 5.
POP 77, C46H72O18；It is colourless, unformed powder,UVλmax(MeOH) (logε)210(4.12)nm.IR(KBr):νmax 3423,2933,1651,1452,1383,1267,1161,1078,989cm- 1.HR-ESI-MS:m/z 935.4586[M+Na]+(C46H72O18Na;calc.935.4661).13C-NMR data are shown in Table 1 He 2.1H-NMR data are shown in Table 3 and 5.
POP 81, C37H88O13；It is colourless, unformed powder,IR(KBr): νmax 3457,2937,1739,1637,1454,1384,1236,1062cm-1.HR-ESI-MS:m/z 733.3764[M+H]+ (C37H88O13Na;calc.733.3775).1H--NMR and13C-NMR data are shown in Table 7.
POP 86, C42H64O15；It is colourless, unformed powder, LC-ESIMS:831.5 ([M+Na]+).13C-NMR data are shown in Table 1 and 2.1H-NMR data are shown in Table 4 and 6.
POP 87, C42H66O15；It is colourless, unformed powder, LC-ESIMS:833.4 [M+Na]+,809.4[M–H]-.HR- ESIMS:833.4271[M+Na]+(C42H66O15Na,calc.833.4299).13C-NMR data are shown in Table 1 and 2.1H-NMR data It is shown in Table 4 and 6.
POP 88, C48H74O20；It is colourless, unformed powder,LC-ESIMS: 969.4([M-H]-),993.4([M+Na]+).IR(KBr):νmax 3427,2933,1736,1707,1649,1369,1269, 1163,1080,1032,922,563cm-1.UVλmax(MeOH)(logε):215(4.25)nm.13C-NMR data are shown in Table 1 He 2.1H-NMR data are shown in Table 4 and 6.
- 12 β of POP 53,11 α-oxygen -2- methylbutyryl-oxy-acetyl Tenacious Condorvine Stem aglycon B, white powder,LC-ESIMS:490([M]+).13C-NMR(CDCl3,100MHz):37.5(t,C-1), 31.1(t,C-2),70.4(d,C-3),38.3(t,C-4),44.0(d,C-5),26.6(t,C-6),31.7(t,C-7),66.7 (s,C-8),51.0(d,C-9),38.7(s,C-10),68.4(d,C-11),75.0(d,C-12),45.7(s,C-13),71.3 (s,C-14),26.5(t,C-15),24.7(t,C-16),60.0(d,C-17),16.7(q,C-18),12.6(q,C-19), 210.6(s,C-20),29.6(q,C-21),175.6(s,C-1′),41.3(d,C-2′),26.1(t,C-3′),11.7(q,C- 4′),15.3(q,C-5′),170.7(s,C-1″),20.7(q,C-2″).
- 12 β of POP 55,11 α-oxygen -2- benzoyl-oxy-acetyl Tenacious Condorvine Stem aglycon B, white powder, LC-ESIMS:490([M]+).13C-NMR(CDCl3,100MHz):37.3(t,C-1),30.3(t, C-2),69.4(d,C-3),38.2(t,C-4),44.0(d,C-5),26.6(t,C-6),31.8(t,C-7),66.9(s,C-8), 51.2(d,C-9),38.8(s,C-10),69.6(d,C-11),75.1(d,C-12),45.8(s,C-13),71.4(s,C-14), 26.6(t,C-15),24.8(t,C-16),59.8(d,C-17),16.7(q,C-18),12.7(q,C-19),210.8(s,C- 20),30.0(q,C-21),165.9(s,C-1′),130.1(s,C-2′),129.5(d,C-3′),128.5(d,C-4′), 133.2 (d, C-5 '), 128.5 (d, C-6 '), 129.5 (d, C-7 '), 170.8 (s, C-1 "), 20.3 (q, C-2 ")
POP 56,11 α-oxygen--12 β of crotonyl-oxy-acetyl Tenacious Condorvine Stem aglycon B, white powder, LC-ESIMS:488.2([M]+).13C-NMR(CDCl3, 100MHz): 37.0 (t, C-1), (29.9 t, C-2), 69.4 (d, C-3), 38.1 (t, C-4), 43.9 (d, C-5), 26.3 (t, C-6), 31.6 (t, C-7), 66.7 (s,C-8),51.0(d,C-9),38.6(s,C-10),68.5(d,C-11),74.9(d,C-12),45.5(s,C-13),71.2 (s,C-14),26.3(t,C-15),24.8(t,C-16),59.6(d,C-17),16.4(q,C-18),12.5(q,C-19), 210.8 (s, C-20), 29.9 (q, C-21), 167.1 (s, C-1 '), 128.4 (s, C-2 '), 137.9 (d, C-3 '), 14.3 (q, C-4 '), 11.8 (q, C-5 '), 170.6 (s, C-1 "), 20.3 (q, C-2 ")
POP 62, Tenacious Condorvine Stem glycosides H, white powder, LC-ESIMS:793 ([M-H]-).1H-NMR(CDCl3,400MHz): 0.81(3H,t,J=7.5Hz,H-4′),0.97(3H,d,J=5.5Hz,H-5′),0.98(3H,s,H-19),1.00(3H,s,H- 18), 1.24,1.30 (each 3H, d, J=6.0Hz, H-6of sugar structure fragment), 1.90 (3H, s, H-2 "), 2.13 (3H, s, H- 21), 2.86 (1H, br.d, J=7.4Hz, H-17 β), 3.33,3.60 (each 3H, s OMe-3of sugar structure fragment), 3.72 (1H, t,J=3.0Hz,Allo-H-3),4.52(1H,dd,J=9.8,1.8Hz,Ole-H-1),4.72(1H,d,J=8.3Hz,Allo-H- 1),4.91(1H,d,J=10.2,H-12α),5.28(1H,t,J=10.0Hz,H-11β),6.68(1H,qq,J=7.2,1.9Hz, H-3′).
POP 63, Tenacious Condorvine Stem glycosides I, white powder, LC-ESIMS:813 ([M-H]-).1H-NMR(CDCl3,400MHz): 1.06 (3H, s, H-19), 1.09 (3H, s, H-18), 1.20,1.27 (each 3H, d, J=6.0Hz, H-6of sugar structure fragment), 1.54 (3H, s, H-2 "), 2.15 (3H, s, H-21), 2.90 (1H, br.d, J=7.3Hz, H-17 β), 3.31,3.60 (each 3H, s OMe-3of sugar structure fragment), 3.73 (1H, t, J=3.0Hz, Allo-H-3), 4.50 (1H, dd, J=9.8,1.8Hz, Ole-H- 1),4.73(1H,d,J=8.2Hz,Allo-H-1),5.06(1H,d,J=10.2,H-12α),5.54(1H,t,J=10.2Hz,H- 11 β), 7.36 (2H, d, J=7.6Hz, H-4 ', 6 '), 7.50 (1H, d, J=7.2Hz, H-5 '), 7.90 (2H, d, J=8.0Hz, H- 3′,7′).
POP 65, Marsdenoside B, colourless powder, LC-ESIMS:855.4 ([M+Na]+).1H-NMR(CDCl3, 400MHz):1.67(6H,s,J=6.9Hz,Me-5′,Me-5″),1.06(s,Me-19),1.11(s,Me-18),1.25(d,J= 6.0Hz,Allo-Me-6),1.36(d,J=5.5Hz,Ole-Me-6),1.75(s,Me-5″),1.69(d,J=7.1Hz,Me- 4 '), 1.71 (d, J=7.1Hz, Me-4 "), 2.03 (1H, d, J=10.1Hz, H-9), 2.20 (s, Me-21), 2.92 (1H, br.d, J=7.1Hz,Hβ17),3.37(s,Ole-OMe),3.66(s,Allo-OMe),4.56(dd,J=9.6,1.6Hz,Ole-H-1), 4.79(1H,d,J=8.3Hz,Allo-H-1),5.05(1H,d,J=10.1Hz,Hα-12),5.46(1H,d,J=10.1Hz,Hβ- 11),6.66(1H,qq,J=7.0Hz,H-3″),6.79(1H,qq,J=6.0Hz,H-3″).
POP 66, Tenacious Condorvine Stem glycosides G, white powder, LC-ESIMS:791 ([M-H] -)1H-NMR(CDCl3,400MHz): 0.97 (3H, s, H-19), 1.02 (3H, s, H-18), 1.17,1.28 (each 3H, d, J=6Hz, H-6of sugar structure fragment), 1.67 (3H, d, J=6.6Hz, H-4 '), 1.68 (3H, s, H-5 '), 1.77 (3H, s, H-2 "), 2.10 (3H, s, H-21), 2.85 (1H, Br.d, J=7.3Hz, H-17 β), 3.11 (1H, m, H-3 α), 3.29,3.60 (each 3H, s OMe-3of sugar structure fragment), 3.70 (1H,t,J=3.0Hz,Allo-H-3),4.50(1H,dd,J=8.8,1.6Hz,Ole-H-1),4.71(1H,d,J=8.2Hz, Allo-H-1),4.92(1H,d,J=10.1,H-12α),5.32(1H,t,J=10.2Hz,H-11β),6.68(1H,qq,J=7.2, 1.9Hz,H-3′).
The test of 4 pharmaceutical activity of embodiment
1, chemicals and reagent
Valspodar (Valspodar, PSC833), Flutoxin C (fumitremorgin C, FTC) and human breast carcinoma Cell strain MK571 is purchased from National Cancer research center.Fetal calf serum, PBS, DMEM and RPMI1640 are purchased from Gibco Invitrogen(Carlsbad,California,USA).It is all to prepare solvent used in polyoxy pregnane class compound It is the pure standard of analysis, is provided by Shanghai Chemical Plant (Shanghai, China).Adriamycin (Doxorubicin, Dox), mitoxantrone (Mitoxantrone), Verapamil, Sulforhodamine B (sulforhodamine B, SRB) and other chemical reagent are purchased from Sigma-Aldrich(St Louis,MO,USA)。
2, cell line and cell culture
The medicine-resistant cell line that specified P-gp, MRP1 or ABCG2 is overexpressed is used to test polyoxy pregnane class compound Reverse multidrug drug resistance activity.SW620/Ad300 [Breedveld P, the et al.The effect of that P-gp is overexpressed Bcrp1(Abcg2)on the in vivo pharmacokinetics and brain penetration of imatinib mesylate(Gleevec):implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of MCF-7/VP that imatinib in patients.Cancer Res.2005,65,2577], MRP-1 is overexpressed [Janneh O, et al.Modulation of the intracellular accumulation of saquinavir in peripheral blood mononuclear cells by inhibitors of MRP1,MRP2,P-gp and BCRP.AIDS.2005,19,2097.] and ABCG2 be overexpressed MCF-7/FLV1000 [Seelig A.A general pattern for substrate recognition by P-glycoprotein.Eur.J.Biochem.1998,251, 252] it is purchased from National Cancer Institute.They are through its mother cell SW620 or MCF-7 respectively in the choosing for increasing concentration With in reagent by step by step selecting, the drug resistance subcellular system of generation, and be incubated at respectively containing 300 μM of adriamycins, 10 μM according to In the culture solution of support pool glycosides and 1000nM Flavopiridol (flavopiridol).Before use, mdr cell will be in no medicine It is cultivated in medium at least two weeks.These drug resistant tumour cells pass through medicament selection gradually, and only a kind of abc transport body was Expression.Moreover, fighting single transporter by specific inhibitor shows only one kind come the drug resistance of reversing drug Transporter contributes to the drug resistance performance of tumor models.SW620 and SW620/Ad300 is incubated at the tire ox containing 10% In the RPMI 1640 culture medium of serum.MCF-7, MCF-7/VP and MCF-7/FLV1000 are incubated at containing 10% fetal calf serum In DMEM culture solution.By respectively with the more drug resistant multiple of mother cell SW620 or MCF-7 of medicaments insensitive and examine P-gp, The expression of MRP1 or ABCG2, cells of resistant tumors SW620/Ad300, MCF-7/VP and MCF-7/FLV1000 are available Verifying.All cell culture are in 37 degree, containing 5% CO2In the incubator of saturated humidity.
3, cytotoxicity test
New polyoxy pregnane class compound is screened in high sensitive MCF-7 human breast cancer cell line.It is based on Four days cell toxicants test of Sulforhodamine B dyeing is [Leslie E.M, et that the method crossed using foregoing descriptions is carried out al.Structural requirements for functional interaction of glutathione tripeptide analogs with the human multidrug resistance protein 1(MRP1) .J.Pharmacol.Exp.Ther.2003,304,643.].Pass through Benchmark Plus Microplate Spectrophotometer (Bio-Rad, Hercules, CA, US) acquires signal.IC50 is by comparing dosing group and blank Obtained from the mean absorbance of control group.
Polyoxy pregnane class compound makes tumour cell to the drug bottom of three kinds of transporters (P-gp, MRP1 or ABCG2) The sensitive activity change of object be exist by comparing them and in the absence of the IC50 value of drug substrates assess, then with The reversal index factor is indicated with percentage is reduced.The reversal index factor=IC50 (antineoplastic does not add POP) ,/IC50 was (antitumor Medicine is combined POP).Reduction percentage=[{/IC50 is (in mdr cell only by IC50 (antineoplastic and POP combination in mdr cell) by 1- With antineoplastic) }] x100.If the reversal index factor and reduction percentage (maximum value=100) are higher, make the work of medicaments insensitive With stronger.PSC833(cyclosporine derivative), MRK571(emtricitabine) and FTC(fumitremorgin C), be known respectively Specific P-gp, MRP1 and ABCG2 inhibitor, they will reverse multidrug drug resistance experiment in be used as positive control.
4, statistical analysis
All experiments are all at least in triplicate.The statistical significance of difference is examined to evaluate by Student ' s t.Significantly The setting value of sex differernce is P < 0.05.
5, the multidrug resistance of polyoxy pregnane class compound reversing drug resistance tumour cell.
Human breast cancer cell line Bcap-37 is National Cancer center (Bethesda, MD, USA) research institute for tumour medicine One in three highly sensitive human tumor cell lines of object screening.Polyoxy pregnane class compound involved in the present invention rises Just screened using MCF-7.In the research of drug enhanced sensitivity, the maximum concentration of this kind of compound test is 10 μM, the pregnant steroid of polyoxy Alkyl compound is shown in Table 9 to the summary of sensitive and mdr cell reduction percentage.This kind of compound is in sensitive mother cell The SW620/Ad300 that SW620 and MCF-7 and P-gp is overexpressed；What the MCF-7/VP and ABCG2 that MRP1 is overexpressed were overexpressed Cytotoxic activity on MCF-7/FLV1000 is (the table 8A ~ C) obtained by SRB test.Blank control and positive control The activity of (PSC833, MK571, FTC), which has also arranged, to be come out to compare.
As can be seen from Table 8, compound POP 86, POP 87, POP 65 can be reversed by three kinds of abc transport body P- The tumor multidrug-resistance that gp, MRP1 and ABCG2 are mediated；Compound POP 53, POP 55 and POP 63 can be reversed The tumor multidrug-resistance mediated by P-gp and MRP1；Compound POP 52 and POP 88 and POP 56, PO P 62 The tumor multidrug-resistance mediated by P-gp can be reversed with POP 66.
Table 1: compound POP 52,73-77,86-88's13C H NMR spectroscopy data (100MHz, CDCl3)(δin ppm)
Ac: acetyl group;Bz: benzoyl;MBu:2- methylbutyryl;Tig: crotonyl
Table 2: sugared structure fragment in compound POP 73-77,86-8813C-NMR spectroscopy data (100MHz, CDCl3)(δ in ppm)
Ole: β-D- oleander pyranose;Allo:6- deoxidation -3- oxygen-methyl-β-D- A Luo pyranose;The Portugal-D- Glu: β Grape sugar
Table 3: sugared structure fragment in compound POP 73-771H-NMR spectroscopy data (400MHz, CDCl3)(δin ppm, Jin Hz)
Table 4: sugared structure fragment in compound POP 52,86-881H H NMR spectroscopy data (400MHz, CDCl3).(δ inppm,J in Hz)
Table 5: sugared structure fragment in compound POP 73-771H H NMR spectroscopy data (400MHz, CDCl3)(δin ppm,J inHz)
Table 6: sugared structure fragment in compound POP 86-881H H NMR spectroscopy data (400MHz, CDCl3)(δin ppm, Jin Hz)
Table 7: compound POP's 811H NMR(400MHz,CDCl3) and13C NMR(100MHz,CDCl3) data in (δ in ppm,J in Hz)
Table 9: polyoxy pregnane class compound is to sensitive and mdr cell reduction percentage (C=10 μM)

Claims (5)

1. the purposes for the polyoxy pregnane compound that a class formation is shown below, which is characterized in that be used to prepare for reversing Or inhibit the drug of tumor multidrug-resistance,
Wherein, the multidrug resistance is selected from the group: the multidrug resistance and ABCG2 transporter that MRP1 transporter is mediated are situated between The multidrug resistance led,
Wherein, S2ForS3ForRb is
Tig isMBu isBz isAc is
2. purposes as described in claim 1, which is characterized in that the multidrug resistance further includes that P-gp transporter is mediated Multidrug resistance.
3. purposes as described in claim 1, which is characterized in that the tumour cell refers to that colon cancer cell, breast cancer are thin Born of the same parents, liver cancer cells, lung carcinoma cell, stomach cancer cell, colorectal cancer cells, osteosarcoma cell or cervical cancer cell.
4. purposes as described in claim 1, which is characterized in that the polyoxy pregnane compound be selected from alkylating agents, purple China fir alkanes, antibiotics, anthracycline, camptothecin, for one of Buddhist nun's class, podophillotoxines and vinca drug or a variety of It is used in combination.
5. a kind of purposes of polyoxy pregnane compound that structure is shown below in medicine preparation, which is characterized in that described Drug is used to reverse or inhibits the Multidrug resistance mediated selected from one or both of MRP1 and ABCG2 transporter:
Wherein, S2ForRb isTig is MBu isAc is
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