CN100343271C - C27-steroid antitumour medicine - Google Patents

C27-steroid antitumour medicine Download PDF

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CN100343271C
CN100343271C CNB2005100308329A CN200510030832A CN100343271C CN 100343271 C CN100343271 C CN 100343271C CN B2005100308329 A CNB2005100308329 A CN B2005100308329A CN 200510030832 A CN200510030832 A CN 200510030832A CN 100343271 C CN100343271 C CN 100343271C
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oac
omom
ome
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silica
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CN1752095A (en
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田伟生
许启海
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention relates to antineoplastic compounds whose structural formula is on the right. The medicines of the present invention can be synthesized by a convenient synthetic method and is suitable for industrial production; intermediates in the process of synthesizing natural product can be fully utilized; in addition, a bioactivity test shows that the compounds have inhibitory activity on various tumour cells such as A-549, MCF-7, BEL-7402, P388, etc.; the present invention is a kind of antineoplastic medicine and can be used for preparing antineoplastic medicines for treating lung cancer, mammary cancer, liver cancer or leukemia.

Description

C 27-steroid antitumour medicine
Technical field
This patent relates to the anticancer usage of a class C27-steroidal compounds.Can utilize synthetic easily this compounds of chemical process, they demonstrate has antitumour activity, is a kind of antitumor drug.
Background technology
Steroidal compounds with 17-hydroxyl all has unique biological activity and pharmaceutical use, as marine natural product Cephalostatine (Cephalostatine) (referring to J.Chem.Soc., Chem., Commun, 1988,865; Ibid, 1988,1440), natural product OSW-1 (OSW-1) is (referring to Bioorg. ﹠amp; Med.Chem.Lett., 1997,7,633) and the inclined to one side promise saponin in Yunnan white powder and the Sichuan baiyao series product (referring to pharmaceutical analysis magazine, 1997,17,153; The pharmaceutical analysis magazine, 1991,11,90; China Medicine University's journal, 1989,20,251).
People such as Tian Weisheng utilize the diosgenin (Diosgenin) of high yield to synthesize pennogenin (Pennogenin) first; From sisalagenin (Tigogenin), adopt similar method, finished synthetic (CN 02150907.7) of the analogue dihydro pennogenin (Dihydropennogenin) of Pennogenin first.They also utilize the complete carbon skeleton of diosgenin to synthesize natural product OSW-1 (CN 02145066.8) first.
In above-mentioned building-up process, the contriver has obtained some and has had 17-hydroxyl or 16, the steroidal compounds intermediate of l7-epoxy, and the biological activity of these compounds seldom has bibliographical information (referring to Bioorg.﹠amp; Med.Chem.Lett., 1999,9,419).
Summary of the invention
The object of the invention provides the anticancer usage of a class C27-steroidal compounds.
The structural formula of C27-steroidal compounds of the present invention is as follows:
Figure C20051003083200041
R 1Be H, Me, MOM, Bn, THP, Ac, Ms, Ts, Bz, Piv, TMS, TES, TBS or TBDPS; R 2Be H:R 3Be H, OH, OMe, OMOM, OBn, OTHP, OAc, OMs, OTs, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; R 4Be H, OH, OMe, OMOM, OBn, OTHP, OAc, OMs, OTs, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS; Perhaps R 2And R 3Become 16, the 17-epoxy; Perhaps R 3And R 4Become carbonyl; R 5And R 6Be X (CH 2) nX; Perhaps R 5And R 6Become carbonyl; X is O or S, n=2 or 3; R 7Be H, OH, OMe, OMOM, OBn, OTHP, OAc, OMs, OTs, OBz, OPiv, OTMS, OTES, OTBS or OTBDPS;
Figure C20051003083200042
Be expressed as singly-bound or two key;
When
Figure C20051003083200043
Be two keys, R 7Be H, R 5And R 6Be O (CH 2) 2O, R 4Be OH, R 3Be H, R 2During for H, R 1Can not be H or Ac;
When Be two keys, R 7Be H, R 5And R 6Be O (CH 2) 2O, R 3And R 4Become carbonyl, R 2During for H, R 1Can not be Ac;
When
Figure C20051003083200045
Be singly-bound, R 7Be H, R 2During for H, R 1Can not be H or Ac;
Wherein, Me is a methyl, and MOM is a methoxyl methyl, and Bn is a benzyl, and THP is a THP trtrahydropyranyl, and Ac is an ethanoyl, and Ms is a methylsulfonyl.Ts is a p-toluenesulfonyl, and Bz is a benzoyl, and Piv is a pivaloyl group, and TMS is trimethyl silicon based, and TES is that triethyl is silica-based, and TBS is that tertiary butyl dimethyl is silica-based, and TBDPS is that tert-butyl diphenyl is silica-based.
In order to understand steroidal compounds of the present invention better, be example with the steroidal compounds of following structural formula:
Figure C20051003083200051
The synthetic method of C27-steroidal compounds of the present invention is referring to CN 02150907.7 and CN02145066.8.
The biological activity test result shows: this compounds is to tumour cell such as A-549 (human lung carcinoma cell line), MCF-7 (human breast cancer cell strain), BEL-7402 (human hepatoma cell strain) and P388 (mouse leukemia cell strain) etc., all has certain inhibition activity, be a kind of anti-tumor drug, can be used for preparation treatment lung cancer, mammary cancer, liver cancer or leukemic antitumor drug.
Medicine of the present invention can be used to prepare antitumor drug, and it can comprise of the present invention a kind of compound of the significant quantity that needs this treatment; Also can be the medicine box that is used for the treatment of anti-tumor drug, it comprises of the present invention a kind of compound for the treatment of significant quantity in one or more sterile chambers.
Medicine of the present invention is simple synthetic method not only, be fit to suitability for industrialized production, and help making full use of intermediate in the synthesis of natural product process, and biological activity test shows that this compounds has the activity of inhibition to tumour cell, be a kind of anti-tumor drug, can be used for preparation treatment lung cancer, mammary cancer, liver cancer or leukemic medicine.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Starting compound 4 that the present invention uses and compound 5 are by the method synthetic (CN 02150907.7 and CN 02145066.8) of patent.
Synthesizing of embodiment 1 compound 1
Figure C20051003083200061
522mg 4 is dissolved in 60ml ether and the 1ml pyridine, and-78 ℃ add 1.2eq OsO 4, rise to room temperature naturally, adding methylene chloride dissolves solid, and logical hydrogen sulfide decomposes osmate, filters, residue methylene dichloride thorough washing, filtrate is spin-dried for, and rapid column chromatography separates, and gets white solid compound 1 319mg (57.1%).
C 31H 50O 6；FW?518；
mp?191-192℃；
1H-NMR：5.37(1H，d，J＝4.8Hz，6-H)，4.61(1H，m，3-H)，4.28(1H，m，16-H)，4.04(1H，d，J＝3.9Hz，16-OH)，3.96(4H，m，OCH 2CH 2O)，3.10(1H，s，17-OH)，2.03(3H，s，OAc)，1.12(3H，d，J＝6.9Hz，21-Me)，1.01(3H，s，19-Me)，0.87?and?0.85(each?3H，d，J＝6.5Hz，26，27-Me)，0.78(3H，s，18-Me)；
MS(EI)：438(M +-18-18-44，1.6％)，382(M +-15-18-44-59，1.5％).
Synthesizing of embodiment 2 compounds 2
Figure C20051003083200062
-78 times, the 1ml dichloromethane solution of 0.2ml dimethyl sulfoxide (DMSO) (5.9eq.) is splashed into 0.2ml (COCl) 2In the 1ml dichloromethane solution (5.0eq.), behind the 15min, drip the 3ml dichloromethane solution of 246mg compound 1 (1.0eq.), reaction 20min drips 0.5ml Et again 3N (7.6eq.), reaction removes low temperature behind the 40min, rises to room temperature naturally and continues reaction 20min, and ethyl acetate is diluted, and organic phase is with saturated NaCl solution washing three times, MgSO 4Drying is filtered, the pressure reducing and steaming solvent, and placement is spent the night, column chromatography for separation (PE: EA=10: 1), get the white solid 148mg (66.0%) of compound 2.
C 31H 48O 6；FW?516；
mp?194-196℃；
[α] D 20＝-170°(C＝0.18，CHCl 3)；
1H-NMR：5.61(1H，s，17-OH)，5.38(1H，d，J＝5.7Hz，6-H)，4.63(1H，m，3-H)，2.03(3H，s，OAc)，1.15(3H，d，J＝7.5Hz，21-Me)，1.04(3H，s，19-Me)，0.92(6H，d，J＝6.0Hz，26，27-Me)，0.78(3H，s，18-Me)；
MS(EI)：472(M ++1，3.0％)，412(M +-60，24.2％)；
IR：3365，1730，1691，1251；
Ultimate analysis: calculated value (%): C 73.69 H 9.38
Measured value (%): C 73.44 H 9.27.
Synthesizing of embodiment 3 compounds 3
Figure C20051003083200071
917mg compound 5 is dissolved in the 40ml methylene dichloride, adds the 1.48g metachloroperbenzoic acid, room temperature reaction 2h adds the 30ml ethyl acetate in reaction solution, 2N NaOH washing, and saturated NaCl is washed till neutrality, MgSO 4Drying is filtered, and filtrate is spin-dried for, and rapid column chromatography separates, and gets white solid compound 3 944mg (99%).
C 31H 48O 6；FW?516；
1H-NMR：4.67(1H，m，3-H)，3.90(2H，m，26-H).3.14(1H，s，16H)，3.10(1H，q，J＝7.0Hz，20-H)，2.06(3H，s，OAc)，2.03(3H，s，OAc)，1.19(3H，d，J＝7.0Hz，21-Me)，0.93(3H，d，J＝6.7Hz，27-Me)，0.85(6H，s，18-Me?and?19-Me)；
13C-NMR：210.37，171.21，170.69，73.61，70.01，68.86，59.84，54.56，44.89，44.78，43.61，43.44，38.87，36.65，35.67，33.99，33.89，32.40，32.06，31.64，28.46，27.46，27.29，26.79，21.48，20.97，20.86，16.78，16.21，13.12，12.22；
MS(EI)：516(M +，2.1％)，498(M +-18，22.7％)，359(M +-157，100％)，；
IR：1732，1702；
Ultimate analysis: calculated value C%72.09 H%9.36
Measured value C%72.40 H%9.70.
Embodiment 4 biological activity test screening methods
Cell strain: A-549 screening method: sulphonyl rhodamine B (sulforhodamine B, SRB) protein staining method action time: 72h Cell strain: MCF-7 screening method: sulphonyl rhodamine B (sulforhodamine B, SRB) protein staining method action time: 72h
Cell strain: BEL-7402 screening method: sulphonyl rhodamine B (sulforhodamine B, SRB) protein staining method action time: 72h Cell strain: P388 screening method: tetrazolium (microcultore tetrozolium, MTT) reduction method action time: 48h
The physiologically active of embodiment 5 compounds 1
The test result of physiologically active is as shown in table 1:
The physiologically active of table 1. compound 1
The physiologically active of embodiment 6 compounds 2
The test result of physiologically active is as shown in table 2:
The physiologically active of table 2. compound 2
The physiologically active of embodiment 7 compounds 3
The test result of physiologically active is as shown in table 3:
The physiologically active of table 3. compound 3
Figure C20051003083200092

Claims (3)

1, a kind of antitumor medicine composition, it is an activeconstituents with the C27-steroidal compounds with following structural formula:
Figure C2005100308320002C1
R 1Be H, Me, MOM, Bn, THP, Ac, Bz, Piv, TMS, TES, TBS or TBDPS; R 2Be H; R 3For H, OH, OMe, OMOM or OAc; R 4Be H, OH, OMe, OMOM or OAc; Perhaps R 2And R 3Become 16, the 17-epoxy; Perhaps R 3And R 4Become carbonyl; R 5And R 6Be X (CH 2) nX; Perhaps R 5And R 6Become carbonyl; X is O or S, n=2 or 3; R 7Be H, OH, OMe, OMOM, OBn, OTHP, OAc, OBz, OTES, OTBS or OTBDPS;
Figure C2005100308320002C2
Be expressed as singly-bound or two key;
When Be two keys, R 7Be H, R 5And R 6Be O (CH 2) 2O, R 4Be OH, R 3Be H, R 2During for H, R 1Can not be H or Ac;
When
Figure C2005100308320002C4
Be two keys, R 7Be H, R 5And R 6Be O (CH 2) 2O, R 3And R 4Become carbonyl, R 2During for H, R 1Can not be Ac;
When
Figure C2005100308320002C5
Be singly-bound, R 7Be H, R 2During for H, R 1Can not be H or Ac;
Wherein, Me is a methyl, and MOM is a methoxyl methyl, and Bn is a benzyl; THP is a THP trtrahydropyranyl, and Ac is an ethanoyl, and Bz is a benzoyl, and Piv is a pivaloyl group; TMS is trimethyl silicon based, and TES is that triethyl is silica-based, and TBS is that tertiary butyl dimethyl is silica-based, and TBDPS is that tert-butyl diphenyl is silica-based.
2, a kind of composition as claimed in claim 1 is characterized in that in the application of preparation antitumor drug described tumour is lung cancer, mammary cancer, liver cancer or leukemia.
3, a kind of medicine box is characterized in that containing the composition as claimed in claim 1 of significant quantity.
CNB2005100308329A 2005-10-28 2005-10-28 C27-steroid antitumour medicine Expired - Fee Related CN100343271C (en)

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CN1416875A (en) * 2002-11-28 2003-05-14 中国科学院上海有机化学研究所 17-hydroxy C27 steroid compound and its synthesis and use

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CN1416875A (en) * 2002-11-28 2003-05-14 中国科学院上海有机化学研究所 17-hydroxy C27 steroid compound and its synthesis and use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Neighboring group participation in epoxide ring cleavage inreactions ofsome 16,17-oxidosteroids with lithium hydroperoxide Jacek W et al,Tetrahedron,Vol.57 2001 *
Some reactions of 16?17?-oxido-steroids: a study related tothe synthesis of the potent anti-tumor Saponin OSW-1aglycone Jacek W et al,Tetrahedron Letters,Vol.41 2000 *

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