WO2021110085A1 - 通过前列腺素含量来关联akr1c3酶表达水平及筛选给药用途 - Google Patents

通过前列腺素含量来关联akr1c3酶表达水平及筛选给药用途 Download PDF

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WO2021110085A1
WO2021110085A1 PCT/CN2020/133538 CN2020133538W WO2021110085A1 WO 2021110085 A1 WO2021110085 A1 WO 2021110085A1 CN 2020133538 W CN2020133538 W CN 2020133538W WO 2021110085 A1 WO2021110085 A1 WO 2021110085A1
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akr1c3
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biological sample
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PCT/CN2020/133538
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French (fr)
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段建新
谢燕彬
姬金凤
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深圳艾欣达伟医药科技有限公司
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Priority to BR112022010833A priority Critical patent/BR112022010833A2/pt
Priority to CN202080082295.5A priority patent/CN114746753A/zh
Priority to CA3163127A priority patent/CA3163127A1/en
Priority to EP20895544.3A priority patent/EP4071473A4/en
Priority to US17/781,206 priority patent/US20230017359A1/en
Priority to KR1020227022515A priority patent/KR20220107273A/ko
Priority to IL293468A priority patent/IL293468A/en
Priority to AU2020396113A priority patent/AU2020396113A1/en
Priority to JP2022532677A priority patent/JP2023505438A/ja
Publication of WO2021110085A1 publication Critical patent/WO2021110085A1/zh

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    • G—PHYSICS
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Definitions

  • the present invention relates to patent application PCT/US2016/021581, publication number WO2016145092A, corresponding to Chinese application number 2016800150788, publication number CN107530556A; corresponding to PCT application number PCT/US2016/062114, publication number WO2017087428A1, corresponding to Chinese application number 2016800446081, publication number CN108290911A; Corresponding to PCT application number PCT/US2016/025665, publication number WO2016/161342, corresponding to Chinese application number 2016800200132, publication number CN108136214A, the development of injections of the compounds disclosed belong to the field of research and development of cancer therapeutic compounds.
  • DNA alkylating agent corresponding to PCT application number PCT/US2016/021581, publication number WO2016/145092A, corresponding to Chinese application number 2016800150788, publication number CN107530556A;
  • Nitrobenzyl derivative anticancer reagent corresponding to PCT application number PCT/US2016/025665, publication number WO2016/161342, corresponding to Chinese application number 2016800200132, publication number CN108136214A
  • DNA alkylation cancer prodrug with aldehyde ketone reductase 1C3 (AKR1C3) as the target.
  • the prodrug form of compound A passes AKR1C3 in the biochemical environment of the cell.
  • One-electron reduction occurs under the catalysis of the enzyme to obtain intermediate B, which is also unstable and then further reduced under the action of the AKR1C3 enzyme to obtain three intermediates C, and these three intermediates C are still unstable and will occur 1,4 eliminate the reaction, and finally get And HL 1 -D, which has cytotoxicity, exerts a cancer cell toxic effect, as shown in Fig. 1:
  • Aldone reductase 1C3 (AKR1C3) is the target of DNA alkylation cancer prodrug metabolism schematic diagram, (above schematic diagram 1 Based on the following documents:
  • Literature 1 Kathryn Evans, JianXinDuan, Tara Pritchard, et al. OBI-3424, a novel AKR1C3-activated prodrug, exhibits potent efficiency against preclinical models of T-ALL[J], ClinicalCancerResearch, 2019/1078 -0432.CCR-19-0551;
  • Literature 2 Richard B. Lock, Kathryn Evans, Raymond Yung et al. Abstract LB-B16: The AKR1 C3-Activated Prodrug OBI-3424 Exerts Profound InVivo Effectiveness against Models of T-Cell T-Cell T-Cell Acute blast; Pediatric Preclinical Testing Consortium Study[C], AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutic s; October 26-30, 2017; Philadelphia, PA, DOI: 10.1158/1535-7163.
  • Literature 3 Jianxin Duan, Zhong Wang, Qing Li et al. Broad In Vitro and In VivoAntitumor Activity of TH-3424: Preclinical Rationale for a Highly SelectiveAKR1C3Prodrug for Treating Cancer, AACR, 2016 Annual 16Meeting 2016 ; New Jersey, LA)
  • the Chinese name is (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxy-4-nitrophenyl)-1-ethyl-N,N'-bis (Ethylene) phosphoramidate, also known as the S configuration compound of OBI-3424 and TH-2870), CAS number is 209713-69-2, and its structure is as follows:
  • the conventional detection method is to directly obtain the patient's tumor tissue section (Document 4: Christopher P.Guise, Maria R. Abbattista, Rachelle S. Singleton, et al, The Bioreductive Prodrug PR-104AIs Activated under Aerobic Conditions by HumanAldo-Keto3Reductase , Cancer Res, 70(4): 1573-1584; DOI: 10.1158/0008-5472.CAN-09-3237) and then perform immunohistochemical staining (IHC) for detection.
  • IHC immunohistochemical staining
  • tumor tissue slices cannot be obtained under certain occasions and conditions: some patients’ tumor tissue slices are lost and cannot or are inconvenient to obtain again (the tumor tissue slices of some patients are lost due to improper storage); some patients are lost due to cultural or cultural reasons. Concepts, religious habits and other reasons, unwilling to accept the slice sampling operation (according to different conditions, the patient’s body part is obtained by forceps, excision or puncture suction); patients with certain cancers or tumors cannot perform the slice operation.
  • the present invention provides a new detection method, which can be adapted to a variety of biological samples to detect the expression level of the associated AKR1C3.
  • Literature 8 Matsuura K, Shiraishi H, HaraA, et al. Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostag of land in D2 11-ketoreductase, Activity, Journal of Biochemistry, 1998 124(5):940-6.) It is known that the aldehyde-ketone reductase AKR1C3 plays an important catalytic role in the biochemical pathway of the conversion of prostaglandin H2/D2 to prostaglandin E2/F2 (prostaglandin F2 is also known as prostaglandin F2 ⁇ ). Specifically, Figure 2: AKR1C3's influence on prostaglandin metabolism is shown in a schematic diagram.
  • AKR1C3 plays a role in the conversion of prostaglandins, can the expression level of AKR1C3 be correlated with the changes in the content of prostaglandin F2 or prostaglandin H2/D2, the product of the conversion process? Specifically, whether there is the following correspondence:
  • the method for measuring the expression level of AKR1C3 enzyme is to measure the content of PGF2 ⁇ and/or PGD2 and/or PGH2 to correlate the level of AKR1C3 enzyme expression in the biological sample.
  • the expression level of AKR1C3 enzyme is generally evaluated using no expression (undetectable), low, medium, and high.
  • the IHC method is used for staining and then the staining is determined and graded according to the degree of staining: diffuse, all cells are It is judged as high expression when staining; moderately, most or many cells are judged as medium expression when staining; a small amount and only a few cells are judged as low expression when staining, and when no staining is observed, it is judged as negative and no expression.
  • the high and low can also be classified according to the percentage of the stained area of the sample after IHC dyeing to the overall area.
  • AKR1C3 enzyme performs a large number of sample statistics to generate the correlation between the content of PGF2 ⁇ and/or PGD2 and/or PGH2 in the population and the expression level of AKR1C3 enzyme (the expression level here is quantified by the percentage of the stained area after IHC staining to the overall area)
  • Formula that is, when a person's PGF2 ⁇ and/or PGD2 and/or PGH2 content is greater than the high value H, it can be directly determined as a high level of AKR1C3 enzyme expression within a certain confidence range; and when a person's PGF2 ⁇ and/or PGD2 And/or when the content of PGH2 is lower than the low value L, the AKR1C3 enzyme expression level can be directly determined to be low within a certain confidence range, and the remaining between the high value H and the low value L is judged as medium expression.
  • the level of AKR1C3 enzyme expression in the biological sample is high;
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the units in the six ranges of A1, B1, C1, A2, B2, and C2 are content units (mass/volume), which are pg/ml in human samples.
  • the minimum value in the A2 range is greater than or equal to the maximum value in the B2 range, and the minimum value in the B2 range is greater than or equal to the maximum value in the C2 range.
  • prostaglandin F2 in the roadmap 1/2/3 is the final product of the metabolic pathway
  • its content is directly related to AKR1C3
  • the metabolism of prostaglandin D2/H2 is also affected by other factors (if there are other Metabolic pathway)
  • the level of AKR1C3 expression is not the only factor that determines prostaglandin D2/H2
  • the method of measuring the content of prostaglandin F2 is the better method among the above three schemes.
  • this program further proposes a method of using drugs for interference: a method of measuring the expression level of AKR1C3 enzyme, measuring changes in the content of PGF2 ⁇ and/or PGD2 and/or PGH2 before and after the administration of the interference drug to correlate the expression level of AKR1C3 enzyme in the biological sample High and low.
  • the above method correlates the level of AKR1C3 enzyme expression by determining the changes in the levels of PGF2 ⁇ and/or PGD2 and/or PGH2 before and after the administration of the interfering drug. Similarly, a large number of sample statistics are performed to generate PGF2 ⁇ in the population before and after the administration of the same interfering drug.
  • And/or PGD2 and/or PGH2 content change and AKR1C3 enzyme expression level (here the expression level is quantified using the percentage of the stained area after IHC staining to the overall area), that is, when a person is applying a certain
  • the AKR1C3 enzyme expression level can be directly determined within a certain confidence range; and when a person has a PGF2 ⁇ before and after the administration of a certain interference drug And/or PGD2 and/or PGH2 content change is lower than the low value L, it can be directly determined as the AKR1C3 enzyme expression level is low within a certain confidence range, and the rest is located between the high value H and the low value L. It was judged as medium expression.
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the minimum value in the range of a1 ⁇ the maximum value in the range of b1 the minimum value in the range of b1 ⁇ the maximum value in the range of c1, namely
  • the minimum value in the a2 range is greater than or equal to the maximum value in the b2 range, and the minimum value in the b2 range is greater than or equal to the maximum value in the c2 range.
  • the expression level of AKR1C3 is not the only factor that determines prostaglandin D2/H2. Therefore, the method of measuring the change in the content of prostaglandin F2 before and after the administration of interfering drugs is the better method among the above three schemes.
  • the above method of using absolute changes for correlation may have a situation where the absolute value of the PGF2 ⁇ and/or PGD2 and/or PGH2 content changes in the statistical sample is large, so that a certain value in the statistical sample is away from the central value (high, medium, low).
  • the expression will each correspond to the problem of three central values) being too far, so the rate of change is introduced to overcome this problem.
  • the method of measuring the expression level of AKR1C3 enzyme measuring the change rate of the content of PGF2 ⁇ and/or PGD2 and/or PGH2 before and after the administration of interference drugs to correlate the level of AKR1C3 enzyme expression in the biological sample.
  • a population PGF2 ⁇ and/or PGD2 and/or PGH2 content change rate (defined as the percentage of content change to the content before drug administration) before and after administration of the same interference drug and AKR1C3 enzyme expression level (the expression level here is stained after IHC staining)
  • the percentage of the area above the total area to quantify the correlation formula that is, when a person before and after the administration of a certain interfering drug, the PGF2 ⁇ and/or PGD2 and/or PGH2 content change rate is greater than the high value H, that is, it can be directly Within the confidence range of AKR1C3, the expression level of AKR1C3 enzyme is considered to be high; and when a person's PGF2 ⁇ and/or PGD2 and/or PGH2 content change rate is lower than the low value L before and after the administration of a certain interfering drug, it can be directly within a certain confidence range
  • the AKR1C3 enzyme expression level is considered to be low,
  • association refers to:
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the minimum value in the range of ⁇ 1 ⁇ the maximum value in the range of ⁇ 1 the minimum value in the range of ⁇ 1 ⁇ the maximum value in the range of ⁇ 1
  • the expression level of AKR1C3 is not the only factor that determines prostaglandin D2/H2. Therefore, the method of measuring the change rate of prostaglandin F2 content before and after the administration of interfering drugs is the better method among the above three schemes.
  • the interfering drug is an AKR1C3 enzyme inhibitor or an AKR1C3 enzyme agonist.
  • AKR1C3 enzyme inhibitors include those disclosed in the following patent applications:
  • An agonist is a chemical substance that binds to and activates the receptor to produce a biological response. Agonists cause effects, antagonists block the effects of agonists, and inverse agonists cause the opposite effects of agonists.
  • the AKR1C3 enzyme inhibitor is Indomethacin.
  • R/S configuration isomer is a compound with AKR1C3 inhibitory activity that has been verified by experiments, and indomethacin is a drug that has been marketed.
  • the biological sample is preferably blood.
  • PGF2 ⁇ and/or PGD2 and/or PGH2 there are relatively mature methods for detecting the content of prostaglandins (PGF2 ⁇ and/or PGD2 and/or PGH2) in the blood.
  • PGF2 ⁇ and/or PGD2 and/or PGH2 there are commercial kits and related methods for the enzyme-linked immunoassay (ELISA) kits for detecting PGF2 ⁇ .
  • ELISA enzyme-linked immunoassay
  • the measurement method, the specific process includes the following operations:
  • Operation 1 Measure the content of PGF2a and/or PGD2 and/or PGH2 in living organisms or living organisms, living organisms and tissues.
  • Operation 2 administering interference drugs to the living body or living body biological organs or living body biological tissues.
  • interfering drugs here needs to be adjusted according to the situation: living organisms (animals or humans) are given by oral or injection (preferably oral, faster action) interfering drugs: AKR1C3 inhibitors or agonists; and for living organisms, both It can be instilled or injected. Living biological tissues can only be immersed in AKR1C3 inhibitor or agonist solution (including appropriate buffer components) for incubation reaction.
  • Operation 3 Measure the content of PGF2 ⁇ and/or PGD2 and/or PGH2 in the living body or living body biological organs, living body biological tissues after the administration of the interference drug.
  • Operation 4 Calculate the content change before and after the interference drug is administered, and the content change rate, and obtain the level of AKR1C3 enzyme expression in the biological sample according to the corresponding relationship.
  • Precancerous drugs Precancerous drugs.
  • AKR1C3 enzyme-activated anti-cancer prodrugs that is, compounds in the form of prodrugs, are catalyzed and activated by AKR1C3 enzymes in the biochemical environment of the cells to finally obtain cytotoxic toxins and exert cancer cell toxic effects, see below patent application:
  • PCT/NZ2019/050030 publication number WO2019190331, corresponding to the compound disclosed in Chinese application number 201980023423.6, publication number CN111918864A.
  • a method for screening and administering patients with cancer, tumors, or diseases caused by cancer, tumors or cell proliferative diseases After the above-mentioned method of measuring AKR1C3 enzyme expression level is used on the patient to obtain the level of AKR1C3 enzyme expression level, when the enzyme level is high , Give anti-cancer prodrugs activated by AKR1C3 enzyme.
  • a method for screening and administering patients with cancer, tumors, or diseases caused by cancer, tumors, or cell proliferative diseases After the above method of measuring AKR1C3 enzyme expression level is used on the patient, the level of AKR1C3 enzyme expression level is obtained, and the enzyme level is high or In the middle, an anti-cancer prodrug activated by the AKR1C3 enzyme was given.
  • the AKR1C3 enzyme-activated anticancer prodrug contains the compound of structural formula I:
  • X 10 is O, S, SO or SO 2 ;
  • X, Y and Z are each independently hydrogen, CN, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • R is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered hetero Ring, 5-15 membered heteroaryl, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • R 13 and R 14 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl Or ether, or R 13 and R 14 groups together with the nitrogen atom to which they are bonded form a 5-7 membered heterocyclic group;
  • T contains an amino phosphate alkylating agent, that is, T is -L-D, including the following six situations:
  • -D is -P(Z 1 )(Z 5 -X 5 -Y 5 ) n , Z 1 is O or S, Z 5 is N, S or O, X 5 is optionally substituted ethylene, Y 5 is Halogen atom or -OSO 2 -R 20 , R 20 is an optionally substituted hydrocarbon group, aryl group, cycloalkyl group, heterocyclic group or heteroaryl group, n is 1 or 2, L is selected from -O-, -S-, -OCOO-, -NR 6 CO-, -OCO-, -NR 6 SO 2 -, -OCONR 6 -, quaternary ammonium group, sulfonate group -OSO 2 -;
  • Z 1 is O or S, and Z 5 -X 5 -Y 5 is an aziridinyl-NCH 2 CH 2 moiety;
  • -L- is -O-
  • -D is -P(Z 1 )(Z 5 -X 5 -Y 5 ) n
  • Z 1 is O or S
  • Z 5 is N, S or O
  • X 5 is any substitution
  • the ethylene group, Y 5 is a halogen atom or -OSO 2 -R 20
  • R 20 is an optionally substituted hydrocarbyl, aryl, cycloalkyl, heterocyclic or heteroaryl group, and n is 1 or 2;
  • -L- is -O-, Z 1 is O or S, Z 5 -X 5 -Y 5 is an aziridinyl-NCH 2 CH 2 moiety;
  • -LD is -OP(Z 1 )(NR 30 CH 2 CH 2 Cl) 2 ,-OP(Z 1 )(NR 30 CH 2 CH 2 Br) 2 ,-OP(Z 1 )(NR 30 2 )(N (CH 2 CH 2 X 1 ) 2 ),-OP(Z 1 )(N(CH 2 ) 2 ) 2 , or -OP(Z 1 )(N(CH 2 CH 2 Cl) 2 ) 2 , where each Each R 30 is independently H, a C 1 -C 6 hydrocarbyl group or two R 30 groups and the connected N atom form a 5-7 membered heterocyclic ring, Z 1 is O or S, X 1 is Cl, Br Or -OSO 2 Me;
  • -LD is -OP(Z 1 )(NHCH 2 CH 2 Cl) 2 ,-OP(Z 1 )(NHCH 2 CH 2 Br) 2 ,-OP(Z 1 )(NH 2 )(N(CH 2 CH 2 X 1 ) 2 ), -OP(Z 1 )(N(CH 2 ) 2 ) 2 , or -OP(Z 1 )(N(CH 2 CH 2 Cl) 2 ) 2 , and X 1 is Cl, Br or -OSO 2 Me;
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, and ether groups are substituted or unsubstituted.
  • Substituents are halogen atoms, cyano or isocyano, thiocyano or isothiocyano, hydroxyl, mercapto, amine, oxime, hydrazone, OTs, OMs, C 1 -C 3 alkyl or substituted alkyl , C 1 -C 3 alkoxy or substituted alkoxy, C 2 -C 3 alkenyl or substituted alkenyl, C 2 -C 3 alkynyl or substituted alkynyl, C 3 -C 8 cycloalkyl or substituted ring Alkyl, aromatic ring, heterocyclic ring, heteroaromatic ring and condensed ring or substituted aromatic ring, heterocyclic ring, heteroaromatic ring and condensed ring, the mode of substitution is mono-substituted or gem-disubstituted, and the substituent is halogen atom, cyano or Isocyano, thiocyano
  • anti-cancer prodrug activated by the AKR1C3 enzyme contains compounds selected from the following structural formulas:
  • the AKR1C3 enzyme-activated anticancer prodrug contains the compound of structural formula II:
  • X 10 is O, S, SO or SO 2 ;
  • X, Y and Z are each independently hydrogen, CN, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • Each R is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 -15 membered heterocyclic ring, 5-15 membered heteroaryl group, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • R 13 and R 14 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl Or ether, or R 13 and R 14 together with the nitrogen atom to which they are bonded form a 5-7 membered heterocyclic group;
  • L 1 and D are as defined in the specification, and the specific definitions are as follows
  • L 1 is selected from:
  • R 40 and R 41 are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 Aryl, 4-15 membered heterocycle or 5-15 membered heteroaryl;
  • R 42 is a C 2 -C 3 alkylene or heteroalkylene substituted with 1-3 C 1 -C 6 alkyl groups as appropriate;
  • V(-) is any anion, preferably pharmaceutically acceptable Anion;
  • D is the part that makes D-OH an anti-cancer drug, where OH is an aliphatic hydroxyl or phenolic hydroxyl; in other words, D is the remaining group after the anti-cancer drug D-OH has removed the hydroxyl group;
  • L 1 is:
  • R 40 is as defined above, R 43 is hydrogen or forms a heterocyclic ring together with D, and the phenyl moiety is optionally substituted;
  • D is the part that makes D-NR 43 H an anti-cancer drug; in other words, D is the remaining group after the anti-cancer drug D-NR 43 H is removed from the amino group or amine;
  • L 1 is a bond, -OC(R 40 R 41 )-, -OC(R 40 R 41 )-NR 40 R 41 (+)-C(R 40 R 41 )-or
  • R 40 , R 41 and V are as defined above;
  • D is an anticancer drug containing a primary or secondary amine, wherein the primary or secondary amine is bonded to L 1 ;
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, and ether groups are substituted or unsubstituted.
  • Substituents are halogen atoms, cyano or isocyano, thiocyano or isothiocyano, hydroxyl, mercapto, amine, oxime, hydrazone, OTs, OMs, C 1 -C 3 alkyl or substituted alkyl , C 1 -C 3 alkoxy or substituted alkoxy, C 2 -C 3 alkenyl or substituted alkenyl, C 2 -C 3 alkynyl or substituted alkynyl, C 3 -C 8 cycloalkyl or substituted ring Alkyl, aromatic ring, heterocyclic ring, heteroaromatic ring and condensed ring or substituted aromatic ring, heterocyclic ring, heteroaromatic ring and condensed ring, the mode of substitution is mono-substituted or gem-disubstituted, and the substituent is halogen atom, cyano or Isocyano, thiocyano
  • D-OH is selected from the following anticancer drugs containing -OH group: gemcitabine gemcitabine, estramustine estramustine, prednimustine pudnimnstine, chlorozotocin chlorozotocin, ramustine ranimustine, mannomustine, Dibromomannitol mitobronitol, dibromodulcitol dibromodulcitol, arubicin alacinomycins, abramycin anthramycin, bleomycin bleomycin, carubicin carubicin, carzinophilin, chromomycin chromomycin, actinomycin Ddactinomycin, daunorubicin, mycophenolic acid, nogalamycin, nogalamycin, olivemycin olivomycin, peplomycin peplomycin, plicamycin, puromycin puromycin, streptomycin streptonigrin, Streptozocin, tubercidin tubercidin, ubenimex, zinostat
  • NR 43 H is selected from the following anticancer drugs: erlotinib, meturedepa, uredepa, imatinib, trimethylolomelamine, gefitinib, uracil mustard uracil mustard, carmustine carmustine, chlorozotocin, formustine fotemustine, nimustine nimustine, ramustine ranimustine, dacarbazine, mannomustine, actinomycin, Anthramycin, bleomycin bleomycin, actinomycin C cactinomycin, carrubicin carubicin, carzinophilin, actinomycin D dactinomycin, peplomycin peplomycin, puromycin puromycin, chain Streptozocin, ubenimex, zinostatin, denoterin denopterin, pteropterin, trimetrexate, 6-mercaptopurine, 6-mercaptopurine, thiamiprine, thioguanine , 6-
  • Anticancer drugs containing tertiary or secondary nitrogen atoms are selected from hexamethylmelamine altretamine, triethylenemelamine, chlorambuci, chlornaphazine, estramustine, gefitinib, mechlorethamine , Nitrogen mustard oxide hydrochloride, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine carmustine, chlorourea chlorozotocin, formustine fotemustine, nimustine, ramustine, ranimustine, dacarbazine, pipobroman, actinomycin, and anthramycin , Carzinophilin, actinomycin D dactinomycin, nogalamycin, pofiromycin porfiromycin, puromycin puromycin, streptozocin, tubercidin tubercidin, fludarabine, fludarabine,
  • AKR1C3 enzyme-activated anti-cancer prodrug contains compounds selected from the following structural formulas:
  • a component for measuring the expression level of AKR1C3 enzyme which includes a reaction measurement component and a control comparison component.
  • the reaction measuring component is a component that reacts when contacted with the biological sample, and quantitatively or semi-quantitatively correlates the content of PGF2 ⁇ and/or PGD2 and/or PGH2 in the biological sample according to the signal of the reaction.
  • Such components are similar to ELISA test well plates.
  • the ELISA test well plate contains reagents that can react with the target prostaglandin (F2 ⁇ /D2/H2) and a special color reagent, and the color of the reaction is quantified by a photometer.
  • test well plate The principle of the test well plate is similar to the ELISA kit sold in the market, and it is quantified by a microplate reader or a photometer.
  • the measurement component is also equipped with various auxiliary reagents: reaction solution, masking agent solution, washing buffer solution, reaction termination solution, etc.
  • Control comparison component used to compare reaction signals to control and compare the content of PGF2 ⁇ and/or PGD2 and/or PGH2 in the biological sample, the content change of PGF2 ⁇ and/or PGD2 and/or PGH2 before and after the administration of the interference drug or the administration interference
  • the level of AKR1C3 enzyme expression corresponding to the change rate of PGF2 ⁇ and/or PGD2 and/or PGH2 content before and after the drug.
  • the comparison component can be a table of the corresponding relationship between known concentration and absorbance: the user directly compares the different colors and corresponding absorbance on the test orifice with the comparison component to directly obtain the corresponding prostaglandin content level.
  • the level of AKR1C3 enzyme expression in the biological sample is high;
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the minimum value in the A1 range ⁇ the maximum value in the B1 range
  • the minimum value in the B1 range ⁇ the maximum value in the C1 range
  • the minimum value in the A2 range is greater than or equal to the maximum value in the B2 range, and the minimum value in the B2 range is greater than or equal to the maximum value in the C2 range.
  • the corresponding prostaglandin content level after the interfering drug is administered, and the two are calculated to obtain the content level difference (the content level difference corresponds to the content difference within a range, which is actually a semi-quantitative The content difference result) and the corresponding AKR1C3 enzyme expression level can be obtained according to the following correlation (association rule 2):
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the minimum value in the range of a1 ⁇ the maximum value in the range of b1 the minimum value in the range of b1 ⁇ the maximum value in the range of c1
  • the minimum value in the a2 range is greater than or equal to the maximum value in the b2 range, and the minimum value in the b2 range is greater than or equal to the maximum value in the c2 range.
  • This comparison component can be a correspondence table: the user takes the reaction and processed test well plate on the photometer or microplate reader to test the reading, and then according to the reading and the standard degree-content (concentration content, for humans (The unit is pg/ml concentration) curve to get the corresponding prostaglandin content in the sample.
  • the principle and operation similar to the above can be used to determine the level of AKR1C3 enzyme expression with a more accurate content change rate (association rule three):
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the level of AKR1C3 enzyme expression in the biological sample is medium;
  • the minimum value in the range of ⁇ 1 ⁇ the maximum value in the range of ⁇ 1 the minimum value in the range of ⁇ 1 ⁇ the maximum value in the range of ⁇ 1
  • the above is only measuring one of the prostaglandins.
  • the reaction measurement components of different formulations corresponding to PGF2 ⁇ , PGD2, PGH2 can quantitatively or semi-quantitatively determine the content of different prostaglandins, and then formulate different correspondence tables accordingly. Detecting the content of different prostaglandins, the content change before and after the interfering drug, and the content change rate will make the test component applicable to a wider range of people, and the test results will be more accurate and credible.
  • a drug delivery device which includes:
  • a drug delivery component which contains an anti-cancer prodrug activated by the AKR1C3 enzyme.
  • the drug delivery device is additionally formulated with a drug delivery component on the basis of the above-mentioned test component: it contains a drug delivery tool and a drug.
  • the drug delivery tool can be a syringe, and the corresponding drugs are powder for injection (lyophilized or aseptically packed) and diluted solution for injection; or the syringe and the drug can be designed as an integrated structure and injected directly into Medicine without other dilution and dissolution operations.
  • the drug delivery tool can be a needle-free syringe, and the corresponding drug is powder for injection (lyophilized or sterile), which is the so-called “needle-free injection system", which relies on compressed gas or explosion to push the powder through the skin Inject into the blood vessel.
  • Figure 1 is a schematic diagram of the metabolism principle of DNA alkylation cancer prodrugs with aldehyde ketone reductase 1C3 (AKR1C3) as the target;
  • Figure 2 is a schematic diagram of the effect of AKR1C3 on prostaglandin metabolism
  • Figure 3 is a schematic diagram of the effect of AKR1C3 inhibitors on prostaglandin metabolism
  • Figure 4 is a schematic diagram of the effect of AKR1C3 agonists on prostaglandin metabolism.
  • C x -C y or “C xy " before the group refers to the range of the number of carbon atoms present in the group.
  • C 1 -C 6 alkyl refers to an alkyl group having at least 1 and at most 6 carbon atoms.
  • Alkoxy refers to -O-alkyl.
  • Amino refers to NR p R q , where R p and R q are independently hydrogen or C 1 -C 6 alkyl, or R p and R q together with the nitrogen atom to which they are bonded form a 4-15 membered heterocyclic ring .
  • Aryl refers to an aromatic group having carbon atoms and no ring heteroatoms and having a single ring (for example, phenyl) or multiple condensed (fused) rings (for example, naphthyl or anthracenyl).
  • aryl Or “Ar” applies (for example, 5,6,7,8 tetrahydronaphthalen-2-yl is an aryl group because the point of attachment is at the 2 position of the aromatic phenyl ring).
  • the C 6 -C 10 aryl group may be phenyl, naphthyl, and various substituted phenyl or naphthyl groups.
  • Heteroaryl refers to an aromatic group having 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and includes a single ring (such as imidazole 2-yl and imidazol-5-yl) and polycyclic systems (e.g. imidazopyridyl, benzotriazolyl, benzimidazol-2-yl and benzimidazol-6-yl).
  • heteroaryl for example, 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl.
  • the nitrogen and/or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
  • heteroaryl or 5-15 membered heteroaryl includes (but is not limited to) acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophene Benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzoisothiazolyl, benzothienyl, benzene Bisimidazolinyl, carbazolyl, NH-carbazolyl, carboline, chromanyl, chromenyl, cinnolinyl, dithiazinyl , Furyl, furanyl, imidazolidinyl, imidazolinyl, imidazopyridyl, imidazolyl, indazolyl, indolenyl, indolinyl, indazinyl, indoly
  • Alkyl refers to a monovalent saturated aliphatic hydrocarbon group having carbon atoms and in some embodiments 1 to 6 carbon atoms.
  • C xy alkyl refers to an alkyl group having x to y carbon atoms.
  • This term includes (for example) straight chain and branched chain hydrocarbon groups, such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl Group ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), second butyl ((CH 3 )( CH 3 CH 2 )CH-), tertiary butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -) and neopentyl ((CH 3 ) 3 CCH 2 -).
  • straight chain and branched chain hydrocarbon groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl Group ((CH 3 ) 2 CH
  • Cycloalkyl refers to a saturated or partially saturated cyclic group having 3 or more carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5, 6, 7, 8-tetrahydronaphthalene-5-yl).
  • cycloalkyl or C 3 -C 8 cycloalkyl includes cycloalkenyl.
  • cycloalkyl or C 3 -C 8 cycloalkyl include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or moiety having carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen
  • Saturated cyclic groups include single rings and polycyclic ring systems including fused, bridged, and spiro ring systems.
  • heterocyclic ring or “heterocyclic ring” when there is at least one ring heteroatom and the point of attachment is at an atom of the non-aromatic ring
  • heterocycloalkyl or “heterocyclyl” is applicable (e.g. 1,2,3,4-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-6-yl and Decahydroquinolin-6-yl).
  • the heterocyclic group herein is a 3-15 membered, 4-14 membered, 5-13 membered, 7-12, or 5-7 membered heterocyclic ring.
  • the heterocyclic ring contains 4 heteroatoms. In some other embodiments, the heterocyclic ring contains 3 heteroatoms. In another embodiment, the heterocyclic ring contains up to 2 heteroatoms. In some embodiments, the nitrogen and/or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl, and sulfonyl moieties.
  • Heterocyclic groups include (but are not limited to) tetrahydropyranyl, hexahydropyridinyl, N-methylhexahydropyridin-3-yl, hexahydropyrazinyl, N-methylpyrrolidin-3-yl, 3 -Pyrrolidinyl, 2-pyrrolidone-1-yl, morpholinyl and pyrrolidinyl.
  • Prefix indicating the number of carbon atoms e.g., C 3 - 10 refers to the total number of carbon number outside the impurity atoms in the heterocyclyl moiety atoms.
  • the divalent heterocyclic group will have an appropriately adjusted hydrogen content.
  • “Ether” refers to 1 to 3 C 1 -C 6 alkoxy-substituted C 1 -C 6 alkyl. Alkoxy refers to -O-alkyl.
  • Halo and halogen refer to one or more of fluorine, chlorine, bromine and iodine.
  • C xy alkenyl refers to alkenyl having x to y carbon atoms and is intended to include, for example, vinyl, propenyl, 1,3-butadienyl, and the like.
  • Alkynyl refers to a straight-chain monovalent hydrocarbon group or a branched monovalent hydrocarbon group having 2 or more carbon atoms and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms and containing at least one triple bond.
  • alkynyl is also intended to include these hydrocarbon groups with one triple bond and one double bond.
  • C 2-6 alkynyl includes ethynyl, propynyl, and the like.
  • Amino phosphate alkylating agent refers to an alkylating agent comprising one or more moieties Z 5 -X 5 -Y 5 bonded to the -OP (Z1) moiety, where Z 5 is such as nitrogen, sulfur or oxygen And other heteroatoms, X 5 is optionally substituted ethylene, Y 5 is halo or another leaving group, or Z 5 -X 5 -Y 5 together form an aziridinyl (NCH 2 CH 2 ) moiety And Z 1 is as defined above.
  • This alkylating agent can react with DNA or another nucleic acid or protein. In some cases, alkylating agents can cross-link DNA.
  • a group may be substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents).
  • the substituent is selected from the group consisting of chlorine, fluorine, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -CO 2 H and its salts and C 1 -C 6 alkyl esters , CONMe 2 , CONHMe, CONH 2 , -SO 2 Me, -SO 2 NH 2 , -SO 2 NMe 2 , -SO 2 NHMe, -NHSO 2 Me, -NHSO 2 CF 3 , -NHSO 2 CH 2 Cl,- NH 2 , -OCF 3 , -CF 3 and -OCHF 2 .
  • Alkylene refers to a divalent saturated aliphatic hydrocarbon group having carbon atoms and in some embodiments 1 to 6 carbon atoms, and the alkyl group loses one more H atom.
  • Cuv alkylene refers to an alkylene group having u to v carbon atoms. Alkylene includes branched and straight chain hydrocarbon groups. For example, “C 1 -C 6 alkylene” includes methylene, ethylene, propylene, 2-methyl propylene, pentylene, and the like.
  • Heteroalkylene refers to an alkylene in which a chain carbon atom is replaced by a heteroatom such as O, S, N, or P, or a substituent containing a heteroatom.
  • the “drugs” of D in this article include (but are not limited to) gemcitabine, erlotinib, meturedepa, uredepa, altretamine , Imatinib, triethylenemelamine, trimethylmelamine, chlorambucil, chlornaphazine, estramustine, gefitinib , Mechlorethamine, nitrogen mustard oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide ), uracil mustard, carmustine, chlorozotocin, fotemustine, nimustine, ranimustine , dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, aclacinomycins, Actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carubicin, Carzinophilin, chromomycin, actinomycin,
  • administering or “administration” of a drug to a patient refers to direct administration or administration (which can be administered or administered to the patient by a medical professional or can be self-administered or administered) and/or indirect administration or administration, which may be the act of prescribing a drug.
  • direct administration or administration which can be administered or administered to the patient by a medical professional or can be self-administered or administered
  • indirect administration or administration which may be the act of prescribing a drug.
  • the physician instructing the patient to self-administer or administer the drug and/or provide the prescription of the drug to the patient is to administer or administer the drug to the patient.
  • Cancer refers to potentially unrestricted growth of leukemia, lymphoma, cancer, and other malignant tumors (including solid tumors) that can expand locally through invasion and expand systemically through metastasis.
  • malignant tumors including solid tumors
  • Examples of cancer include, but are not limited to, adrenal glands, bones, brain, breast, bronchus, colon and/or rectum, gallbladder, head and neck, kidney, larynx, liver, lung, nerve tissue, pancreas, prostate, parathyroid, Cancer of the skin, stomach and thyroid.
  • cancers include acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, poorly differentiated cervical epithelium and carcinoma in situ, Ewing’s sarcoma, epidermoid carcinoma, giant cell tumor, multiple Glioblastoma, hair cell tumor, enteric gangliocytoma, hyperplastic corneal nerve tumor, pancreatic islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemia, lymphoma, malignant carcinoid tumor, malignant melanoma , Malignant hypercalcemia, Mafang-like tumors, medullary epithelial carcinoma, metastatic skin cancer, mucosal neuroma, myeloma, fungous granuloma, neuroblastoma, osteosarcoma, osteogenic and other sarcomas, Ovarian tumor, pheochromocytoma, polycy
  • Patient and “individual” are used interchangeably and refer to mammals in need of cancer treatment. Usually, the patient is a human. Generally, the patient is a human being diagnosed with cancer. In certain embodiments, “patient” or “individual” may refer to non-human mammals for screening, characterizing, and evaluating drugs and therapies, such as non-human primates, dogs, cats, rabbits, pigs, mice Or rat.
  • Prodrug refers to a compound that is metabolized or otherwise converted into a compound (or drug) with at least one property of biological activity or higher activity after administration or administration.
  • prodrugs are chemically modified in such a way that they are less or inactive relative to the drug.
  • chemical modification allows the production of the corresponding drug through metabolism or other biological processes after the prodrug is administered.
  • Prodrugs can have altered metabolic stability or delivery characteristics, fewer side effects or lower toxicity, or improved flavors relative to the active drug (see (for example) Reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388 to 392, which are incorporated herein by reference).
  • Prodrugs can be synthesized using reactants other than the corresponding drugs.
  • the patient in this application refers to a patient with a disease or disease or complication related to the AKR1C3 enzyme and its corresponding gene, or, further, defined as a cancer, tumor or cancer, tumor corresponding to a cytotoxic prodrug activated by the AKR1C3 enzyme The resulting disease or cell proliferative disease.
  • Solid tumor refers to a solid tumor including (but not limited to) metastatic tumors in bone, brain, liver, lung, lymph nodes, pancreas, prostate, skin, and soft tissue (sarcoma).
  • the "therapeutically effective amount" of a drug refers to a drug that, when administered or administered to a patient suffering from cancer, will have the expected therapeutic effect (for example, alleviation, improvement, alleviation or elimination of the clinical manifestations of one or more cancers in the patient) ⁇ The amount.
  • the therapeutic effect does not have to occur through administration or administration of one dose, and may only occur after administration or administration of a series of doses. Therefore, the therapeutically effective amount can be administered or administered one or more times.
  • Treatment of a condition or patient refers to taking steps to obtain beneficial or desired results (including clinical results).
  • beneficial or desired clinical results include (but are not limited to) alleviation or improvement of one or more cancer symptoms; reduction of disease degree; delay or reduction of disease progression; improvement, alleviation or stabilization of disease state; Or other beneficial results.
  • the treatment of cancer can result in a partial response or stabilize the disease.
  • Tumor cells refer to tumor cells of any appropriate species (e.g., mammals, such as murine, dog, cat, horse, or human).
  • the AKR1C3 inhibitor mentioned in the invention has research literature (Higaki, Y, Usami, et al. Selective and potent inhibitors of human 20a-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone [J].
  • An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3(type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies.[J].BiochemicalPharmacology ,2008,75(2):484-493;Bauman,DRDevelopment of nonsteroidal anti-inflammatory drug analogs and steroid carboxylates selective for human aldo-ketoreductase isoforms:potential antineoplastic agents that work independent of cyclooxygenase [dependent].
  • Cinnamic acids as new inhibitors of 17beta-hydroxysteroid dehydrogenase type 5(AKR1C3).[J]. Molecular & Cellular Endocrinology, 2006,248(1-2):233-235; Yining Zhao, Xuehua Zheng, Hong Zhang, et al. Invitro inhibition of AKR1Cs by sulphonylureas and the str uctural basis.[J].Chemico-Biological Interactions,2015,240:310-315.) It was found that some drugs on the market have AKR1C3 inhibitory effect, and these drugs are also inhibitors of AKR1C3 enzyme:
  • Glycyrrhetinic acid Glycyrrhizinate glycyrrhizinic acid and its salts, glycosides, Ursodeoxycholic acid, medroxyprogesterone acetate (MPA), medroxyprogesterone acetate (MPA), Estradiol, Hexestrol, Diethylstilbestrol, Betamethasone, Cortisone Cortisone, Prednisone, Methylprednisolone, Triamcinolone, Hydrocortisone, Dexamethasone, Spironolactone, Brotizolam, Estazolam, Estazolam, Flunitrazepam, Flunitrazepam Azepam Flurazepam, Meclonazepan Meclonazepan, Lometazepam, Midazolam Midazolam, Nimetazepam, Nitrazepam, Temazepam, Temazepam, Triazolam, Alpra
  • the compound (that is, the racemic isomer of compound AST-3424, and its S configuration is AST-3424 ) It has AKR1C3 enzyme inhibitory activity test.
  • Negative control ( ⁇ L) Sample ( ⁇ L) PBS 68 58 NADPH (20mM) 10 10 AKR1C3(250 ⁇ g/mL) 10 10 AST-3424(250 ⁇ M) 0 10
  • Step 2 Pre-incubate the above mixture in duplicate at 37°C for 30 minutes and 60 minutes.
  • Step 3 Add another 10 ⁇ L of 20 mM NADPH PBS phosphate buffered saline solution and 2 ⁇ L of 250 ⁇ M progesterone 50% MeOH/H2O solution to each Eppendorf tube and mix gently.
  • Step 4 Immediately transfer 50 ⁇ L of the mixture in the above step to 100 ⁇ L of 1 ⁇ g/mL propranolol (propranolol, internal standard IS) 100% acetonitrile solution.
  • propranolol propranolol, internal standard IS
  • Step 5 Incubate the remaining samples at 37°C for 30 minutes, and add 100 ⁇ L of 1 ⁇ g/mL propranolol (propranolol, internal standard IS) 100% acetonitrile solution.
  • propranolol propranolol, internal standard IS
  • Step 6 For all samples, add 100 ⁇ L of reagent water, vortex at 1100 rpm for 5 minutes, and centrifuge at 15000 rpm for 10 minutes at room temperature.
  • Step 7 Load all samples on LC/MS to determine the content of reduced progesterone, namely 20 ⁇ -dihydroprogesterone.
  • test conditions of the LC-MS instrument are the test conditions of the LC-MS instrument.
  • Cone gas flow rate Cone Gas(L/h) 50 Desolvation Gas(L/h) 600 Ionization method (Interface Type) ES electron bombardment, Positive Analyzer Mode Sensitivity Scan Range (Scan Range) 50-800m/z
  • Step 9 Calculation of reduced progesterone (20 ⁇ -dihydroprogesterone): Determine the peak area of reduced progesterone, namely 20 ⁇ -dihydroprogesterone and propranolol in each sample by LC/MS. Calculate the peak area ratio of reduced progesterone to propranolol (that is, the ratio in the above table), and set the ratio when the time is 0 to 0%.
  • test value of indomethacin is 92.4% at a concentration of 5um/L.
  • AST-3424 The effect of AST-3424 on the production process of reduced progesterone: The above in vitro experiments confirmed that after 30 minutes and 60 minutes of pre-incubation, AST-3424 at a concentration of 25 ⁇ M/L basically inhibited the activity of AKR1C3: Compared with the negative control, The production of reduced progesterone, 20 ⁇ -dihydroprogesterone, was reduced to 3.9% and 9.2%, respectively, proving that the AST-3424 compound is an inhibitor of the AKR1C3 enzyme.
  • Prostaglandin F2 in serum samples was analyzed by conventional ELISA methods. The measurement results are as follows.
  • the absolute value/relative rate of change of prostaglandin F2a content in 3 cynomolgus monkeys without interfering drugs and 6 hours after administering the same amount of interfering drugs in the same intravenous injection The PGF2a of cynomolgus monkeys without interfering drugs is positively correlated: the change in blood prostaglandin F2a content of cynomolgus monkeys with high levels of prostaglandin F2a in the blood before interfering drugs is administered/ The rate of change is also the highest.
  • the level of AKR1C3 enzyme expression in the relevant biological sample that is, the level of AKR1C3 enzyme expression in patients can be directly obtained by measuring the prostaglandin content in the clinic, so as to screen cancer or tumor patients with appropriate AKR1C3 enzyme expression levels. For these patients The AKR1C3 enzyme-activated anticancer prodrug disclosed in the present invention is administered.

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Abstract

通过前列腺素含量来关联AKR1C3酶表达水平及筛选给药的用途，具体而言：测量前列腺素含量来关联生物试样中的AKR1C3酶表达水平的高低；测量施用干扰药物前后前列腺素的含量变化、含量变化率来关联生物试样中AKR1C3酶表达水平的高低。测量AKR1C3酶表达水平的组件，其包含：与生物试样接触发生反应，根据反应的信号来定量或半定量关联该生物试样中前列腺素含量的构件；对照比较构件，用于比较反应的信号来对照比较得出该生物试样中前列腺素的含量、施用干扰药物前后前列腺素的含量变化、含量变化率所对应的AKR1C3酶表达水平的高低。给药装置，其包含：测量AKR1C3酶表达水平的组件；给药组件，其含有AKR1C3酶活化的抗癌前药。

Description

通过前列腺素含量来关联AKR1C3酶表达水平及筛选给药用途 技术领域
本发明涉及对专利申请PCT/US2016/021581，公开号WO2016145092A，对应中国申请号2016800150788，公开号CN107530556A；对应PCT申请号PCT/US2016/062114,公开号WO2017087428A1，对应中国申请号2016800446081，公开号CN108290911A；对应PCT申请号PCT/US2016/025665，公开号WO2016/161342，对应中国申请号2016800200132，公开号CN108136214A所公开的化合物的注射液研发，属于癌症治疗化合物的制剂研发领域。
背景技术
我公司开发的以过表达醛酮还原酶1C3(AKR1C3)为标靶的DNA烷化癌症前药(参见专利申请：
DNA烷化剂，对应PCT申请号PCT/US2016/021581，公开号WO2016/145092A，对应中国申请号2016800150788，公开号CN107530556A；
(R)-及(S)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N’-双(伸乙基)胺基磷酸酯、组合物及其使用及制备方法，对应PCT申请号PCT/US2016/062114，公开号WO2017087428A1，对应中国申请号2016800446081，公开号CN108290911A中的S构型化合物；
硝基苄基衍生物抗癌试剂，对应PCT申请号PCT/US2016/025665，公开号WO2016/161342，对应中国申请号2016800200132，公开号CN108136214A)
是一种醛酮还原酶1C3(AKR1C3)为标靶的DNA烷化癌症前药，前药prodrug形式的化合物A(即本发明要求保护的通式化合物I)在细胞中的生化环境中通过AKR1C3酶的催化下发生单电子的还原，得到中间体B，其也不稳定随后在AKR1C3酶的作用下进一步被还原而得到三种中间体C，而这三个中间体C依然不稳定，会发生1，4消除反应，最终得到
Figure PCTCN2020133538-appb-000001
以及具有细胞毒性的H-L 1-D而发挥癌细胞毒杀作用，具体如图1：醛酮还原酶1C3(AKR1C3)为标靶的DNA烷化癌症前药代谢原理示意图所示，(以上原理图1根据以下文献绘制：
文献1：Kathryn Evans,JianXinDuan,Tara Pritchard,et al.OBI-3424,a novel AKR1C3-activ ated prodrug,exhibits potent efficacy against preclinical models of T-ALL[J]，ClinicalCancerRe search,2019,DOI:10.1158/1078-0432.CCR-19-0551；
文献2：Richard B.Lock,Kathryn Evans,Raymond Yung et al.Abstract LB-B16:The AKR1 C3-Activated Prodrug OBI-3424Exerts Profound InVivo Efficacy Against Preclinical Models of T-Cell Acute Lymphoblastic Leukemia(T-ALL)；a Pediatric Preclinical Testing Consortium St udy[C]，AACR-NCI-EORTC International Conference:Molecular Targetsand Cancer Therapeutic s；October 26-30,2017；Philadelphia,PA，DOI:10.1158/1535-7163.
文献3：Jianxin Duan，Zhong Wang，Qing Li et al.Broad In Vitro and In VivoAntitumorActivity of TH-3424:Preclinical Rationale for a Highly SelectiveAKR1C3Prodrug for Treating Cancer，AACR Annual Meeting 2016,Abstract#1369，April 16-20,2016；New Orleans，LA)
特别的，中文名为(S)-1-(3-(3-N,N-二甲氨基羰基)苯氧基-4-硝基苯基)-1-乙基-N,N'-双(亚乙基)氨基磷酸酯，也称为OBI-3424、TH-2870的S构型化合物)，CAS号为2097713-69-2，其结构如下：
Figure PCTCN2020133538-appb-000002
AST-3424的化学结构式
已分别在美国和中国进行一期临床试验。
根据文献3以及药物机理可知该药物只对AKR1C3有表达的患者有效，因此有必要对患者的AKR1C3的表达水平进行检测。
常规的检测方法是直接获取患者的肿瘤组织切片(文献4：Christopher P.Guise,Maria R.Abbattista,Rachelle S.Singleton,et al，The Bioreductive Prodrug PR-104AIs Activated under Aerobic Conditions by HumanAldo-Keto Reductase 1C3，Cancer Res，70(4)：1573-1584；DOI:10.1158/0008-5472.CAN-09-3237)然后进行免疫组织化学染色方法(IHC)进行检测。
然后在某些场合和条件下无法获取到肿瘤组织切片：某些患者肿瘤组织切片丢失而无法或不方便再次获取(某些患者的肿瘤组织切片保管不善而丢失)；某些患者出于文化或观念、宗教习惯等原因，不愿意接受切片采样操作(根据不同情况从患者身体部分采用钳取、切除或穿刺吸取等方法获取)；患有某些癌症或肿瘤的患者无法进行切片操作。
发明内容
本发明提供一种新的检测方法，其能适应多种生物样品来检测关联AKR1C3的表达水平高低。
研发团队构想，由于上述三个发明申请公开的化合物作为醛酮还原酶AKR1C3特异性底物(以下简称特异性底物)，其特异性的在醛酮还原酶AKR1C3的作用下被活化并代谢得到具有细胞毒性的烷化剂，也就是说，醛酮还原酶AKR1C3需要和特异性底物结合来发挥作用。
根据研究文献(文献5：Samad T A,Moore K A,Sapirstein A,et al.Interleukin-1[beta]-mediated induction of Cox-2in the CNS contributes to inflammatory pain hypersensitivity[J].Nature,2001,410(6827):471-5.；
文献6：Baojian Z,Yanbing Y,Gele A,et al.Tanshinone IIA Attenuates Diabetic Peripheral Neuropathic Pain in Experimental Rats via Inhibiting Inflammation[J].Evidence-Based Complementary andAlternative Medicine,2018,2018:1-8.；
文献7：Lovering A,Ride J,Bunce C,et al.Crystal Structures of Prostaglandin D2 11-Ketoreductase(AKR1C3)in Complex with the Nonsteroidal Anti-Inflammatory Drugs FlufenamicAcid and Indomethacin[J].Cancer Research,2004,64(5):1802-1810.；
文献8：Matsuura K,Shiraishi H,HaraA,et al.Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform(AKR1C3)that exhibits high prostaglandin D2 11-ketoreductase activity.[J].Journal of Biochemistry,1998,124(5):940-6.)可知醛酮还原酶AKR1C3在前列腺素H2/D2转化为前列腺素E2/F2(前列腺素F2又称为前列腺素F2α)的生化路径中扮演重要的催化作用，具体如图2：AKR1C3对前列腺素代谢的影响示意图所示。
发明人设想，由于AKR1C3在前列腺素的转化过程中起作用，那么是否可以用转化过程的产物前列腺素F2或是转化过程的反应物前列腺素H2/D2的含量变化来关联AKR1C3的表达水平呢？具体就是，是否存在如下的对应关系：
在施加AKR1C3的抑制剂或激动剂前后，毕竟对应的转化过程前后的产物前列腺素F2或是转化过程的反应物前列腺素H2/D2的含量变化，是否变化大就意味着AKR1C3的表达水平 高(具体如图3：AKR1C3抑制剂对前列腺素代谢的影响示意图所示)，是否变化小就意味着AKR1C3的表达水平低(具体如图4：AKR1C3激动剂对前列腺素代谢的影响示意图所示)？
经过动物体内实验可以证实上述想法具有合理性，实验结果经分析可以验证上述猜想和推理。
为此提供以下的技术方案。
方案一：测量AKR1C3酶表达水平的方法
测量AKR1C3酶表达水平的方法，测量PGF2α和/或PGD2和/或PGH2含量来关联生物试样中的AKR1C3酶表达水平的高低。
AKR1C3酶表达水平的高低一般使用无表达(检测不到)、低、中、高来进行评价，比如根据文献4中的表述使用IHC方法染色后根据染色程度进行判定分级：弥散，所有细胞均被染色时判定为高表达；适度，大部分或许多细胞被染色时判定为中等表达；少量，仅有少量细胞被染色时判定为低表达，而在观察不到染色时判定为阴性，无表达。
当然，高低也可以根据试样在经过IHC染色后被染上的面积占整体面积的百分比来进行高中低分级。
在本方案中，直接通过测量PGF2α和/或PGD2和/或PGH2含量高低来进行判断：
进行大量的样本统计，生成人群中PGF2α和/或PGD2和/或PGH2含量与AKR1C3酶表达水平(这里的表达水平使用经过IHC染色后被染上的面积占整体面积的百分比来进行定量)的相关式，即当某个人的PGF2α和/或PGD2和/或PGH2含量大于高值H时，即可以直接在一定的置信范围内认定为AKR1C3酶表达水平高；而当某个人的PGF2α和/或PGD2和/或PGH2含量低于低值L时，即可以直接在一定的置信范围内认定为AKR1C3酶表达水平低，而剩下的位于高值H和低值L之间的即判定为中等表达。
进一步，在上述方案中关联是指：
当PGF2α含量处于A1范围时，生物试样中的AKR1C3酶表达水平的高低程度为高；
当PGF2α含量处于B1范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGF2α含量处于C1范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
和/或
当PGD2和/或PGH2含量处于A2范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
当PGD2和/或PGH2含量处于B2范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGD2和/或PGH2含量处于C2范围时，生物试样中的AKR1C3酶表达水平的高低程度为高，
其中，A1范围中的最小值≥B1范围中的最大值，B1范围中的最小值≥C1范围中的最大值，即A1范围为(m，n)区间，B1范围为(p，q)区间，C1范围为(r，s)区间，则A1范围中的最小值n≥B1范围中的最大值p，B1范围中的最小值q≥C1范围中的最大值r。A1、B1、C1以及A2、B2、C2这六个范围的单位为含量单位(质量/体积)，在人体样本中为pg/ml。
A2范围中的最小值≥B2范围中的最大值，B2范围中的最小值≥C2范围中的最大值。
显然，使用上述直接判定的方法，最为迅速，而且便捷方便。
进一步的，考虑到路线图1/2/3中的前列腺素F2为代谢路径的最终产物，其含量高低与AKR1C3直接相关，而前列腺素D2/H2的代谢还受到其他因素的影响(如存在其他代谢路径)，因此AKR1C3表达水平的高低不是决定前列腺素D2/H2的唯一因素，因此测量前列腺素F2的含量的方法是上述3个方案中较优的方法。
由于需要分别确定6个范围：A1、B1、C1以及A2、B2、C2，而这六个范围是通过人群抽烟统计得到，因此有可能存在统计样本的结论未必能代表某个具体的受试者的问题：事实上， 不能排除某个样本刚好属于统计样本之外的情形，而且大量样本的统计和关联也是比较耗时和浪费资源的工作，更重要的是，由于种族、生活地域的不同将可能导致该方法的结果不够准确或是在适用人群较窄的问题。
为此，本方案进一步提出使用药物进行干扰的方法：测量AKR1C3酶表达水平的方法，测量施用干扰药物前后PGF2α和/或PGD2和/或PGH2的含量变化来关联生物试样中AKR1C3酶表达水平的高低。
上述方法通过求取施用干扰药物前后，PGF2α和/或PGD2和/或PGH2的含量变化来关联AKR1C3酶表达水平的高低，同样的，进行大量的样本统计，生成人群中施用同一种干扰药物前后PGF2α和/或PGD2和/或PGH2含量变化与AKR1C3酶表达水平(这里的表达水平使用经过IHC染色后被染上的面积占整体面积的百分比来进行定量)的相关式，即当某个人在施用某种干扰药物前后PGF2α和/或PGD2和/或PGH2含量变化大于高值H时，即可以直接在一定的置信范围内认定为AKR1C3酶表达水平高；而当某个人在施用某种干扰药物前后PGF2α和/或PGD2和/或PGH2含量变化低于低值L时，即可以直接在一定的置信范围内认定为AKR1C3酶表达水平低，而剩下的位于高值H和低值L之间的即判定为中等表达。
由于该方法，可以统计得到不同干扰药物(不同的AKR1C3抑制剂、不同的AKR1C3激动剂)的不同数据，从而相互印证，所以能在一定程度上减轻或是削弱种族、生活地域的不同的影响，更小的样本得到的结论可以适应更广的人群。
进一步，在上述方案中关联是指：
当PGF2α的含量变化处于a1范围时，生物试样中的AKR1C3酶表达水平的高低程度为高；
当PGF2α和/或PGD2和/或PGH2的含量变化处于b1范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGF2α和/或PGD2和/或PGH2的含量变化处于c1范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
和/或
当PGD2和/或PGH2的含量变化处于a2范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
当PGD2和/或PGH2的含量变化处于b2范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGD2和/或PGH2的含量变化处于c2范围时，生物试样中的AKR1C3酶表达水平的高低程度为高，
其中，a1范围中的最小值≥b1范围中的最大值，b1范围中的最小值≥c1范围中的最大值，即
a2范围中的最小值≥b2范围中的最大值，b2范围中的最小值≥c2范围中的最大值。
进一步的，考虑到路线图1/2/3中的前列腺素F2为代谢路径的最终产物，其含量高低与AKR1C3直接相关，而前列腺素D2/H2的代谢还受到其他因素的影响(如存在其他代谢路径)，因此AKR1C3表达水平的高低不是决定前列腺素D2/H2的唯一因素，因此测量施用干扰药物前后前列腺素F2的含量变化的方法是上述3个方案中较优的方法。
更进一步，上述使用绝对变化来进行关联的方法，有可能存在统计样本中PGF2α和/或PGD2和/或PGH2含量变化绝对值较大的情况，使得统计样本中某个值距离中心值(高中低表达会各对应三个中心值)过远的问题，因此引入变化率来克服这个问题。
测量AKR1C3酶表达水平的方法，测量施用干扰药物前后PGF2α和/或PGD2和/或PGH2的含量变化率来关联生物试样中AKR1C3酶表达水平的高低，同样的，进行大量的样本统计，生成人群中施用同一种干扰药物前后PGF2α和/或PGD2和/或PGH2含量变化率(定义为含量 变化与施用药物前的含量的百分比)与AKR1C3酶表达水平(这里的表达水平使用经过IHC染色后被染上的面积占整体面积的百分比来进行定量)的相关式，即当某个人在施用某种干扰药物前后PGF2α和/或PGD2和/或PGH2含量变化率大于高值H时，即可以直接在一定的置信范围内认定为AKR1C3酶表达水平高；而当某个人在施用某种干扰药物前后PGF2α和/或PGD2和/或PGH2含量变化率低于低值L时，即可以直接在一定的置信范围内认定为AKR1C3酶表达水平低，而剩下的位于高值H和低值L之间的即判定为中等表达。
由于该方法，可以统计得到不同干扰药物(不同的AKR1C3抑制剂、不同的AKR1C3激动剂)的不同数据，从而相互印证，而且引入了变化率的概念，一定程度上使得个体绝对的PGF2α和/或PGD2和/或PGH2含量的影响减弱，更突出了变化率这个与AKR1C3表达水平高低的关联关系，所以能更好地减轻、削弱种族、生活地域的不同的影响，样本统计分析得到的结论的适应人群更广，关联结果更准确。
更进一步，在上述方案中关联是指：
当PGF2α的含量变化率处于α1范围时，生物试样中的AKR1C3酶表达水平的高低程度为高；
当PGF2α的含量变化率处于β1范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGF2α的含量变化率处于γ1范围时，生物试样中的AKR1C3酶表达水平的高低程度为低，
和/或
当PGD2和/或PGH2的含量变化率处于α2范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
当PGD2和/或PGH2的含量变化率处于β2范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGD2和/或PGH2的含量变化率处于γ2范围时，生物试样中的AKR1C3酶表达水平的高低程度为高，
其中，α1范围中的最小值≥β1范围中的最大值，β1范围中的最小值≥γ1范围中的最大值，
α2范围中的最小值≥β2范围中的最大值，β2范围中的最小值≥γ2范围中的最大值。
进一步的，考虑到路线图1/2/3中的前列腺素F2为代谢路径的最终产物，其含量高低与AKR1C3直接相关，而前列腺素D2/H2的代谢还受到其他因素的影响(如存在其他代谢路径)，因此AKR1C3表达水平的高低不是决定前列腺素D2/H2的唯一因素，因此测量施用干扰药物前后前列腺素F2的含量变化率的方法是上述3个方案中较优的方法。
进一步的，干扰药物为AKR1C3酶抑制剂或AKR1C3酶激动剂。
已知的AKR1C3酶抑制剂包括如下专利申请中公开的抑制剂：
Figure PCTCN2020133538-appb-000003
Figure PCTCN2020133538-appb-000004
和吲哚美辛以及其他的中草药等，当然还包括TH-2870等。
Figure PCTCN2020133538-appb-000005
TH2870化学结构式
激动剂是一种与受体结合并激活受体以产生生物反应的化学物质。激动剂引起作用，而拮抗剂阻断激动剂的作用，而反向激动剂引起与激动剂相反的作用。
优选的，AKR1C3酶抑制剂为
Figure PCTCN2020133538-appb-000006
Figure PCTCN2020133538-appb-000007
吲哚美辛。
上述优选的化合物中，
Figure PCTCN2020133538-appb-000008
及其R/S构型异构体是经过试验验证的具有AKR1C3抑制活性的化合物，而吲哚美辛是已经上市销售的药物。
本领域技术人员可以根据情况选取不同形式的生物试样，包括血液或血清、组织或是皮肤或是肿瘤组织切片，根据不同的情况进行检测。相比较而言，由于血液容易获得，优选的，生物试样(生物样本)为血液。
从血液中检测前列腺素(PGF2α和/或PGD2和/或PGH2)的含量有比较成熟的方法，比如检测PGF2α的酶联免疫(ELISA)试剂盒就有商业试剂盒和相关方法。
测量方法，其具体过程包括以下操作：
操作一、测量生命体或活体生物器官、活体生物组织中的PGF2a和/或PGD2和/或PGH2含量。
显然，如果我们拥有与该测量生命体或活体生物器官、活体生物组织受试者对应的生活地域、种族匹配的可靠的(置信水平足够高)统计数据结论，通过操作一就可以根据对应的关联关系获得对应该生命体或器官、组织的AKR1C3表达水平。
如果没有适合的统计数据结论，需要进行以下的干扰操作：
操作二、对该生命体或活体生物器官、活体生物组织施用干扰药物。
这里的施用干扰药物需要根据情况不同做调整：生命体(动物或人)通过口服或是注射(优选口服，作用更快)给予干扰药物：AKR1C3抑制剂或激动剂；而对于活体生物器官则既可以进行灌输也可以进行注射，活体生物组织则只能将组织浸泡在AKR1C3抑制剂或激动剂的溶液(包含适当的缓冲成分)中进行孵育反应。
当然，不同的施用方法会有不同的最佳测量时间：一般而言，不同的生命体或是不同生命体的不同器官、不同组织的施用药物的量或是暴露时间浓度(对于进行浸泡孵育的组织)应进行实验探索，得到最佳的施用药物的量或是暴露时间以及施用后再次取样测试的时间。
操作三、测量施用干扰药物后生命体或活体生物器官、活体生物组织中的PGF2α和/或PGD2和/或PGH2含量。
显然，“施用干扰药物后”的具体时间需要进行实验探索，对于施用到生命体而言，这个具体时间与干扰药物的半衰期T 1/2有关。
操作四、计算施用干扰药物前后含量变化、含量变化率并根据对应关系得到生物试样中的AKR1C3酶表达水平的高低。
方案二：筛选并给药的方法
癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病患者筛选并给药的方法，在对患者使用上述测量AKR1C3酶表达水平的方法获知AKR1C3酶表达水平的高低后给予AKR1C3酶活化的抗癌前药。
在本发明中，AKR1C3酶活化的抗癌前药，即前药形式的化合物在细胞中的生化环境中通 过AKR1C3酶的催化激活最终得到具有细胞毒性的毒素而发挥癌细胞毒杀作用，参见以下专利申请：
PCT/US2016/021581，公开号WO2016145092A1，对应中国申请号2016800150788，公开号CN107530556A；
PCT/US2016/025665，公开号WO2016161342，对应中国申请号2016800446081，公开号CN108290911A；
PCT/US2016/062114，公开号WO2017087428，对应中国申请号2016800200132，公开号CN108136214A；以及
PCT/NZ2019/050030，公开号WO2019190331，对应中国申请号201980023423.6，公开号CN111918864A中公开的化合物。
上述专利申请公开的通式化合物、具体化合物均属于AKR1C3活化的抗癌前药(化合物)，在此将上述申请引用到本申请说明书中。
癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病患者筛选并给药的方法，在对患者使用上述测量AKR1C3酶表达水平的方法获知AKR1C3酶表达水平的高低后，在酶水平高时，给予AKR1C3酶活化的抗癌前药。
癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病患者筛选并给药的方法，在对患者使用上述测量AKR1C3酶表达水平的方法获知AKR1C3酶表达水平的高低后，在酶水平高或中时，给予AKR1C3酶活化的抗癌前药。
进一步，上述给药方法中，根据专利申请PCT/US2016/021581，公开号WO2016145092A1，对应中国申请号2016800150788，公开号CN107530556A公开的化合物，AKR1C3酶活化的抗癌前药含有的结构式I的化合物：
Figure PCTCN2020133538-appb-000009
其中，
X 10是O、S、SO或SO 2；
A是C 6-C 10芳基或取代芳基、5-15元杂芳基或取代杂芳基或-N＝CR 1R 2；其中，R 1和R 2各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
X、Y和Z各自独立地是氢、CN、卤基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
R是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
R 13和R 14各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基或醚，或者R 13和R 14基团与其所键结的氮原子一起形成5-7元杂环基；
T包含胺基磷酸酯烷化剂，即T为-L-D，包括以下六种情况：
-D为-P(Z 1)(Z 5-X 5-Y 5) n，Z 1为O或S，Z 5为N、S或O，X 5为任意取代的亚乙基,Y 5为卤素原子或-OSO 2-R 20,R 20为任意取代的烃基、芳基、环烷基、杂环基或杂芳基，n为1或2，L选自-O-、-S-、-OCOO-、-NR 6CO-、-OCO-、-NR 6SO 2-、-OCONR 6-、季铵根、磺酸酯基-OSO 2-；
或者
Z 1为O或S，Z 5-X 5-Y 5为吖丙啶基-NCH 2CH 2部分；
或者
-L-为-O-，-D为-P(Z 1)(Z 5-X 5-Y 5) n，Z 1为O或S，Z 5为N、S或O，X 5为任意取代的亚乙基,Y 5为卤素原子或-OSO 2-R 20,R 20为任意取代的烃基、芳基、环烷基、杂环基或杂芳基，n为1或2；
或者
-L-为-O-，Z 1为O或S，Z 5-X 5-Y 5为吖丙啶基-NCH 2CH 2部分；
或者
-L-D为-OP(Z 1)(NR 30CH 2CH 2Cl) 2,-OP(Z 1)(NR 30CH 2CH 2Br) 2,-OP(Z 1)(NR 30 2)(N(CH 2CH 2X 1) 2),-OP(Z 1)(N(CH 2) 2) 2,或-OP(Z 1)(N(CH 2CH 2Cl) 2) 2,其中，每个R 30各自独立的为H、C 1-C 6的烃基或两个R 30基团与连接的N原子形成5-7元的杂环，Z 1为O或S，X 1为Cl、Br或-OSO 2Me；
或者
-L-D为-OP(Z 1)(NHCH 2CH 2Cl) 2,-OP(Z 1)(NHCH 2CH 2Br) 2,-OP(Z 1)(NH 2)(N(CH 2CH 2X 1) 2),-OP(Z 1)(N(CH 2) 2) 2,或-OP(Z 1)(N(CH 2CH 2Cl) 2) 2，且X 1为Cl、Br或-OSO 2Me；
且烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基被取代或未取代。
取代基为卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 3烷基或取代烷基、C 1-C 3烷氧基或取代烷氧基、C 2-C 3烯基或取代烯基、C 2-C 3炔基或取代炔基、C 3-C 8环烷基或取代环烷基、芳环、杂环、杂芳环和稠环或取代芳环、杂环、杂芳环和稠环，取代的方式为单取代或偕二取代，取代基为卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs。
进一步，AKR1C3酶活化的抗癌前药含有化合物选自以下结构式：
Figure PCTCN2020133538-appb-000010
Figure PCTCN2020133538-appb-000011
Figure PCTCN2020133538-appb-000012
Figure PCTCN2020133538-appb-000013
Figure PCTCN2020133538-appb-000014
Figure PCTCN2020133538-appb-000015
Figure PCTCN2020133538-appb-000016
Figure PCTCN2020133538-appb-000017
Figure PCTCN2020133538-appb-000018
Figure PCTCN2020133538-appb-000019
及
Figure PCTCN2020133538-appb-000020
根据专利申请PCT/US2016/025665，公开号WO2016161342，对应中国申请号2016800446081，公开号CN108290911A，上述I结构式的化合物还包括：
Figure PCTCN2020133538-appb-000021
进一步，上述给药方法，根据专利申请PCT/US2016/062114，公开号WO2017087428，对应中国申请号2016800200132，公开号CN108136214A，AKR1C3酶活化的抗癌前药含有的结构式II的化合物：
Figure PCTCN2020133538-appb-000022
其中
X 10是O、S、SO或SO 2；
A是C 6-C 10芳基或取代芳基、5-15元杂芳基或取代杂芳基或-N＝CR 1R 2；其中，R 1和R 2各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
X、Y和Z各自独立地是氢、CN、卤基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
每个R独立地是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
R 13和R 14各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基或醚，或者R 13和R 14与其所键结的氮原子一起形成5-7元杂环基；
L 1和D如说明书中定义，具体定义如下
L 1选自：
Figure PCTCN2020133538-appb-000023
Figure PCTCN2020133538-appb-000024
其中，R 40和R 41独立地是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环或5-15元杂芳基；
R 42是视情况经1-3个C 1-C 6烷基取代的C 2-C 3伸烷基或伸杂烷基；V(-)为任何阴离子，较佳为医药学上可接受的阴离子；和
D是使得D-OH为抗癌药物的部分，其中OH为脂族羟基或酚羟基；换言之，D是抗癌药物D-OH脱去羟基后剩余的基团；
或者
L 1为：
Figure PCTCN2020133538-appb-000025
其中R 40如上文所定义，R 43为氢或与D一起形成杂环，且苯基部分视情况经取代；和
D是使得D-NR 43H为抗癌药物的部分；换言之，D是抗癌药物D-NR 43H脱去氨基或胺后剩余的基团；
或者
L 1是键、-O-C(R 40R 41)-、-O-C(R 40R 41)-NR 40R 41(+)-C(R 40R 41)-或
Figure PCTCN2020133538-appb-000026
其中R 40、R 41和V如上文所定义；和
D是含有伯胺或仲胺的抗癌药物，其中该伯胺或该仲胺键接至L 1；且
且烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基被取代或未取代。
取代基为卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 3烷基或取代烷基、C 1-C 3烷氧基或取代烷氧基、C 2-C 3烯基或取代烯基、C 2-C 3炔基或取代炔基、C 3-C 8环烷基或取代环烷基、芳环、杂环、杂芳环和稠环或取代芳环、杂环、杂芳环和稠环，取代的方式为单取代或偕二取代，取代基为卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs。
进一步，上述的给药方法，AKR1C3酶活化的抗癌前药含有的结构式II的化合物中，
D-OH选自以下含有-OH基团的抗癌药物：吉西他滨gemcitabine、雌莫司汀estramusting、泼尼莫司汀pudnimnstine、氯脲霉素chlorozotocin、雷莫司汀ranimustine、甘露莫司汀mannomustine、二溴甘露醇mitobronitol、二溴卫矛醇dibromodulcitol、阿柔比星aclacinomycins、安曲霉素anthramycin、博来霉素bleomycin、卡柔比星carubicin、嗜癌霉素carzinophilin、色霉素chromomycin、放线菌素Ddactinomycin、道诺霉素daunorubicin、霉酚酸mycophenolic acid、 诺加霉素nogalamycin、橄榄霉素olivomycin、培洛霉素peplomycin、普卡霉素plicamycin、嘌呤霉素puromycin、链黑霉素streptonigrin、链脲佐菌素streptozocin、杀结核菌素tubercidin、乌苯美司ubenimex、净司他丁zinostatin、左柔比星zorubicin、迪诺特宁denopterin、氟达拉宾fludarabine、安西他滨ancitabine、阿扎胞苷azacitidine、6-氮杂尿苷6-azauridine、阿糖胞苷cytarabine、双脱氧尿苷dideoxyuridine、脱氧氟尿苷doxifluridine、依诺他滨enocitabine、氟尿苷floxuridine、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、醋葡醛内酯aceglatone、依利醋铵elliptinium acetate、依托格鲁etoglucid、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、蘑菇多醣lentinan、米托蒽醌mitoxantrone、莫哌达醇mopidamol、喷司他丁pentostatin、吡柔比星pirarubicin、鬼臼酸podophyllinic acid、西索菲兰sizofiran、太平洋紫杉醇paclitaxel、替尼泊苷teniposide、细交链孢菌酮酸tenuazonic acid、长春碱vinblastine、长春新碱vincristine；
NR 43H选自以下的抗癌药物：埃罗替尼erlotinib、美妥替哌meturedepa、乌瑞替派uredepa、伊马替尼imatinib、三甲密胺trimethylolomelamine、吉非替尼gefitinib、尿嘧啶氮芥uracil mustard、卡莫司汀carmustine、氯脲菌素chlorozotocin、福莫司汀fotemustine、尼莫司汀nimustine、雷莫司汀ranimustine、达喀尔巴嗪dacarbazine、甘露氮芥mannomustine、放射菌素actinomycin、安曲霉素anthramycin、博莱霉素bleomycin、放线菌素C cactinomycin、卡柔比星carubicin、嗜癌菌素carzinophilin、放线菌素D dactinomycin、培洛霉素peplomycin、嘌呤霉素puromycin、链脲菌素streptozocin、乌苯美司ubenimex、净司他丁zinostatin、迪诺特宁denopterin、蝶罗呤pteropterin、曲美沙特trimetrexate、6-巯基嘌呤6-mercaptopurine、硫米嘌呤thiamiprine、硫鸟嘌呤thioguanine、6-氮杂尿苷6-azauridine、卡莫氟carmofur、双脱氧尿苷dideoxyuridine、脱氧氟尿苷doxifluridine、依诺他滨enocitabine、氟尿苷floxuridine、5-氟尿嘧啶5-fluorouracil、替加氟tegafur、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、安吖啶amsacrine、比生群bisantrene、地美可辛demecolcine、地吖醌diaziquone、依利醋铵elliptinium acetate、氟他胺flutamide、羟基尿素hydroxyurea、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、米托蒽醌mitoxantrone、二胺硝吖啶nitracrine、喷司他丁pentostatin、蛋胺氮芥phenamet、2-乙基酰肼2-ethylhydrazide、丙卡巴肼procarbazine、雷佐生razoxane、埃罗替尼erlotonib、尿烷urethane、长春碱vinblastine、长春新碱vincristine；
含有三级或二级氮原子的抗癌药物选自六甲蜜胺altretamine、曲他胺triethylenemelamine、苯丁酸氮芥chlorambuci、萘氮芥chlornaphazine、雌氮芥estramustine、吉非替尼gefitinib、氮芥mechlorethamine、氮芥氧化物盐酸盐mechlorethamine oxide hydrochloride、美法仑melphalan、新氮芥novembichin、芬司特瑞phenesterine、泼尼氮芥prednimustine、曲磷胺trofosfamide、尿嘧啶氮芥uracil mustard、卡莫司汀carmustine、氯脲菌素chlorozotocin、福莫司汀fotemustine、尼莫司汀nimustine、雷莫司汀ranimustine、达喀尔巴嗪dacarbazine、哌泊溴烷pipobroman、放线菌素actinomycin、安曲霉素anthramycin、嗜癌菌素carzinophilin、放线菌素D dactinomycin、诺加霉素nogalamycin、泊非罗霉素porfiromycin、嘌呤霉素puromycin、链脲菌素streptozocin、杀结核菌素tubercidin、氟达拉宾fludarabine、安西他滨ancitabine、阿扎胞苷azacitidine、阿糖胞苷cytarabine、双脱氧尿苷dideoxyuridine、依诺他滨enocitabine、氟尿苷floxuridine、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、醛磷酰胺糖苷aldophosphamide glycoside、贝斯布西bestrabucil,地吖醌diaziquone、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、丙脒腙mitoguazone、莫哌达醇mopidamol、二胺硝吖啶nitracrine、喷司他丁pentostatin、蛋胺氮芥phenamet、雷佐生razoxane、锗螺胺spirogermanium、他莫昔芬tamoxifen、三亚胺醌triaziquone、2,2',2"-三氯三乙胺2,2',2"-trichlorotriethylamine、长春碱vinblastine、长春新碱vincristine。
进一步的，AKR1C3酶活化的抗癌前药(结构式II)含有化合物选自以下结构式：
Figure PCTCN2020133538-appb-000027
方案三：测量AKR1C3酶表达水平的组件
测量AKR1C3酶表达水平的组件，其包含反应测量构件和对照比较构件。
反应测量构件，与生物试样接触发生反应，根据反应的信号来定量或半定量关联该生物试样中PGF2α和/或PGD2和/或PGH2含量的构件。
该类构件类似于ELISA测试孔板。
ELISA测试孔板中含有能与目标前列腺素(F2α/D2/H2)反应的试剂以及特殊的显色剂，通过反应颜色的深浅通过光度计进行定量。
测试孔板的原理与市场销售的ELISA试剂盒类似，通过酶标仪或光度计度数来进行定量。
显然，为了使得反应测量构件能准确、不受干扰的与目标前列腺素反应，在测量组件中还配有相应的各种辅助试剂：反应溶液，掩蔽剂溶液、冲洗缓冲溶液，反应终止溶液等。
对照比较构件，用于比较反应的信号来对照比较得出生物试样中PGF2α和/或PGD2和/或PGH2的含量、施用干扰药物前后PGF2α和/或PGD2和/或PGH2的含量变化或施用干扰药物前后PGF2α和/或PGD2和/或PGH2的含量变化率所对应的AKR1C3酶表达水平的高低。
这个对照比较构件可以是一已知浓度和吸光度对应关系表：使用者直接根据测试孔板上的不同颜色及相应吸光度与对照比较构件进行对比，直接得出其对应的前列腺素含量等级。
得到含量等级后可以直接得到对应的AKR1C3酶表达水平(关联规则一)：
当PGF2α含量处于A1范围时，生物试样中的AKR1C3酶表达水平的高低程度为高；
当PGF2α含量处于B1范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGF2α含量处于C1范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
和/或
当PGD2和/或PGH2含量处于A2范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
当PGD2和/或PGH2含量处于B2范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGD2和/或PGH2含量处于C2范围时，生物试样中的AKR1C3酶表达水平的高低程度为高，
其中，A1范围中的最小值≥B1范围中的最大值，B1范围中的最小值≥C1范围中的最大值，
A2范围中的最小值≥B2范围中的最大值，B2范围中的最小值≥C2范围中的最大值。
或者在施用干扰药物后，得到施用干扰药物后的对应的前列腺素含量等级，两者进行运算得到含量等级差值(含量等级差对应的是一个范围内的含量差，实际上是得到了半定量的含量差结果)并根据以下关联关系即可以得到对应的AKR1C3酶表达水平(关联规则二)：
当PGF2α的含量变化处于a1范围时，生物试样中的AKR1C3酶表达水平的高低程度为高；
当PGF2α和/或PGD2和/或PGH2的含量变化处于b1范围时，生物试样中的AKR1C3酶表 达水平的高低程度为中；
当PGF2α和/或PGD2和/或PGH2的含量变化处于c1范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
和/或
当PGD2和/或PGH2的含量变化处于a2范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
当PGD2和/或PGH2的含量变化处于b2范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGD2和/或PGH2的含量变化处于c2范围时，生物试样中的AKR1C3酶表达水平的高低程度为高，
其中，a1范围中的最小值≥b1范围中的最大值，b1范围中的最小值≥c1范围中的最大值，
a2范围中的最小值≥b2范围中的最大值，b2范围中的最小值≥c2范围中的最大值。
这个对照比较构件可以是对应关系表：使用者将反应完并进过处理后的测试孔板在光度计或酶标仪上进行测试读数，然后根据读数与标准度数-含量(浓度含量，对于人而言单位为pg/ml浓度)曲线得到试样中对应的前列腺素含量。与上述类似的原理和操作，可以使用更精确的含量变化率进行AKR1C3酶表达水平的高低程度的判定(关联规则三)：
当PGF2α的含量变化率处于α1范围时，生物试样中的AKR1C3酶表达水平的高低程度为高；
当PGF2α的含量变化率处于β1范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGF2α的含量变化率处于γ1范围时，生物试样中的AKR1C3酶表达水平的高低程度为低，
和/或
当PGD2和/或PGH2的含量变化率处于α2范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
当和/或PGD2和/或PGH2的含量变化率处于β2范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
当PGD2和/或PGH2的含量变化率处于γ2范围时，生物试样中的AKR1C3酶表达水平的高低程度为高，
其中，α1范围中的最小值≥β1范围中的最大值，β1范围中的最小值≥γ1范围中的最大值，
α2范围中的最小值≥β2范围中的最大值，β2范围中的最小值≥γ2范围中的最大值。
本领域技术知晓，虽然上述只是以含量等级为进行了说明，但对于测试孔板使用光度计或是酶标仪直接进行读数得到对应的前列腺素含量进而使用关联规则一或规则二进行判定也是可行的，或者根据含量变化值、含量变化率使用规则二或三也是可行的，以上的说明并不得限定为某种对应限制。
显然以上只是测量前列腺素中的某一种，实际上使用与PGF2α、PGD2、PGH2相对应的不同配方的反应测量构件可以定量或半定量测定不同的前列腺素含量，然后对应制定不同的对应关系表，分别测得不同前列腺素的含量、施用干扰药物前后的含量变化、含量变化率将使得该测试构件的适用人群更广泛，测试结果更准确、更可信。
方案四：给药装置
给药装置，其包含：
上述的测量AKR1C3酶表达水平的组件；
给药组件，其含有AKR1C3酶活化的抗癌前药。
显然，该给药装置就是在上述的测试组件的基础上另外配制了给药组件：包含给药工具以及药物。
举例而言，给药工具可以是注射器，对应的药物则为注射用粉末(冻干或无菌分装)和注射用稀释溶液；或直接将注射器和药物设计为一体结构，使用时直接注射给药而无需进行其他稀释溶解操作。
给药工具可以是无针注射器，对应的药物则为注射用粉末(冻干或无菌分装)，即为所谓的“无针注射系统”，其依靠压缩气体或是爆炸推动将药粉通过皮肤注入血管内。
附图说明
图1为醛酮还原酶1C3(AKR1C3)为标靶的DNA烷化癌症前药代谢原理示意图；
图2为AKR1C3对前列腺素代谢的影响示意图；
图3为AKR1C3抑制剂对前列腺素代谢的影响示意图；
图4为AKR1C3激动剂对前列腺素代谢的影响示意图。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。
提供以下定义以帮助阅读者。除非另有定义，否则本文所用的所有业内术语、符号及其他科学或医学术语或术语学均意欲具有熟习化学及医学领域的技术者通常所了解的含义。在一些情形下，为清楚和/或供及时参考，具有通常所了解含义的术语定义于本文中，且本文中此等定义的纳入不应解释为表示与如业内通常所了解的术语的定义有实质差异。
所有数值指定(例如pH、温度、时间、浓度及重量)(包括其中每一者的范围)通常可为适当以0.1、1.0或10.0的增量改变(+)或(-)的近似值。所有数值指定均可理解为前面有术语“约”。本文试剂为实例性的且此等的同等物可为业内所已知。
基团前的“C x-C y”或“C x-y”是指存在于该基团中的碳原子数目的范围。举例而言，C 1-C 6烷基是指具有至少1个且最多6个碳原子的烷基。
“烷氧基”是指-O-烷基。“胺基”是指NR pR q，其中R p及R q独立是氢或C 1-C 6烷基，或R p及R q与其所键结的氮原子一起形成4-15元杂环。
“芳基”是指具有碳原子且不含环杂原子且具有单环(例如，苯基)或多个缩合(稠合)环(例如，萘基或蒽基)的芳香族基团。对于包括不具有环杂原子之具有芳香族环及非芳香族环之稠合、桥连及螺环系统之多环系统而言，当附接点位于芳香族碳原子处时，术语“芳基”或“Ar”适用(例如，5,6,7,8四氢萘-2-基是芳基，此乃因其附接点是位于芳香族苯基环的2位处)。
根据本申请的具体实施方式，C 6-C 10芳基可以是苯基、萘基及各种取代的苯基或萘基。
“杂芳基”(杂环芳基)是指具有1至14个碳原子及1至6个选自由氧、氮及硫组成的群的杂原子的芳香族基团且包括单环(例如咪唑基-2-基及咪唑-5-基)及多环系统(例如咪唑并吡啶基、苯并三唑基、苯并咪唑-2-基及苯并咪唑-6-基)。对于包括具有芳香族及非芳香族环的稠合、桥连及螺环系统的多环系统而言，若存在至少一个环杂原子且附接点是位于芳香族环的原子处，则应用术语“杂芳基”(例如1,2,3,4-四氢喹啉-6-基及5,6,7,8-四氢喹啉-3-基)。在一些实施例中，杂芳基的氮和/或硫环原子视情况经氧化以提供N-氧化物(N→O)、亚磺酰基或磺酰基部分。术语杂芳基或5-15元杂芳基包括(但不限于)吖啶基、吖辛因基(azocinyl)、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基(benzothiophenyl)、苯并恶唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、 苯并异噻唑基、苯并噻吩基(benzothienyl)、苯并咪唑啉基、咔唑基、NH-咔唑基、咔啉基、苯并二氢吡喃基(chromanyl)、苯并吡喃基(chromenyl)、噌啉基(cinnolinyl)、二噻嗪基、呋喃基、呋呫基、咪唑啶基、咪唑啉基、咪唑并吡啶基、咪唑基、吲唑基、二氢吲哚基(indolenyl)、吲哚啉基、吲嗪基、吲哚基、异苯并呋喃基、异苯并二氢吡喃基(isochromanyl)、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基(isoquinolinyl)、异喹啉基(isoquinolyl)、异噻唑基、异恶唑基、萘啶基、八氢异喹啉基、恶二唑基、恶唑啶基、恶唑基、嘧啶基、啡啶基、啡啉基、吩嗪基、吩噻嗪基、吩恶噻基、吩恶嗪基、酞嗪基、六氢吡嗪基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑啶基、吡唑啉基、吡唑基、唑嗪基、吡啶并恶唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喏啉基、奎宁环基、四氢异喹啉基、四氢喹啉基、四唑基、噻二嗪基、噻二唑基、噻蒽基、噻唑基、噻吩基(thienyl)、噻吩并噻唑基、噻吩并恶唑基、噻吩并咪唑基、噻吩基(thiophenyl)、三嗪基及呫吨基。
“烷基”是指具有碳原子且在一些实施例中具有1至6个碳原子的单价饱和脂肪族烃基。“C x-y烷基”是指具有x至y个碳原子的烷基。此术语包括(举例而言)直链及具支链烃基，例如甲基(CH 3-)、乙基(CH 3CH 2-)、正丙基(CH 3CH 2CH 2-)、异丙基((CH 3) 2CH-)、正丁基(CH 3CH 2CH 2CH 2-)、异丁基((CH 3) 2CHCH 2-)、第二丁基((CH 3)(CH 3CH 2)CH-)、第三丁基((CH 3) 3C-)、正戊基(CH 3CH 2CH 2CH 2CH 2-)及新戊基((CH 3) 3CCH 2-)。
“环烷基”是指具有3个以上碳原子且没有环杂原子且具有单环或包括稠合、桥连及螺环系统的多环的饱和或部分饱和环状基团。对于不具有环杂原子的具有芳香族及非芳香族环的多环系统而言，当附接点是位于非芳香族碳原子处时，术语“环烷基”适用(例如5,6,7,8-四氢萘-5-基)。术语“环烷基”或C 3-C 8环烷基包括环烯基。环烷基或C 3-C 8环烷基的实例包括(例如)金刚烷基、环丙基、环丁基、环戊基、环辛基及环己烯基。
“杂环状”或“杂环”或“杂环烷基”或“杂环基”是指具有碳原子及1至6个选自由氮、硫或氧组成的群的杂原子的饱和或部分饱和环状基团且包括单环及包括稠合、桥连及螺环系统的多环系统。对于具有芳香族及/或非芳香族环的多环系统而言，当存在至少一个环杂原子且附接点是位于非芳香族环的原子处时，术语“杂环状”或“杂环”或“杂环烷基”或“杂环基”适用(例如1,2,3,4-四氢喹啉-3-基、5,6,7,8-四氢喹啉-6-基及十氢喹啉-6-基)。在一些实施例中，此处杂环基是3-15元、4-14元、5-13元、7-12或5-7元杂环。在一些其他实施例中，杂环含有4个杂原子。在一些其他实施例中，杂环含有3个杂原子。在另一实施例中，杂环含有最多2个杂原子。在一些实施例中，杂环基的氮及/或硫原子视情况经氧化以提供N-氧化物、亚磺酰基、磺酰基部分。杂环基包括(但不限于)四氢吡喃基、六氢吡啶基、N-甲基六氢吡啶-3-基、六氢吡嗪基、N-甲基吡咯啶-3-基、3-吡咯啶基、2-吡咯啶酮-l-基、吗啉基及吡咯啶基。指示碳原子数的前缀(例如，C 3- 10)是指杂环基部分中除杂原子数之外的总碳原子数。二价杂环基将具有适当调整的氢含量。
“醚”是指经1-3个C 1-C 6烷氧基取代的C 1-C 6烷基。烷氧基是指-O-烷基。
“卤基”“卤素”是指氟、氯、溴及碘中的一或多者。
“烯基”是指具有碳原子且在一些实施例中2至6个碳原子或2至4个碳原子且具有至少1个乙烯基不饱和位点(>C＝<)的直链或具支链烃基。举例而言，C x-y烯基是指具有x至y个碳原子的烯基且意欲包括(例如)乙烯基、丙烯基、1,3-丁二烯基及诸如此类。
“炔基”是指2个以上碳原子且在一些实施例中2至6个碳原子或2至4个碳原子且含有至少一个三键的直链单价烃基或具支链单价烃基。术语“炔基”亦意欲包括具有一个三键及一个双键的这些烃基。举例而言，C 2-6炔基包括乙炔基、丙炔基及诸如此类。
“胺基磷酸酯烷化剂”是指包含一或多个键结至-O-P(Z1)部分的Z 5-X 5-Y 5部分的烷化剂，其中Z 5是诸如氮、硫或氧等杂原子，X 5是视情况经取代的伸乙基，Y 5是卤基或另一离去基，或 Z 5-X 5-Y 5一起形成氮丙啶基(NCH 2CH 2)部分且Z 1如上文所定义。此一烷化剂可与DNA或另一核酸或蛋白质反应。在一些情形下，烷化剂可交联DNA。
基团可经一或多个取代基(例如1、2、3、4或5个取代基)取代。较佳地，取代基选自由以下组成的群：侧氧基、卤基、-CN、NO 2、-N 2+、-CO 2R 100、-OR 100、-SR 100、-SOR 100、-SO 2R 100、-NR 100SO 2R 100、-NR 101R 102、-CONR 101R 102、-SO 2NR 101R 102、C 1-C 6烷基、C 1-C 6烷氧基、-CR 100＝C(R 100) 2、-CCR 100、C 3-C 10环烷基、C 3-C 10杂环基、C 6-C 12芳基及C 2-C 12杂芳基或诸如-O-(CH 2)-O-、-O-(CH 2) 2-O-及其1-4个甲基经取代的形式等二价取代基，其中R 100、R 101及R 102各自独立是氢或C 1-C 8烷基；C 3-C 12环烷基；C 3-C 10杂环基；C 6-C 12芳基；或C 2-C 12杂芳基；或R 100及R 102与其附接至的氮原子一起形成5-7元杂环；其中烷基、环烷基、杂环基、芳基或杂芳基各自视情况经1-3个卤基、1-3个C 1-C 6烷基、1-3个C 1-C 6卤烷基或1-3个C 1-C 6烷氧基取代。较佳地，取代基选自由以下组成的群：氯、氟、-OCH3、甲基、乙基、异丙基、环丙基、-CO 2H及其盐及C 1-C 6烷基酯、CONMe 2、CONHMe、CONH 2、-SO 2Me、-SO 2NH 2、-SO 2NMe 2、-SO 2NHMe、-NHSO 2Me、-NHSO 2CF 3、-NHSO 2CH 2Cl、-NH 2、-OCF 3、-CF 3及-OCHF 2。
“亚烷基”(Alkylene)是指具有碳原子且在一些实施例中具有1至6个碳原子的二价饱和脂肪族烃基，及烷基再失去一个H原子。“C u-v伸烷基”是指具有u至v个碳原子的压烷基。亚烷基(Alkylene)包括具支链及直链烃基。举例而言，“C 1-C 6伸烷基”包括亚甲基、伸乙基、伸丙基、2-甲基伸丙基、伸戊基及诸如此类。
“亚杂烷基”是指其中链碳原子经诸如O、S、N或P等杂原子或含有杂原子的取代基替代的亚烷基。
在本文中关于D的“药物”包括(但不限于)吉西他滨(gemcitabine)、埃罗替尼(erlotinib)、美妥替哌(meturedepa)、乌瑞替派(uredepa)、六甲蜜胺(altretamine)、伊马替尼(imatinib)、曲他胺(triethylenemelamine)、三甲密胺、苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、雌氮芥(estramustine)、吉非替尼(gefitinib)、氮芥(mechlorethamine)、氮芥氧化物盐酸盐、美法仑(melphalan)、新氮芥(novembichin)、芬司特瑞(phenesterine)、泼尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard)、卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine)、达喀尔巴嗪(dacarbazine)、甘露氮芥(mannomustine)、二溴甘露醇(mitobronitol)、二溴卫矛醇(mitolactol)、哌泊溴烷(pipobroman)、阿克拉霉素(aclacinomycins)、放射菌素(actinomycin)、安曲霉素(anthramycin)、偶氮丝胺酸(azaserine)、博莱霉素(bleomycin)、放线菌素C(cactinomycin)、卡柔比星(carubicin)、嗜癌菌素(carzinophilin)、色霉素(chromomycin)、放线菌素d(dactinomycin)、道诺霉素(daunorubicin)、柔红霉素(daunomycin)、6-重氮-5-侧氧基-1-正白胺酸、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、普卡霉素(plicamycin)、泊非罗霉素(porfiromycin)、嘌呤霉素(puromycin)、链黑霉素(streptonigrin)、链脲菌素(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、左柔比星(zorubicin)、迪诺特宁(denopterin)、蝶罗呤(pteropterin)、曲美沙特(trimetrexate)、氟达拉宾(fludarabine)、6-巯基嘌呤、硫米嘌呤(thiamiprine)、硫鸟嘌呤、安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮杂尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine)、5-氟尿嘧啶、替加氟(tegafur)、L-天冬酰胺酶、百慕时(pulmozyme)、醋葡醛内酯、醛磷酰胺糖苷、胺基乙酰丙酸、安吖啶(amsacrine)、贝斯布西(bestrabucil)、比生群 (bisantrene)、得佛酰胺(defofamide)、地美可辛(demecolcine)、地吖醌(diaziquone)、艾弗鸟胺酸(elfornithine)、依利醋铵(elliptinium acetate)、依托格鲁(etoglucid)、氟他胺(flutamide)、羟基尿素(hydroxyurea)、干扰素-α、干扰素-β、干扰素-γ、介白素-2、蘑菇多醣(lentinan)、丙脒腙(mitoguazone)、米托蒽醌(mitoxantrone)、莫哌达醇(mopidamol)、二胺硝吖啶(nitracrine)、喷司他丁(pentostatin)、蛋胺氮芥(phenamet)、吡柔比星(pirarubicin)、鬼臼酸(podophyllinic acid)、2-乙基酰肼、丙卡巴肼(procarbazine)、雷佐生(razoxane)、西索菲兰(sizofiran)、锗螺胺(spirogermanium)、太平洋紫杉醇(paclitaxel)、他莫昔芬(tamoxifen)、埃罗替尼(erlotonib)、替尼泊苷(teniposide)、细交链孢菌酮酸(tenuazonic acid)、三亚胺醌、2,2',2"-三氯三乙胺、尿烷、长春碱(vinblastine)及长春新碱(vincristine)。
向患者“投与”或“施用”药物是指直接投与或施用(其可由医学专业人士向患者投与或施用或者可自投与或施用)及/或间接投与或施用，其可是开处药物的行为。举例而言，指示患者自投与或施用药物及/或将药物的处方提供给患者的医师是向患者投与或施用药物。
“癌症”是指可通过侵袭而局部扩展且通过转移而全身扩展的潜在无限制生长的白血病、淋巴瘤、癌及其他恶性肿瘤(包括实体肿瘤)。癌症的实例包括(但不限于)肾上腺、骨、脑、乳房、支气管、结肠及/或直肠、胆囊、头及颈、肾、喉、肝、肺、神经组织、胰脏、前列腺、副甲状腺、皮肤、胃及甲状腺的癌症。癌症的某些其他实例包括急性及慢性淋巴细胞及粒细胞肿瘤、腺癌、腺瘤、基底细胞癌、子宫颈上皮分化不良及原位癌、尤文氏肉瘤、表皮样癌、巨细胞瘤、多型性神经胶母细胞瘤、毛细胞肿瘤、肠神经节细胞瘤、增生性角膜神经肿瘤、胰岛细胞癌、卡波西肉瘤、平滑肌瘤、白血病、淋巴瘤、恶性类癌瘤、恶性黑色素瘤、恶性高钙血症、马方样体型肿瘤、髓样上皮癌、转移性皮肤癌、黏膜神经瘤、骨髓瘤、蕈状肉芽肿、神经胚细胞瘤、骨肉瘤、骨原性及其他肉瘤、卵巢瘤、嗜铬细胞瘤、真性红血球增多症、原发性脑瘤、小细胞肺癌、溃疡型及乳头型二者的鳞状细胞癌、增生、精原细胞瘤、软组织肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肾细胞肿瘤、局部皮肤病灶、网状细胞肉瘤及威尔姆氏肿瘤。
“患者”及“个体”可互换使用，是指需要癌症治疗的哺乳动物。通常，患者是人类。通常，患者是诊断患有癌症的人类。在某些实施例中，“患者”或“个体”可指用于筛选、表征及评估药物及疗法的非人类哺乳动物，例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
“前药”是指投与或施用之后经新陈代谢或以其他方式转化为关于至少一种性质的生物学活性或活性更高的化合物(或药物)的化合物。相对于药物，前药以使其相对于药物活性较低或无活性的方式化学修饰，但化学修饰使得在前药投与之后通过代谢或其他生物过程产生相应药物。前药可相对于活性药物具有改变的代谢稳定性或输送特征、较少副作用或较低毒性或经改良的风味(参见(例如)参考文献Nogrady，1985，Medicinal Chemistry A Biochemical Approach，0xford University Press，New York，第388页至392页，其以引用式并入本文中)。前药可使用除相应药物以外的反应物来合成。
本申请中的患者是指与AKR1C3酶及其对应基因相关疾病或是病症、并发症的患者，或者进一步而言，限定为AKR1C3酶活化的细胞毒性前药对应的癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病。
“实体肿瘤”是指包括(但不限于)骨、脑、肝、肺、淋巴结、胰脏、前列腺、皮肤及软组织(肉瘤)中的转移肿瘤的实体肿瘤。
药物的“治疗有效量”是指当向患有癌症的患者投与或施用时，将具有预期的治疗效应(例如患者中一或多种癌症的临床表现的缓和、改善、缓解或消除)的药物的量。治疗效应不必通过投与或施用一个剂量而出现，且可仅在投与或施用一系列剂量后出现。因此，治疗有效量可以一或多次来投与或施用。
病况或患者的“治疗”是指采取步骤以获得有益或期望结果(包括临床结果)。出于本发明的目的，有益或期望临床结果包括(但不限于)一或多种癌症症状的缓和或改善；疾病程度的减弱；疾病进展的延迟或减缓；疾病状态的改善、缓解或稳定；或其他有益结果。在一些情形下，癌症的治疗可使得部分反应或稳定疾病。
“肿瘤细胞”是指任何适当物种(例如，哺乳动物，例如鼠类、犬、猫、马或人类)的肿瘤细胞。
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。
由于本发明是基于以下三个发明申请而做出的：
申请号PCT/US2016/021581，公开号WO2016/145092对应中国申请号2016800150788，公开号CN107530556A；
申请号PCT/US2016/025665，公开号WO2016/061342对应中国申请号2016800200132，公开号CN108136214A；
申请号PCT/US2016/062114，公开号WO2017/087428对应中国申请号2016800446081，公开号CN108290911A，为此将上述三个申请援引到本申请的文本中来。
进一步的，本发明提及的AKR1C3抑制剂，为此也将以下申请援引到本申请中来：
Figure PCTCN2020133538-appb-000028
Figure PCTCN2020133538-appb-000029
发明提及的AKR1C3抑制剂，已经有研究文献(Higaki,Y,Usami,et al.Selective and potent inhibitors of human 20a-hydroxysteroid dehydrogenase(AKR1C1)that metabolizes neurosteroids derived from progesterone[J].CHEMICOBIOLOGICAL INTERACTIONS,2003，503-513；Bydal P,Luu-The V,Labrie F,et al.Steroidal lactones as inhibitors of 17beta-hydroxysteroid dehydrogenase type 5:chemical synthesis,enzyme inhibitory activity,and assessment of estrogenic and androgenic activities.[J].European Journal of Medicinal Chemistry,2009,44(2):632-644；Skarydova L,Wsol V,Zivna L,et al.AKR1C3as a potential target for the inhibitory effect of dietary flavonoids[J].Chemico-biological interactions,2010，178:138-144；Byrns M C,Steckelbroeck S,Penning T M.An indomethacin analogue,N-(4-chlorobenzoyl)-melatonin,is a selective inhibitor of aldo-keto reductase 1C3(type 2 3alpha-HSD,type 5 17beta-HSD,and prostaglandin F synthase),a potential target for the treatment of hormone dependent and hormone independent malignancies.[J].Biochemical Pharmacology,2008,75(2):484-493；Bauman,D.R.Development of nonsteroidal anti-inflammatory drug analogs and steroid carboxylates selective for human aldo-keto reductase isoforms:potential antineoplastic agents that work independently of cyclooxygenase isozymes.[J].Molecular Pharmacology,2005,67(1):60-68；Penning,T,M,et al.Inhibition of a major NAD(P)-linked oxidoreductase from rat liver cytosol by steroidal and nonsteroidal anti-inflammatory agents and by prostaglandins.[J].Proceedings of the National Academy of Sciences,1983，8:4504-4508；Davies N J,Hayden R E,Simpson P J,et al.AKR1C isoforms represent a novel cellular target for jasmonates alongside their mitochondrial-mediated effects.[J].Cancer Research,2009,69(11):4769-75；Brozic P,Golob B,Gomboc N,et al.Cinnamic acids as new inhibitors of 17beta-hydroxysteroid dehydrogenase type 5(AKR1C3).[J].Molecular & Cellular Endocrinology,2006,248(1-2):233-235；Yining Zhao，Xuehua Zheng，Hong Zhang,et al.Invitro inhibition of AKR1Cs by sulphonylureas and the structural basis.[J].Chemico-Biological Interactions,2015,240:310-315.)发现报道部分上市销售的药物具有AKR1C3抑制作用，这些药物也是AKR1C3酶的抑制剂：
Glycyrrhetinic acid甘草次酸、Glycyrrhizinate甘草酸及其盐、苷，Ursodeoxycholic acid熊去氧胆酸，medroxyprogesterone acetate(MPA)醋酸甲羟孕酮，雌二醇Estradiol，Hexestrol己烯雌酚，Bethamethasone倍他米松，考的松cortisone，泼尼松Prednisone，甲泼尼龙methylprednisolone，曲安西龙triamcinolone，氢化考的松Hydrocortisone，地塞米松Dexamethasone，Spironolactone螺内酯，溴替唑仑Brotizolam，艾司唑仑Estazolam，氟硝西泮Flunitrazepam，氟西泮Flurazepam，甲氯西泮meclonazepan，氯甲西泮Lormetazepam，咪达唑仑Midazolam，硝甲西泮nimetazepam，硝西泮Nitrazepam，替马西泮 Temazepam，三唑仑triazolam，阿普唑仑alprazolam，溴西泮Bromazepam，利眠宁(氯氮卓)Chlordiazepoxide，氯巴占clobazam，氯硝西泮clonazepam，地洛西泮Delorazepam，地西泮diazepam，氟地西泮fludiazepam，哈拉西泮Halazepam，劳拉西泮Lorazepam，美达西泮Medazepam，去甲西泮nordazepam，奥沙西泮oxazepam，普拉西泮Prazepam，Cloxazolam氯噁唑仑，Phenolphthalein酚酞，依普黄酮Ipriflavone，盐酸黄酮哌酯Flavoxate Hydrochloride，纯化微粒化黄酮成份Purified Micronised Flavonoid Fraction，醋柳黄酮Seabuckthorn flavone，水飞蓟宾silibinin，乙氧黄酮efloxate，Quercetin槲皮素等总黄酮，木犀草素Luteolin，阿司匹林Aspirin，水杨酸钠Sodium salicylate，对乙酰氨基酚Paracetamol，萘普生Naproxen，萘普酮Nabumetone，双氯芬酸Diclofenac，布洛芬Ibuprofen，罗非昔布rofecoxib，塞来昔布Celecoxib，醋氯芬酸Aceclofenac，二氟尼柳Diflunisal，依托度酸Etodolac，非诺洛芬Fenoprofen，氟比洛芬Flurbiprofen，酮洛芬ketoprofen，噻酮布洛芬(噻丙吩、舒洛芬)suprofen，噻洛芬酸Tiaprofenic Acid，酮咯酸Ketorolac，佐美酸Zomepirac，甲芬那酸Mefenamic acid，氟芬那酸Flufenamic acid，甲氯芬那酸Meclofenamic Acid，美洛昔康Meloxicam，奥沙普秦Oxaprozin，吡罗昔康Piroxicam，替诺昔康Tenoxicam，氯诺昔康Lornoxicam，双水杨酯Sasapyrine，舒林酸Sulindac，托美汀Tolmetin，非那西丁Phenacetin，洛索洛芬钠Loxoprofen Sodium，氨基比林Aminopyrine，安乃近Metamizole Sodium，舒多昔康Sudoxicam，保泰松Phenylbutazone，羟布宗Oxyphenbutazone，氯磺丙脲Chlorpropamide，甲苯磺丁脲Tolbutamide，格列齐特Gliclazide，格列苯脲Glibenclamide，格列喹酮Gliquidone，格列吡嗪Glipizide，格列美脲Glimepiride，
以下是本发明的具体试验和实施例部分。
以下试验将揭示申请人为了证明本申请的相关结论和相关实验事实的实验数据，申请人在此声明，以下的实验数据的权利属于申请人。
Figure PCTCN2020133538-appb-000030
化合物(即为化合物AST-3424的消旋异构体，其S构型即为AST-3424
Figure PCTCN2020133538-appb-000031
)具有AKR1C3酶抑制活性实验。
化合物对AKR1C3体外活性抑制实验
实验仪器：
Waters Acquity I Class UPLC超高效液相色谱仪配有Xevo G2-XS Q Tof HRMS四极杆飞行时间高分辨率质谱仪。
缓冲液和物料：
1. PBS磷酸缓冲盐溶液，
2. 20mM NADPH的PBS磷酸缓冲盐溶液
3. 250μg/mL AKR1C3的PBS磷酸缓冲盐溶液
4. 250μM AST-3424的50％MeOH/H2O溶液
5. 250μM黄体酮(progesterone)的50％MeOH/H2O溶液
6. 1μg/mL普萘洛尔(propranolol)的100％乙腈溶液
实验操作流程
步骤1，将反应混合物按照下表一式四份(n＝4)制成Eppendorf管(微量离心管)，轻轻混合。
物料 阴性对照(μL) 样本(μL)
PBS 68 58
NADPH(20mM) 10 10
AKR1C3(250μg/mL) 10 10
AST-3424(250μM) 0 10
步骤2，将以上一式两份混合物在37℃下预孵育30分钟，60分钟。
步骤3，在每个Eppendorf管中加入另外10μL的20mM NADPH的PBS磷酸缓冲盐溶液和2μL的250μM黄体酮(progesterone)的50％MeOH/H2O溶液并轻轻混合。
步骤4，立即将以上步骤中的50μL混合物转移到100μL的1μg/mL普萘洛尔(propranolol，内标IS)的100％乙腈溶液中。
步骤5，将剩余样品在37℃下孵育30分钟，并加入100μL1μg/mL普萘洛尔(propranolol，内标IS)的100％乙腈溶液。
步骤6，对于所有样品，加入100μL试剂水，以1100rpm涡旋混合5分钟，并在室温下以15000rpm离心10分钟。
步骤7，将所有样品加载到LC/MS上以测定还原的黄体酮即20α-二氢孕酮的含量。
LC-MS仪器的测试条件为
Figure PCTCN2020133538-appb-000032
液相洗脱梯度
时间Time(min) A(％) B(％)
0.00 90.0 0.0
1.5 5.0 95.0
2.00 5.0 95.0
2.30 90.0 10.0
3.00 90.0 10.0
四极杆飞行时间质谱参数
项目 参数
毛细管电压(CapilarykV) 2.5
进样锥电压(SamplingConeV) 40
源温度Sourcetemperature(℃) 100
进样锥气体流速Cone Gas(L/h) 50
脱溶剂气体流速Desolvation Gas(L/h) 600
电离方式(Interface Type) ES电子轰击,Positive阳性
分析器模式(Analyser Mode) Sensitivity敏感
扫描范围(Scan Range) 50-800m/z
步骤9，还原黄体酮(20α-二氢孕酮)的计算：通过LC/MS测定每种样品中还原黄体酮即20α-二氢孕酮和普萘洛尔峰面积。计算还原黄体酮与普萘洛尔的峰面积比(即上表中的比率)，并将时间为0时的比率设定为0％。
AKR1C3活性(％)＝[(样品标准化后的还原黄体酮量)30min-(样品标准化后的还原黄体酮量)0min]/[(阴性对照组标准化后的还原黄体酮量)30min-(阴性对照组标准化后还原黄体酮量)0min]*100。
根据以上计算得到上表的AKR1C3活性结果。
实验结果
Figure PCTCN2020133538-appb-000033
实验结果分析与总结
AST-3424对AKR1C3活性的影响结果表
Figure PCTCN2020133538-appb-000034
吲哚美辛的测试值为5um/L浓度时活性为92.4％。
AST-3424对还原黄体酮生产过程的的影响：经过以上的体外实验证实，预孵育30分钟和60分钟后，25μM/L浓度的AST-3424基本上抑制了AKR1C3活性：与阴性对照相比，还原黄体酮即20α-二氢孕酮的产生分别降低至3.9％和9.2％，证明了AST-3424化合物是AKR1C3酶的抑制剂。
食蟹猴施用AKR1C3抑制剂AST-3424前后体内血液中前列腺素含量变化实验
3只食蟹猴，按下表进行实验。
Figure PCTCN2020133538-appb-000035
从广西雄森灵长类开发实验有限公司购入4只雄性食蟹猴，所有动物均为体检合格、无异常的健康食蟹猴。其中3只用于给药实验，其余的动物用于制备空白血浆。
给药前、给药开始后6、24、48和72小时。经股静脉或其他合适的静脉采血1mL，置于无抗凝剂采血管中，血液样本采集后置于冰上，静置30-60分钟离心分离血清(离心条件：3500转/分钟，10分钟，2-8℃)。收集的血清分析前存放于–80℃。
血清样本中前列腺素F2由常规的ELISA方法进分析。测定结果如下表。
食蟹猴单次静脉滴注给药后的血清中前列腺素E2和F2的浓度结果
Figure PCTCN2020133538-appb-000036
食蟹猴给予0.58mg/kg的AST-3424的6小时后，3只食蟹猴的前列腺素F2a含量均降低，表明给予AST-3424后能抑制食蟹猴分泌前列腺素F2a的过程。
明显的可以发现：
I：在未使用干扰药物前，三只食蟹猴血液中前列腺素F2a的含量水平具有非常大的差别，彼此相差悬殊。
II：进一步，考察三只食蟹猴(101/102/103)在使用感染药物后，前列腺素F2a含量的变化情况可知，在使用AKR1C3抑制剂(AST-3424)后其在6小时内都是下降的，而在24小时、48小时以及72小时则有减少有升高，这个实验事实显示使用AKR1C3酶活性的干扰药物(抑制剂)后应当在合适的时间内检测前列腺素的变化情况，对于本实验中使用的3只食蟹猴而言，6小时是合适的。
III：更进一步，综合I/II考察3只食蟹猴在相同的静脉注射方式、施用相同量的干扰药物的6小时后，前列腺素F2a含量的变化的绝对值也是完全不同的：未施用干扰药物前血液中前列腺素F2a的含量水平高的食蟹猴在施用干扰药物后其血液中前列腺素F2a含量的变化值也是最高的。
IV：更进一步，综合I/II考察3只食蟹猴在相同的静脉注射方式、施用相同量的干扰药物的6小时后，前列腺素F2a含量变化的变化率也是完全不同的：未施用干扰药物前血液中前列腺素F2a的含量水平高的食蟹猴在施用干扰药物后其血液中前列腺素F2a含量的变化率也是最高的。
总之，综合考察3只食蟹猴在未施用干扰药物，以及在以相同的静脉注射方式、施用相同量的干扰药物的6小时后，前列腺素F2a含量的变化的绝对值/相对变化率与该食蟹猴在未施用干扰药物时的PGF2a具有正相关性：未施用干扰药物前血液中前列腺素F2a的含量水平高的食蟹猴在施用干扰药物后其血液中前列腺素F2a含量的变化值/变化率也是最高的。
实际上，使用传统的免疫组织化学染色方法(IHC)对获取到的这三只食蟹猴的肝脏组织 进行AKR1C3进行检测后发现101和103编号的食蟹猴的染色面积高于102编号食蟹猴，即101和103编号的食蟹猴的AKR1C3酶的表达水平高于102编号食蟹猴。
以上的体外和体内实验证实路线1/2/3是真实存在的，在体外通过测量PGF2α和/或PGD2和/或PGH2含量或施用干扰药物前后含量变化、含量变化率再结合数据统计的结论能够关联生物试样中的AKR1C3酶表达水平的高低，即在临床上可以通过测量前列腺素含量来直接获知患者AKR1C3酶表达水平的高低，从而筛选AKR1C3酶表达水平合适的癌症或肿瘤患者，对这些患者给予本发明披露的AKR1C3酶活化的抗癌前药。

Claims (20)

  1. 测量AKR1C3酶表达水平的方法，测量PGF2α和/或PGD2和/或PGH2含量来关联生物试样中的AKR1C3酶表达水平的高低。
  2. 测量AKR1C3酶表达水平的方法，测量施用干扰药物前后PGF2α和/或PGD2和/或PGH2的含量变化来关联生物试样中AKR1C3酶表达水平的高低。
  3. 测量AKR1C3酶表达水平的方法，测量施用干扰药物前后PGF2α和/或PGD2和/或PGH2的含量变化率来关联生物试样中AKR1C3酶表达水平的高低。
  4. 根据权利要求1所述的测量方法，关联是指：
    当PGF2α含量处于A1范围时，生物试样中的AKR1C3酶表达水平的高低程度为高；
    当PGF2α含量处于B1范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
    当PGF2α含量处于C1范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
    和/或
    当PGD2和/或PGH2含量处于A2范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
    当PGD2和/或PGH2含量处于B2范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
    当PGD2和/或PGH2含量处于C2范围时，生物试样中的AKR1C3酶表达水平的高低程度为高，
    其中，A1范围中的最小值≥B1范围中的最大值，B1范围中的最小值≥C1范围中的最大值，
    A2范围中的最小值≥B2范围中的最大值，B2范围中的最小值≥C2范围中的最大值。
  5. 根据权利要求2所述的测量方法，关联是指：
    当PGF2α的含量变化处于a1范围时，生物试样中的AKR1C3酶表达水平的高低程度为高；
    当PGF2α和/或PGD2和/或PGH2的含量变化处于b1范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
    当PGF2α和/或PGD2和/或PGH2的含量变化处于c1范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
    和/或
    当PGD2和/或PGH2的含量变化处于a2范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
    当PGD2和/或PGH2的含量变化处于b2范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
    当PGD2和/或PGH2的含量变化处于c2范围时，生物试样中的AKR1C3酶表达水平的高低程度为高，
    其中，a1范围中的最小值≥b1范围中的最大值，b1范围中的最小值≥c1范围中的最大值，
    a2范围中的最小值≥b2范围中的最大值，b2范围中的最小值≥c2范围中的最大值。
  6. 根据权利要求3所述的测量方法，关联是指：
    当PGF2α的含量变化率处于α1范围时，生物试样中的AKR1C3酶表达水平的高低程度为高；
    当PGF2α的含量变化率处于β1范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
    当PGF2α的含量变化率处于γ1范围时，生物试样中的AKR1C3酶表达水平的高低程度为低，
    和/或
    当PGD2和/或PGH2的含量变化率处于α2范围时，生物试样中的AKR1C3酶表达水平的高低程度为低；
    当PGD2和/或PGH2的含量变化率处于β2范围时，生物试样中的AKR1C3酶表达水平的高低程度为中；
    当PGD2和/或PGH2的含量变化率处于γ2范围时，生物试样中的AKR1C3酶表达水平的高低程度为高，
    其中，α1范围中的最小值≥β1范围中的最大值，β1范围中的最小值≥γ1范围中的最大值，
    α2范围中的最小值≥β2范围中的最大值，β2范围中的最小值≥γ2范围中的最大值。
  7. 根据权利要求2或3所述的测量方法，其中，所述干扰药物为AKR1C3酶抑制剂或AKR1C3酶激动剂。
  8. 根据权利要求7所述的测量方法，所述AKR1C3酶抑制剂为
    Figure PCTCN2020133538-appb-100001
    吲哚美辛。
  9. 根据权利要求1或2或3所述的测量方法，其中，所述生物试样为血液或血清。
  10. 根据权利要求2或3所述的测量方法，其过程包括以下操作：
    测量生命体或活体生物器官、活体生物组织中的PGF2α和/或PGD2和/或PGH2含量；
    对该生命体或活体生物器官、活体生物组织施用干扰药物；
    测量施用干扰药物后生命体或活体生物器官、活体生物组织中的PGF2α和/或PGD2和/或PGH2含量；
    计算施用干扰药物前后含量变化、含量变化率并根据对应关系得到生物试样中的AKR1C3酶表达水平的高低。
  11. 癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病患者筛选并给药的方法，在对患者使用上述权利要求1-10中任意一项所述的测量AKR1C3酶表达水平的方法获知AKR1C3酶表达水平的高低后给予AKR1C3酶活化的抗癌前药。
  12. 癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病患者筛选并给药的方法，在对患者使用上述权利要求1-10中任意一项所述的测量AKR1C3酶表达水平的方法获知AKR1C3酶表达水平的高低后，在酶水平高时，给予AKR1C3酶活化的抗癌前药。
  13. 癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病患者筛选并给药的方法，在对患者使用上述权利要求1-10中任意一项所述的测量AKR1C3酶表达水平的方法获知AKR1C3酶表达水平的高低后，在酶水平高或中时，给予AKR1C3酶活化的抗癌前药。
  14. 根据权利要求11或12或13所述的给药方法，所述AKR1C3酶活化的抗癌前药含有的结构式I的化合物：
    Figure PCTCN2020133538-appb-100002
    其中，
    X 10是O、S、SO或SO 2；
    A是C 6-C 10芳基或取代芳基、5-15元杂芳基或取代杂芳基或-N＝CR 1R 2；其中，R 1和R 2各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    X、Y和Z各自独立地是氢、CN、卤基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    R是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    R 13和R 14各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基或醚，或者R 13和R 14基团与其所键结的氮原子一起形成5-7元杂环基；
    T包含胺基磷酸酯烷化剂，即T为-L-D，包括以下六种情况：
    -D为-P(Z 1)(Z 5-X 5-Y 5) n，Z 1为O或S，Z 5为N、S或O，X 5为任意取代的亚乙 基,Y 5为卤素原子或-OSO 2-R 20,R 20为任意取代的烃基、芳基、环烷基、杂环基或杂芳基，n为1或2，L选自-O-、-S-、-OCOO-、-NR 6CO-、-OCO-、-NR 6SO 2-、-OCONR 6-、季铵根、磺酸酯基-OSO 2-；
    或者
    Z 1为O或S，Z 5-X 5-Y 5为吖丙啶基-NCH 2CH 2部分；
    或者
    -L-为-O-，-D为-P(Z 1)(Z 5-X 5-Y 5) n，Z 1为O或S，Z 5为N、S或O，X 5为任意取代的亚乙基,Y 5为卤素原子或-OSO 2-R 20,R 20为任意取代的烃基、芳基、环烷基、杂环基或杂芳基，n为1或2；
    或者
    -L-为-O-，Z 1为O或S，Z 5-X 5-Y 5为吖丙啶基-NCH 2CH 2部分；
    或者
    -L-D为-OP(Z 1)(NR 30CH 2CH 2Cl) 2,-OP(Z 1)(NR 30CH 2CH 2Br) 2,-OP(Z 1)(NR 30 2)(N(CH 2CH 2X 1) 2),-OP(Z 1)(N(CH 2) 2) 2,或-OP(Z 1)(N(CH 2CH 2Cl) 2) 2,其中，每个R 30各自独立的为H、C 1-C 6的烃基或两个R 30基团与连接的N原子形成5-7元的杂环，Z 1为O或S，X 1为Cl、Br或-OSO 2Me；
    或者
    -L-D为-OP(Z 1)(NHCH 2CH 2Cl) 2,-OP(Z 1)(NHCH 2CH 2Br)2,-OP(Z 1)(NH 2)(N(CH 2CH 2X 1) 2),-OP(Z 1)(N(CH 2) 2) 2,或-OP(Z 1)(N(CH 2CH 2Cl) 2) 2，且X 1为Cl、Br或-OSO 2Me；
    且所述烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基被取代或未取代。
  15. 根据权利要求11或12或13所述的给药方法，所述AKR1C3酶活化的抗癌前药含有化合物选自以下结构式：
    Figure PCTCN2020133538-appb-100003
    Figure PCTCN2020133538-appb-100004
    Figure PCTCN2020133538-appb-100005
    Figure PCTCN2020133538-appb-100006
    Figure PCTCN2020133538-appb-100007
    Figure PCTCN2020133538-appb-100008
    Figure PCTCN2020133538-appb-100009
    Figure PCTCN2020133538-appb-100010
    Figure PCTCN2020133538-appb-100011
    Figure PCTCN2020133538-appb-100012
    及
    Figure PCTCN2020133538-appb-100013
  16. 根据权利要求11或12或13所述的给药方法，所述AKR1C3酶活化的抗癌前药含有的结构式II的化合物：
    Figure PCTCN2020133538-appb-100014
    其中
    X 10是O、S、SO或SO 2；
    A是C 6-C 10芳基或取代芳基、5-15元杂芳基或取代杂芳基或-N＝CR 1R 2；其中，R 1和R 2各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    X、Y和Z各自独立地是氢、CN、卤基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    每个R独立地是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    R 13和R 14各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基或醚，或者R 13和R 14与其所键结的氮原子一起形成5-7元杂环基；
    L 1和D如说明书中定义，具体定义如下
    L 1选自：
    Figure PCTCN2020133538-appb-100015
    其中，R 40和R 41独立地是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环或5-15元杂芳基；
    R 42是视情况经1-3个C 1-C 6烷基取代的C 2-C 3伸烷基或伸杂烷基；V(-)为任何阴离子，较佳为医药学上可接受的阴离子；和
    D是使得D-OH为抗癌药物的部分，其中OH为脂族羟基或酚羟基；换言之，D是抗癌药物D-OH脱去羟基后剩余的基团；
    或者
    L 1为：
    Figure PCTCN2020133538-appb-100016
    其中R 40如上文所定义，R 43为氢或与D一起形成杂环，且苯基部分视情况经取代；和
    D是使得D-NR 43H为抗癌药物的部分；换言之，D是抗癌药物D-NR 43H脱去氨基或胺后剩余的基团；
    或者
    L 1是键、-O-C(R 40R 41)-、-O-C(R 40R 41)-NR 40R 41(+)-C(R 40R 41)-或
    Figure PCTCN2020133538-appb-100017
    其中R 40、R 41和V如上文所定义；和
    D是含有伯胺或仲胺的抗癌药物，其中该伯胺或该仲胺键接至L 1；且
    且所述烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基被取代或未取代。
  17. 根据权利要求16所述的给药方法，所述AKR1C3酶活化的抗癌前药含有的结构式II的化合物中，
    D-OH选自以下含有-OH基团的抗癌药物：吉西他滨gemcitabine、雌莫司汀estramusting、泼尼莫司汀pudnimnstine、氯脲霉素chlorozotocin、雷莫司汀ranimustine、甘露莫司汀mannomustine、二溴甘露醇mitobronitol、二溴卫矛醇dibromodulcitol、阿柔比星aclacinomycins、安曲霉素anthramycin、博来霉素bleomycin、卡柔比星carubicin、嗜癌霉素carzinophilin、色霉素chromomycin、放线菌素Ddactinomycin、道诺霉素daunorubicin、霉酚酸mycophenolic acid、诺加霉素nogalamycin、橄榄霉素olivomycin、培洛霉素peplomycin、普卡霉素plicamycin、嘌呤霉素puromycin、链黑霉素streptonigrin、链脲佐菌素streptozocin、杀结核菌素tubercidin、乌苯美司ubenimex、净司他丁zinostatin、左柔比星zorubicin、迪诺特宁denopterin、氟达拉宾fludarabine、 安西他滨ancitabine、阿扎胞苷azacitidine、6-氮杂尿苷6-azauridine、阿糖胞苷cytarabine、双脱氧尿苷dideoxyuridine、脱氧氟尿苷doxifluridine、依诺他滨enocitabine、氟尿苷floxuridine、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、醋葡醛内酯aceglatone、依利醋铵elliptinium acetate、依托格鲁etoglucid、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、蘑菇多醣lentinan、米托蒽醌mitoxantrone、莫哌达醇mopidamol、喷司他丁pentostatin、吡柔比星pirarubicin、鬼臼酸podophyllinic acid、西索菲兰sizofiran、太平洋紫杉醇paclitaxel、替尼泊苷teniposide、细交链孢菌酮酸tenuazonic acid、长春碱vinblastine、长春新碱vincristine；
    D-NR 43H选自以下的抗癌药物：埃罗替尼erlotinib、美妥替哌meturedepa、乌瑞替派uredepa、伊马替尼imatinib、三甲密胺trimethylolomelamine、吉非替尼gefitinib、尿嘧啶氮芥uracil mustard、卡莫司汀carmustine、氯脲菌素chlorozotocin、福莫司汀fotemustine、尼莫司汀nimustine、雷莫司汀ranimustine、达喀尔巴嗪dacarbazine、甘露氮芥mannomustine、放射菌素actinomycin、安曲霉素anthramycin、博莱霉素bleomycin、放线菌素C cactinomycin、卡柔比星carubicin、嗜癌菌素carzinophilin、放线菌素D dactinomycin、培洛霉素peplomycin、嘌呤霉素puromycin、链脲菌素streptozocin、乌苯美司ubenimex、净司他丁zinostatin、迪诺特宁denopterin、蝶罗呤pteropterin、曲美沙特trimetrexate、6-巯基嘌呤6-mercaptopurine、硫米嘌呤thiamiprine、硫鸟嘌呤thioguanine、6-氮杂尿苷6-azauridine、卡莫氟carmofur、双脱氧尿苷dideoxyuridine、脱氧氟尿苷doxifluridine、依诺他滨enocitabine、氟尿苷floxuridine、5-氟尿嘧啶5-fluorouracil、替加氟tegafur、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、安吖啶amsacrine、比生群bisantrene、地美可辛demecolcine、地吖醌diaziquone、依利醋铵elliptiniumacetate、氟他胺flutamide、羟基尿素hydroxyurea、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、米托蒽醌mitoxantrone、二胺硝吖啶nitracrine、喷司他丁pentostatin、蛋胺氮芥phenamet、2-乙基酰肼2-ethylhydrazide、丙卡巴肼procarbazine、雷佐生razoxane、埃罗替尼erlotonib、尿烷urethane、长春碱vinblastine、长春新碱vincristine；
    含有三级或二级氮原子的抗癌药物选自六甲蜜胺altretamine、曲他胺triethylenemelamine、苯丁酸氮芥chlorambuci、萘氮芥chlornaphazine、雌氮芥estramustine、吉非替尼gefitinib、氮芥mechlorethamine、氮芥氧化物盐酸盐mechlorethamine oxide hydrochloride、美法仑melphalan、新氮芥novembichin、芬司特瑞phenesterine、泼尼氮芥prednimustine、曲磷胺trofosfamide、尿嘧啶氮芥uracil mustard、卡莫司汀carmustine、氯脲菌素chlorozotocin、福莫司汀fotemustine、尼莫司汀nimustine、雷莫司汀ranimustine、达喀尔巴嗪dacarbazine、哌泊溴烷pipobroman、放线菌素actinomycin、安曲霉素anthramycin、嗜癌菌素carzinophilin、放线菌素D dactinomycin、诺加霉素nogalamycin、泊非罗霉素porfiromycin、嘌呤霉素puromycin、链脲菌素streptozocin、杀结核菌素tubercidin、氟达拉宾fludarabine、安西他滨ancitabine、阿扎胞苷azacitidine、阿糖胞苷cytarabine、双脱氧尿苷dideoxyuridine、依诺他滨enocitabine、氟尿苷floxuridine、L-天冬酰胺酶L-asparaginase、百慕时 pulmozyme、醛磷酰胺糖苷aldophosphamide glycoside、贝斯布西bestrabucil,地吖醌diaziquone、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、丙脒腙mitoguazone、莫哌达醇mopidamol、二胺硝吖啶nitracrine、喷司他丁pentostatin、蛋胺氮芥phenamet、雷佐生razoxane、锗螺胺spirogermanium、他莫昔芬tamoxifen、三亚胺醌triaziquone、2,2',2"-三氯三乙胺2,2',2"-trichlorotriethylamine、长春碱vinblastine、长春新碱vincristine。
  18. 根据权利要求11或12或13所述的给药方法，所述AKR1C3酶活化的抗癌前药含有化合物选自以下结构式：
    Figure PCTCN2020133538-appb-100018
  19. 测量AKR1C3酶表达水平的组件，其包含：
    与生物试样接触发生反应，根据反应的信号来定量或半定量关联该生物试样中PGF2α和/或PGD2和/或PGH2含量的构件；
    对照比较构件，用于比较反应的信号来对照比较得出所述生物试样中PGF2α和/或PGD2和/或PGH2的含量、施用干扰药物前后PGF2α和/或PGD2和/或PGH2的含量变化或施用干扰药物前后PGF2α和/或PGD2和/或PGH2的含量变化率所对应的AKR1C3酶表达水平的高低。
  20. 给药装置，其包含：
    权利要求19所述的测量AKR1C3酶表达水平的组件；
    给药组件，其含有AKR1C3酶活化的抗癌前药。
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