CN111170943A - Benzo [ f ] cyclopentano [ c ] quinoline derivatives and use thereof - Google Patents
Benzo [ f ] cyclopentano [ c ] quinoline derivatives and use thereof Download PDFInfo
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- CN111170943A CN111170943A CN202010075312.4A CN202010075312A CN111170943A CN 111170943 A CN111170943 A CN 111170943A CN 202010075312 A CN202010075312 A CN 202010075312A CN 111170943 A CN111170943 A CN 111170943A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract
The invention discloses a benzo [ f ] cyclopentano [ c ] quinoline derivative and application thereof in preparing a medicament for treating prostatic cancer, belonging to the field of medicines. The benzo [ f ] cyclopenta [ c ] quinoline compound with the structural formula shown in the formula (I) has obvious antagonistic activity on androgen receptors, can be used as an androgen receptor antagonist to be applied to the treatment of diseases related to the androgen receptors, and provides a new choice for the development of the existing medicaments for treating prostate cancer.
Description
Technical Field
The invention belongs to the field of medicines, relates to benzo [ f ] cyclopenta [ c ] quinoline derivatives and medical application thereof, and particularly relates to application of the benzo [ f ] cyclopenta [ c ] quinoline derivatives in preparation of androgen receptor antagonists for treating prostatic cancer.
Background
Prostate cancer is one of the high-incidence and high-mortality tumors in men worldwide. In China, with the increasing improvement of living standard of people and the change of dietary structure, the incidence rate of prostate cancer shows a trend of rising year by year. Because early clinical symptoms of the prostate cancer are not obvious, the disease is hidden, and the popularization screening is difficult, most patients are confirmed to be in the middle and late stages of the tumor with tissue infiltration and metastasis, and the optimal treatment opportunity of the radical prostate cancer therapy is missed.
Targeted drug therapy is an important choice for patients with advanced prostate cancer or patients with metastatic prostate cancer. Among them, androgen receptor is one of the key therapeutic targets. The structure of the androgen receptor comprises 920 amino acid residues and consists of 4 key domains, including an N-terminal domain, a DNA binding domain, a hinge region and a C-terminal domain. Wherein the C-terminal domain is also referred to as ligand binding domain, the ligand binding domain comprises a ligand binding pocket, i.e. a hormone binding pocket. The current androgen receptor targeted antagonist targets the ligand binding pocket, competes for a natural ligand, and blocks the conformational change of the androgen receptor, thereby blocking the androgen receptor dependent signal pathway and achieving the purpose of targeted therapy of prostate cancer.
Androgen receptor targeted antagonists can be chemically classified into steroids and non-steroids. Steroid antagonists have serious limited clinical benefit due to their toxic and side effects such as liver and cardiovascular diseases, and interference with libido. Since the advent of nonsteroidal antagonists, particularly enzalutamide and apaluramide represented by the second generation antagonists, have achieved great benefit and public praise in clinical application. However, the development of intrinsic or acquired resistance, and the excessive similarity of chemical structures of marketed drugs, has led to the development of simultaneous resistance in multiple antagonists. In addition, few and few alternative drugs severely restrict the clinical application and selection of the antagonist.
Therefore, designing androgen receptor antagonists with novel structures can help increase the drug use selection of clinical patients and has important significance for prolonging the life of the patients.
Disclosure of Invention
The invention aims to provide a compound with androgen receptor antagonistic activity, which is applied to the preparation of an anti-prostate tumor medicament.
In order to achieve the purpose, the following technical scheme is adopted in the application:
the invention discovers a lead compound of a targeted androgen receptor through computer-assisted virtual screening, obtains a series of novel benzo [ f ] cyclopentano [ c ] quinoline derivatives through molecular structure modification, and obtains a compound with androgen receptor antagonistic activity through biological screening.
The structural formula of the benzo [ f ] cyclopentano [ c ] quinoline derivative is shown as a formula (I),
wherein R1 is any one of the following substituents:
the specific structural formula is shown in table 1. The research shows that the compound has the functions of specifically targeting androgen receptor and obviously inhibiting the proliferation of prostate cancer cells, and has no obvious toxic or side effect on cells.
The invention also provides the application of the benzo [ f ] cyclopentano [ c ] quinoline derivative or the medicinal salt thereof in preparing an androgen receptor antagonist.
The invention also provides application of the benzo [ f ] cyclopentano [ c ] quinoline derivative or the pharmaceutically acceptable salt thereof in preparing anti-prostate cancer drugs.
The invention also provides application of the benzo [ f ] cyclopentano [ c ] quinoline derivative or the pharmaceutically acceptable salt thereof in preparing an anti-metastatic prostate cancer medicament. The metastatic prostate cancer is bone metastasis or brain metastasis of prostate cancer, and researches show that the compound also has the effect of inhibiting the proliferation activity of metastatic prostate cancer cells PC3 (bone metastasis) and DU145 (brain metastasis).
The invention also provides a pharmaceutical composition for treating prostatic cancer, which comprises the benzo [ f ] cyclopentano [ c ] quinoline derivative or the pharmaceutically acceptable salt thereof as an effective component.
The medicinal salt is hydrochloride, phosphate, sulfate, acetate, maleate, citrate, benzene sulfonate, methyl benzene sulfonate, fumarate or tartrate.
The pharmaceutical composition further comprises a pharmaceutically acceptable excipient, diluent or carrier. Specifically, syrup, gum arabic, starch, etc. can be used. The pharmaceutical composition can be administered by intravenous, oral, sublingual, intramuscular or subcutaneous routes, or by the skin mucosa route.
The pharmaceutical composition is prepared in a liquid preparation or a solid preparation. Such as tablet, capsule and injection. The preparation can be prepared by a conventional pharmaceutical method.
The invention has the following beneficial effects:
the invention discovers for the first time that benzo [ f ] cyclopentano [ c ] quinoline compounds have obvious antagonistic activity on androgen receptors based on a virtual screening and structural analogue design method and biological activity measurement, can be used as androgen receptor antagonists to be applied to the treatment of androgen receptor-related diseases, and provides a new choice for the development of the current medicaments for treating prostate cancer.
Drawings
FIG. 1 shows the results of the test of the binding ability of the compounds 1-9 with significant antagonistic activity on androgen receptor at 10. mu.M.
FIG. 2 shows the results of androgen receptor binding ability test of compound 3 under a series of concentration gradients.
FIG. 3 shows the results of the inhibition of Prostate Specific Antigen (PSA) by Compound 3 at mRNA levels over a series of concentration gradients.
FIG. 4 shows the results of the inhibition of the aminopeptidase 2(TMPRSS2) by Compound 3 at the mRNA level in a series of concentration gradients.
FIG. 5 shows the results of experiments on the inhibition of cell proliferation of mouse embryonic fibroblasts (NIH-3T3) by Compound 3 in a series of concentration gradients.
FIG. 6 shows the results of the experiment of inhibiting androgen receptor nuclear transcription in LNCaP cells under 10. mu.M condition with Compound 3.
Fig. 7 shows the results of experiments on LNCaP cell proliferation inhibition by compound 3 and compound 1 over a series of concentration gradients.
FIG. 8 shows the results of a series of concentration gradients of compound 3 and compound 1 on the inhibition of C4-2 cell proliferation.
Fig. 9 shows the results of experiments on the inhibition of PC3 cell proliferation by compound 3 and compound 1 in a series of concentration gradients.
FIG. 10 shows the results of a series of concentration gradients of compound 3 and compound 1 for the inhibition of DU-145 cell proliferation.
Detailed Description
The present invention will be further described with reference to the following specific examples.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
(1) Virtual screening based on structure
The experimental principle is as follows: and (3) utilizing a virtual screening based on the structure to predict the binding mode and the binding free energy between the compounds in the compound database and the androgen receptor, and screening the antagonistic small-molecule compound capable of binding with the androgen receptor.
The experimental method comprises the following steps: based on the crystal structure of androgen receptor (PDB number: 2PNU), a Glide molecular docking module of a Schrodinger molecular simulation software package is adopted to perform virtual screening based on the structure on a Specs small molecule database, 200 compounds with the best score are subjected to conformational analysis, and finally 32 compounds are purchased for activity screening.
The experimental results are as follows: the screening results 32 potential androgen receptor antagonists, and possess different chemical frameworks. These molecules were subjected to activity tests based on molecular level binding experiments to confirm the activity of the compounds by experimental means.
(2) Evaluation test of androgen receptor antagonistic ability
The experimental principle is as follows: the androgen receptor, as a transcription factor, needs to bind to a specific sequence, i.e., an androgen response element, to exert transcriptional activity. Therefore, ARR is introduced into androgen receptor dependent prostate cancer cell LNCaP2After the reporter gene enhanced green fluorescent protein EGFP controlled by the PB promoter is subjected to administration treatment by different concentration gradient test compounds, the expression level of EGPF in cells is measured, and the androgen receptor antagonistic capability of the compound can be obtained.
The experimental steps are as follows: ARR having a strong response using androgen receptor2An EGFP reporter gene plasmid controlled by a PB promoter, and a lentivirus are stably transfected into LNCaP cells, so that the LNCaP cells express an EGFP prostate cancer cell line (LN-ARR) regulated by an androgen receptor2PB-EGFP)。
The specific screening process comprises the following steps: firstly LN-ARR2PB-EGFP cells were cultured in androgen-free complete medium for several days to reduce background fluorescence to a low level, and then cultured at 3.5X 104And inoculating the density of each hole into a black bottom-penetrating 96-well plate, after cells are stably attached to the wall, simultaneously giving androgen and test compounds with different concentration gradients, incubating for 24-48h, detecting the fluorescence intensity value near 530nm wavelength by using a multifunctional microplate reader under excitation light with the wavelength of 485nm, and quantitatively calculating the inhibition rate of the test compound on an androgen receptor.
The experimental results are as follows: after finding lead compound 1 (see table 1) by virtual screening, a series of compounds were obtained by commercial compound purchase and chemical synthesis to find antagonistic activity IC50Compounds 2-60 (Table 1 and Table 2), all at less than 50. mu.M. In particular, Compound 3 exhibited the strongest antagonistic activity of 0.06. mu.M, on the same IC as the positive drug Enzalutamide (Enzalutamide, Enz)50And (4) concentration. These active compounds are further used for target validation based on good androgen receptor antagonistic activity.
TABLE 1
TABLE 2
(3) Androgen receptor competitive binding experiment verification of binding target
The experimental principle is as follows: the androgen receptor targeting ability of the compound was determined using the fluorescence correction experiment by Invitrogen corporation. Androgen receptor { AR-LBD (His-GST) } binds to a fluorescent androgen ligand (FluormomoneTMALGeren) to form a binary complex with a higher fluorescence deviation value. When the complex is added into a micropore plate containing a test compound, the test compound serving as a competitive ligand replaces a fluorescent ligand (fluoromone ML Green) in a binary complex, so that the fluorescence bias positive value is reduced. If the test compound does not target the site, the bias will remain at the original level. Thus, using changes in positive fluorescence bias enables the determination of targeting of compounds to androgen receptors.
The experimental method comprises the following steps: androgen receptor ligand domain protein and high affinity fluorescent ligand are mixed in buffer, and test compound is added in different concentration, and androgen Dihydrotestosterone (DHT) is used as positive control. And measuring the change of the fluorescence polarization value of the system by using a multifunctional microplate reader, and quantitatively measuring whether the compound with the antagonistic activity targets the androgen receptor.
The experimental results are as follows: as shown in figure 1, the compounds with antagonistic activity include lead compound 1, and structural analogs 2, 3, 5-8, all of which can correctly target androgen receptor ligand domain at a concentration of 10 μ M, and show different binding strengths.
By combining the strength of androgen receptor antagonism and the strength of binding, we selected compound 3 for further concentration gradient assay of binding capacity. As shown in fig. 2, the affinity of compound 3 and the positive drug enzalutamide to the target are both concentration-dependent, indicating that compound 3 correctly targets the androgen receptor ligand domain and exerts an antagonistic effect.
(4) Quantitative PCR detection of androgen receptor target gene expression
The experimental principle is as follows: prostate Specific Antigen (PSA), one of the key clinical indicators for prostate cancer, was found to have a positive correlation between its expression and androgen receptor transcriptional level, and to further verify the effect of the compounds in inhibiting androgen transcriptional activity, the present inventors next examined the mRNA levels of the endogenous target genes of androgen receptor, including the mRNA of prostate specific antigen and transmembrane serine protease 2(TMPRSS2), for optimal antagonist compound 3 at the mRNA level.
The experimental steps are as follows: LNCap cells were cultured in fetal bovine serum (CSS) containing 5% charcoal/dextran treatmentNutrient 6-well plates. After 48h of processing, mRNA was extracted using the EZ-10 DNAway RNA Mini-Preps kit and reverse transcribed to cDNA. Use of
III 1st cDNA SuperMix was subjected to qPCR, and finally amplified by q-PCR using a qPCR SYBR GreenMaster Mix.
The experimental results are as follows: the compound 3 can obviously inhibit the transcription of the endogenous prostate specific antigen (figure 3) and the transmembrane serine protease 2 (figure 4) at the mRNA level, and further indicates that the compound has androgen receptor antagonism.
(5)3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazole bromide (MTT) method for detecting toxicity of compound to mouse fibroblast
The experimental principle is as follows: in order to verify that the source of the antagonistic activity is not from cytotoxicity but is specific to androgen receptor dependent prostate cancer cells, the MTT method is adopted to detect whether the compound has an inhibitory effect on the proliferation of mouse embryonic fibroblasts (NIH-3T3) so as to detect the toxicity. The basic principle of this experiment is that succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-violet crystalline Formazan (Formazan) and deposit it in cells, while dead cells do not have this function, buffer is added to dissolve Formazan formed in cells, and the light absorption value is measured at 490nm wavelength by enzyme linked immunosorbent detector, which can quantitatively reflect the number of living cells.
The experimental steps are as follows: using complete medium at 5X 103NIH-3T3 cells were seeded at density per well in 96-well plates, and after cells were stably attached to the wall, after incubation at 37 ℃ for 24h, the cells were treated with compounds at different concentrations and then incubated for 72 h. Subsequently, 10. mu.L of 5mg/ml MTT was added to each well, incubation was continued in an incubator for 4 hours, then 100. mu.L of SDS-HCl-PBS triple buffer was added to each well, and after overnight incubation at 37 ℃, the absorbance value of each well at 570nm was measured under a microplate reader and converted into the survival rate.
The experimental results are as follows: as shown in fig. 5, no significant cytotoxicity occurred in compound 3, lead compound 1 and positive compound enzalutamide at each concentration, which indicates that the compound of the present invention has good antagonistic activity without toxicity and high safety.
(6) Immunofluorescence detection for blocking androgen receptor nuclear entry condition
The experimental principle is as follows: currently marketed non-steroidal androgen receptor drugs are primarily first and second generation antagonists. Particularly, the second generation antagonists are not only significantly superior in antagonistic activity to the first generation, but also are more capable of blocking androgen receptor entry. The invention adopts an immunofluorescence technique to detect the influence of the compound on androgen receptor nuclear entry.
The experimental steps are as follows: LNCaP cells were grown on coverslips of 12-well plates and incubated for 24 h. LNCaP cells were treated with 5nM DHT for 1.5h, and then groups of LNCaP cells were treated with DMSO,5nM DHT, 10. mu.M enzalutamide and 5nM DHT, 10. mu.M test compound, example 3 and 5nM DHT, respectively. After 12h, LNCaP cells were fixed with 4% (v/v) paraformaldehyde pre-cooled at 4 ℃ and then washed three times with PBS. Cells were then permeabilized with Triton X-100 and incubated overnight with addition of androgen receptor antibody. Cells were stained with 4', 6-diamidino-2-phenylindole (DAPI), and micrographs were taken using a Nikon AR fluorescence microscope at 60 magnifications and then analyzed using NIS-Elements Viewer software.
The experimental results are as follows: as shown in fig. 6, compound 3 was able to significantly block androgen receptor nuclear entry, similar to the positive drug enzalutamide, distinguishing compound 3 as a second generation androgen receptor antagonist.
(7) MTT method for detecting proliferation inhibition activity of multiple prostate cancer cells
The experimental principle is as follows: the invention not only defines the molecular mechanism and targeting of the compound, but also detects the actual anti-prostate cancer cell proliferation. The experiments used were the MTT experiments mentioned above, detecting LNCaP and C4-2 cells expressing androgen receptors to varying degrees, and androgen receptor independent PC3 and DU145 cells.
The experimental steps are as follows: using androgen-free complete medium at 5X 103、1.5×103、1.5×103And 1.5X 103LNCaP with density per pore,PC3, C4-2 and DU145 cells are inoculated in a 96-well plate, after the cells are stably attached to the wall, 1nMDHT and test compounds with different concentrations are simultaneously given, 10 mu L of 5mg/ml MTT is added into each well after incubation for 72h, incubation is continued for 4h in an incubator, then 100 mu L of SDS-HCl-PBS triple buffer is added into each well, after overnight incubation at 37 ℃, the absorbance value of each well at 570nm is detected under an enzyme-labeling instrument, and the survival rate is converted.
The experimental results are as follows: as shown in fig. 7, compound 3 and the positive drug enzalutamide were able to significantly inhibit androgen receptor-dependent LNCap cells and exhibit similar inhibitory activity at high concentrations. Compound 3 was shown to be resistant to androgen receptor-responsive receptor-splicing receptor (Enzalutamide-resistant cell line) in C4-2 cells as well as positive cells (FIG. 8). In androgen receptor independent PC3 (fig. 9) and DU145 (fig. 10) cells, both compound 3 and lead compound 1 exhibited superior proliferation inhibitory activity than the positive drug enzalutamide. The compounds of the present invention, in addition to exerting a cell proliferation inhibitory effect directly by targeting androgen receptor, have other targets, inhibiting metastatic prostate cancer cells PC3 (bone metastasis) and DU145 (brain metastasis).
Claims (8)
1. A benzo [ f ] cyclopentano [ c ] quinoline derivative is characterized in that the structural formula is shown as a formula (I),
wherein R1 is any one of the following substituents:
2. use of a benzo [ f ] cyclopenta [ c ] quinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of an androgen receptor antagonist.
3. Use of a benzo [ f ] cyclopenta [ c ] quinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for the treatment of prostate cancer.
4. Use of a benzo [ f ] cyclopenta [ c ] quinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for the treatment of metastatic prostate cancer.
5. A pharmaceutical composition for treating prostate cancer, comprising the benzo [ f ] cyclopenta [ c ] quinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable salt is a hydrochloride, phosphate, sulfate, acetate, maleate, citrate, benzenesulfonate, methylbenzenesulfonate, fumarate, or tartrate salt.
7. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable excipient, diluent or carrier.
8. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is formulated as a liquid formulation or a solid formulation.
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| WO2003034987A2 (en) * | 2001-10-19 | 2003-05-01 | Merck & Co., Inc. | Androgen receptor modulators and methods of use thereof |
| WO2008154207A1 (en) * | 2007-06-08 | 2008-12-18 | The Burnham Institute For Medical Research | Methods and compounds for regulating apoptosis |
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| CN109700804A (en) * | 2017-03-01 | 2019-05-03 | 浙江大学 | Tetrahydro carbazole structure type androgen receptor antagonists and its application |
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