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1.
《Cytokine》2014,65(2):167-174
Interleukin-17A (IL-17A) is the prototype of IL-17 family and has been implicated in the pathogenesis of a variety of autoimmune diseases. Therefore its structural and functional properties are of great medical interest. During our research on a recombinant human IL-17A (rhIL-17A) variant, four isoforms were obtained when it was refolded. While isoforms 1 and 2 represented non-covalent dimers, isoforms 3 and 4 were determined to be covalent dimers. All four isoforms were structurally similar by Circular Dichroism and fluorescence spectroscopy studies, but differential scanning calorimetry demonstrated thermal stability in the order of isoform 1 = isoform 2 < isoform 4 < isoform 3. In addition, compared to covalent dimers (isoform 3 and 4), the non-covalent dimers (isoforms 1 and 2) are slightly less active in a receptor-binding assay but at least 5-fold less active in a cell-based assay. 相似文献
2.
Dynamin-1 is a GTP-hydrolyzing protein and a key element in the clathrin-mediated endocytosis of secretory granules and neurovesicles at the plasma membrane. The unique receptor-like protein tyrosine phosphatase, PTP-NP/Phogrin/IAR/IA-2, is associated with neuroendocrine secretory granules and is highly expressed in the brain. Here, we show by confocal microscopy and biochemical studies that PTP-NP rapidly associates with Dynamin-1 in a depolarization-dependent manner and regulates Dynamin-1 GTPase activity upon KCl depolarization of rat primary hippocampal neurons. Depolarization of primary neurons induced direct association of PTP-NP with Dynamin-1 within 30 s. This association resulted in significant inhibition of Dynamin-1 GTPase activity (approximately 75% inhibition). Mutation within the phosphatase domain of PTP-NP (PTP-NP(D947A)) abolished the direct interaction of PTP-NP with Dynamin-1 and failed to inhibit Dynamin-1 GTPase activity. To further confirm the endogenous interaction of Dynamin-1 with wild-type PTP-NP, Dynamin-1 was purified biochemically from rat brain and its interaction with purified PTP-NP was analyzed. Highly purified Dynamin-1 specifically associated with wild-type PTP-NP and not with mutated PTP-NP, resulting in significant inhibition (approximately 70%) of Dynamin-1 GTPase activity. This is the first report to suggest a novel function of this unique receptor-type tyrosine phosphatase as a potential regulator of Dynamin-1 GTPase activity upon neuronal depolarization. 相似文献
3.
We have previously reported the presence of a relatively heat-stable α-amylase with a low Km for starch in kilned malted sorghum. In order to establish the industrially useful and more efficient isoforms, we have separated this α-amylase into different isoforms using both cation and anion-exchange chromatographies. Unkilned malted α-amylase crude was separated into three different isoforms (a1, a2 and a3) whereas kilned samples were separated into two (a1 and a2). Apparently one isoform (a3) was lost during kilning due to heat lability. a1 isoform which appears to have a neutral pI and constitute about 60% of the total α-amylases protein that were induced during germination, have the lowest Km for starch. They are more generally stable than other isoforms at all the temperatures studied. These isoforms lost only 10% activity at 80 °C for 30 min and still had some residual activity at 100 °C incubation for 30 min. a1 isoform could therefore be adapted for industrial starch conversion processes which are carried out within this range of gelatinizing temperatures because of its properties. 相似文献
4.
《Neurochemistry international》2007,50(8):729-736
The aim of the current study was to characterize the effects of chemical ischemia and reperfusion at the transductional level in the brain. Protein kinase C isoforms (α, β1, β2, γ, δ and ɛ) total levels and their distribution in the particulate and cytosolic compartments were investigated in superfused rat cerebral cortex slices: (i) under control conditions; (ii) immediately after a 5-min treatment with 10 mM NaN3, combined with 2 mM 2-deoxyglucose (chemical ischemia); (iii) 1 h after chemical ischemia (reperfusion). In control samples, all the PKC isoforms were detected; immediately after chemical ischemia, PKC β1, δ and ɛ isoforms total levels (cytosol + particulate) were increased by 2.9, 2.7 and 9.9 times, respectively, while α isoform was slightly reduced and γ isoform was no longer detectable. After reperfusion, the changes displayed by α, β1, γ, δ and ɛ were maintained and even potentiated, moreover, an increase in β2 (by 41 ± 12%) total levels became significant. Chemical ischemia-induced a significant translocation to the particulate compartment of PKC α isoform, which following reperfusion was found only in the cytosol. PKC β1 and δ isoforms particulate levels were significantly higher both in ischemic and in reperfused samples than in the controls. Conversely, following reperfusion, PKC β2 and ɛ isoforms displayed a reduction in their particulate to total level ratios. The intracellular calcium chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, 1 mM, but not the N-methyl-d-asparate receptor antagonist, MK-801, 1 μM, prevented the translocation of β1 isoform observed during ischemia. Both drugs were effective in counteracting reperfusion-induced changes in β2 and ɛ isoforms, suggesting the involvement of glutamate-induced calcium overload. These findings demonstrate that: (i) PKC isoforms participate differently in neurotoxicity/neuroprotection events; (ii) the changes observed following chemical ischemia are pharmacologically modulable; (iii) the protocol of in vitro chemical ischemia is suitable for drug screening. 相似文献
5.
Kalyan K. Sethi Daniella Vullo Saurabh M. Verma Muhammet Tanç Fabrizio Carta Claudiu T. Supuran 《Bioorganic & medicinal chemistry》2013,21(19):5973-5982
A series of 4,5,6,7-tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1–8) was synthesized by reaction of benzene sulfonamide derivatives with 4,5,6,7-tetrabromophthalic anhydride moiety. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I, II and VII and the transmembrane tumor-associated isoform hCA IX and XII. The new compounds were good hCA I inhibitors (Kis in the range of 143 to >10,000 nM), but were moderately effective, as hCA II inhibitors (Kis of 47–190 nM) and poor hCA VII inhibitors (Kis in the range of 54–175 nM) compared to acetazolamide. The tumor-associated hCA IX was effectively inhibited with Kis ranging between 8.5 and 234 nM and hCA XII with inhibition constants in the range of 6.1–197 nM with high selectivity ratio. The structure–activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking study of compounds was performed to rationalize the SAR reported over here. 相似文献
6.
Dayan Fu Mingrui Yu Tanwei Tan Xin Zhou 《Journal of Molecular Catalysis .B, Enzymatic》2009,56(2-3):115-121
Lipase (EC.3.1.1.3) from Candida sp. 99-125 was separated into four isoforms (isoform A, isoform B, isoform C, and isoform D) by two steps of ion exchange chromatography. As analyzed on SDS- and non-denaturing PAGE, the four isoforms were homogenous and had the same molecular weight of approximate 38 kDa. MALDI-TOF peptide mass fingerprinting maps and circular dichroism spectra showed the isoforms had similar peptide patterns belonging to the same protein encoded by the YLlip2 gene and different secondary structures. The isoforms had a little distinct optimum temperature in the range of 20–35 °C, and the same optimum pH (8.0). They remained to be active in methanol, ethanol and ethylene glycol at the concentration of 10% and 20% (v/v) and acetone at the concentration of 10% (v/v), and sensitive to EDTA. Triton X-100, Sodium cholate and CHAPS slightly increased their activities. The metal ion Ca2+ and Mg2+ had mild effect on lipase activity. The isoforms showed a preference for long chain fatty acid triglyceride (triolein and olive). The lipase purified by one step of ion exchange chromatography and isoforms were less active than crude enzyme to catalyze cetyl alcohol and oleic acid in n-hexane, whereas the presence of small concentration of added water dramatically activated crude lipase but less the purified preparations. 相似文献
7.
Edita Čapkauskaitė Asta Zubrienė Alexey Smirnov Jolanta Torresan Miglė Kišonaitė Justina Kazokaitė Joana Gylytė Vilma Michailovienė Vaida Jogaitė Elena Manakova Saulius Gražulis Sigitas Tumkevičius Daumantas Matulis 《Bioorganic & medicinal chemistry》2013,21(22):6937-6947
Two groups of benzenesulfonamide derivatives, bearing pyrimidine moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CA). Their binding affinities to six recombinant human CA isoforms I, II, VI, VII, XII, and XIII were determined by the thermal shift assay (TSA). The binding of several inhibitors was measured by isothermal titration calorimetry (ITC). Direct demonstration of compound inhibition was achieved by determining the inhibition constant by stopped-flow CO2 hydration assay. The most potent compounds demonstrated selectivity towards isoform I and affinities of 0.5 nM. The crystal structures of selected compounds in complex with CA II, XII, and XIII were determined to atomic resolution. Compounds described here were compared with previously published pyrimidinebenzenesulfonamides.1 Systematic structure–activity analysis of 40 compound interactions with six isoforms yields clues for the design of compounds with greater affinities and selectivities towards target CA isoforms. 相似文献
8.
9.
Keigo Okamura Hidekazu Koike Yoshitaka Sekine Hiroshi Matsui Kazuhiro Suzuki 《Cancer epidemiology》2009,33(2):137-141
Background: Survivin has been implicated in inhibition of apoptosis. To date, alternatively spliced isoforms, Survivin-2α, -2B, -ΔEx3, -3B, have been described. We assessed the effect of survivin gene expression on the proliferation of renal cancer (RCC) cells, and studied the association of survivin and its spliced isoform gene expression levels with the clinical stage of RCC. Methods: Gene expression of survivin and its spliced isoform in RCC cells, Caki-1, were performed by RT-PCR. We knocked down the gene expression of Survivin using small interfering RNA (siRNA), and assessed the cell proliferation by MTS assay. Next, we quantified the gene expression levels of survivin and its isoform in nephrectomy samples using quantitative real-time PCR. Results: In Caki-1 cells, survivin and survivin-2α, -2B were expressed higher than survivin-ΔEx3. Decrease of Survivin gene expression by transfection of siRNA was accompanied by inhibition of the proliferation of Caki-1 cell with 36% decrease in comparison with negative control transfected cells (p < 0.01). In clinical RCC tissues, survivin expression levels in metastatic stage were significantly higher compared with those in distant metastasis stage (M0:M1 = 1:4.81, p = 0.014); survivin 2B gene expression levels in pT3 tumors were associated significantly higher than those in pT1 (pT1:pT3 = 1:4.50, p = 0.043). No significant differences were found in survivin-2α expression levels and the ratio of survivin-2B/survivin gene expression levels among any clinical stages. Conclusion: We first demonstrated the gene expression of survivin-2α in renal cancer cells, and also showed that survivin and its spliced isoforms had associations with renal cancer cell proliferation and distant metastases. 相似文献
10.
《Bioorganic & medicinal chemistry letters》2014,24(5):1256-1260
A series of 6-substituted sulfocoumarins incorporating substituted-1,2,3-triazol-4-yl-/5-yl moieties were synthesized by employing click chemistry. The new sulfocoumarins incorporated cycloalkyl, tert-butyl and substituted aryl moieties at the triazole ring, and were investigated for the inhibition of four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, the cytosolic hCA I and II; and the transmembrane, tumor-associated hCA IX and XII. The triazole-substituted sulfocoumarins did not inhibit the ubiquitous, off-target cytosolic isoforms hCA I and II (KIs >10 μM) but showed effective inhibition against the two transmembrane CAs, with KIs ranging from 7.2 to 10.5 nM against hCA IX, and between 5.5 and 17.7 nM against hCA XII. As hCA IX and XII are validated anti-tumor targets, such prodrug, isoform-selective inhibitors as the sulfocoumarins reported here, may be useful for identifying suitable drug candidates for clinical trials. 相似文献
11.
Alessio Innocenti Claudiu T. Supuran 《Bioorganic & medicinal chemistry letters》2010,20(21):6208-6212
Carbonic anhydrases (CAs, EC 4.2.1.1) belonging to α-, β-, γ- and ζ-classes and from various organisms, ranging from the bacteria, archaea to eukarya domains, were investigated for their esterase/phosphatase activity with 4-nitrophenyl acetate, 4-nitrophenyl phosphate and paraoxon as substrates. Only α-CAs showed esterase/phosphatase activity, whereas enzymes belonging to the β-, γ- and ζ-classes were completely devoid of such activity. Paraoxon, the metabolite of the organophosphorus insecticide parathione, was a much better substrate for several human/murine α-CA isoforms (CA I, II and XIII), with kcat/KM in the range of 2681.6–4474.9 M?1 s?1, compared to 4-nitrophenyl phosphate (kcat/KM of 14.9–1374.4 M?1 s?1). 相似文献
12.
Kristoff T. Homan Deepa Balasubramaniam Adam P.R. Zabell Olaf Wiest Paul Helquist Cynthia V. Stauffacher 《Bioorganic & medicinal chemistry》2010,18(14):5449-5456
The human cytoplasmic protein tyrosine phosphatase (HCPTP) has been identified as a potential target for inhibition in order to downregulate metastatic transformation in several human epithelial cancers such as breast, prostate and colon cancer. Docking with two scoring functions on both isoforms of HCPTP was employed as an initial virtual screen to identify potential inhibitors. Compounds identified as potential inhibitors via this in silico screen were subjected to kinetic analysis in order to validate their selection as improved inhibitors. Eleven compounds with IC50’s of less than 100 μM were identified in a single concentration screen. Five of these compounds were determined to have an IC50 of less than 10 μM; however, all but one of these compounds inhibited via non-specific aggregation. The validated effective inhibitor, which is based on a naphthyl sulfonic acid, strongly resembles a previously synthesized rationally designed azaindole phosphonic acid. This similarity suggests subsequent inhibitor optimization based on this scaffold may generate effective inhibitors of HCPTP. The structural elements of the computationally identified inhibitors are discussed to analyze the combined use of rational design and virtual screening to reduce false negatives in the identification of multiple strong inhibitors of HCPTP. 相似文献
13.
Shadan Ali Sana Al-Sukhun Bassel F. El-Rayes Fazlul H. Sarkar Lance K. Heilbrun Philip A. Philip 《Life sciences》2009,84(21-22):766-771
AimsThe protein kinase C (PKC) family of enzymes has been implicated in cellular proliferation, differentiation, and apoptosis. However, the distribution of specific PKC isoforms with varying functions in normal and malignant human tissues remains to be determined. The objective of this study was to investigate the expression of certain PKC isoforms (α, βI, βII, ε) in human breast cancer specimens relative to adjacent uninvolved tissue (n = 24) and in the normal breast tissue obtained from patients undergoing reduction mammoplasty (n = 12).Main methodsWestern blot analysis using PKC isoform specific antibodies was performed on tissue extracts from breast tumors, adjacent uninvolved tissues, and reduction mammoplasty tissues.Key findingsMean levels of cytosolic and membrane PKC-α, PKC-βI, and PKC-βII were significantly higher in the cancer specimens than in the adjacent uninvolved breast tissues (Wilcoxon signed-ranks test; P < 0.05 for each, after adjustment for multiple comparisons). There was a notably higher mean level of membrane PKC-βII isozyme in Her-2 positive and in poorly differentiated tumors. No significant differences were observed when normal tissue adjacent to tumor was compared to breast tissue obtained from reduction mammoplasty specimens.SignificanceHigher level of PKC-α, PKC-βI, and PKC-βII in cancer specimens and higher level of PKC-βII in Her-2 positive tumors require further exploration of the intracellular pathways involving PKC-α and -β isoforms in breast cancer because both could be specific targets for the development of new therapies and for the prevention and treatment of this disease. 相似文献
14.
Oxytocin is involved in the control of different behaviors, from sexual behavior and food consumption to empathy, social and affective behaviors. An imbalance of central oxytocinergic neurotransmission has been also associated with different mental pathologies, from depression, anxiety and anorexia/bulimia to schizophrenia, autism and drug dependence. This study shows that oxytocin may also play a role in the control of locomotor activity. Accordingly, intraperitoneal oxytocin (0.5–2000 μg/kg) reduced locomotor activity of adult male rats. This effect was abolished by d(CH2)5Tyr(Me)2-Orn8-vasotocin, an oxytocin receptor antagonist, given into the lateral ventricles at the dose of 2 μg/rat, which was ineffective on locomotor activity. Oxytocin (50–200 ng/site) also reduced and d(CH2)5Tyr(Me)2-Orn8-vasotocin (2 μg/site) increased locomotor activity when injected bilaterally into the substantia nigra, a key area in the control of locomotor activity. Conversely, the destruction of nigral neurons bearing oxytocin receptors by the recently characterized neurotoxin oxytocin-saporin injected into the substantia nigra, increased basal locomotor activity. Since oxytocin-saporin injected into the substantia nigra caused a marked reduction of neurons immunoreactive for tyrosine hydroxylase (e.g., nigrostriatal dopaminergic neurons) and for vesicular glutamate transporters VGluT1, VGluT2 and VGluT3 (e.g., glutamatergic neurons), but not for glutamic acid decarboxylase (e.g., GABAergic neurons), together these findings suggest that oxytocin influences locomotor activity by acting on receptors localized presynaptically in nigral glutamatergic nerve terminals (which control the activity of nigral GABAergic efferent neurons projecting to brain stem nuclei controlling locomotor activity), rather than on receptors localized in the cell bodies/dendrites of nigrostriatal dopaminergic neurons. 相似文献
15.
Hélène Carreyre Jean-Marie Coustard Grégoire Carré Clarisse Vandebrouck Jocelyn Bescond Maurice Ouédraogo Jérôme Marrot Daniella Vullo Claudiu T. Supuran Sébastien Thibaudeau 《Bioorganic & medicinal chemistry》2013,21(13):3790-3794
The natural product dodoneine (a dihydropyranone phenolic compound), extracted from African mistletoe Agelanthus dodoneifolius, has been investigated as inhibitor of several human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms. By using superacid chemistry, analogues of the lactone phenolic hybrid lead compound have been synthesized and tested as CA inhibitors. Small chemical modifications of the basic scaffold revealed strong changes in the selectivity profile against different CA isoforms. These new compounds selectively inhibited isoforms CA I (KIs in the range of 0.13–0.76 μM), III (KIs in the range of 5.13–10.80 μM), XIII (KIs in the range of 0.34–0.96 μM) and XIV (KIs in the range of 2.44–7.24 μM), and can be considered as new leads, probably acting as non-zinc-binders, similar to other phenols/lactones investigated earlier. 相似文献
16.
《Matrix biology》2015
The LTBPs (or latent transforming growth factor β binding proteins) are important components of the extracellular matrix (ECM) that interact with fibrillin microfibrils and have a number of different roles in microfibril biology. There are four LTBPs isoforms in the human genome (LTBP-1, − 2, − 3, and − 4), all of which appear to associate with fibrillin and the biology of each isoform is reviewed here.The LTBPs were first identified as forming latent complexes with TGFβ by covalently binding the TGFβ propeptide (LAP) via disulfide bonds in the endoplasmic reticulum. LAP in turn is cleaved from the mature TGFβ precursor in the trans-golgi network but LAP and TGFβ remain strongly bound through non-covalent interactions. LAP, TGFβ, and LTBP together form the large latent complex (LLC). LTBPs were originally thought to primarily play a role in maintaining TGFβ latency and targeting the latent growth factor to the extracellular matrix (ECM), but it has also been shown that LTBP-1 participates in TGFβ activation by integrins and may also regulate activation by proteases and other factors. LTBP-3 appears to have a role in skeletal formation including tooth development. As well as having important functions in TGFβ regulation, TGFβ-independent activities have recently been identified for LTBP-2 and LTBP-4 in stabilizing microfibril bundles and regulating elastic fiber assembly. 相似文献
17.
AimsAmlodipine, a dihydropyridine Ca2+ channel blocker, inhibits the proliferation of human epidermoid carcinoma A431 cells in vitro and in vivo. This study examined the underlying mechanism of this antiproliferative effect in relation to epidermal growth factor receptor (EGFR) signaling.Main methodsThe tyrosine phosphorylated active state of EGFR in A431 cells incubated with the test agents was evaluated by western blot with anti-phosphotyrosine antibody. EGFR phosphorylation levels in A431 xenograft tumors were assessed by immunostaining of matrigel plug sections and western blotting for phosphoEGFR in A431 xenograft tumor homogenates.Key findingsIn vitro treatment of exponentially growing A431 cells with amlodipine decreased the tyrosine phosphorylation states of EGFR. Amlodipine also suppressed the EGF-stimulated phosphorylation of EGFR and a membrane scaffolding protein, caveolin-1, in serum-starved A431 cells. Amlodipine attenuated the EGF-stimulated phosphorylation of EGFR coimmunoprecipitated with caveolin-1 without affecting the EGFR/caveolin-1 interaction. Crosslinking experiments showed that amlodipine also suppressed the EGF-stimulated phosphorylation of EGFR predimers. Addition of cholesterol abolished these inhibitory effects of amlodipine plus its inhibition of cell growth. Furthermore, treatment of mice with amlodipine (10 mg/kg/day × 7 days, i.p.) decreased the levels of phosphorylated EGFR in A431 xenograft tumors.SignificanceThe results indicated that amlodipine inhibits tyrosine phosphorylation of EGFR in vitro and in vivo, possibly via modulating cholesterol-rich, caveolin-1-containing membrane microdomains. 相似文献
18.
Changon Seo Jae Hak Sohn Jong Seog Ahn Joung Han Yim Hong Kum Lee Hyuncheol Oh 《Bioorganic & medicinal chemistry letters》2009,19(10):2801-2803
Seven phenolic lichen metabolites (1–7) have been isolated from a methanol extract of the Antarctic lichen Stereocaulon alpinum by various chromatographic methods. The structures of these compounds were determined mainly by analysis of NMR spectroscopic data. A depsidone-type compound, lobaric acid (1) and two pseudodepsidone-type compounds, 2 and 3, exhibited potent inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 0.87 μM, 6.86 μM, and 2.48 μM, respectively. Kinetic analyses of PTP1B inhibition by compounds 1 and 2 suggested that these compounds inhibited PTP1B activity in a non-competitive manner. 相似文献
19.
In the present study a series of fifteen 2-heteroarylidene-1-indanone derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. These compounds are structurally related to series of heterocyclic chalcone derivatives which have previously been shown to act as MAO-B specific inhibitors. The results document that the 2-heteroarylidene-1-indanones are in vitro inhibitors of MAO-B, displaying IC50 values of 0.0044–1.53 μM. Although with lower potencies, the derivatives also inhibit the MAO-A isoform with IC50 values as low as 0.061 μM. An analysis of the structure-activity relationships for MAO-B inhibition indicates that substitution with the methoxy group on the A-ring leads to a significant enhancement in MAO-B inhibition compared to the unsubstituted homologues while the effect of the heteroaromatic substituent on activity, in decreasing order is: 5-bromo-2-furan > 5-methyl-2-furan > 2-pyridine ≈ 2-thiophene > cyclohexyl > 3-pyridine ≈ 2-furan. It may therefore be concluded that 2-heteroarylidene-1-indanone derivatives are promising leads for the design of MAO inhibitors for the treatment of Parkinson’s disease and possibly other neurodegenerative disorders. 相似文献
20.
《Bioorganic & medicinal chemistry》2016,24(13):3083-3092
Current results identified 4-substituted 2-phenylaminoquinazoline compounds as novel Mer tyrosine kinase (Mer TK) inhibitors with a new scaffold. Twenty-one 2,4-disubstituted quinazolines (series 4–7) were designed, synthesized, and evaluated against Mer TK and a panel of human tumor cell lines aimed at exploring new Mer TK inhibitors as novel potential antitumor agents. A new lead, 4b, was discovered with a good balance between high potency (IC50 0.68 μM) in the Mer TK assay and antiproliferative activity against MV4-11 (GI50 8.54 μM), as well as other human tumor cell lines (GI50 < 20 μM), and a desirable druglike property profile with low log P value (2.54) and high aqueous solubility (95.6 μg/mL). Molecular modeling elucidated an expected binding mode of 4b with Mer TK and necessary interactions between them, thus supporting the hypothesis that Mer TK might be a biologic target of this kind of new active compound. 相似文献