CN103100080B - Application of cGP and derivatives in preparation of medicine for inhibiting tumor growth and regeneration - Google Patents
Application of cGP and derivatives in preparation of medicine for inhibiting tumor growth and regeneration Download PDFInfo
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Abstract
The invention relates to application of cGP and derivatives in preparation of a medicine for inhibiting tumor growth and regeneration, and belongs to the field of antitumor drugs. The cGP and various congeners of the cGP have the function of inhibiting IGF-1 (Insulin-like Growth Factor) signaling pathway, so that the pathological level of the IGF-1 can be inhibited and also can be maintained at the normal physiological level; as the further study shown, the cGP and various congeners of the cGP can inhibit the growth and the regeneration of tumors by inhibiting the IGF-1 mediated vessel. The cGP and the various congeners of the cGP break through the defect of easy recurrence of the conventional medical medicine and can be used together with other chemotherapeutics for treating cancer at phase I, so that the toxicity generated in chemotherapy can be reduced, the tumor is prevented from recurring.
Description
Technical field
The invention belongs to field of antineoplastic medicaments, found that cGP and multiple congener thereof make IGF-1 maintain generation and regeneration that stable physiological level suppresses tumor by the pathology level that suppresses IGF-1.
Background technology
Cancer is a class disease of puzzlement and harm humans health always, lacks at present effective means and prevents or treat cancer.Existing research shows, the development of revascularization and cancerous cell has significant relationship, and cancerous cell can be controlled tissue and produce neovascularity, for its transport oxygen and needed nutrition, so the speed of growth is faster than normal cell.The principal character of cancer is the uncontrollable propagation of cancerous cell and high transfer ability, and in this process, cancerous cell need to rely on this physiological phenomenon of revascularization nutrition [1] is provided for this reason.Thereby for the method that reaches treatment cancer by angiogenesis inhibitor, the main means that adopt are exactly line artery endothelial cell growth factor (ECGF) (VEGF) family member and receptor performance function thereof, the method that this also becomes the promising treatment kinds cancer of a kind of tool, is applied in the treatment of kinds cancer, such as colorectal carcinoma [2], carcinoma of prostate [3], breast carcinoma [4], hepatocarcinoma [5], ovarian cancer [6, pulmonary carcinoma [7], cancer of pancreas [8] and leukemia [9] etc.But the medicine of angiogenesis inhibitor, can be owing to causing the limitation that cardiovascular system, nervous system and hematotoxicity are applied [10] in conjunction with other chemotherapy during in clinical middle treatment cancer.When the defect of anti-angiogenic medicaments is to suppress tumor at present, normal wound healing and the generation that maintains the necessary neovascularity of health in body are also suppressed.Meanwhile, these medicines also have a lot of toxic and side effects, comprise and are not limited to the hemorrhage of nose, harmonization of the stomach intestinal and perforation, more serious coronary artery disease and the vascular change at lower extremities etc. [11] of also comprising.
Insulin like growth factor (IGF) signal path, in all multiple entities and hematologic cancers including breast carcinoma, has all played important facilitation for angiogenesis.IGF-1 (IGF-1) is a kind of activated protein peptide material, is subordinated to IGF family, and in human body, nearly all tissue can synthesize.Research shows, IGF-1 plays a significant role in angiogenesis, can raise the expression of the gene (comprising VEGF VEGF and hypoxia inducible factor HIF1 α) that promotes angiogenesis, lower the gene expression [12] that suppresses angiogenesis simultaneously, IGF-1 is in breast carcinoma, carcinoma of prostate, general high expressed in the cancers such as colon cancer, far above the physiological level in normal structure [13].Therefore, suppress the IGF-1 of pathology level and make it maintain normal physiological level and be expected to become the effective means of the diseases such as treatment cancer.
The N end of IGF-1 can spontaneous metabolism become GPE salt (GPE).The half-life of GPE is very short, the rapid metabolism ring formation Gly-Pro of meeting (cGP), and cGP is more stable with respect to GPE.For the research of cGP, shown its potential [14,15] in disease (comprising Parkinson's disease and senile dementia etc.) aspect treatment neurologic disorder before.CGP separates [16] from cerebral tissue, and according to research before, it has the effect [17] that strengthens rodent memory and improve cognitive competence.Verified in several animal models; cGP has the multiple biological functions [18] such as neuroprotective system; but for cGP and multiple congener thereof by suppressing IGF signal path, suppress the pathology level of IGF-1 and maintain that stable physiological level suppresses the generation of tumor and the mechanism of revascularization have not been reported.
Above-mentioned appended list of references is specific as follows:
[1] Bagnasco L, Piras D, Parodi S, Bauer I, Zoppoli G, Patrone F, the effect of Ballestrero A 2012Role of angiogenesis inhibitors in colorectal cancer:sensitive and insensitive tumors. angiogenesis inhibitor in responsive and insensitive colon cancer.Curr?Cancer?Drug?Targets?12:303-315。
[2] .Kim DD, the drug research present situation of Eng C 2012 The current state of targeted agents in rectal cancer. targeting rectal cancer.Int?J?Surg?Oncol?2012:406830。
[3] .Antonarakis ES, Carducci MA 2012 Targeting angiogenesis for the treatment of prostate cancer. target vascular therapies generate treatment carcinoma of prostate.Expert?Opin?Ther?Targets?16:365-376。
[4] .Bareschino MA, Schettino C, Colantuoni G Rossi E, Rossi A, Maione P, Ciardiello F, Gridelli C 2011 effects of The role of antiangiogenetic agents in the treatment of breast cancer. angiogenesis inhibitor in breast cancer treatment.Curr?Med?Chem?18:5022-5032。
[5] .Tazi eM, Essadi I, M'rabti H, Touyar A, system and the targeted therapy of Errihani PH 2011 Systemic treatment and targeted therapy in patients with advanced hepatocellular carcinoma. advanced liver cancers.NAm?J?Med?Sci?3:167-175。
[6] .Sato S, Itamochi H 2012 Bevacizumab and ovarian cancer. bevacizumab and ovarian cancers.Curr?Opin?Obstet?Gynecol?24:8-13。
[7] .Gori B, Ricciardi S, Fulvi A, Del SE, de MF 2012 application of New oral multitargeted antiangiogenics in non-small-cell lung cancer treatment. Novel multi-effect angiogenesis inhibitor preparation in Treatment for Non-small Cell Lung.Future?Oncol?8:559-573。
[8] .Aggarwal S, Gupta S, Gupta MK, Murthy RS, Vyas SP 2011 application of Possible role of epidermal growth factor receptors in the therapy of pancreatic cancer. EGF-R ELISA in treatment of pancreatic cancer.Crit?Rev?Ther?Drug?Carrier?Syst?28:293-356。
[9] .Cocco C, Ferretti E, Airoldi I, Pistoia V 2011 Cytokines as anti-angiogenic agents in haematological malignancies. cytokines are the effect in hematologic malignancies treatment as angiogenesis inhibitor preparation.Curr?Cancer?Drug?Targets?11:997-1004。
[10] .Hollebecque A, Massard C, effect and the side effect of Soria JC 2012 Vascular disrupting agents:a delicate balance between efficacy and side effects. angiolysis preparations.Curr?Opin?Oncol?24:305-315。
[11] .Semenza GL 2008 A new weapon for attacking tumor blood vessels. tumor vascular weapon of novel attack.N?Engl?J?Med?358:2066-2067。
[12] .Tang X, Zhang Q, Shi S, Yen Y, Li X, Zhang Y, Zhou K, Le AD 2010Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells. diphosphate suppresses the angiogenesis of type-1 insulin like growth factor induction in breast carcinoma by HIF-1alpha/VEGF path.Int?J?Cancer?126:90-103。
[13] .Oh JS, Kucab JE, Bushel PR, Martin K, Bennett L, Collins J, DiAugustine RP, Barrett JC, Afshari CA, the gene profile in the generation of galactophore epithelial cell medium vessels and the cancer process of Dunn SE 2002 Insulin-like growth factor-1inscribes a gene expression profile for angiogenic factors and cancer progression in breast epithelial cells. type-1 insulin like growth factor mediations.Neoplasia4:204-217。
[14] .Guan J, little peptide and the congener thereof in Gluckman PD 2009 IGF-1 derived small neuropeptides and analogues:a novel strategy for the development of pharmaceuticals for neurological conditions.IGF-1 sources: a kind of new therapy for the treatment of sacred disease.Br?J?Pharmacol1?57:881-891。
[15] .Sizonenko SV; Sirimanne ES; Williams CE; Gluckman PD 2001 Neuroprotective effects of the N-terminal tripeptide of IGF-1; glycine-proline-glutamate; in the immature rat brain after hypoxic-ischemic injury.IGF-1 nitrogen end, GPE, in immaturity Mus brain anoxia-induced apoptosis for neural protective effect.Brain?Res?922:42-50。
[16] .Remacle-Bonnet M, Garrouste F, el AF, Roccabianca M, Marvaldi J, Pommier G1992 des-(1-3)-IGF-I, an insulin-like growth factor analog used to mimic a potential IGF-II autocrine loop, promotes the differentiation of human colon-carcinoma cells. insulin like growth factor analog des-(1-3)-IGF-I, autocrine loop that can Simulation with I GF-II, promotes the differentiation of colon cancer.Int?J?Cancer?52:910-917。
[17] .Samonina G, Ashmarin I, Lyapina L 2002 Glyproline peptide family:review on bioactivity and possible origins. Gly-Pro peptide families: biological activity and origin.Pathophysiology?8:229-234。
[18] .Guan J, Mathai S, Harris P, Wen JY, Zhang R, Brimble M, Gluckman P 2007Peripheral administration of a novel diketopiperazine, NNZ 2591, prevents brain injury and improves somatosensory-motor function following hypoxia-ischemia in adult rats. novel diketopiperazine NNZ 2591, can suppress adult rat brain damage and improve the body sense changing function that hypoxia injury is induced.Neuropharmacology?53:749-762。
Summary of the invention
The invention provides a kind of cGP and derivant and suppress the application in tumor growth and regenerating medicine in preparation.
The technical scheme that the present invention takes is: the application of cGP in the medicine of preparation inhibition tumor growth and regeneration; CGP has the function that suppresses kinds of tumor cells propagation,
Another technical scheme of the present invention is: the application of cGP in the medicine of preparation inhibition vascular endothelial cell formation pipe spline structure; CGP has the function that suppresses vascular endothelial cell formation pipe spline structure and suppress mouse tumor growth and regeneration.
Another technical scheme of the present invention is: suppress the application in the growth of tumor and the medicine of regeneration thereby cGP maintains by the pathology level of inhibition IGF signal path inhibition IGF-1 the physiological level that IGF-1 is stable in preparation.
Another technical scheme of the present invention is: the congener of cGP suppresses the application in tumor growth and regenerating medicine in preparation; The congener of described cGP is: (S)-2-methyl hexahydropyrrolo also [1,2-a] pyrazine-1,4-diketone, (S)-six hydrogen-1H-pyrrolo-[1,2-a] (1,4) diaza-1,5 (2H)-diketone, (R)-dihydro-1H-thiazole also [3,4-a) pyrazine-5,8 (3H, 8aH)-diketone.
(the S)-2-methyl hexahydropyrrolo of the present invention also preparation method of [1,2-a] pyrazine-Isosorbide-5-Nitrae-diketone is:
(S)-six hydrogen-1H-pyrrolo-of the present invention [1,2-a] (Isosorbide-5-Nitrae) diaza-1, the preparation method of 5 (2H)-diketone is:
The present invention has found the anti-tumor function of cGP, and cGP can suppress the vascular endothelial cell proliferation of IGF-1 mediation; CGP can suppress the formation of the vascular endothelial cell tubular structure of IGF-1 mediation; In mouse model, cGP has the function that suppresses tumor formation, development and tumor regrowth.
When cGP and three kinds of novel congeners thereof are used to medicine in the present invention, can carry out administration by conventional route, comprising oral, intravenous injection and intramuscular injection etc.Meanwhile, in the time that these three kinds of medicines are used for mammal, effective dose is 2-200 microgram/kg body weight.Certainly, concrete dosage also should be considered the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
Advantage of the present invention: cGP and multiple congener thereof have been broken through the easy recurrence defect of traditional chemical medicine, can jointly use with the chemotherapeutics of other treatment I phase cancer, to weaken chemicotherapy toxicity and to prevent the recurrence again of tumor.Meanwhile, cGP and multiple congener thereof preventing aspect revascularization, broken through the defect that other drug suppresses the normal physiological function of IGF-1, also maintained the normal physiological level of IGF-1 on the basis that suppresses IGF-1 pathology level.
Brief description of the drawings
Fig. 1 is the experimental data figure that cGP suppresses the vascular endothelial cell proliferation effect of IGF-1 induction;
Fig. 2 A is the experimental data figure that cGP suppresses the vascular endothelial cell proliferation effect of high concentration IGF-1 induction, for not adding IGF-1;
Fig. 2 B is the experimental data figure that cGP suppresses the vascular endothelial cell proliferation effect of high concentration IGF-1 induction, for adding the IGF-1 of low concentration, 10nM;
Fig. 2 C is the experimental data figure that cGP suppresses the vascular endothelial cell proliferation effect of high concentration IGF-1 induction, for adding the IGF1 of high concentration, 50nM;
Fig. 3 is the pipe spline structure effect of experimental data figure cGP forms to(for) the vascular endothelial cell that suppresses IGF-1 mediation;
Fig. 4 A is cGP for suppressing the generation of tumor and the experimental data figure of Development effect, directly carries out cGP processing after implantation tumour;
Fig. 4 B is cGP for suppressing the generation of tumor and the experimental data figure of Development effect, and implantation tumour carries out cGP processing after 10 days;
Fig. 5 A be cGP congener (S)-2-methyl hexahydropyrrolo also [1,2-a] pyrazine-Isosorbide-5-Nitrae-diketone for the experimental data figure of inhibition tumor cell multiplication effect;
Fig. 5 B is congener (S)-six hydrogen-1H-pyrrolo-[1,2-a] (Isosorbide-5-Nitrae) diaza-1 of cGP, and 5 (2H)-diketone are for the experimental data figure of inhibition tumor cell multiplication effect;
Fig. 5 C be cGP congener (R)-dihydro-1H-thiazole also [3,4-a) pyrazine-5,8 (3H, 8aH)-diketone is for the experimental data figure of inhibition tumor cell multiplication effect.
Detailed description of the invention
Below embodiment is by specific embodiment further described in detail content of the present invention.But embodiment should be interpreted as to limitation of the present invention.Without departing from the idea case in the present invention described above, various replacement means or the change made according to ordinary skill knowledge and conventional means, within being all included in the present invention.
Embodiment 1cGP can suppress the vascular endothelial cell proliferation of IGF-1 mediation
Experimental technique: for the effect of cGP in the vascular endothelial cell proliferation of IGF-1 mediation is described, use respectively IGF-1, IGF-1+cGP and the irrelevant contrast culture human microvascular endothelial cell (mvec) HMEC-1 of 100nM, carried out respectively total cell counting, Control (contrast) at the the 4th, 6,8 and the 10th day.Every group of Data duplication 3 times.For the effect of cGP to various dose IGF-1 is described, HMEC-1 cell is laid in six orifice plates with the density in 30000/hole, after 24h, use respectively 0 (A), IGF-1 and the cGP Combined Treatment of 10 (B) or 50 (C) nM, cell counting after 48h, Control (contrast).
Experimental apparatus: cell counter, cell culture incubator etc.
Experiment conclusion is than matched group, the propagation that IGF-1 can stimulating endothelial cell, and referring to Fig. 1, Control (contrast)
*p<0.01, one factor analysis of variance, Du Kai Shi inspection.The 4th, 6 and the 8th days, the ability of cell proliferation not obviously difference of the cell of simultaneously processing with IGF-1+cGP when separately processing cell with IGF-1, but at the 10th day that processes, the cell number of simultaneously processing with IGF-1+cGP has obvious minimizing when processing with IGF-1 separately.Thereby can determine that cGP can suppress the vascular endothelial cell proliferation of IGF-1 mediation.
Can find out from Fig. 2 A ~ 2C, Control (contrast),
* *p<0.001,
##p<0.01,
###p<0.001; In the time not adding IGF-1, cGP promotes cell proliferation (Fig. 2 A), and when adding the IGF1 (10nM, Fig. 2 B) of low concentration, cGP also can promote the propagation of cell; And for the IGF1 (50nM, Fig. 2 C) of high concentration, cGP can significantly suppress the cell proliferation of IGF-1 mediation.
Embodiment 2cGP can suppress vascular endothelial cell and form pipe spline structure
Experimental technique: human microvascular endothelial cell (mvec) HMEC-1 is processed 6 days with IGF-1, IGF-1+cGP and irrelevant contrast control respectively, then cell is transferred on matrigel and analyzed.Every group of Data duplication 15 times.
Experimental apparatus: cell culture incubator, inverted microscope etc.
Experiment conclusion: Fig. 3 shows, in figure
*p<0.01,
* *p<0.001, than the processed group that only adds IGF-1, the total length of the pipe spline structure that the cell that adds IGF-1+cGP to organize forms is short.Thereby determine that cGP can obviously suppress the formation of the vascular endothelial cell pipe spline structure that IGF-1 induces.
Embodiment 3cGP can suppress the generation of tumor in mice and further develop
Experimental technique: for verify cGP have can prophylaxis of tumours the effect of growth, we have obtained 12 Mus (8 weeks are greatly, male C57BL/c) from University of Auckland.We six every group, are called matched group and cGP group be divided into two groups random mice.We make mouse anesthesia by inject Kate's method bright or xylazine in mouse peritoneum.Then, at every mouse back, approach the otch of the middle about 5-10mm of position incision of omoplate, so just formed a subcutaneous pocket.Then, we have embedded the mini alzet osmotic pumps that has filled with 100 microlitre cGP peptide section solution in this pocket, and otch are sealed by wound clips.Osmotic pump transmits cGP medicine with the dosage of 25mg/kg/ every day.But, because mice is in narcotism, thus on the right side of mice again simultaneously subcutaneous injection EL-4 thymic lymphoma oncocyte (PBS of every 50 microlitres is suspended with 2*10
5individual cell).We after implantation tumour, directly carry out cGP processing (Fig. 4 A) and implantation tumour carries out cGP processing (Fig. 4 B) after 10 days, detect respectively gross tumor volume.
After what Fig. 4 A represented is in tumor cell is just implanted to mice, every other day just detect the measurement whether tumor occurs and carry out tumor size.Fig. 4 A shows that cGP can suppress the tumor growth of tumor.Fig. 4 B processes with cGP after 10 days for implantation tumour cell in mice again, in the time of 10 days, has formed obvious tumor in Mice Body.After processing with cGP, the size of mouse interior tumor is measured and compared.After Fig. 4 B shows that cGP processes, the further growth of inhibition tumor clearly can be after tumor cell injection the 18th day to the 22nd day time.Be generation development and the regeneration that cGP can suppress tumor in mice.The impact of cGP on mouse interior tumor volume.AcGP can suppress the tumor growth of tumor; B cGP can suppress in regeneration Fig. 4 A and Fig. 4 B of tumor
*p<0.05,
*p<0.001.
Synthesizing of 4 three kinds of cGP congeners of embodiment
Synthesized the chemical congener of three kinds of cGP according to following methods.
(S) also [1,2-a] pyrazine-Isosorbide-5-Nitrae-diketone of-2-methyl hexahydropyrrolo
To being dissolved with the chloro-1-hydroxy benzo triazole of proline methyl ester 1 (1mmol) and 6-(6-Cl-HOBt) dichloromethane (CH (1mmol)
2cl
2, 12.5mL) successively add N in solution, N'-DIC (DIC) is (1mmol) and Cbz-Sarcosine 2 (1mmol).Reactant liquor stirring at normal temperature is spent the night, and according to sodium bicarbonate (NaHCO
3, 6mL), 1M hydrochloric acid (HCl, 2x6mL), water (H
2o, 6mL) sequencing washing.By sodium sulfate (Na for organic layer
2sO
4) dry after, vacuum concentration obtains dipeptides 3 except desolventizing; Dipeptides 3 (1mmol) and 10% palladium carbon electrode (1mmol) are dissolved in to methanol (MeOH, 6mL), and in hydrogen balloon, stirring at normal temperature 10 hours.With methanol (MeOH, 3mL) dilution mixed liquor, then filter by Celite pad.Filter cake vacuum drying, and crude product is purified with silica gel column chromatography.Product is dissolved in oxolane (THF, 6mL), is cooled to 0 DEG C, add sodium hydride (NaH 1.5mmol), stirring at normal temperature 1 hour.Phosphate buffer (pH=7,10mL) is joined in reaction system, and by ethyl acetate (EtOAc, 3x10mL) aqueous layer extracted.Sodium sulfate (the Na for organic layer merging
2sO
4) dry, vacuum concentration, obtains crude product and purifies with silica gel column chromatography, finally obtains target compound 4.R
f0.37(7.5%MeOH/CH
2Cl
2);α
D 20–27.6(0.29,CHCl
3),lit.
2α
D–9.24(0.72,CHCl
3);
1H?NMR(CDCl3,300MHz)δ1.78-2.06(m,3H),2.30-2.39(m,1H),2.93(s,3H),3.43-3.63(m,2H),3.74(d,J=16.6Hz,1H),4.02(t,J=7.6Hz,1H),4.12(d,J=16.7Hz,1H);
13C?NMR(CDCl3,75MHz)δ22.4,28.9,33.4,45.1,53.5,58.8,162.7,167.1。
Synthetic skeleton symbol is as follows:
(S)-six hydrogen-1H-pyrrolo-[1,2-a] (Isosorbide-5-Nitrae) diaza-1,5 (2H)-diketone
To being dissolved with proline methyl ester 1 (1mmol), Cbz-Beta-alanine 5 (1mmol) and azimidobenzene-1-tri-(three methylaminos)-trifluoro phosphate ester (BoP) dichloromethane (CH (1.1mmol)
2cl
2, 13mL) and add triethylamine (Et in solution
3n, 3mmol).Reaction mixture stirring at normal temperature is spent the night, and with 2M hydrochloric acid (HCl, 8mL) and sodium bicarbonate (NaHCO
3, 8mL) and washing.By organic layer sodium sulfate (Na for extract
2sO
4) dry after, vacuum concentration is dissolved in methanol (MeOH, 6mL) except desolventizing obtains dipeptides 6. by dipeptides 6, adds 10% palladium carbon electrode (1mmol), by reaction system stirring at normal temperature 10 hours in hydrogen balloon.With methanol (MeOH3mL) dilution mixed liquor, then filter by Celite pad.Filter cake vacuum drying, and crude product is purified with silica gel column chromatography.Product 6 is dissolved in oxolane (THF, 6mL), is cooled to 0 ° of C, add sodium hydride (NaH, 1.5mmol) to stirring at normal temperature in reaction system 1 hour.Phosphate buffer (pH=7,10mL) is joined in reaction system, and by ethyl acetate (EtOAc, 3x10mL) aqueous layer extracted.Sodium sulfate (the Na for organic layer merging
2sO
4) dry, vacuum concentration, obtains crude product and purifies with silica gel column chromatography, finally obtains target compound 7.R
f0.2(7.5%MeOH/CH
2Cl
2);mp?139-142°C,lit.
3mp?166-167°C;α
D 20–24.4(c?0.13,CHCl
3),lit.
3α
D–30(c?1.0,CHCl
3);
1H?NMR(CDCl
3,300MHz)δ1.84-2.15(m,3H),2.58-2.89(m,3H),3.31-3.42(m,1H),3.53-3.74(m,3H),4.52(t,J=7.2Hz,1H),6.39(br?s,1H);
13C?NMR(CDCl
3,75MHz)δ22.5,28.3,36.5,37.6,47.9,57.0,168.8,171.9。
Synthetic skeleton symbol is as follows:
-dihydro-1H-thiazole also [3,4-a) pyrazine-5,8 (3H, 8aH)-diketone
To being dissolved with 3-thioproline methyl ester 8 (1mmol), triethylamine (Et
3n, 1mmol) 0 ° of C solution of oxolane (THF, 5mL) in add isobutyl chlorocarbonate (1mmol).Within 10 minutes, there is white depositions in reaction mixture stirring at normal temperature.By Boc-glycine 9 (1mmol) and triethylamine (Et
3n, 1mmol) water (H
2o, 1.8mL) solution adds in reaction system stirring at normal temperature 1 hour, and with 2M hydrochloric acid (HCl, 4.5mL) dilution, by ethyl acetate (EtOAc, 3x8mL) aqueous layer extracted.Sodium sulfate (the Na for organic layer merging
2sO
4) be dried and use vacuum concentration, obtain crude product dipeptides 10. dipeptides 10 (1mmol) is dissolved in to dichloromethane (CH
2cl
2, 20mL), add trifluoroacetic acid (2mL), stirring at normal temperature 3 hours.Distilling under reduced pressure is except desolventizing, by residue and ether (Et
2o) grind, obtain trifluoroacetate.It is dissolved in to oxolane (THF, 6mL) at 0 ° of C, adds sodium hydride (NaH, 1.5mmol) to stirring at normal temperature in reaction system 1 hour.Phosphate buffer (pH=7,10mL) is joined in reaction system, and by ethyl acetate (EtOAc, 3x10mL) aqueous layer extracted.Sodium sulfate (the Na for organic layer merging
2sO
4) dry, vacuum concentration, obtains crude product and purifies with silica gel column chromatography, finally obtains target compound 11.R
f0.29 (7.5%MeOH/CH
2cl
2); Mp 133-135 ° C; < due to 11 in alcoholic solution part solvable, so α
dvalue is not measured >
1h NMR (MeOD, 300MHz) δ 3.25 (dd, J=11.4,9.3Hz; 1H), 3.40 (dd, J=11.4,6.4Hz; 1H), 3.85 (d, J=17.2Hz; 1H), 4.14 (d, J=17.2Hz; 1H), 4.42-4.50 (m, 2H); 4.87 (d, J=9.8Hz, 1H);
13c NMR (MeOD, 75MHz) δ 33.8,46.8,48.7,62.0,169.4,178.1; IR (film) 724,1132,1203,1447,1652,1675,2853,2922,3431; HRMS Found (ESI+): (M+Na)
+, 195.0205, C
6h
8n
2naO
2s requires 195.0199.
Synthetic skeleton symbol is as follows:
Three kinds of congeners of embodiment 5cGP can inhibition tumor cell propagation
Experimental technique: use respectively IGF-1, IGF-1+ (S)-2-methyl hexahydropyrrolo also [1,2-a] pyrazine-1,4-diketone (A), IGF-1+ (S)-six hydrogen-1H-pyrrolo-[1,2-a] (1,4) diaza-1,5 (2H)-diketone (B) and IGF-1+ (R)-dihydro-1H-thiazole also [3,4-a) pyrazine-5,8 (3H, 8aH)-diketone (C) is processed T47D breast cancer cell, after 48h, cell is carried out to cell counting.
Experimental apparatus: cell culture incubator, inverted microscope etc.
Fig. 5 A, Fig. 5 B and Fig. 5 C show, are processing after T47D breast cancer cell 48h, and than matched group, IGF-1 can significantly promote the propagation of cell.And than the cell of processing with IGF-1 separately, use IGF-1+ (S)-2-methyl hexahydropyrrolo also [1 simultaneously, 2-a] pyrazine-Isosorbide-5-Nitrae-diketone, IGF-1+ (S)-six hydrogen-1H-pyrrolo-[1,2-a] (1,4) diaza-1,5 (2H)-diketone or IGF-1+ (R)-dihydro-1H-thiazole also [3,4-a) pyrazine-5,8 (3H, 8aH)-diketone, can significantly suppress the propagation of T47D breast cancer cell.Data show, three kinds of congeners (S)-2-methyl hexahydropyrrolo of cGP also [1,2-a] pyrazine-1,4-diketone, (S)-six hydrogen-1H-pyrrolo-[1,2-a] (Isosorbide-5-Nitrae) diaza-1,5 (2H)-diketone and (R)-dihydro-1H-thiazole also [3,4-a) pyrazine-5,8 (3H, 8aH)-diketone all can suppress the T47D Cells Proliferation of Human Breast Cancer of IGF-1 induction.In each figure
*p<0.05,
*p<0.001,
* *p<0.001,
##p<0.01,
###p<0.001.
Claims (4)
1. the congener of ring (dried meat-Gan) dipeptides suppresses the application in tumor growth and regenerating medicine in preparation; The congener of described ring (dried meat-Gan) dipeptides is: (S)-2-methyl hexahydropyrrolo also [1,2-a] pyrazine-1,4-diketone, (S)-six hydrogen-1H-pyrrolo-[1,2-a] (1,4) diaza-1,5(2H)-diketone, also [3,4-a] pyrazine-5 of (R)-dihydro-1H-thiazole, 8(3H, 8aH)-diketone.
2. the congener of ring according to claim 1 (dried meat-Gan) dipeptides suppresses the application in tumor growth and regenerating medicine in preparation, and described (the S)-2-methyl hexahydropyrrolo also preparation method of [1,2-a] pyrazine-Isosorbide-5-Nitrae-diketone is:
3. the congener of ring according to claim 1 (dried meat-Gan) dipeptides suppresses the application in tumor growth and regenerating medicine, described (S)-six hydrogen-1H-pyrrolo-[1,2-a] (Isosorbide-5-Nitrae) diaza-1,5(2H in preparation) preparation method of-diketone is:
4. the congener of ring according to claim 1 (dried meat-Gan) dipeptides suppresses the application in tumor growth and regenerating medicine, described also [3,4-a] pyrazine-5 of (R)-dihydro-1H-thiazole, 8(3H, 8aH in preparation) preparation method of-diketone is:
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