Modified cyclic pentapeptide compounds, methods of making and uses thereof, and cyclic pentapeptides and compositions containing modified cyclic pentapeptides

Abstract

The present application provides a modified cyclic pentapeptide compound, a preparation method and use thereof, and a cyclic pentapeptide and a composition containing the modified cyclic pentapeptide. Specifically provided is a modified cyclic pentapeptide compound, in formula (I), R 1 , R 2 , R 3 and R 4 are independently H, methyl, hydroxymethyl or phenyl, wherein the phenyl is optionally substituted by one or more R a , R a is independently hydroxyl, and n is an integer from 3 to 10. The modified cyclic pentapeptide provided by the present application has one or more aspects of effects such as oil control, moisturizing, repair and soothing, and has a good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of cosmetics, and particularly relates to a modified cyclopentapeptide compound, a preparation method and use thereof, and a cyclopentapeptide and a composition containing the modified cyclopentapeptide. BACKGROUND

[0002] With the aggravation of environmental pollution and the upgrading of consumer skin care needs, cosmetic ingredients with multiple effects of oil control, soothing repair, and moisture retention have become a research hotspot. The sebaceous gland unit is composed of sebaceous glands, hair follicles, and surrounding matrix, and its abnormal activity is regulated by multiple signaling pathways. The problem of oily skin caused by excessive secretion of sebum (such as acne, large pores, seborrheic dermatitis, etc.) is often accompanied by impaired barrier function, leading to inflammatory reactions and skin sensitivity. Traditional oil control ingredients (such as zinc salt, salicylic acid) can regulate oil secretion in the short term, but they can easily cause dryness or irritation of the skin, and damage the skin barrier; while repair ingredients (such as ceramides, plant extracts) are difficult to meet the demand for oil control, and have the problem of single efficacy.

[0003] In recent years, cyclic peptides have attracted attention due to their high structural stability, strong transdermal absorption, and multifunctional biological activity. For example, natural or synthetic cyclic peptides can exhibit anti-inflammatory repair potential by inhibiting inflammatory factors (such as TNF-α, IL-6, etc.), or regulate sebaceous glands by regulating lipid metabolism-related pathways (such as the mTOR pathway, the PPARγ pathway, etc.), thereby affecting oil secretion. However, there are still problems in the prior art: the extraction efficiency of natural cyclic peptides is low, the separation process is complex and costly, and it is difficult to be industrialized; synthetic cyclic peptides have single function, most of which only focus on a single effect (such as antibacterial or anti-inflammatory), and lack the design of integrating oil control, anti-inflammatory soothing, and repair and moisturizing effects; the mechanism is not clear, it is easy to destroy the balance of skin microecology, and lacks precise regulation of key targets of lipid metabolism. In the prior art, multiple active ingredients are often introduced into cosmetic compositions to have multiple effects, and there is no report of synthetic cyclic peptides with the above multiple effects.

[0004] Therefore, the development of cyclic peptide molecules with multiple effects of oil control, soothing, and repair, the breakthrough of the limitation of single effect of traditional ingredients, and the optimization of the structure of cyclic peptides to enhance their transdermal absorption and stability will have great application prospects in the field of cosmetics. SUMMARY

[0005] The technical problem to be solved by the present application is to overcome the defect of single function of cyclic peptides in the prior art. Therefore, the present application provides a modified cyclopentapeptide compound, a preparation method and use thereof, and a cyclopentapeptide and a composition containing the modified cyclopentapeptide. The cyclic polypeptide provided by the present application has one or more aspects of effects such as oil control, moisturizing, repair, and soothing, and has good application prospects.

[0006] The present application solves the above technical problems through the following scheme.

[0007] The present invention provides a modified cyclic pentapeptide compound;

[0008]

[0009] In formula (I), R 1 、R 2 、R 3 and R 4 are independently H, methyl, hydroxymethyl or phenyl, wherein the phenyl group is optionally replaced by one or more R a replace;

[0010] R a are independently hydroxyl groups;

[0011] n is an integer from 3 to 10.

[0012] In one embodiment, certain groups in the modified cyclic pentapeptide compound have the following definitions, and the definitions of the groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "one embodiment"):

[0013] In one embodiment, n is 4, 5, 6, 7 or 8.

[0014] In one embodiment, R1, R2, R3 and R4 are independently H, methyl, -CH2OH, phenyl or -C6H4OH (e.g. ), for example, R1, R2, R3 and R4 are independently H, methyl or -CH2OH.

[0015] In one embodiment, one, two, three or four of R1, R2, R3 and R4 are H. Preferably, R1, R2, R3 and R4 are H.

[0016] In one plan, for 、 、 、 、 、 、 or .

[0017] In one plan, is any of the following groups:

[0018]

[0019]

[0020] .

[0021] In one aspect, the modified cyclic pentapeptide compound has a structure of:

[0022]

[0023] In Formula (II), n is an integer of 3 to 10 (e.g., an integer of 4 to 8).

[0024] In one aspect, the modified cyclic pentapeptide compound is any one of Formula (1-1) to Formula (1-24):

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032] .

[0033] The present application provides a modified cyclic pentapeptide-containing composition comprising the modified cyclic pentapeptide compound according to any one of the aspects of the present application.

[0034] The modified cyclic pentapeptide-containing composition can comprise an auxiliary material, which is a conventional auxiliary material in the art, e.g., one or more of a filler, a humectant, an emulsifier, a thickening agent, a metal ion masking agent, a colorant, a pH adjustor, a skin nutrient, a vitamin, a preservative, an antioxidant, an antioxidant aid, and a fragrance.

[0035] The modified cyclic pentapeptide compound can be contained in the composition in an amount of 50 to 1000 ppm, e.g., 50 ppm, 100 ppm, 125 ppm, 200 ppm, 250 ppm, or 1000 ppm.

[0036] The composition can comprise the modified cyclic pentapeptide compound, 4% 1,3-butanediol, 0.5% betaine, 0.02% sodium hyaluronate, 0.08% xanthan gum, 0.3% phenoxyethanol, and water, wherein the percentages (%) are the mass percentages of the components in the composition, and the modified cyclic pentapeptide compound is contained in the composition in an amount of 50 to 1000 parts per million (ppm).

[0037] The composition can be used as a skin care product or a cosmetic product.

[0038] The composition can have one or more of the following effects: oil control, moisturization, repair (barrier-related proteins), and soothing (e.g., reducing inflammatory response, relieving redness, itching, stinging, burning).

[0039] The modified cyclic pentapeptide compound in the composition has an inhibition rate of 29.12% to 43.70% for inhibiting 5α-reductase activity when the content of the modified cyclic pentapeptide compound is, for example, 1000 ppm.

[0040] The modified cyclic pentapeptide compound in the composition has an inhibition rate of 20.10% or more for reducing the lipid secretion amount of sebaceous gland cells when the content of the modified cyclic pentapeptide compound is, for example, 125 ppm or more.

[0041] The modified cyclic pentapeptide compound in the composition has an inhibition rate of 40.01% or more for reducing the lipid secretion amount of sebaceous gland cells when the content of the modified cyclic pentapeptide compound is, for example, 250 ppm or more.

[0042] The modified cyclic pentapeptide compound in the composition has a skin water content increase of 38.7% or more when the percentage content of the modified cyclic pentapeptide compound is, for example, 0.1% or more.

[0043] The modified cyclic pentapeptide compound in the composition has a skin water content increase of 58.57% or more when the percentage content of the modified cyclic pentapeptide compound is, for example, 1% or more.

[0044] The modified cyclic pentapeptide compound in the composition has a skin water content increase of 101.46% or less when the percentage content of the modified cyclic pentapeptide compound is, for example, 2% or less.

[0045] The modified cyclic pentapeptide compound in the composition has a FLG content increase rate of 99.19% and a TGM1 content increase rate of 540.76% when the percentage content of the modified cyclic pentapeptide compound is, for example, 0.1%.

[0046] The modified cyclic pentapeptide compound in the composition has an inhibition rate of 48.44% to 57.93% and 22.48% to 29.16% for inhibiting the expression of inflammatory factors IL-6 and TNF-α, respectively, when the content of the modified cyclic pentapeptide compound is, for example, 100 ppm.

[0047] The modified cyclic pentapeptide compound in the composition has an inhibition rate of 8.4% to 10.5% for water loss, a skin stratum corneum water content increase rate of 13.8% to 15.4%, a skin surface oil content reduction of 2.5% to 3.8%, and a skin redness relief rate of 14.7% to 16.6% over a 28-day test period when the content of the modified cyclic pentapeptide compound is, for example, 50 ppm.

[0048] The present application also provides a use of the modified cyclic pentapeptide compound according to any one of the present application; the use includes (1) for preparing a cosmetic or skin care product; and (2) for preparing a cleansing and care product. In the use, the cleansing and care product, the cosmetic and the skin care product can have one or more of the following effects: oil control, moisturizing, repair (barrier-related proteins) and soothing (e.g. reducing inflammatory response, relieving redness, itching, stinging, burning).

[0049] The present application also provides a use of the modified cyclic pentapeptide compound according to any one of the present application; the use includes (1) for preparing a cosmetic or skin care product; and (2) for preparing a cleansing and care product. In the use, the cleansing and care product, the cosmetic and the skin care product can have one or more of the following effects: oil control, moisturizing, repair (barrier-related proteins) and soothing (e.g. reducing inflammatory response, relieving redness, itching, stinging, burning).

[0050] The present application provides a preparation method of the modified cyclic pentapeptide compound according to any one of the present application, which comprises the following steps: carrying out a nucleophilic addition reaction between a cyclic pentapeptide and an acyl halide compound in an organic solvent to obtain a modified cyclic pentapeptide compound.

[0051]

[0052] In formula (Ib), X is halogen, for example Cl.

[0053] In formula (Ib), n is a numerical value as defined in any one of the present application.

[0054] In formula (Ia), R 1 , R 2 , R 3 and R 4 are substituents as defined in any one of the present application.

[0055] In the nucleophilic addition reaction, the organic solvent is for example an ether solvent, for example THF.

[0056] The nucleophilic addition reaction can be carried out in the presence of an organic base, for example triethylamine.

[0057] The nucleophilic addition reaction can be carried out at 5-30°C, for example at 5-10°C or at 25°C.

[0058] The present application provides a cyclic pentapeptide;

[0059]

[0060] In formula (Ia), R 1 , R 2 , R3 and R 4 independently is a substituent as defined in any aspect of the present invention.

[0061] Preferably, the cyclic pentapeptide is any one of the following compounds:

[0062]

[0063]

[0064]

[0065]

[0066]

[0067] .

[0068] The method for preparing the modified cyclic pentapeptide compound can comprise the following preparation steps:

[0069] Step S1: reacting the CTC resin with an Fmoc group-protected amino acid or substituted amino acid to obtain a peptide resin of H-AA1-AA2-AA3-AA4-AA5-CTC resin;

[0070] Step S2: removing the resin from the peptide resin to obtain a fully protected linear polypeptide H-AA1-AA2-AA3-AA4-AA5-OH;

[0071] Step S3: subjecting the fully protected linear polypeptide H-AA1-AA2-AA3-AA4-AA5-OH to a cyclization reaction to obtain a fully protected cyclic peptide Cyclo(AA1-AA2-AA3-AA4-AA5);

[0072] Step S4: removing the protecting groups from the above-mentioned fully protected cyclic peptide to obtain a deprotected crude peptide powder Cyclo(BB1-BB2-BB3-BB4-BB5);

[0073] Step S5: reacting the above-mentioned crude peptide Cyclo(B1-BB2-BB3-BB4-BB5) with an alkyl acid chloride to obtain an acylated crude peptide powder CH3(CH2) n CO-Cyclo(BB1-BB2-BB3-BB4-BB5), n is an integer from 3 to 10;

[0074] Step S6: purifying by reverse-phase preparative HPLC and lyophilizing to obtain an acylated modified cyclic pentapeptide pure product, i.e., an oil control, repair, and soothing modified cyclic pentapeptide compound CH3(CH2) nCO-Cyclo(BB1-BB2-BB3-BB4-BB5), n is an integer from 3 to 10;

[0075] AA1, AA2, AA3, AA5 are selected from Gly, Gly(Ph), Gly(Ph-4-OH), Ala or Ser, AA4 is Lys(Boc); BB1, BB2, BB3, BB5 are selected from Gly, Gly(Ph), Gly(Ph-4-OH), Ala or Ser, BB4 is Lys. Preferably, the amino acid reagent protected with Fmoc group in the step S1 includes Fmoc-Gly-OH, Fmoc-Gly(Ph)-OH, Fmoc-Gly(Ph-4-OH), Fmoc-Ala-OH, Fmoc-Ser-OH, Fmoc-Lys(Boc)-OH. Preferably, the alkyl chloride reagent in the step S5 includes valeryl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, undecanoyl chloride, lauryl chloride.

[0076] Terminology :

[0077] In the present application, those skilled in the art can understand that the "adjuvant" should meet the application purpose of the present application, which refers to the conventional adjuvant of cosmetics.

[0078] On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, that is, the preferred examples of the present application are obtained.

[0079] The reagents and raw materials used in the present application are commercially available.

[0080] The positive progress effect of the present application is that the modified cyclic pentapeptide compound provided by the present application has one or more of the following advantages:

[0081] (1) The modified cyclic pentapeptide skeleton is derived from natural amino acids or modified natural amino acids, and has low cytotoxicity;

[0082] (2) It can significantly reduce the activity of 5α-reductase and inhibit the lipid secretion amount of human sebaceous gland cells, and has the effects of controlling oil and acne removal;

[0083] (3) It can significantly increase the water content of epidermal skin models, and has the effect of moisturizing;

[0084] (4) It can increase the expression of barrier-related proteins (FLG, TGM1), and has the effect of repair;

[0085] (5) It can significantly reduce the expression of inflammatory factors interleukin-6 and TNF-α, and has the effect of anti-inflammatory and soothing.

[0086] Therefore, the modified cyclic pentapeptide compound provided by the application has good oil control, anti-inflammatory soothing and repair and moisturizing effects, can be used for preparing skin care products, regulates the secretion of sebaceous gland oil, and has skin barrier repair effect. BRIEF DESCRIPTION OF DRAWINGS

[0087] Figure 1 The mass spectrum of the modified cyclic pentapeptide of formula (1-1).

[0088] Figure 2 The HPLC spectrum of the modified cyclic pentapeptide of formula (1-1).

[0089] Figure 3 The column chart of the skin water content.

[0090] Figure 4 The column chart of the FLG integral optical density (IOD) value.

[0091] Figure 5 The immunofluorescence chart of the FLG of each group.

[0092] Figure 6 The column chart of the TGM1 integral optical density (IOD) value.

[0093] Figure 7 The immunofluorescence chart of the TGM1 of each group. DETAILED DESCRIPTION

[0094] The application will be further described below by way of examples, but the application is not limited to the scope of the examples. The experimental methods in the following examples are not specified, and are selected according to conventional methods and conditions, or according to the instructions of the products.

[0095] Example 1 Preparation method of modified cyclic pentapeptide

[0096] The structures and numbers of the compounds of formula (1-1) to formula (1-24) synthesized in the embodiments of the application are the same as described above.

[0097] The reagent information used in the preparation process of the embodiments of the application is shown in Table 1.

[0098] Table 1 Reagent information used

[0099]

[0100] The modified cyclic pentapeptide is prepared by the method of amide condensation by using a solid-phase synthesizer. For example, the modified cyclic pentapeptide of formula (1-1) is prepared by using Gly as AA1, AA2, AA3 and AA5, Lys (Boc) as AA4, and octanoyl chloride as the alkyl chlorides.

[0101] The step S1 specifically includes:

[0102] Step S11: Take Fmoc-Gly-OH (21.41 g, 72 mmol), HOBt (9.73 g, 72 mmol), DMF 250 mL in a 500 mL beaker, ice bath cooling to 4 °C, then add DIC (9.09 g, 72 mmol) and stir for 10 minutes. Pour the reaction solution into a 500 mL solid phase synthesis reactor containing 50 g of 2-CTC resin (substitution degree 0.72 mmol / g), stir for 1.5 hours, and the reaction is complete. The resin is washed with DMF three times, 250 mL each time. After washing is complete, 20% Pip / DMF solution 250 mL is added to the resin, stirred for 30 min, filtered, and the deprotection solution is removed. Then wash the resin with DMF 6 times, 250 mL each time, rotary evaporate the solvent under reduced pressure, and add it again into the solid phase synthesis reactor.

[0103] Step S12: Repeat step S11, and sequentially take Fmoc-Lys(Boc)-OH (33.74 g, 72 mmol), Fmoc-Gly-OH (21.41 g, 72 mmol), Fmoc-Gly-OH (21.41 g, 72 mmol), and Fmoc-Gly-OH (21.41 g, 72 mmol) and add them into the solid phase synthesis reactor. After each coupling and deprotection reaction is complete, wash the resin thoroughly with DMF. After the last amino acid coupling, wash with DMF 6 times, 250 mL each time; methanol 2 times, 250 mL each time; DCM 2 times, 250 mL each time, and rotary evaporate the solvent under reduced pressure to obtain the peptide resin.

[0104] Step S2: After drying the resin, add 1% TFA / DCM solution 5.0 L, stir at 30 °C for 30 minutes, filter, remove the resin, and obtain the filtrate. Rotary evaporate the solvent under reduced pressure to obtain the protected linear peptide H-Gly-Gly-Gly-Lys(Boc)-Gly-OH.

[0105] Step S3: 2 L of dichloromethane, 27.17 g of HBTU, H-Gly-Gly-Gly-Lys(Boc)-Gly-OH obtained in the previous step were added to a 5 L reaction flask, and after the solution was stirred to be clear, the internal temperature was kept at 5-10 °C, and DIEA (37.04 g) was added dropwise. After the dropwise addition was completed, the reaction was carried out at room temperature for 5 h while controlling the pH of the solution to be 7.0-7.5. After the reaction was completed by HPLC detection, the filtrate was concentrated under reduced pressure at 40 °C. The obtained solid was dissolved in 170 g of ethyl acetate, and the solution was washed with saturated sodium bicarbonate solution three times, washed with saturated sodium chloride solution three times, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C to obtain a solid, forming a cyclic peptide Cyclo(Gly-Gly-Gly-Lys(Boc)-Gly).

[0106] Step S4: 1,4-dioxane (100 g), the solid Cyclo(Gly-Gly-Gly-Lys(Boc)-Gly) obtained in the previous step were added to a 250 mL three-necked flask, and the solution was stirred to be clear at room temperature while controlling the temperature to be 5-15 °C, 50 mL of HCL / 1,4-dioxane solution was added, and after the dropwise addition was completed, the reaction was continued for 2 h, a large amount of white solid was precipitated, and the solid was filtered and dried to obtain a crude deprotected cyclic peptide Cyclo(Gly-Gly-Gly-Lys-Gly).

[0107] Step S5: 100 g of THF, 7.25 g of triethylamine, the solid Cyclo(Gly-Gly-Gly-Lys-Gly) obtained in the previous step were added to a 250 mL three-necked flask, and the solution was stirred while keeping the internal temperature at 5-10 °C, and a solution containing octanoyl chloride in THF (8.74 g of octanoyl chloride dissolved in 10.00 g of THF) was added dropwise; after the dropwise addition was completed, the reaction was continued for 1 h while keeping the temperature, and then the temperature was increased to 25 °C and the reaction was continued for 2 h. After the reaction was completed by HPLC detection, the filtrate was concentrated under reduced pressure at 45 °C, the obtained solid was dissolved in 75 g of methanol, and then added dropwise into 300 g of methyl tert-butyl ether, and a white solid was precipitated and filtered. The solid was dried under vacuum at 45 °C to obtain a crude modified cyclic pentapeptide (Formula 1-1) CH3(CH2)6CO-Cyclo(Gly-Gly-Gly-Lys-Gly).

[0108] Step S6: Purification by reverse phase C18 preparative chromatography, and freeze-drying to obtain a pure modified cyclic pentapeptide of Formula (1-1). The sample was subjected to structure confirmation by nuclear magnetic resonance spectroscopy, high resolution mass spectrometry, and high performance liquid chromatography.

[0109] (I) Nuclear magnetic resonance spectroscopy (NMR)

[0110] Instrument: BRUKER AVANCE III 600 nuclear magnetic resonance spectrometer

[0111] Solvent: DMSO-d6 (Deuterated dimethyl sulfoxide)

[0112] 1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.38 (10H, 1.24 (quint, J =7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.25 (quint, J =7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.28 (h, J =7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.31 (tt, J = 7.3, 7.1 Hz), 1.31 (tt, J = 7.3,7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H,1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19(t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz),3.18 (t, J = 7.0 Hz)), 3.61-4.06 (8H, 3.68 (d, J = 17.3 Hz), 3.72 (d, J =17.3 Hz), 3.85 (d, J = 17.3 Hz), 3.88 (d, J = 17.1 Hz), 3.89 (d, J = 17.3Hz), 3.92 (d, J = 17.3 Hz), 3.96 (d, J = 17.1 Hz), 3.99 (d, J = 17.3 Hz)),4.41 (1H, t, J = 4.7 Hz).

[0113] (II) High resolution mass spectrometry

[0114] Instrument model: Thermo Fisher Q Exactive

[0115] Ion source: ESI source

[0116] Mobile phase: 80% MeOH in water

[0117] Test data and interpretation: Molecular formula C 22 H 38 N6O6, [M+Na]+ found 505.2745, 505.2738. Mass spectrum is shown in Figure 1 .

[0118] (III) HPLC

[0119] Instrument model: SHIMADZU Prominence LC-20A high performance liquid chromatograph

[0120] Column: ACE Excel 5 AQ, 250 x 4.6 mm

[0121] Elution conditions: 5%-95% MeCN / H2O gradient elution for 20 minutes, peak time t = 15.6 min

[0122] Sample concentration: 1 mg / mL

[0123] Injection volume: 20 μL

[0124] Detection wavelength: 200 nm

[0125] Sample purity: 96%

[0126] HPLC spectrum is shown in Figure 2 .

[0127] The preparation method of the modified cyclopentapeptide of formula (1-2) is as follows: the raw materials and the preparation method are basically the same as those in Example 1, except that the Gly of AA1 is replaced by Gly(Ph), and the modified cyclopentapeptide compound CH3(CH2)6CO-Cyclo(Gly(Ph)-Gly-Gly-Lys-Gly) shown in formula (1-2) is prepared.1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.39 (10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.32 (tt, J = 7.3, 7.1 Hz), 1.32 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.66-4.07 (6H, 3.73 (d, J = 17.3 Hz), 3.86 (d, J = 17.3 Hz), 3.88 (d, J = 17.2 Hz), 3.90 (d, J = 17.3 Hz), 3.97 (d, J = 17.2 Hz), 3.99 (d, J = 17.3 Hz)), 4.41 (1H, t, J = 4.7 Hz), 5.41 (1H, s), 7.27-7.52 (5H, 7.33 (tt, J = 7.7, 1.6 Hz), 7.45 (dddd, J = 7.9, 7.7, 1.6, 0.5 Hz), 7.45 (dddd, J = 7.9, 1.6, 1.3, 0.5 Hz)).

[0128] The preparation method of the modified cyclic pentapeptide of formula (1-3) is as follows: the raw materials and preparation method are basically the same as those in Example 1, except that the Gly of AA1 and AA2 are both replaced by Gly(Ph), to obtain the modified cyclic pentapeptide compound CH3(CH2)6CO-Cyclo(Gly(Ph)-Gly(Ph)-Gly-Lys-Gly) shown in formula (1-3).1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.39 (10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J= 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J= 7.7, 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.32 (tt, J =7.3, 7.1 Hz), 1.32 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7,7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J= 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J =7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)),3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.79-4.07 (4H,3.87 (d, J = 17.3 Hz), 3.87 (d, J = 17.3 Hz), 3.94 (d, J = 17.3 Hz), 4.00 (d,J = 17.3 Hz)), 4.41 (1H, t, J = 4.7 Hz), 5.33 (1H, s), 5.52 (1H, s), 7.28-7.52 (10H, 7.34 (tt, J = 7.7, 1.6 Hz), 7.34 (tt, J = 7.7, 1.6 Hz), 7.45 (dddd, J = 7.9, 7.7, 1.6, 0.5 Hz), 7.45 (dddd, J = 7.9, 7.7, 1.6, 0.5 Hz),7.45 (dddd, J = 7.9, 1.6, 1.3, 0.5 Hz), 7.45 (dddd, J = 7.9, 1.6, 1.3, 0.5Hz))..

[0129] The preparation method of the modified cyclic pentapeptide of formula (1-4) is as follows: the raw materials and preparation method are basically the same as those in Example 1, except that the Gly of AA1, AA2 and AA3 is replaced by Gly(Ph), to obtain the modified cyclic pentapeptide compound CH3(CH2)6CO-Cyclo(Gly(Ph)-Gly(Ph)-Gly(Ph)-Lys-Gly) shown in formula (1-4).1H NMR: δ 0.86 (3H, t, J = 7.0Hz), 1.18-1.34 (10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25(quint, J = 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz),1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J = 7.3, 7.1 Hz), 1.26 (tt, J = 7.3,7.1 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz)), 1.46-1.64 (4H, 1.53(tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.57 (tt, J = 7.3, 7.0Hz), 1.57 (tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.74 (td, J = 7.1, 4.7 Hz),1.74 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J= 7.4 Hz)), 3.11-3.23 (2H, 3.17 (t, J = 7.0 Hz), 3.17 (t, J = 7.0 Hz)), 3.80-4.07 (2H, 3.87 (d, J = 17.3 Hz), 4.00 (d, J = 17.3 Hz)), 4.45 (1H, t, J = 4.7Hz), 5.33 (1H, s), 5.56-5.69 (2H, 5.61 (s), 5.64 (s)), 7.28-7.52 (15H, 7.34(tt, J = 7.7, 1.7 Hz), 7.34 (tt, J = 7.7, 1.7 Hz), 7.34 (tt, J = 7.7, 1.6Hz), 7.45 (dddd, J = 7.9, 7.7, 1.6, 0.5 Hz), 7.45 (dddd, J = 7.9, 7.7, 1.6,0.5 Hz), 7.45 (dddd, J = 7.9, 7.7, 1.6, 0.5 Hz), 7.45 (dddd, J = 7.9, 1.6,1.3, 0.5 Hz), 7.46 (dddd, J = 7.9, 1.7, 1.4, 0.5 Hz), 7.46 (dddd, J = 7.9,1.7, 1.3, 0.5 Hz))..

[0130] The preparation method of the modified cyclic pentapeptide of formula (1-5) is as follows: the raw materials and preparation method are basically the same as those in Example 1, except that the Gly of AA1, AA2, AA3 and AA5 is replaced by Gly(Ph) to obtain the modified cyclic pentapeptide compound CH3(CH2)6CO-Cyclo(Gly(Ph)-Gly(Ph)-Gly(Ph)-Lys-Gly(Ph)) shown in formula (1-5).1H NMR: δ 0.86 (3H, t, J =7.0 Hz), 1.18-1.34 (10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz),1.25 (tt, J = 7.3, 7.0 Hz), 1.25 (tt, J = 7.3, 7.0 Hz), 1.25 (quint, J = 7.0Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (quint, J =7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz)), 1.46-1.64 (4H, 1.53(tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.58 (tt, J = 7.3, 7.0Hz), 1.58 (tt, J = 7.3, 7.0 Hz)), 1.68-1.81 (2H, 1.75 (td, J = 7.0, 4.7 Hz),1.75 (td, J = 7.0, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J= 7.4 Hz)), 3.11-3.23 (2H, 3.17 (t, J = 7.0 Hz), 3.17 (t, J = 7.0 Hz)), 4.53(1H, t, J = 4.7 Hz), 5.37 (1H, s), 5.56-5.79 (3H, 5.61 (s), 5.64 (s), 5.74(s)), 7.28-7.52 (20H, 7.34 (tt, J = 7.7, 1.7 Hz), 7.34 (tt, J = 7.7, 1.7 Hz),7.34 (tt, J = 7.7, 1.7 Hz), 7.34 (tt, J = 7.7, 1.7 Hz), 7.45 (dddd, J = 7.9, 7.7, 1.6, 0.5 Hz), 7.45 (dddd, J = 7.9, 7.7, 1.6, 0.5 Hz), 7.45 (dddd, J = 7.9, 7.7, 1.6, 0.5 Hz), 7.45 (dddd, J = 7.9, 7.7, 1.6, 0.5 Hz), 7.46 (dddd, J = 7.9, 1.7, 1.4, 0.5 Hz), 7.46 (dddd, J = 7.9, 1.7, 1.4, 0.5 Hz), 7.46 (dddd, J = 7.9, 1.7, 1.3, 0.5 Hz), 7.46 (dddd, J = 7.9, 1.7, 1.3, 0.5 Hz))..

[0131] Preparation method of modified cyclopentapeptide of formula (1-6): the raw materials and preparation method used are basically the same as those in Example 1, except that the Gly of AA1 is replaced by Gly(Ph-4-OH), to obtain a modified cyclopentapeptide compound CH3(CH2)6CO-Cyclo(Gly(Ph-4-OH)-Gly-Gly-Lys-Gly) shown in formula (1-6).1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.39 (10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J= 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J= 7.7, 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.32 (tt, J =7.3, 7.1 Hz), 1.32 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7,7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J= 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J =7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)),3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.66-4.07 (6H,3.73 (d, J = 17.3 Hz), 3.86 (d, J = 17.3 Hz), 3.88 (d, J = 17.2 Hz), 3.90 (d,J = 17.3 Hz), 3.97 (d, J = 17.2 Hz), 4.00 (d, J = 17.3 Hz)), 4.41 (1H, t, J =4.7 Hz), 5.29 (1H, s), 6.68 (2H, ddd, J = 8.3, 1.1, 0.5 Hz), 7.26 (2H, ddd, J= 8.3, 1.3, 0.5 Hz).

[0132] Preparation method of modified cyclopentapeptide of formula (1-7): the raw materials and preparation method used are basically the same as those in Example 1, except that the Gly of AA1 and AA2 are both replaced by Gly(Ph-4-OH), to obtain a modified cyclopentapeptide compound CH3(CH2)6CO-Cyclo(Gly(Ph-4-OH)-Gly(Ph-4-OH)-Gly-Lys-Gly) shown in formula (1-7).1H NMR: δ 0.86 (3H, t, J= 7.0 Hz), 1.18-1.39 (10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0Hz), 1.25 (quint, J = 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7,7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0Hz), 1.32 (tt, J = 7.3, 7.1 Hz), 1.32 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H,1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3,7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7Hz), 1.73 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19(t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)),3.79-4.07 (4H, 3.87 (d, J = 17.3 Hz), 3.87 (d, J = 17.3 Hz), 3.94 (d, J =17.3 Hz), 4.00 (d, J = 17.3 Hz)), 4.41 (1H, t, J = 4.7 Hz), 5.21 (1H, s),5.40 (1H, s), 6.62-6.75 (4H, 6.68 (ddd, J = 8.3, 1.1, 0.5 Hz), 6.68 (ddd, J =8.3, 1.1, 0.5 Hz)), 7.20-7.33 (4H, 7.26 (ddd, J = 8.3, 1.3, 0.5 Hz), 7.26(ddd, J = 8.3, 1.3, 0.5 Hz)).

[0133] Preparation method of modified cyclopentapeptide of formula (1-8): the raw materials and preparation method used are basically the same as those in Example 1, except that the Gly of AA1, AA2 and AA3 are all replaced by Gly(Ph-4-OH), to prepare a modified cyclopentapeptide compound CH3(CH2)6CO-Cyclo(Gly(Ph-4-OH)-Gly(Ph-4-OH)-Gly(Ph-4-OH)-Lys-Gly) shown in formula (1-8).1H NMR: δ 0.86(3H, t, J = 7.0 Hz), 1.18-1.34 (10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J= 7.0 Hz), 1.25 (quint, J7 ( quint 7.0 = Hz) 1.26 (tt, J =7.7, 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J = 7.3, 7.1 Hz), 1.26(tt, J = 7.3, 7.1 Hz), 1.27 (J = 7.0, J = Hz)), 1.46-1.64(4H, 1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.57 (tt, J =7.3, 7.0 Hz), 1.57 (tt, J =7.3, 7.0 Hz), 1.57 (tt, J = 7.8.3). (2H, 1.74 (td, J = 7.1,4.7 Hz), 1.74 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz),2.19 (t, J = 7.3.3.1 Hz) (t, J = 7.0 Hz), 3.17 (t, J = 7.0Hz)), 3.80–4.07 (2H, 3.87 (d, J = 17.3 Hz)), 4.00 (d, J = 17.3 Hz)), 4.45 (1H,t, J = 4.7), 4.7. 5.37–5.56 (2H, 5.42 (s), 5.51 (s)), 6.62–6.75(6H, 6.68 (ddd, J = 8.3, 1.1, 0.5 Hz), 6.69 (ddd, J = 8.3, 1.5 = 0.6(8). 1.1, 0.5 Hz)), 7.20-7.33 (6H, 7.26 (ddd, J = 8.3, 1.3, 0.5Hz), 7.26 (ddd, J = 8.3, 1.3, 0.5 Hz), 7.26 (ddd, J. = 1 = 8.3).

[0134] The preparation method of the modified cyclic pentapeptide of formula (1-9) is as follows: the raw materials and preparation method are basically the same as those in Example 1, except that the Gly of AA1, AA2, AA3 and AA5 is replaced by Gly(Ph-4-OH), and the modified cyclic pentapeptide compound CH3(CH2)6CO-Cyclo(Gly(Ph-4-OH)-Gly(Ph-4-OH)-Gly(Ph-4-OH)-Lys-Gly(Ph-4-OH)) shown in formula (1-9) is prepared.1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.34 (10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (tt, J = 7.3, 7.0 Hz), 1.25 (tt, J = 7.3, 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (quint, J = 7.0 Hz), 1.26 (quint, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz)), 1.46-1.64 (4H, 1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.58 (tt, J = 7.3, 7.0 Hz), 1.58 (tt, J = 7.3, 7.0 Hz)), 1.68-1.81 (2H, 1.75 (td, J = 7.0, 4.7 Hz), 1.75 (td, J = 7.0, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.11-3.23 (2H, 3.17 (t, J = 7.0 Hz), 3.17 (t, J = 7.0 Hz)), 4.53 (1H, t, J = 4.7 Hz), 5.25 (1H, s), 5.30-5.56 (3H, 5.35 (s), 5.42 (s), 5.51 (s)), 6.62-6.75 (8H, 6.69 (ddd, J = 8.3, 1.1, 0.5 Hz), 6.69 (ddd, J = 8.3, 1.1, 0.5 Hz), 6.69 (ddd, J = 8.3, 1.1, 0.5 Hz), 6.69 (ddd, J = 8.3, 1.1, 0.5 Hz)), 7.20-7.33 (8H, 7.26 (ddd, J = 8.3, 1.3, 0.5 Hz), 7.26 (ddd, J = 8.3, 1.3, 0.5 Hz), 7.26 (ddd, J = 8.3, 1.3, 0.5 Hz), 7.26 (ddd, J = 8.3, 1.3, 0.5 Hz))..

[0135] The preparation method of the modified cyclic pentapeptide of formula (1-10) is as follows: the raw materials and preparation method are basically the same as those in Example 1, except that Gly in AA1 is replaced by Ala to prepare the modified cyclic pentapeptide compound CH3(CH2)6CO-Cyclo(Ala-Gly-Gly-Lys-Gly) shown in formula (1-10).1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.38 (13H, 1.24(quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.25(quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz),1.26 (d, J = 6.8 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.31 (tt, J= 7.3, 7.1 Hz), 1.31 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J =7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56(tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td,J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.68 (1H,d, J = 17.3 Hz), 3.78-4.05 (5H, 3.85 (d, J = 17.3 Hz), 3.87 (d, J = 17.3 Hz),3.88 (d, J = 17.1 Hz), 3.97 (d, J = 17.1 Hz), 3.98 (d, J = 17.3 Hz)), 4.26(1H, q, J = 6.8 Hz), 4.41 (1H, t, J = 4.7 Hz).

[0136] The preparation method of the modified cyclic pentapeptide of formula (1-11) is as follows: the raw materials and preparation method are basically the same as those in Example 1, except that the Gly of AA1 and AA2 is replaced by Ala to prepare the modified cyclic pentapeptide compound CH3(CH2)6CO-Cyclo(Ala-Ala-Gly-Lys-Gly) shown in formula (1-11).1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.39(16H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J =7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J =7.7, 7.0 Hz), 1.26 (d, J = 7.0 Hz), 1.26 (d, J = 6.8 Hz), 1.28 (h, J = 7.0Hz), 1.28 (h, J = 7.0 Hz), 1.32 (tt, J = 7.3, 7.1 Hz), 1.32 (tt, J = 7.3, 7.1Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz),1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73(td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J= 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18(t, J = 7.0 Hz)), 3.78-4.05 (4H, 3.85 (d, J = 17.3 Hz), 3.89 (d, J = 17.2Hz), 3.95 (d, J = 17.2 Hz), 3.98 (d, J = 17.3 Hz)), 4.12-4.33 (2H, 4.18 (q, J= 7.0 Hz), 4.28 (q, J = 6.8 Hz)), 4.41 (1H, t, J = 4.7 Hz).

[0137] Method for preparing modified cyclopentapeptide of formula (1-12): the raw materials and preparation method are basically the same as those in Example 1, the difference is that the Gly of AA1, AA2 and AA3 are all replaced by Ala, and the modified cyclopentapeptide compound CH3(CH2)6CO-Cyclo(Ala-Ala-Ala-Lys-Gly) shown in formula (1-12) is prepared.1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.40(19H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J =7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J =7.7, 7.0 Hz), 1.26 (d, J = 7.0 Hz), 1.26 (d, J = 6.8 Hz), 1.27 (d, J = 6.9Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.33 (tt, J = 7.3, 7.1 Hz),1.33 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7, 7.4 Hz), 1.53(tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J = 7.3, 7.0Hz)), 1.68-1.81 (2H, 1.75 (td, J = 7.1, 4.7 Hz), 1.75 (td, J = 7.1, 4.7 Hz)),2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.12-3.24 (2H,3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.78-4.05 (2H, 3.86 (d, J = 17.3Hz), 3.98 (d, J = 17.3 Hz)), 4.15-4.47 (4H, 4.21 (q, J = 7.0 Hz), 4.28 (q, J= 6.8 Hz), 4.36 (q, J = 6.9 Hz), 4.41 (t, J = 4.7 Hz))。

[0138] Method for preparing modified cyclopentapeptide of formula (1-13): the raw materials and preparation method are basically the same as those in Example 1, the difference is that the Gly of AA1, AA2, AA3 and AA5 is replaced by Ala, and the modified cyclopentapeptide compound CH3(CH2)6CO-Cyclo(Ala-Ala-Ala-Lys-Ala) shown in formula (1-12) is prepared.1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.34 (22H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J= 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.25 (d, J = 6.8 Hz), 1.26 (tt, J = 7.7,7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.27 (tt, J= 7.3, 7.1 Hz), 1.27 (tt, J= 7.3, 7.1 Hz), 1.26 (d, J = 7.0 Hz), 1.27 (d, J = 6.9 Hz), 1.27 (d, J = 6.8Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz)), 1.46-1.64 (4H, 1.53 (tt, J= 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.57 (tt, J = 7.3, 7.0 Hz), 1.57(tt, J = 7.3, 7.0 Hz)), 1.69-1.82 (2H, 1.75 (td, J = 7.1, 4.7 Hz), 1.75 (td,J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4Hz)), 3.13-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 4.15-4.42(4H, 4.21 (q, J = 7.0 Hz), 4.29 (q, J = 6.8 Hz), 4.35 (q, J = 6.8 Hz), 4.36(q, J = 6.9 Hz)), 4.47 (1H, t, J = 4.7 Hz).

[0139] The method for preparing the modified cyclic pentapeptide of formula (1-14) is substantially the same as that of Example 1, except that Gly of AA1 is replaced by Ser to prepare the modified cyclic pentapeptide compound CH3(CH2)6CO-Cyclo(Ser-Gly-Gly-Lys-Gly) shown in formula (1-14).1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.39 (10H, 1.24(quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.25(quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz),1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.32 (tt, J = 7.3, 7.1 Hz), 1.32(tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt,J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz)),1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18(t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.68 (1H, d, J = 17.3 Hz), 3.78-4.05(7H, 3.85 (d, J = 17.3 Hz), 3.87 (d, J = 17.3 Hz), 3.88 (d, J = 17.1 Hz),3.97 (d, J = 17.1 Hz), 3.98 (d, J = 17.3 Hz), 4.00 (d, J = 4.6 Hz)), 4.21(1H, t, J = 4.6 Hz), 4.41 (1H, t, J = 4.7 Hz).

[0140] Method for preparing modified cyclopentapeptide of formula (1-15): the raw materials and preparation method are basically the same as those in Example 1, the difference is that the Gly of AA1 and AA2 are all replaced by Ser, and the modified cyclopentapeptide compound CH3(CH2)6CO-Cyclo(Ser-Ser-Gly-Lys-Gly) shown in formula (1-15) is prepared.1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.39(10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J =7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J =7.7, 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.32 (tt, J = 7.3,7.1 Hz), 1.32 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7, 7.4Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J =7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1,4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.78-4.06 (8H, 3.85(d, J = 17.3 Hz), 3.89 (d, J = 17.2 Hz), 3.92 (d, J = 17.2 Hz), 3.98 (d, J =17.3 Hz), 4.00 (d, J = 4.6 Hz), 4.00 (d, J = 4.1 Hz)), 4.21-4.47 (3H, 4.27(t, J = 4.6 Hz), 4.38 (t, J = 4.1 Hz), 4.41 (t, J = 4.7 Hz))。

[0141] Method for preparing modified cyclic pentapeptide of formula (1-16): the raw materials and preparation method are basically the same as those in Example 1, except that the Gly of AA1, AA2 and AA3 are all replaced by Ser, to obtain the modified cyclic pentapeptide compound CH3(CH2)6CO-Cyclo(Ser-Ser-Ser-Lys-Gly) shown in formula (1-16).1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.38(10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J =7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J =7.7, 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.31 (tt, J = 7.3,7.1 Hz), 1.31 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7, 7.4Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J =7.3, 7.0 Hz)), 1.69-1.81 (2H, 1.75 (td, J = 7.1, 4.7 Hz), 1.75 (td, J = 7.1,4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.78-4.07 (8H, 3.85(d, J = 17.3 Hz), 3.98 (d, J = 17.3 Hz), 3.97 (d, J = 4.4 Hz), 4.00 (d, J =4.6 Hz), 4.01 (d, J = 4.4 Hz)), 4.27 (1H, t, J = 4.6 Hz), 4.35-4.48 (3H, 4.40(t, J = 4.4 Hz), 4.42 (t, J = 4.7 Hz), 4.43 (t, J = 4.4 Hz)).

[0142] The preparation method of the modified cyclic pentapeptide of formula (1-17) is as follows: the raw materials and preparation method are basically the same as those in Example 1, except that the Gly of AA1, AA2, AA3 and AA5 is replaced by Ser, to obtain the modified cyclic pentapeptide compound CH3(CH2)6CO-Cyclo(Ser-Ser-Ser-Lys-Ser) shown in formula (1-17).1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.18-1.34 (10H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (quint, J= 7.0 Hz), 1.25 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J= 7.7, 7.0 Hz), 1.27 (tt, J = 7.3, 7.1 Hz), 1.27 (tt, J = 7.3, 7.1 Hz), 1.28(h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz)), 1.46-1.64 (4H, 1.53 (tt, J = 7.7, 7.4Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.57 (tt, J = 7.3, 7.0 Hz), 1.57 (tt, J =7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1,4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.13-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.92-4.03 (8H, 3.97(d, J = 4.6 Hz), 3.97 (d, J = 4.4 Hz), 3.97 (d, J = 4.5 Hz), 3.97 (d, J = 4.4Hz)), 4.28-4.53 (5H, 4.33 (t, J = 4.6 Hz), 4.36 (t, J = 4.5 Hz), 4.40 (t, J =4.4 Hz), 4.43 (t, J = 4.4 Hz), 4.47 (t, J = 4.7 Hz)).

[0143] Method for preparing modified cyclic pentapeptide of formula (1-18): the raw materials and preparation method are basically the same as those in Example 1, except that octanoyl chloride in step S5 is replaced by valeryl chloride to prepare the modified cyclic pentapeptide compound CH3(CH2)3CO-Cyclo(Gly-Gly-Gly-Lys-Gly) shown in formula (1-18).1H NMR: δ 0.87 (3H, t, J = 7.0 Hz), 1.21-1.38 (4H, 1.28 (tq, J = 7.4, 7.0 Hz), 1.28 (tq, J = 7.4, 7.0 Hz), 1.31 (tt, J = 7.3, 7.1 Hz), 1.31 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.52 (quint, J = 7.4 Hz), 1.52 (quint, J = 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.14-3.25 (2H, 3.19 (t, J = 7.0 Hz), 3.19 (t, J = 7.0 Hz)), 3.61-4.06 (8H, 3.68 (d, J = 17.3 Hz), 3.72 (d, J = 17.3 Hz), 3.85 (d, J = 17.3 Hz), 3.88 (d, J = 17.1 Hz), 3.89 (d, J = 17.3 Hz), 3.92 (d, J = 17.3 Hz), 3.96 (d, J = 17.1 Hz), 3.99 (d, J = 17.3 Hz)), 4.41 (1H, t, J = 4.7 Hz).

[0144] The preparation method of the modified cyclic pentapeptide of formula (1-19) is as follows: the raw materials and preparation method are basically the same as those in Example 1, except that the octanoyl chloride in step S5 is replaced by hexanoyl chloride to obtain the modified cyclic pentapeptide compound CH3(CH2)4CO-Cyclo(Gly-Gly-Gly-Lys-Gly) shown in formula (1-19).1H NMR: δ 0.87 (3H, t, J = 7.0 Hz), 1.17-1.38 (6H, 1.24 (tt, J = 7.7, 7.0 Hz), 1.24 (tt, J = 7.7, 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.31 (tt, J = 7.3, 7.1 Hz), 1.31 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.61-4.06 (8H, 3.68 (d, J = 17.3 Hz), 3.72 (d, J = 17.3 Hz), 3.85 (d, J = 17.3 Hz), 3.88 (d, J = 17.1 Hz), 3.89 (d, J = 17.3 Hz), 3.92 (d, J = 17.3 Hz), 3.96 (d, J = 17.1 Hz), 3.99 (d, J = 17.3 Hz)), 4.41 (1H, t, J = 4.7 Hz).

[0145] The preparation method of the modified cyclic pentapeptide of formula (1-20) is as follows: the raw materials and preparation method are basically the same as those in Example 1, except that the octanoyl chloride in step S5 is replaced by heptanoyl chloride to obtain the modified cyclic pentapeptide compound CH3(CH2)5CO-Cyclo(Gly-Gly-Gly-Lys-Gly) shown in formula (1-20).1H NMR: δ 0.87 (3H, t, J = 7.0 Hz), 1.18-1.38 (8H, 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.27 (tt, J = 7.7, 7.0 Hz), 1.27 (tt, J = 7.7, 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.31 (tt, J = 7.3, 7.1 Hz), 1.31 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.61-4.06 (8H, 3.68 (d, J = 17.3 Hz), 3.72 (d, J = 17.3 Hz), 3.85 (d, J = 17.3 Hz), 3.88 (d, J = 17.1 Hz), 3.89 (d, J = 17.3 Hz), 3.92 (d, J = 17.3 Hz), 3.96 (d, J = 17.1 Hz), 3.99 (d, J = 17.3 Hz)), 4.41 (1H, t, J = 4.7 Hz).

[0146] Preparation method of modified cyclopentapeptide of formula (1-21): the raw materials and preparation method used are basically the same as those in Example 1, except that octanoyl chloride in step S5 is replaced by nonanoyl chloride to prepare the modified cyclopentapeptide compound CH3(CH2)7CO-Cyclo(Gly-Gly-Gly-Lys-Gly) shown in formula (1-21).1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.17-1.38(12H, 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J = 7.0 Hz), 1.24 (quint, J =7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.26 (tt, J = 7.7, 7.0 Hz), 1.26 (tt, J =7.7, 7.0 Hz), 1.26 (quint, J = 7.0 Hz), 1.26 (quint, J = 7.0 Hz), 1.28 (h, J= 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.31 (tt, J = 7.3, 7.1 Hz), 1.31 (tt, J =7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7,7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz)), 1.67-1.80(2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1, 4.7 Hz)), 2.13-2.25 (2H,2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0Hz), 3.18 (t, J = 7.0 Hz)), 3.61-4.06 (8H, 3.68 (d, J = 17.3 Hz), 3.72 (d, J= 17.3 Hz), 3.85 (d, J = 17.3 Hz), 3.88 (d, J = 17.1 Hz), 3.89 (d, J = 17.3Hz), 3.92 (d, J = 17.3 Hz), 3.96 (d, J = 17.1 Hz), 3.99 (d, J = 17.3 Hz)),4.41 (1H, t, J = 4.7 Hz).

[0147] Preparation method of modified cyclopentapeptide of formula (1-22): the raw materials and preparation method used are basically the same as those in Example 1, except that octanoyl chloride in step S5 is replaced by decanoyl chloride to prepare the modified cyclopentapeptide compound CH3(CH2)8CO-Cyclo(Gly-Gly-Gly-Lys-Gly) shown in formula (1-22).1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.17-1.38(14H, 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J =7.2 = 3 Hz), 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J =7.0 Hz), 1.25 (tt, J = 7.7, 7.0 Hz), 1.25 (tt, J = 7.7, 7.0 Hz), 1.26 (quint,J = 7.0 Hz = 6), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0Hz), 1.31 (tt, J = 7.3, 7.1 Hz), 1.31 (tt, J = 7.3, 7.1 Hz)), 1.46–1.63 (4.5tt, J =1.53), (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3,7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.7, d 1.7 =4), Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19(t, J = 7.4 Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.018 (t, 8H) = 7.4). 3.68 (d, J = 17.3 Hz), 3.72 (d, J = 17.3 Hz), 3.85 (d, J =17.3 Hz), 3.88 (d, J = 17.1 Hz), 3.89 (d, J = 17.3 Hz), 3.9 = 1 (d, J = 17.3 Hz), 3.9 = 1 Hz. 17.1 Hz), 3.99 (d, J = 17.3 Hz)), 4.41 (1H, t, J = 4.7 Hz)。

[0148] Preparation method of modified cyclic pentapeptide of formula (1-23): The raw materials and preparation method used are basically the same as those in Example 1, except that octanoyl chloride in step S5 is replaced by undecanoyl chloride to obtain a modified cyclic pentapeptide compound CH3(CH2)9CO-Cyclo(Gly-Gly-Gly-Lys-Gly) shown in formula (1-23). 1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.17-1.38 (16H, 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J= 7.0 Hz), 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J= 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (tt, J =7.7, 7.0 Hz), 1.25 (tt, J = 7.7, 7.0 Hz), 1.26 (quint, J = 7.0 Hz), 1.26(quint, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.31 (tt, J= 7.3, 7.1 Hz), 1.31 (tt, J = 7.3, 7.1 Hz)), 1.46-1.63 (4H, 1.53 (tt, J =7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56(tt, J = 7.3, 7.0 Hz)), 1.67-1.80 (2H, 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td,J = 7.1, 4.7 Hz)), 2.13-2.25 (2H, 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4Hz)), 3.12-3.24 (2H, 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz)), 3.61-4.06(8H, 3.68 (d, J = 17.3 Hz), 3.72 (d, J = 17.3 Hz), 3.85 (d, J = 17.3 Hz), 3.88 (d, J = 17.1 Hz), 3.89 (d, J = 17.3 Hz), 3.92 (d, J = 17.3 Hz), 3.96 (d, J = 17.1 Hz), 3.99 (d, J = 17.3 Hz)), 4.41 (1H, t, J = 4.7 Hz).

[0149] The preparation method of the modified cyclic pentapeptide of formula (1-24) is as follows: the raw materials and the preparation method are basically the same as those in Example 1, except that octanoyl chloride in step S5 is replaced by lauroyl chloride to prepare the modified cyclic pentapeptide compound CH3(CH2) 10CO-Cyclo(Gly-Gly-Gly-Lys-Gly). 1H NMR: δ 0.86 (3H, t, J = 7.0 Hz), 1.17-1.38 (18H, m), 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J = 7.0 Hz), 1.23 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.24 (quint, J = 7.0 Hz), 1.25 (tt, J = 7.7, 7.0 Hz), 1.25 (tt, J = 7.7, 7.0 Hz), 1.26 (quint, J = 7.0 Hz), 1.26 (quint, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.28 (h, J = 7.0 Hz), 1.31 (tt, J = 7.3, 7.1 Hz), 1.31 (tt, J = 7.3, 7.1 Hz), 1.46-1.63 (4H, m), 1.53 (tt, J = 7.7, 7.4 Hz), 1.53 (tt, J = 7.7, 7.4 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.56 (tt, J = 7.3, 7.0 Hz), 1.67-1.80 (2H, m), 1.73 (td, J = 7.1, 4.7 Hz), 1.73 (td, J = 7.1, 4.7 Hz), 2.13-2.25 (2H, m), 2.19 (t, J = 7.4 Hz), 2.19 (t, J = 7.4 Hz), 3.12-3.24 (2H, m), 3.18 (t, J = 7.0 Hz), 3.18 (t, J = 7.0 Hz), 3.61-4.06 (8H, m), 3.68 (d, J = 17.3 Hz), 3.72 (d, J = 17.3 Hz), 3.85 (d, J = 17.3 Hz), 3.88 (d, J = 17.1 Hz), 3.89 (d, J = 17.3 Hz), 3.92 (d, J = 17.3 Hz), 3.96 (d, J = 17.1 Hz), 3.99 (d, J = 17.3 Hz)), 4.41 (1H, t, J = 4.7 Hz). .

[0150] Example 2 In vitro oil control efficacy test of modified cyclic pentapeptide

[0151] 1. Background

[0152] Sebum is produced by sebaceous gland cells in the dermis and then secreted into the surface layer of the skin. Research has shown that human sebum is a mixture of various components, primarily phospholipids, triglycerides, fatty acids, squalene, cholesterol esters, small amounts of cholesterol, and ditriglycerides. Oily skin is caused by excessive oil secretion, resulting in shiny skin, an unpleasant appearance, and an uncomfortable feel. Excessive sebum in the epidermis can also easily cause inflammation, attract dust, accumulate, clog pores, and cause rough cuticles, leading to acne.

[0153] 5α-reductase is a key enzyme in skin androgen metabolism, catalyzing the conversion of testosterone into dihydrotestosterone (DHT). When DHT enters the sebaceous glands and accumulates to a certain level, it can cause sebaceous gland cell damage, leading to excessive sebum secretion. Therefore, reducing or inhibiting 5α-reductase activity can effectively reduce sebaceous gland secretion.

[0154] Oil Red O staining utilizes the dye to bind to lipids, rendering them red, facilitating microscopic observation and quantitative analysis. By measuring intracellular lipid content, Oil Red O staining can be used to assess the oil-control effects of a sample on sebaceous gland cells (SZ95 cells).

[0155] 2. Experimental methods

[0156] 2.1 5α-reductase inhibition assay

[0157] (1) Sample loading in a 96-well plate: The test set up a standard well group, a sample well group (modified cyclic pentapeptide (Formula 1-1 to Formula 1-24), 1000 ppm), a control group A (dipeptide-15, 1000 ppm), a control group B (octanoylglycine, 1000 ppm), and a blank control well group (the blank control well group did not add sample and HRP enzyme-labeled reagent, and the rest of the steps were the same). Each experimental group was prepared with 3 parallel wells. The test was performed according to the kit steps.

[0158] (2) After the OD 450 nm value test of each standard hole, sample hole, control hole and blank hole is completed, first calculate the standard curve of different enzyme activity concentration and OD 450 nm value of the standard hole, then calculate the OD 450 nm value corresponding to the theoretical enzyme activity concentration (50 pg / mL) of the sample hole according to the curve, which is used as the OD 450 nm value of the standard hole of the sample test concentration. The OD 450 nm value corresponding to the theoretical enzyme activity concentration (0 pg / mL) of the blank hole is calculated as the OD 450 nm value of the blank hole.

[0159] (3) Result calculation: sample 5 alpha reductase inhibition rate (%) = (OD450 standard hole-OD450 sample hole) / (OD450 standard hole-OD450 blank hole) x 100 %.

[0160] 2.2 Oil red O staining experiment

[0161] (1) Human sebaceous gland cells (SZ95) are cultured under 5% CO2, 37 °C culture conditions. When the cells grow to 60-70% confluence, they are digested and inoculated into a 24-well plate with trypsin, returned to the incubator for 24 h to allow the cells to fuse, then washed with PBS, and then added according to Table 2. The positive group adds 1 mL of culture solution containing 0.01 mmol / L isotretinoin per well, and the control group A, B and sample group add 1 mL of culture solution containing the corresponding concentration of sample per well.

[0162] Table 2 Test grouping of oil red O staining experiment

[0163]

[0164] (2) After returning to the incubator for 24 h, discard the DME culture medium, add 4% paraformaldehyde solution, and fix at room temperature for 15 min. Discard the excess solution, add 0.5% oil red O solution, and stain at room temperature for 15 min. Wash with distilled water until no red residue is left, then take pictures under a microscope to observe the lipid content.

[0165] (3) Result calculation: analyze the pictures using Image J, calculate the IOD of the stained area, and take the IOD of the control group as 100%. Relative lipid content % = IOD of each group / IOD of control group Mean x 100%.

[0166] 3, Experimental results

[0167] The results of the 5 alpha reductase inhibition rate experiment of different concentrations of samples are shown in Table 3, and the calculation results of the lipid inhibition rate are shown in Table 4. Compared with the BC group, **P<0.01, ***P<0.001, ****P<0.0001.

[0168] Table 3 5α-reductase inhibition rate experimental results

[0169]

[0170]

[0171] Table 4 Lipid inhibition rate experimental results

[0172]

[0173]

[0174] The experimental results in Table 3 show that all modified cyclic pentapeptides (Formulas 1-1 to 1-24) exhibited significant 5α-reductase inhibition at a concentration of 1000 ppm, with inhibition rates ranging from 29% to 44%. Modified cyclic pentapeptide (Formula 1-1) exhibited the highest inhibitory effect, achieving a 43.70% inhibition rate against 5α-reductase, demonstrating excellent oil-control efficacy. In contrast, the classic oil-control ingredients on the market—Dipeptide-15 (Control A) and Capryloylglycine (Control B)—only exhibited 5α-reductase inhibition rates of 23.15% and 28.91% at 1000 ppm, respectively, both inferior to the inhibition rates of modified cyclic pentapeptides (Formulas 1-1 to 1-24) at 1000 ppm. This demonstrates that modified cyclic pentapeptides significantly enhance oil-control efficacy compared to existing classic ingredients on the market.

[0175] As shown in the experimental results in Table 4, the modified cyclic pentapeptides (Formulas 1-1, 1-2, 1-5, 1-9, 1-10, 1-13, and 1-17) significantly reduced lipid production in sebaceous gland cells at concentrations of 125 ppm and 250 ppm, with lipid inhibition rates ranging from 20.10% to 30.13% and 40.01% to 55.24%, respectively. This indicates that at these concentrations, they significantly inhibit lipid synthesis in human sebaceous gland cells (SZ95) and can, to a certain extent, provide oil control. Among them, the modified cyclic pentapeptide (Formula 1-1) showed the best lipid synthesis inhibition effect, with a lipid inhibition rate of 55.24% at a concentration of 250 ppm. In contrast, the inhibition rates of dipeptide-15 (Control A) and octanoylglycine (Control B) on lipid production at a concentration of 500 ppm were only 30.56% and 36.98%, respectively, far lower than those of the modified cyclic pentapeptide (Formula 1-1) at 250 ppm. This example demonstrates that the modified cyclic pentapeptide provided by the present invention exhibits significant oil-control and acne-removing effects at relatively low concentrations. Compared to classic commercially available oil-control ingredients, dipeptide-15 and capryloylglycine, which also share a glycine backbone, it exhibits significantly greater effectiveness in inhibiting 5α-reductase and sebaceous gland cell lipid synthesis. This novel modified cyclic pentapeptide exhibits excellent oil-control effects at low concentrations, demonstrating broad application prospects in skincare products.

[0176] Example 3 In-vitro moisturizing efficacy test of modified cyclic pentapeptide

[0177] This example is based on a 3D epidermal skin model (EpiKutis ® ), and the moisturizing efficacy of the sample to be tested is evaluated by detecting the change in skin water content (for example, formula (1-1)).

[0178] 1. Experimental method

[0179] (1) Experimental grouping: The test sets up a blank control group, a positive control group and a sample group, as shown in Table 5.

[0180] Table 5 Grouping of 3D epidermal skin model moisturizing efficacy test

[0181]

[0182] (2) Drug administration: According to the test grouping in Table 5, the model is transferred to a 6-well plate (0.9 mL of EpiGrowth culture solution is added in advance), and the test group number is marked on the 6-well plate.

[0183] The PC group changes the culture solution, and the surface is added with 20% glycerol working solution (400 μL of glycerol stock solution is added to 1.6 mL of PBS), and the sample group changes the culture solution, and the surface is coated with different concentrations of the sample to be tested (the modified cyclic pentapeptide is dissolved in 20 μL of DMSO to prepare a stock solution, which is then added to 1980 μL of PBS), and the sample is evenly distributed on the surface of the model and incubated in a CO2 incubator (37 °C, 5% CO2) for 24 h.

[0184] (3) Skin water content test: After washing, prepare a 24-well plate according to the number of models, and make appropriate markings. Add 0.3 mL of EpiGrowth culture solution to each well. Place the 24-well plate containing the model in a clean bench, open the lid of the 24-well plate, and after standing for 30 min, wipe off the water on the bottom of the model, cut off the model around it, and place it in the probe position of the tester. Press the probe to measure three times for each model, and take the average value.

[0185] (4) Water content improvement rate calculation: Improvement rate (%) = (sample group - blank control group / blank control group) x 100%.

[0186] 2. Experimental results

[0187] The experimental results are shown in Table 6 and Figure 3 (**P<0.01 vs. BC, ##P<0.01 vs. PC), wherein Table 6 is a summary table of the skin water content improvement rate, Figure 3 and Fig. 1 is a column chart of the skin water content test results.

[0188] Table 6 Skin moisture content rate summary table

[0189]

[0190] From the experimental results of Table 6 and Figure 3 Compared with the BC group, the skin moisture content of the sample at 0.1%, 1%, and 2% concentrations was significantly increased, with an increase rate of 38.70%, 58.57%, and 101.46%, respectively. Compared with the 20% glycerol group, the skin moisture content of the 2% modified cyclic pentapeptide (formula 1-1) was significantly increased. These experimental results show that the modified cyclic pentapeptide (formula 1-1) provided by the present application has excellent moisturizing effect, and the effect at a concentration of 2% is significantly better than that of the commonly used moisturizing agent (20% glycerol) on the market. Adding it to skin care products can effectively prevent water loss, relieve dry and tight skin, and the modified cyclic pentapeptide also has the advantage of small molecular weight, which can penetrate into the stratum corneum and dermis for deep moisturizing and repair.

[0191] Example 4 In vitro repair efficacy test of modified cyclic pentapeptide

[0192] 1. Background

[0193] Some compounds with strong skin contact irritation or ultraviolet rays, etc. can cause clinical acute damage to the skin barrier, leading to dry skin and redness. Anionic surfactant SLS has amphiphilic (hydrophilic and lipophilic) characteristics, and can damage the skin barrier, especially the lipid components in the barrier and the cell membrane, when contacting the skin at a high concentration.

[0194] Filaggrin (FLG) is a key component in the assembly process of CE, and FLG, in addition to being a structural component of the skin barrier, can also be hydrolyzed by Caspase-14 to form natural moisturizing factor. Transglutaminase 1 (TGM1) is the main subtype of three TGMs expressed in the epidermis, and is involved in the formation of ε-(γ glutamyl) lysine crosslinks during the formation of the keratin envelope. This cross-linking is very stable and can resist protease hydrolysis, and is a key step in the terminal differentiation of keratinocytes to form a keratin envelope, and is the material basis for the function of the skin barrier. A decrease in TGM1 protein content is another key indicator of weakened skin barrier function. Therefore, in this embodiment, the changes in the contents of filaggrin (FLG) and transglutaminase 1 (TGM1) after administration are detected to evaluate the repair efficacy of the modified cyclic pentapeptide, for example, formula (1-1).

[0195] 2. Experimental method

[0196] (1) Experimental grouping: The test sets up a blank control group, a negative control group, a positive control group, and a sample group, as shown in Table 7.

[0197] Table 7 3D epidermal skin model repair efficacy test grouping

[0198]

[0199] (2) 0.2% SLS working solution configuration: 1 mL of 0.4% SLS solution is taken and 1 mL of PBS is added to prepare 0.2% SLS working solution.

[0200] Positive control group (50 μM WY14643) working solution configuration: 10 μL of WY14643 stock solution (30 mM) is added to 6 mL of model culture solution to prepare a 50 μM working solution.

[0201] Sample group solution preparation: modified cyclic pentapeptide (formula 1-1) is dissolved in 6 mL of model culture solution to prepare a 0.1% sample working solution.

[0202] (3) Dosing: according to the test grouping in Table 7, the model is transferred to a 6-well plate (0.9 mL of EpiGrowth culture solution is added in advance), and the test group number is marked on the 6-well plate. The surface of the sample group is added with 12.5 μL of 0.4% SLS solution and 12.5 μL of sample working solution of corresponding concentration, and the sample is distributed on the surface of the model and incubated in a CO2 incubator (37 °C, 5% CO2) for 24 h. After incubation, the residual test substances on the surface of the model are washed with sterile PBS solution, and the residual liquid inside and outside the model is wiped off with a sterile cotton swab.

[0203] (4) Immunofluorescence detection: the model for detection is fixed with 4% paraformaldehyde, and after 24 h of fixation, immunofluorescence detection of filaggrin (FLG) and transglutaminase 1 (TGM1) content is performed, and the pictures are collected and analyzed under a microscope.

[0204] 3. Experimental results

[0205] The experimental results are shown in Figures 4-7 , wherein Figure 4 is the FLG integrated optical density (IOD) value column chart, wherein, ###P<0.001 vs. BC, **P<0.01 vs. NC, ***P<0.001 vs. NC; Figure 5 is the FLG immunofluorescence photo of each group; Figure 6 is the TGM1 integrated optical density (IOD) value column chart, wherein, ###P<0.001 vs. BC, ***P<0.001 vs. NC, Figure 7 is the TGM1 immunofluorescence photo of each group.

[0206] From Figures 4-7It can be seen that ① compared with the BC group, the FLG and TGM1 contents of the NC group decreased significantly, indicating that the test stimulation was effective; compared with the NC group, the FLG and TGM1 contents of the PC group increased significantly, indicating that the positive control of this test was effective. ② Compared with the NC group, the FLG content of the sample modified cyclic pentapeptide (formula 1-1) at a concentration of 0.1% increased significantly, with an increase rate of 99.19%; the TGM1 content increased significantly, with an increase rate of 540.76%. The experimental results show that the modified cyclic pentapeptide (formula 1-1) at a lower concentration can restore and strengthen the normal physiological function of the skin by increasing the expression of barrier-related proteins (FLG and TGM1), thereby protecting the skin barrier, repairing skin damage caused by stimulation, and achieving repair efficacy.

[0207] Example 5 In vitro soothing efficacy test of modified cyclic pentapeptide

[0208] In this test, RAW264.7 macrophages were stimulated by LPS (bacterial lipopolysaccharide), and the soothing efficacy of the sample was evaluated by detecting the changes in the contents of inflammatory factors (IL-6 and TNF-α) after the sample was applied.

[0209] 1. Experimental method

[0210] (1) Experimental grouping: The experiment was set up with a blank control group, a negative control group, a positive control group, and a sample group, as shown in Table 8.

[0211] Table 8 Grouping of macrophage soothing efficacy test

[0212]

[0213] (2) Cell inoculation: Cells were inoculated into a 6-well plate at a seeding density of 2.2 x 10 5 cells / well, 2 mL of cell suspension was added to each well, and the inoculated cell culture plate was placed in an incubator for further culture for 24 h (5% CO2, 37°C).

[0214] (3) Drug administration: According to the test grouping, when the cell plating rate in the 6-well plate reached 40%-60%, grouping administration was performed, with 3 replicate wells in each group. The blank control group and the negative control group were each added with 1.8 mL of culture solution, the positive control group was each added with 1.8 mL of culture solution containing dexamethasone, and the sample group was each added with 1.8 mL of culture solution containing modified cyclic pentapeptide (formula 1-1, formula 1-2, formula 1-5, formula 1-9, formula 1-10, formula 1-13, formula 1-17). After drug administration, the 6-well plate was placed in an incubator for 2 h.

[0215] (4) LPS stimulation: After 2 h of drug administration, 200 μL of LPS-containing working solution was added to each well of each group, and the plate was placed in a cell incubator for further culture for 22 h.

[0216] (5) IL-6, TNF-a detection: collect cell culture supernatant, according to the ELISA kit instruction to detect.

[0217] (6) Inhibition rate calculation: inhibition rate (%) = (negative control group-sample group) / negative control group x 100%.

[0218] 2. Experimental results

[0219] The experimental results are shown in Table 9. All data are expressed as mean ± standard deviation, ##P<0.01 vs. BC, *P<0.05 vs. NC, **P<0.01 vs. NC, ***P<0.001 vs. NC.

[0220] Table 9 Summary of IL-6, TNF-a content test results

[0221]

[0222] From Table 9, ① compared with the BC group, the IL-6, TNF-a content of the NC group increased significantly, indicating that the test stimulation was effective; compared with the NC group, the IL-6, TNF-a content of the PC group decreased significantly, indicating that the positive control of this test was effective. ② Compared with the NC group, the IL-6, TNF-a content of the sample group 100 ppm modified cyclic pentapeptide (formula 1-1, formula 1-2, formula 1-5, formula 1-9, formula 1-10, formula 1-13, formula 1-17) decreased significantly, and the inhibition rates were 48.44%-57.93% and 22.48%-29.16%, respectively. Among them, the modified cyclic pentapeptide (formula 1-1) had the best anti-inflammatory effect, with an IL-6 inhibition rate of 57.93% and a TNF-a inhibition rate of 29.16%. It is proved that the modified cyclic pentapeptide at this concentration can reduce inflammation by inhibiting the content of inflammatory factors IL-6 and TNF-a, and achieve the effect of soothing. Adding it to skin care products can help to reduce the common symptoms of redness, itching, stinging, burning and other discomforts of sensitive skin, enhance the tolerance of the skin, and relieve the problem of sensitive skin.

[0223] Example 6 Human efficacy of oil control repair soothing serum containing modified cyclic pentapeptide

[0224] (1) Preparation of oil control repair soothing serum: 4% 1,3-butanediol, 0.5% betaine, 0.02% sodium hyaluronate, 0.08% xanthan gum, 0.3% phenoxyethanol and deionized water (added to 100%) were stirred and mixed to prepare a base material serum. 50 ppm modified cyclic pentapeptide (formula 1-1, formula 1-2, formula 1-5, formula 1-9, formula 1-10, formula 1-13, formula 1-17) were added to the base material serum as sample groups A-G.

[0225] (2) Volunteer selection: The selection of subjects follows the medical and ethical standards of human testing, and all tests on subjects must be voluntary on the part of the subject and signed an informed consent form before the test. 140 healthy female subjects aged 18-40 were recruited and randomly divided into 7 groups, 20 in each group.

[0226] (3) Experimental sample usage: After cleansing in the morning and evening, the subjects used the sample A-G essence, 0.2 g each time, gently massage until absorbed, and did not use other oil control and soothing skin care products during the experiment.

[0227] (4) Before using the sample, and 14 days and 28 days after using the sample, the subjects used each probe of the German CK instrument: Tewameter TM300 to measure trans-epidermal water loss (TEWL value), Corneometer CM 825 to measure facial stratum corneum moisture content, Colorimeter CL400 to measure skin color; Sebumeter SM815 to measure skin oil content. Using SPSS analysis software, the measured values at different time points were compared with the baseline values (Day 0) before using the sample, and Shapiro-Wilk Test was used for significance test of normal distribution of data improvement value.

[0228] Before the test, the subjects were asked to wash their faces with the same cleansing product, and the skin state was stabilized in a constant temperature and humidity (temperature: 21 °C ± 1 °C, humidity: 50% ± 10%) stable room for 20 min, then the above detection was carried out.

[0229] (5) The results are shown in the following table:

[0230] Change rate after using the product = (data after use-data before use) / data before use x 100%.

[0231] Table 10 Results of each skin parameter test before and after using the sample essence

[0232]

[0233] According to the data in Table 10, after 14 days and 28 days of using the serum containing the modified cyclic pentapeptide, the skin stratum corneum water content of the subjects was significantly improved, the transepidermal water loss was greatly reduced, the cheek oil content was reduced, and the skin redness was significantly improved. The overall oil control, repair and soothing effects of the serum were recognized by more than 95% of the subjects, and the serum A group added with the modified cyclic pentapeptide (formula 1-1) had the best performance in various skin indicators. The above results show that the serum containing the modified cyclic pentapeptide provided by the present application has the effects of oil control, acne removal, moisturizing and water locking, skin barrier repair and skin redness repair, so that the skin looks more energetic and the appearance looks more youthful, and has a significant soothing and repairing effect.

Claims

1. A modified cyclic pentapeptide compound, characterized in that, ， in the formula (I), R1, R2, R3 and R4 are independently H, methyl, -CH2OH, phenyl or -C6H4OH; n is 4, 5, 6, 7 or 8.

2. The modified cyclic pentapeptide compound of claim 1, wherein, n is 5, 6 or 7.

3. The modified cyclic pentapeptide compound of claim 1, wherein one, two, three or four of R1, R2, R3 and R4 are H.

4. The modified cyclic pentapeptide compound of claim 1, wherein which satisfies one or two of the following conditions: (1) For , , , or ; and (2) is either of the following groups: 。 5. A modified cyclic pentapeptide compound characterized by, the modified cyclic pentapeptide compound is any one of the compounds of formulae (1-1) to (1-24): 。 6. A composition containing a modified cyclic pentapeptide, characterized in that which comprises the modified cyclic pentapeptide compound of any one of claims 1-5.

7. The composition comprising the modified cyclic pentapeptide according to claim 6, wherein, which satisfies one or more of the following conditions: (1) the modified cyclic pentapeptide-containing composition has an adjuvant, which comprises one or more of a bulking agent, a humectant, an emulsifier, a thickening agent, a metal ion sequestering agent, a colorant, a pH adjuster, a skin nutrient, a vitamin, a preservative, an antioxidant, an antioxidant aid and a fragrance; (2) the content of the modified cyclic pentapeptide compound is 50-1000 ppm; (3) the composition is a skin care product or a cosmetic product; and (4) the composition has an oil control effect, and has one or more of the following effects: moisturizing, repairing and soothing.

8. Use of a modified cyclic pentapeptide compound according to any one of claims 1 to 5, characterized in that, the use includes (1) for preparing a cosmetic product or a skin care product; and (2) for preparing a washing and caring product.

9. Use according to claim 8, characterized in that, the washing and caring product, the cosmetic product and the skin care product have an oil control effect, and have one or more of the effects of moisturizing, repairing and soothing.

10. Use of a composition containing a modified cyclic pentapeptide according to claim 6 or 7, characterized in that: the use includes (1) for preparing a cosmetic product or a skin care product; and (2) for preparing a washing and caring product.

11. Use according to claim 10, characterized in that, the washing and caring product, the cosmetic product and the skin care product have an oil control effect, and have one or more of the effects of moisturizing, repairing and soothing.

12. A method for preparing the modified cyclic pentapeptide compound according to claim 1, characterized in that: comprising the step of: subjecting a cyclic pentapeptide to a nucleophilic addition reaction with an acyl halide compound to obtain a modified cyclic pentapeptide compound; ， in the formula (Ib), X is halogen; in the formula (Ib), n is a value as defined in claim 1; in the formula (Ib), n is a value as defined in claim 1; In formula (Ia), R 1 , R 2 , R 3 and R 4 are independently a substituent as defined in claim 1.

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