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ISARIDIN CYCLODEPSIPEPTIDE DERIVATIVES, AND PREPARATION AND APPLICATION THEREOF

20230022841 · 2023-01-26

    Inventors

    Cpc classification

    International classification

    Abstract

    Provided herein are an isaridin cyclodepsipeptide derivative, and a preparation and an application thereof. The isaridin cyclodepsipeptide derivative is shown in formula (I), and is isolated from ascidian-associated fungi.

    ##STR00001##

    Claims

    1. An isaridin cyclodepsipeptide derivative of formula (I), or a pharmaceutically-acceptable salt thereof: ##STR00014## wherein R.sub.1 is —H or —CH.sub.3; R.sub.2 is —H or —OH; R.sub.3 and R.sub.8 are each independently —H or —CH.sub.3; R.sub.4 and R.sub.5 are each independently selected from the group consisting of —CH.sub.3, —CH.sub.2CH.sub.3, —CH(CH.sub.3).sub.2, —CH.sub.2CH(CH.sub.3).sub.2, —CH(CH.sub.3)CH.sub.2CH.sub.3, —CH(OH)CH.sub.3 and —CH.sub.2Ar; R.sub.6 is —CH.sub.2CH.sub.2—; and R.sub.7 is —O—; and the isaridin cyclodepsipeptide derivative is selected from the group consisting of: ##STR00015## ##STR00016##

    2. A method for preparing the isaridin cyclodepsipeptide derivative of claim 1, comprising: preparing the isaridin cyclodepsipeptide derivative from Beauveria felina SYSU-MS7908 by isolation and purification; wherein a deposit number of the Beauveria felina SYSU-MS7908 is GDMCC No: 61059.

    3. The method of claim 2, wherein the isaridin cyclodepsipeptide derivative is prepared through steps of: (1) subjecting the Beauveria feline SYSU-MS7908 to enlarged culture to collect a fungal fermentation broth extract by an organic solvent; and (2) subjecting the fungal fermentation broth extract to liquid separation extraction, concentration, silica gel column chromatography, Sephadex LH-20 gel column chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC) to obtain the isaridin cyclodepsipeptide derivative.

    4. The method of claim 3, wherein in step (1), the organic solvent is selected from the group consisting of acetone, ethyl acetate, methanol and ethanol.

    5. The method of claim 3, wherein in step (2), the extraction is performed in ethyl acetate, chloroform or a combination thereof.

    6. A method for treating inflammation in a subject in need thereof, comprising: administering a therapeutically effective amount of the isaridin cyclodepsipeptide derivative of claim 1 or a pharmaceutically-acceptable salt thereof to the subject.

    7. A method for treating thrombosis in a subject in need thereof, comprising: administering a therapeutically effective amount of the isaridin cyclodepsipeptide derivative of claim 1 or a pharmaceutically-acceptable salt thereof to the subject.

    8. A pharmaceutical composition, comprising: the isaridin cyclodepsipeptide derivative of claim 1 or a pharmaceutically-acceptable salt thereof.

    Description

    BRIEF DESCRIPTION OF THE DRAWINGS

    [0056] FIG. 1 is a Single-crystal X-ray diffraction pattern of compound I-2 prepared in Example 1 of the present disclosure.

    [0057] FIG. 2 is a Single-crystal X-ray diffraction pattern of compound I-13 prepared in Example 1 of the present disclosure.

    DETAILED DESCRIPTION OF EMBODIMENTS

    [0058] The technical solutions of the present disclosure will be described completely and clearly below with reference to the accompanying drawings and embodiments. Obviously, provided below are merely some embodiments of the disclosure, which are not intended to limit the disclosure. Unless otherwise specified, the following experiments are all performed by using conventional methods, and the equipment and reagents used in the following examples are all commercially available.

    [0059] Seed medium: 10 g of yeast extract, 20 g of peptone, 20 g of glucose and 1 L of water;

    [0060] Fermentation medium: 90 g of rice, 3 g of sea salt, 0.5 g of peptone, 0.2 g of yeast extract and 100 mL of water.

    Example 1 Preparation of Isaridin Cyclodepsipeptide Derivatives

    [0061] The ascidian-associated fungus Beauveria felina SYSU-MS7908 has been deposited in the GDMCC (5th floor, experimental building, No. 100, Xianlie Middle Road, Guangzhou, Guangdong Province, China), and has a deposit number of GDMCC No: 61059. The Beauveria felina SYSU-MS7908 was employed to conduct fermentation, and a fermentation liquid was collected, and subjected to separation and extraction to obtain compounds I-1 to I-15.

    [0062] The fermentation, separation and extraction were specifically described as follows.

    [0063] 1. Seed culture

    [0064] 1.1 A seed medium containing 10 g of yeast extract, 20 g of peptone, 20 g of glucose and 1 L of water was evenly loaded into five 500 mL conical flasks, and sterilized at 121° C. for 15 min.

    [0065] 1.2 The marine-derived ascidian-associated fungus Beauveria felina SYSU-MS7908 was seeded into the seed medium, and cultured at 28° C. and 180 rpm for 120 h to obtain a seed culture liquid.

    [0066] 2. Fermentation

    [0067] 2.1 Fermentation medium

    [0068] 90 g of rice, 3 g of sea salt, 0.5 g of peptone and 0.2 g of yeast extract were dissolved in 100 mL of water in each 1 L conical flask.

    [0069] 2.2 Fermentation

    [0070] 5 mL of the seed culture liquid was aseptically inoculated into the conical flask containing the fermentation medium and cultured at 25° C. for 28 days.

    [0071] 3. Isolation and purification

    [0072] The Beauveria felina SYSU-MS7908 cells were subjected to extraction in methanol and concentration under reduced pressure at a temperature lower than 50° C. to obtain 105 g of an extract. The extract was separated by silica gel column chromatography gradient elution sequentially with a series of ethyl acetate-petroleum ether solutions (respectively containing 10%, 20%, 30%, 45%, 60% and 100% by volume of ethyl acetate) and 5% and 10% methanol-ethyl acetate solutions, and eight fractions were correspondingly collected (i.e., Fr. A-Fr. H).

    [0073] The fractions Fr. C and Fr. D eluted respectively by 30% and 45% ethyl acetate-petroleum ether solutions were collected and subjected to reverse-phase silica gel column chromatography using gradient elution with 30%, 50%, 70% and 90% methanol/water solutions. The fractions respectively eluted with 50%, 70% and 90% methanol/water solutions were collected, dissolved in hot ethanol and recrystallized to obtain compound I-13. The remaining fractions Fr. C-L1 and Fr. D-L1 were collected.

    [0074] The fraction Fr. C-L1 was allowed to pass through Sephadex LH-20 (a volume ratio of dichloromethane to methanol was 1:1), and then purified by RP-HPLC, where the chromatographic column was RP-C18 (250×10 mm, 5 μm); a detection wavelength was 210 nm; a mobile phase was 60% methanol/water, and a flow rate was 4 mL/min. Fractions with a retention time of 11.9-12.3 min were collected and further purified by HPLC to obtain compounds I-5 and I-8; the fraction with a retention time of 13.6 min was collected to obtain compound I-6; fractions with a retention time of 15.2-16.5 min were collected and further purified by HPLC to obtain compounds I-9 and I-4; and the fraction with a retention time of 18.2 min was collected to obtain compound I-14.

    [0075] The fraction Fr. D-L1 was allowed to pass through Sephadex LH-20 (a volume ratio of dichloromethane to methanol was 1:1), and then purified by RP-HPLC, where the chromatographic column was RP-C18 (250×10 mm, 5 μm); a detection wavelength was 210 nm; a mobile phase was 65% methanol/water, and a flow rate was 4 mL/min. The fraction with a retention time of 13.4 min was collected to obtain compound I-10; the fraction with a retention time of 16.8 min was collected to obtain compound I-11; the fraction with a retention time of 20.5 min was collected to obtain compound I-1, and the fraction with a retention time of 25.6 min was collected to obtain compound I-3.

    [0076] The fraction Fr. E eluted by 60% ethyl acetate-petroleum ether solution was allowed to pass through Sephadex LH-20 (methanol) and treated by reversed-phase silica gel column chromatography using gradient elution with 30%, 50%, 70% and 90% methanol/water solutions, and the fraction eluted by the 70% methanol/water solution was collected and subjected to RP-HPLC, where the chromatographic column was RP-C18 (250×10 mm, 5 μm); a detection wavelength was 210 nm; a mobile phase was 50% methanol/water, and a flow rate was 4 mL/min. The fraction with a retention time of 13.4 min was collected to obtain compound I-12; the fraction with a retention time of 16.7 min was collected to obtain compound I-15; the fraction with a retention time of 19.5 min was collected to obtain compound I-7, and the fraction with a retention time of 22.3 min was collected to obtain compound I-2.

    [0077] Compounds I-1 to I-15 were structurally shown as follows:

    ##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013##

    [0078] The isaridin derivatives were physically and chemically characterized as follows.

    [0079] Compound I-1: white powder; mp 129-132° C.; [α].sub.D.sup.25−164.3 (c 0.08, MeOH); UV (MeOH) λ.sub.max (log ε) 201 (2.10) nm; IR (neat) ν.sub.max 3278, 2956, 2877, 1620, 1543, 1446 cm.sup.−1; .sup.1H and .sup.13C NMR data was shown in Table 1; HRESIMS m/z 655.41752 [M+H].sup.+ (calcd for C.sub.35H.sub.55O.sub.6N.sub.6, 655.41776).

    [0080] Compound I-2: colourless crystal; mp 145-157° C.; [α].sub.D.sup.25−122.2 (c 0.59, MeOH); UV (MeOH) λ.sub.max (log ε) 201 (2.06), 266 (0.66), 277 (0.08) nm; IR (neat) ν.sub.max 3496 (br), 3270 (br), 2950, 1722, 1680, 1645, 1608, 1516, 1238, 1167 cm.sup.−1; .sup.1H and .sup.13C NMR data was shown in Table 1; HRESIMS m/z 628.37022 [M+H].sup.+ (calcd for C.sub.33H.sub.50O.sub.7N.sub.5, 628.37048).

    [0081] Compound I-3: white powder; mp 186-190° C.; [α].sub.D.sup.25−133.9 (c 0.64, MeOH); UV (MeOH) λ.sub.max (log ε) 201 (2.10) nm; IR (neat) ν.sub.max 3350, 3292, 2958, 2871, 1724, 1665, 1624, 1527, 1417, 1172 cm.sup.−1; .sup.1H and .sup.13C NMR data was shown in Table 1; HRESIMS m/z 670.41704 [M+H].sup.+ (calcd for C.sub.36H.sub.56O.sub.7N.sub.5, 670.41743).

    [0082] Compound I-4: white powder; mp 154-156° C.; [α].sub.D.sup.25−133.9 (c 0.64, MeOH); UV (MeOH) λ.sub.max (log ε) 201 (2.10) nm; IR (neat) ν.sub.max 3538 (br), 3348 (br), 3296 (br), 2964, 2871, 1728, 1691, 1645, 1548, 1238, 1180 cm.sup.−1; .sup.1H and .sup.13C NMR data was shown in Table 2; HRESIMS m/z 642.38629 [M+H].sup.+ (calcd for C.sub.34H.sub.52O.sub.7N.sub.5, 642.38613).

    [0083] Compound I-5: white powder; mp 160-163° C.; [α].sub.D.sup.25−180.4 (c 0.05, MeOH); UV (MeOH) λ.sub.max (log ε) 201 (2.10) nm; IR (neat) ν.sub.max 3350, 3292, 2958, 2871, 1724, 1665, 1624, 1527, 1417, 1172 cm.sup.−1; .sup.1H and .sup.13C NMR data was shown in Table 2; HRESIMS m/z 628.37055 [M+H].sup.+ (calcd for C.sub.33H.sub.50O.sub.8N.sub.5, 628.37048).

    [0084] Compound I-6: white powder; mp 105-107° C.; [α].sub.D.sup.25−115.2 (c 0.70, MeOH); UV (MeOH) λ.sub.max (log ε) 201 (2.06) nm; IR (neat) ν.sub.max 3359, 3282, 2958, 2873, 1724, 1668, 1620, 1520, 1450, 1169 cm.sup.−1; .sup.1H and .sup.13C NMR data was shown in Table 2; HRESIMS m/z 642.38590 [M+H].sup.+ (calcd for C.sub.34H.sub.52O.sub.7N.sub.5, 642.38613).

    [0085] Compound I-7: white powder; mp 123-125° C.; [α].sub.D.sup.25−139.0 (c 0.27, MeOH); UV (MeOH) λ.sub.max (log ε) 201 (2.10) nm; IR (neat) ν.sub.max 3351, 2962, 2873, 1724, 1666, 1521, 1448, 1342, 1170 cm.sup.−1; .sup.1H and .sup.13C NMR data was shown in Table 2; HRESIMS m/z 658.38091 [M+H].sup.+ (calcd for C.sub.34H.sub.52O.sub.8N.sub.5, 658.38104).

    [0086] Compound I-8: white powder; mp 154-156° C.; [α].sub.D.sup.25−133.9 (c 0.64, MeOH); UV (MeOH) λ.sub.max (log ε) 201 (2.10) nm; IR (neat) ν.sub.max 3538 (br), 3348 (br), 3296 (br), 2964, 2871, 1728, 1691, 1645, 1548, 1238, 1180 cm.sup.−1; .sup.1H and .sup.13C NMR data was shown in Table 3; HRESIMS m/z 670.38274 [M+H].sup.+ (calcd for C.sub.35H.sub.52O.sub.8N.sub.5, 670.38214).

    [0087] Compound I-9: white powder; mp 135-137° C.; [α].sub.D.sup.25−121.5 (c 0.32, MeOH); UV (MeOH) λ.sub.max (log ε) 201 (2.10) nm; IR (neat) ν.sub.max 3350, 3292, 2958, 2871, 1724, 1665, 1624, 1527, 1417, 1172 cm.sup.−1; .sup.1H and .sup.13C NMR data was shown in Table 3; HRESIMS m/z 642.38602 [M+H].sup.+ (calcd for C.sub.34H.sub.52O.sub.7N.sub.5, 642.38613).

    [0088] Compound I-12: colorless crystal; mp 136-139° C.; [α].sub.D.sup.25−62.8 (c 0.12, MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.14 (d, J=7.5 Hz, 1H), 7.42 (d, J=10.2 Hz, 1H), 7.27 (m, 2H), 7.25 (m, 2H), 7.25 (m, 1H), 5.34 (d, J=10.2 Hz, 1H), 5.12 (d, J=10.7 Hz, 1H), 4.65 (ddd, J=10.9, 7.5, 5.0 Hz, 1H), 4.29 (d, J=10.7 Hz, 1H), 4.15 (m, 1H), 3.71 (d, J=2.4 Hz, 1H), 3.66 (m, 1H), 3.26 (m, 1H), 3.17 (m, 1H), 3.14 (s, 3H), 3.01 (m, 1H), 2.97 (s, 3H), 2.63 (dd, J=11.6, 2.8 Hz, 1H), 2.48 (m, 1H), 2.44 (m, 1H), 2.39 (m, 1H), 2.48 (m, 1H), 1.96 (m, 1H), 1.96 (m, 1H), 1.56 (m, 1H), 1.44 (m, 1H), 1.24 (m, 1H), 1.06 (d, J=7.0 Hz, 3H), 1.01 (d, J=3.2 Hz, 3H), 0.99 (d, J=3.2 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H), 0.89 (d, 3H), 0.87 (d, 3H), 0.87 (d, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 19.0, 19.3, 19.6, 19.8, 20.4, 20.6, 23.5, 24.9, 27.8, 27.8, 29.2, 29.8, 30.2, 35.2, 35.5, 35.7, 38.9, 40.1, 45.6, 53.9, 57.7, 68.1, 66.6, 73.5, 127.4, 128.8, 128.9, 136.5, 168.8, 169.9, 170.1, 172.2, 173.8, 174.2. HRESIMS m/z 670.42432 [M+H].sup.+ (calcd for C.sub.36H.sub.56O.sub.7N.sub.5, 670.42258).

    [0089] Compound I-13: colorless crystal; mp 198-200° C.; [α].sub.D.sup.25−143.8 (c 0.18, MeOH); .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.14 (d, J=7.5 Hz, 1H), 7.42 (d, J=10.2 Hz, 1H), 7.27 (m, 2H), 7.25 (m, 2H), 7.25 (m, 1H), 5.34 (d, J=10.2 Hz, 1H), 5.12 (d, J=10.7 Hz, 1H), 4.65 (ddd, J=10.9, 7.5, 5.0 Hz, 1H), 4.29 (d, J=10.7 Hz, 1H), 4.15 (m, 1H), 4.09 (d, J=7.6 Hz, 1H), 3.50 (dd, J=9.8, 6.4 Hz, 2H), 3.17 (m, 1H), 3.14 (s, 3H), 3.01 (m, 1H), 2.97 (s, 3H), 2.63 (dd, J=11.6, 2.8 Hz, 1H), 2.48 (m, 1H), 2.44 (m, 1H), 2.39 (m, 1H), 2.22 (mp, 1H), 2.13 (m, 1H), 1.96 (m, 1H), 1.96 (m, 1H), 1.77 (m, 1H), 1.30 (m, 1H), 1.24 (m, 1H), 1.01 (d, J=3.2 Hz, 3H), 0.99 (d, J=3.2 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H), 0.89 (d, 3H), 0.87 (d, 3H), 0.87 (d, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 19.0, 19.6, 19.8, 20.4, 20.6, 22.1, 23.5, 24.9, 27.8, 27.8, 29.2, 29.8, 32.4, 35.2, 35.5, 35.7, 38.9, 47.3, 53.9, 57.7, 61.1, 66.6, 73.5, 127.4, 128.8, 128.9, 136.5, 168.8, 169.9, 170.1, 172.2, 173.8, 174.2. HRESIMS m/z 656.40183 [M+H].sup.+ (calcd for C.sub.35H.sub.54O.sub.7N.sub.5, 656.40178).

    [0090] Compound I-14: white powder; mp 138-140° C.; [α].sub.D.sup.25−103.6 (c 0.85, MeOH); .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H: 8.07 (1H, d, J 8.1), 7.23 (2H, m), 7.17 (3H, m), 6.98 (1H, d, J 8.7), 5.19 (1H, d, J 9.5), 4.71 (1H, m), 4.48 (1H, t, J 9.2), 4.33 (1H, d, J 10.7), 4.11 (1H, d, J 8.3), 3.50-3.45 (1H, m), 3.44 (1H, m), 3.21 (1H, t, J 12.5), 3.09 (1H, dd, J 14.4, 5.9), 2.99-2.93 (1H, m), 2.92 (3H, s), 2.64 (1H, d, J 15.7), 2.53 (1H, dd, J 12.1, 3.5), 2.49 (1H, m), 2.24 (1H, m), 2.16-2.10 (1H, m), 2.09 (1H, m), 2.00 (1H, m), 1.93 (2H, m), 1.73 (1H, m), 1.30-1.24 (1H, m), 0.98 (3H, d, J 6.5), 0.96-0.91 (9H, m), 0.88 (6H, t, J 6.4); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 18.9, 19.6, 19.7, 20.3, 21.0, 21.9, 23.4, 25.0, 27.1, 29.3, 31.6, 32.2, 35.0, 35.3, 37.4, 39.0, 47.2, 55.0, 55.2, 61.1, 66.6, 73.3, 127.2, 128.8, 129.0, 136.7, 168.5, 169.9, 171.6, 172.1, 172.8, 173.7. HRESIMS m/z 642.38624 [M+H].sup.+ (calcd for C.sub.34H.sub.52O.sub.7N.sub.5, 642.38613).

    [0091] Compound I-15: white powder; mp 131-133° C.; [α].sub.D.sup.25−64.2 (c 0.11, MeOH); UV (MeOH) λ.sub.max (log ε) 201 (2.10) nm; IR (neat) ν.sub.max 3282, 2956, 1728, 1639, 1541, 1444 cm.sup.−1; .sup.1H and .sup.13C NMR data was shown in Table 1; HRESIMS m/z 628.37012 [M+H].sup.+ (calcd for C.sub.33H.sub.50O.sub.7N.sub.5, 628.37048).

    [0092] The NMR data of compounds I-1 to I-9 and I-15 were shown in Tables I-3.

    TABLE-US-00001 TABLE 1 NMR data of compounds I-1 to I-3 and I-15 (100 MHz/400 MHz, CDCl.sub.3/DMSO-d6, ppm) I-15 I-1 I-2 I-3 NO.  δ.sub.C, δ.sub.H, δ.sub.C, δ.sub.H,  δ.sub.C, δ.sub.H, δ.sub.C, δ.sub.H, type mult, J (Hz) type mult, J (Hz) type mult, J (Hz) type mult, J (Hz) HMPA.sup.1 Leu.sup.1 HMPA.sup.1 HMPA.sup.1 CO 169.8, C  .sup.   171.3, C  .sup.   170.4, C  .sup.   169.0, C  .sup.   α 72.6, CH.sup.  5.04, d (11.0) 52.2, CH.sup.  4.66, dd (11.3; 73.4, CH.sup.  5.29, dd (11.2, 73.0, CH.sup.  5.26, d (10.7) 1.8) 1.8) β 39.6, CH.sub.2 1.95, m 38.8, CH.sub.2 1.76, m 38.7, CH.sub.2 1.93, m 37.5, CH.sub.2 1.68, m 1.21, m 1.34, m 1.25, m 1.53, m γ 24.7, CH.sup.  1.95, m 25.4, CH.sup.  1.74, m 24.8, CH.sup.  1.93, m 24.3, CH.sup.  1.85, m δ 23.5, CH.sub.3 0.98, d (3.3) 23.7, CH.sub.3 1.00, d (3.3) 23.4, CH.sub.3 0.97, d (3.3) 23.1, CH.sub.3 0.94, d (3.8) δ′ 21.4, CH.sub.3 0.93, d (3.3) 20.5, CH.sub.3 1.00, d (3.3) 20.5, CH.sub.3 0.97, d (3.3) 20.0, CH.sub.3 0.94, d (3.8)) NH 6.29, s Pro.sup.2 Pro.sup.2 Pro.sup.2 Pro.sup.2 CO 172.0, C  .sup.   172.6, C  .sup.   171.8, C  .sup.   171.4, C  .sup.   α 60.9, CH.sup.  4.11, d(8.3) 61.2, CH.sup.  4.16, dd (8.6; 61.1, CH.sup.  4.09, m 60.2, CH.sup.  4.14, d (8.3) 2.0) β 32.0, CH.sub.2 2.33, m 32.5, CH.sub.2 2.24, m 32.3, CH.sub.2 2.22, m 31.7, CH.sub.2 2.13, m 2.09, m 2.10, m 2.11, m 1.98, m γ 21.5, CH.sub.2 1.74, m 22.2, CH.sub.2 1.74, m 22.0, CH.sub.2 1.76, m 21.5, CH.sub.2 1.70, m 1.31, m 1.34, m 1.36, m 1.10, m δ 47.1, CH.sub.2 3.42, m 47.4, CH.sub.2 3.52, m 47.3, CH.sub.2 3.49, m 46.8, CH.sub.2 3.30, m Phe.sup.3 Phe.sup.3 Tyr.sup.3 Phe.sup.3 CO 170.7, C  .sup.   174, C.sup.  173.8, C  .sup.   173.5, C  .sup.   α 54.9, CH.sup.  5.11, m 54.2, CH.sup.  4.66, m 54.1, CH.sup.  4.57, m 53.1, CH.sup.  4.62, m β 38.3, CH.sub.2 3.16, m 35.1, CH.sub.2 2.95, m 34.4, CH.sub.2 2.93, m 34.1, CH.sub.2 2.82, m; 3.08, m Φ1′ 136.5, C  .sup.   137.1, C  .sup.   127.2, C  .sup.   136.9, C  .sup.   Φ3′, 129.2, CH .sup.  7.12, m 129.1, CH .sup.  7.27, m 115.7, CH .sup.  6.78, d (8.2) 129.0, CH .sup.  7.29, m Φ5′ Φ2′, 128.7, CH .sup.  7.08, m 128.7, CH .sup.  7.27, m 129.8, CH .sup.  7.06, d (8.2) 128.3, CH .sup.  7.29, m Φ6′ Φ4′ 127.3, CH .sup.  7.24, m 127.2, CH .sup.  7.22, m 156.2, C  .sup.   126.8, CH .sup.  7.25, m NH 8.32, d (8.4) 8.96, d (7.5) 8.07, d (7.5) 7.92, d (7.6) Val.sup.4 NMe-Val.sup.4 NMe-Val.sup.4 NMe-Ile.sup.4 CO 173.9, C  .sup.   170.0, C  .sup.   170.0, C  .sup.   168.9, C  .sup.   α .sup. 58, CH 4.42, dd (9.1, 57.7, CH.sup.  5.13, d (10.7) 57.6, CH.sup.  5.08, d (10.6) 54.3, CH.sup.  5.16, d (10.9) 3.2) β 28.8, CH.sup.  2.66, m 27.7, CH.sup.  2.41, m 27.7, CH.sup.  2.36, m 32.4, CH.sup.  2.20, m γ 16.9, CH.sub.3 0.81, d (6.8) 18.9, CH.sub.3 0.86, d (6.8) 18.9, CH.sub.3 0.84, d (6.6) 23.7, CH.sub.2 1.40, m γ′ 20.0, CH.sub.3 0.93, d (6.8) 20.4, CH.sub.3 1.00, d (6.8) 20.3, CH.sub.3 0.84, d (6.8) 15.7, CH.sub.3 0.77, d (6.8) δ  9.3, CH.sub.3 0.75, d (6.8) NH/NMe 6.09, d (9.1) 29.7, CH.sub.3 3.12, s 29.7, CH.sub.3 3.06, s 29.4, CH.sub.3 3.00, s Val.sup.5 NMe-Val.sup.5 NMe-Val.sup.5 NMe-Val.sup.5 CO 170.7, C  .sup.   168.9, C  .sup.   168.8 C .sup.   167.9, C  .sup.   α 62.0, CH.sup.  3.90, d (4.0) 66.4, CH.sup.  4.35, d (10.7) 66.5, CH.sup.  4.27, d (10.7) 65.6, CH.sup.  4.31, d (10.7) β 29.0 CH.sup.  2.31, m 27.7, CH.sup.  2.44, m 27.7, CH.sup.  2.41, m 27.2, CH.sup.  2.31, m γ 17.6, CH.sub.3 0.95, d (6.8) 19.7, CH.sub.3 0.86, d (6.8) 19.5, CH.sub.3 0.88, d (6.6) 19.1, CH.sub.3 0.86, d (6.8) γ′ 19.7, CH.sub.3 0.93, d (6.8) 19.8, CH.sub.3 0.86, d (6.8) 19.5, CH.sub.3 0.84, d (6.6) 19.4, CH.sub.3 0.82, d (6.8) NH/NMe 7.71, s 29.2, CH.sub.3 2.97, s 29.2, CH.sub.3 2.93, s 28.7, CH.sub.3 2.82, s β-Ala.sup.6 β-Ala.sup.6 β-Ala.sup.6 β-Ala.sup.6 CO 173.4, C  .sup.   172.2, C  .sup.   174.2, C  .sup.   173.7, C  .sup.   α 35.9, CH.sub.2 4.04, m 35.4, CH.sub.2 4.11, m 35.6, CH.sub.2 4.08, m 35.4, CH.sub.2 3.97, m 3.35, m 3.16, m 3.07, m 3.08  m β 35.9, CH.sub.2 2.73, dd (14.2; 36.9, CH.sub.2 2.48, dt (14.5; 35.2, CH.sub.2 2.51, dt (14.5; 34.9, CH.sub.2 2.72, dt (14.5; 7.2) 3.1) 3.1) 3.1) 2.40, m 2.14, m 2.41, m 2.33, m NH 6.87, m 7.38, d (10.1) 7.39, d (10.1) 7.31, d (10.1)

    TABLE-US-00002 TABLE 2 NMR data of compounds I-4 to I-7 (100 MHz/400 MHz, CDCl.sub.3, ppm) NO. I-4 I-5 I-6 I-7 δ.sub.C, δ.sub.H, δ.sub.C, δ.sub.H, δ.sub.C, δ.sub.H, δ.sub.C, δ.sub.H, type mult, J (Hz) type mult, J (Hz) type mult, J (Hz) type mult, J (Hz) HMPA.sup.1 HMPA.sup.1 HMPA.sup.1 HMPA.sup.1 CO 170.0, C  .sup.   169.9, C  .sup.   169.9, C  .sup.   170.0, C  .sup.   α 73.2, CH.sup.  5.20, m 73.1, CH.sup.  5.06, m 72.9, CH.sup.  5.20, m 73.3, CH.sup.  5.27, m β 38.8, CH.sub.2 1.93, m 38.8, CH.sub.2 1.93, m 38.5, CH.sub.2 1.95, m 38.7, CH.sub.2 1.96, m 1.24, m 1.26, m 1.26, m 1.28, m γ 24.9, CH.sup.  1.95, m 25.0, CH.sup.  1.91, m 24.7, CH.sup.  1.94, m 24.9, CH.sup.  1.96, m δ 23.5, CH.sub.3 0.98, d (3.5) 23.4, CH.sub.3 0.96, d (3.3) 23.2, CH.sub.3 0.98, d (3.3) 23.4, CH.sub.3 1.00, d (3.3) δ′ 20.8, CH.sub.3 0.96, d (3.5) 21.2, CH.sub.3 0.92, d (3.3) 20.5, CH.sub.3 0.96, d (3.3) 20.6, CH.sub.3 1.00, d (3.3) Pro.sup.2 Pro.sup.2 Pro.sup.2 Pro.sup.2 CO 171.9, C  .sup.   171.2, C  .sup.   171.7, C  .sup.   171.9, C  .sup.   α 61.0, CH.sup.  4.09, d (8.2) 61.0, CH.sup.  4.07, m 60.8, CH.sup.  4.10, dd (8.6; 2.0) 60.9, CH.sup.  4.10, m β 32.3, CH.sub.2 2.23, m 32.1, CH.sub.2 2.25, m 32.1, CH.sub.2 2.24, m 32.3, CH.sub.2 2.23, m 2.11, m 2.01, m 2.12, m 2.13, m γ 22.3, CH.sub.2 1.74, m 21.8, CH.sub.2 1.71, m 21.8, CH.sub.2 1.77, m 22.0, CH.sub.2 1.78, m 1.26, m 1.11, m 1.29, m 1.31, m δ 47.3, CH.sub.2 3.48, m 47.2,CH.sub.2 3.43, m 47.1, CH.sub.2 3.50, m 47.2, CH.sub.2 3.50, m Phe.sup.3 Phe.sup.3 Phe.sup.3 Phe.sup.3 CO 173.8, C  .sup.   173.1, C  .sup.   173.8, C  .sup.   170.9, C  .sup.   α 53.5, CH.sup.  4.75, m 53.1, CH.sup.  4.82, m 53.2, CH.sup.  4.73, m 53.6, CH.sup.  4.70, m β 35.9, CH.sub.2 3.04, m 36.1, CH.sub.2 3.02, dd(14.0, 35.6, CH.sub.2 2.93, m 35.2, CH.sub.2 2.97, m 4.1) 2.92, m 2.59, m 3.02, m 3.03, m Φ1′ 136.4, C  .sup.   136.5, C  .sup.   136.1, C  .sup.   136.3, C  .sup.   Φ3′ 129.0, CH .sup.  7.28, m 129.0, CH .sup.  7.20, m 128.7, CH .sup.  7.28, m 128.8, CH .sup.  7.29, m Φ5′ Φ2′ 128.9, CH .sup.  7.20, m 128.9, CH .sup.  7.29, m 128.7, CH .sup.  7.20, m 128.8, CH .sup.  7.29, m Φ6′ Φ4′ 127.4, CH .sup.  7.26, m 127.3, CH .sup.  7.25, m 127.2, CH .sup.  7.26, m 127.3, CH .sup.  7.25, m NH 8.09, d (7.6) 8.16, d (7.9) 8.08, d (7.5) 8.12, d (7.4) NMe-Abu.sup.4 NMe-Ala.sup.4 NMe-Val.sup.4 NMe-Val.sup.4 CO 171.1, C  .sup.   172.4, C  .sup.   169.9, C  .sup.   173.8, C  .sup.   α 52.9, CH.sup.  5.36, d (10.7) 47.1, CH.sup.  5.51, d (6.9) 57.6, CH.sup.  5.10, d (10.7) 57.8, CH.sup.  5.09, d (10.7) β 23.2, CH.sub.2 2.05, 1.58, m 16.1, CH.sub.3 1.43, d (6.9) 27.2, CH.sup.  2.34, m 27.5, CH.sup.  2.38, m γ 10.5, CH.sub.3 0.87, d (6.8) 19.0, CH.sub.3 0.90, d (6.8) 19.0, CH.sub.3 0.88, d (6.5) γ′ 19.6, CH.sub.3 0.88, d (6.8) 20.2, CH.sub.3 0.91, d (6.5) NMe 29.6, CH.sub.3 3.14, s .sup. 30.4, CH3 3.28, s .sup. 29.9, CH3 3.15, s .sup. 29.8, CH3 3.10, s NMe-Val.sup.5 NMe-Val.sup.5 NMe-Abu.sup.5 NMe-Thr.sup.5 CO 168.5, C  .sup.   168.5, C  .sup.   168.2, C  .sup.   168.2, C  .sup.   α 67.1, CH.sup.  4.37, d (10.9) 66.9, CH.sup.  4.44, d (10.9) 61.8, CH.sup.  4.73, d (10.7) 66.1, CH.sup.  4.70, d (10.7) β 26.6, CH.sup.  2.41, m 26.3, CH.sup.  2.44, m 23.2, CH.sub.2 2.26, 1.39 64.1, CH.sup.  4.32, m γ 22.1, CH.sub.3 0.94, d (6.8) 19.8, CH.sub.3 0.94, d (6.8) 10.7, CH.sub.3 0.92, d (6.8) 19.6, CH.sub.3 1.23, d (5.9) γ′ 19.6, CH.sub.3 0.81, d (6.8) 19.1, CH.sub.3 0.81, d (6.8) NMe 28.8, CH.sub.3 2.83, s 28.9, CH.sub.3 2.78, s 28.6, CH.sub.3 2.86, s 29.3, CH.sub.3 3.00, s β-Ala.sup.6 β-Ala.sup.6 β-Ala.sup.6 β-Ala.sup.6 CO 174.1, C  .sup.   173.6, C  .sup.   173.5, C  .sup.   173.9, C  .sup.   α 35.5, CH.sub.2 4.15, m 35.3, CH.sub.2 4.09, m 35.5, CH.sub.2 4.13, m 35.5, CH.sub.2 4.15, m 3.16, m 3.19, m 3.19, m 3.18, m β 35.4, CH.sub.2 2.59, m 35.3, CH.sub.2 2.59, m 35.2, CH.sub.2 2.60, m 35.4, CH.sub.2 2.63, d (14.7) 2.59, m 2.59, m 2.60, m 2.55, m NH 7.57, d (7.8) 7.56, d (7.9) 7.52, d (10.1) 7.57, d (10.0)

    TABLE-US-00003 TABLE 3 NMR data of compounds I-8 to I-9 (100 MHz/400 MHz, CDCl.sub.3, ppm) NO. I-8 I-9 δ.sub.C, δ.sub.H, δ.sub.C δ.sub.H type mult, J (Hz) type mult, J (Hz) HMPA.sup.1 HMPA.sup.1 CO 169.8, C  .sup.   171.3, C  .sup.   α 72.7, CH.sup.  5.07, m 73.9, CH.sup.  5.29, m β 38.6, CH.sub.2 1.93, m 39.6, CH.sub.2 1.94, m 1.27, m 1.40, m γ 24.6, CH.sup.  1.92, m 24.8, CH.sup.  1.94, m δ 23.2, CH.sub.3 0.98, d (6.5) 23.4, CH.sub.3 1.00, d (6.5) δ′ 20.5, CH.sub.3 0.98, d (6.5) 21.2, CH.sub.3 0.96, d (6.5) Pro.sup.2 Pro.sup.2 CO 171.5, C  .sup.   169.6, C  .sup.   α 60.7, CH.sup.  4.11, d (8.2) 61.4, CH.sup.  4.11, d (8.2) β 31.9, CH.sub.2 2.27, m 32.1, CH.sub.2 2.11, m 2.07, m γ 21.7, CH.sub.2 1.74, m 22.1, CH.sub.2 1.73, m 1.20, m 1.20, m δ 47.0, CH.sub.2 3.48, m 47.3, CH.sub.2 3.50, m Phe.sup.3 Phe.sup.3 CO 173.8, C  .sup.   172.3, C  .sup.   α 52.9, CH.sup.  4.83, ddt (10.9, 53.6, CH.sup.  4.74, m 7.8, 4.7) β 35.9, CH.sub.2 2.90, m 35.3, CH.sub.2 2.82, m 3.05, dd(13.9, 3.03, m 4.7) Φ1′ 136.1, C  .sup.   136.6, C  .sup.   Φ3′, 128.8, CH .sup.  7.29, m 128.9, CH .sup.  7.27, m Φ5′ Φ2′, 128.6, CH .sup.  7.21, m 128.9, CH .sup.  7.23, m Φ6′ Φ4′ 127.1, CH .sup.  7.26, m 127.3, CH .sup.  7.23, m NH 8.12, d (7.9) 7.43, d (7.9) NMe-Val.sup.4 NMe-Val.sup.4 CO 170.3, C  .sup.   170.8, C  .sup.   α 57.7, CH.sup.  5.05, m 57.1, CH.sup.  5.25, m β 27.1, CH.sup.  2.34, m 28.8, CH.sup.  2.42, m γ 19.1, CH.sub.3 0.92, d (6.8) 20.2, CH.sub.3 0.94, d (6.8) γ′ 19.6, CH.sub.3 0.92, d (6.8) 20.2, CH.sub.3 0.96, d (6.8) NMe 30.1, CH.sub.3 3.21, s 30.3, CH.sub.3 3.23, s NMe-Ala.sup.5 NMe-Val.sup.5 CO 169.3, C  .sup.   169.7, C  .sup.   α 55.5, CH.sup.  5.06, m 67.1, CH.sup.  4.03, d (10.9) β 15.0, CH.sub.3 1.37, d(6.7) 27.4, CH.sup.  2.42, m γ — 20.3, CH.sub.3 1.03, d (6.8) γ′ — 18.7, CH.sub.3 0.89, d (6.8) NMe 28.1, CH.sub.3 2.85, s 30.3, CH.sub.3 3.03, s β-Ala.sup.6 Gly.sup.6 CO 173.3, C  .sup.   169.5, C  .sup.   α 35.4, CH.sub.2 4.07, m 43.9, CH.sub.2 4.09, m 3.23, m 3.85, m β 34.8, CH.sub.2 2.63, m — 2.67, m — NH 7.42, dd (9.7, 6.95, dd (9.6, 2.7) 2.7)

    [0093] Among them, the Crystallographic Data of I-2 and I-13 was shown as follows, and their X-ray crystallographic structures were respectively shown in FIGS. 1-2.

    [0094] Crystallographic Data of I-2. C.sub.35H.sub.53N.sub.5O.sub.8, Mr=671.84, monoclinic, space group P2.sub.1, a=10.13190 (10) Å, b=36.2803 (2) Å, c=10.23540 (10) Å; a=90°, β=95.7220 (10°), γ=90°, V=3743.67 (6) Å.sup.3, T=100.0 (8) K, Z=4, ρ.sub.calcd=1.256 g/m.sup.3, crystal size 0.44×0.35×0.06 mm.sup.3, F(000)=1528, 2θ range for data collection 4.872 to 149.028, absorption coefficient 0.757 mm.sup.−1, reflections collected 70852, independent reflections 14639 [R.sub.int=0.0308, R.sub.sigma=0.0249], final R indices [I>2σ(I)] R.sub.1=0.0387, wR.sub.2=0.1046. The goodness of fit on F.sup.2 was 1.047. Flack parameter −0.02 (4); Hooft parameter −0.00 (3). Crystallographic data for the structure of isaridin J (2) have been deposited in the Cambridge Crystallographic Data Centre (deposition numbers: CCDC 2108990).

    [0095] Crystallographic Data of I-13. C.sub.35H.sub.53N.sub.5O.sub.7, Mr=655.84, Orthorhombic, space group P2.sub.12.sub.12.sub.1, a=17.88018 (14) Å, b=22.1738 (2) Å, c=22.7060 (2) Å; a=90°, β=90°, γ=90°, V=9002.29 (13) Å.sup.3, T=100.0 (8) K, Z=8, ρ.sub.calcd=1.034 g/m.sup.3, crystal size 0.25×0.15×0.05 mm.sup.3, F(000)=3033, 20 range for data collection 7.45 to 148.174, absorption coefficient 0.592 mm.sup.−1, reflections collected 36641, independent reflections 17785 [R.sub.int=0.0296, R.sub.sigma=0.0385], final R indices [I>2σ(I)] R.sub.1=0.0550, wR.sub.2=0.1550; The goodness of fit on F.sup.2 was 1.018. Flack parameter 0.02 (6); Hooft parameter −0.04 (6). CCDC deposition numbers: CCDC 2109162.

    Example 2 Anti-Inflammatory Activity Test

    [0096] The effect of the compounds I-1 to I-9 and I-13 to I-15 prepared in Example 1 on the NO release from LPS-induced macrophage RAW264.7 cells was investigated to evaluate the anti-inflammatory activity, which was specifically described as follows.

    [0097] 1.1 Experimental Materials

    [0098] Lipopolysaccharide (LPS); indomethacin (Indomethacin, Indo, positive control); mouse mononuclear macrophages (RAW264.7); dimethyl sulfoxide (DMSO); Methylthiazolyldiphenyl-tetrazolium bromide (MTT, 5 mg/mL); and Griess reagent nitrite measurement kit (Beyotime Biotechnology Co., Ltd).

    [0099] 1.2 Experimental Method

    [0100] The compounds were respectively dissolved in DMSO to obtain a series of 10 mM stock solutions, which were diluted with Dulbecco's modified eagle medium (DMEM) to a required concentration (DMSO<2%) for use.

    [0101] RAW264.7 cells (1×10.sup.5 cells/mL) were inoculated into a 96-well plate at 100 μL per well and incubated at 37° C. and 5% CO.sub.2 for 12 h. Different concentrations of samples containing LPS (with a final concentration of 1 μg/mL) were respectively loaded on the plate. The experimental groups were established as follows: blank group (100 μL DMEM), LPS-induced model group (1 μL LPS+99 μL DMEM), LPS+Indo group (1 μL LPS+25 μL Indo+74 μL DMEM) and LPS+ sample group (1 μL LPS+99 μL sample-containing medium), where a concentration of lipopolysaccharide was 100 μg/mL, and a concentration of indomethacin was 200 μg/mL. After that, the 96-well plate was cultured for 24 h. 50 μL of the supernatant was carefully pipetted to another 96-well plate, added with NO I and NO II reagents from the Griess kit, mixed evenly and subjected to standing at room temperature for 10 min. After that, the absorbance of each well of the 96-well plate at 540 nm was measured with a microplate reader and then plugged into the standard curve to calculate the NO release level.

    [0102] 50 μL of residual culture medium was carefully pipetted, added with 100 μL of MTT solution diluted with DMEM, and cultured in an incubator for 4 h. The supernatant was pipetted, added with 110 μL of DMSO solution, shaken for 10 min and measured with a microplate reader for the absorbance at 490 nm to evaluate the cell viability.


    NO release inhibition rate (%)=(OD.sub.LPS-induced model group−OD.sub.LPS+sample group)/(OD.sub.LPS-induced model group−OD blank group)×100%; and


    cell viability (%)=[(mean OD of sample groups)/mean OD of control groups]×100%.

    [0103] 2. Results

    [0104] The tested compounds all had a half maximal inhibitory concentration (IC.sub.50) of 6-30 μM, which was lower than that of the positive control indomethacin (IC.sub.50: 38 μM), indicating an excellent anti-inflammatory activity. In the MTT test, all compounds were confirmed to be non-cytotoxic to RAW264.7 cells, and thus have high safety.

    Example 3 In-Vitro Anti-Thrombotic Activity Test

    [0105] Compounds I-1 to I-9 and I-13 to I-15 prepared in Example 1 were tested for their inhibitory effects on the ADP-induced platelet aggregation in vitro to evaluate the anti-thrombotic activities, and the test process was specifically described as follows.

    [0106] Kunming mice were anesthetized with pentobarbital sodium, and blood was collected from the celiac artery, where the syringe was added with 3.2% sodium citrate for anti-coagulation in advance (a volume ratio of whole blood to the anticoagulant was 9:1). The mixture was gently mixed and centrifuged at 1000 r/min for 10 min to collect the supernatant as the platelet-rich plasma (PRP). The remaining part was centrifuged at 3000 r/min for 10 min to obtain platelet-poor plasma (PPP). A platelet count of the PRP was adjusted to 3×10.sup.8/mL with PPP.

    [0107] For the blank control group, 1% DMSO was mixed with 295 μL of PRP; for the drug group, 5 μL of the isaridin derivatives with different concentrations (a final concentration of 0-100 μM) was mixed with 295 μL of PRP; and regarding the positive control group, aspirin was mixed with plasma to a final concentration of 120 μM. After incubated at 37° C. for 5 min, the individual mixed systems were respectively transferred to a detection hole of the platelet aggregation analyzer, and the measurement channels were zeroed with PPP in turn. After that, the sample group and the control group were respectively added with 15 μL (0.5 mg/mL) of the inducer ADP. Three parallel samples were tested for each group, and the platelet aggregation rate was measured at 37° C. by turbidimetric method, where the maximum aggregation rate within 5 min was recorded.

    [0108] The platelet aggregation rate was expressed as the maximum platelet aggregation rate, and the results were expressed as the inhibition rate.


    Inhibition rate (%)=(platelet aggregation rate of the blank control group−platelet aggregation rate of the drug group)/the platelet aggregation rate of the blank control group×100%.

    [0109] The results showed that with the increase in the concentration of the isaridin drug, the maximum platelet aggregation rate decreases gradually, that was, in a concentration-dependent manner. The IC.sub.50 values of the 12 tested isaridin compounds were approximately 10-100 μM, which were all lower than that of the positive control aspirin (IC.sub.50: 120 μM), indicating that the isaridin compounds of the disclosure were superior to the aspirin in terms of the anti-thrombotic activity.

    [0110] The formation of thrombus mainly includes three stages: (1) platelet adhesion and aggregation; (2) blood coagulation; and (3) fibrinolysis. Isaridin cyclodepsipeptide derivatives can inhibit the ADP-induced platelet aggregation, and further reduce the blood viscosity, directly affecting the first stage of the thrombosis. Therefore, the isaridin cyclodepsipeptide compounds have an anti-thrombotic activity.

    [0111] Described above are only preferred embodiments of the present disclosure and are not intended to limit the present disclosure. It should be understood that any modifications, replacements and improvements made by those skilled in the art without departing from the spirit and scope of the present disclosure should fall within the scope of the present disclosure defined by the appended claims.