CN115624547A - Sesquiterpene compound and preparation method and application thereof - Google Patents

Sesquiterpene compound and preparation method and application thereof Download PDF

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CN115624547A
CN115624547A CN202010534211.9A CN202010534211A CN115624547A CN 115624547 A CN115624547 A CN 115624547A CN 202010534211 A CN202010534211 A CN 202010534211A CN 115624547 A CN115624547 A CN 115624547A
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sesquiterpene
sesquiterpene compound
alkyl
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张文
庄春林
李冉
李娇
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Zichen Ocean Pharmaceutical Technology Shanghai Co ltd
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a sesquiterpene compound and a preparation method and application thereof. The invention extracts and separates sesquiterpene nitrobenzoate from fermentation liquor of Aspergillus ochracea sp. The invention also discovers that the compound with the sesquiterpene mother nucleus structure and partial derivatives thereof have better apoptosis inhibition activity, can effectively inhibit apoptosis, and can be used for research and development of prevention and treatment medicines for diseases related to apoptosis. The invention provides a lead compound and a new active skeleton for the development of a medicine for preventing and treating diseases related to programmed cell necrosis, and is beneficial to the development and utilization of marine medicinal resources.

Description

Sesquiterpene compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a sesquiterpene compound and a preparation method and application thereof.
Background
Aspergillus sp, a rich variety of fungi, is an important source of pharmaceutically active compounds, and lead compounds such as penicillin and viridivatin were first discovered from Aspergillus (Frisvad JC, larsen to. Appl Microbiol Biotechnol,2015,99 (19): 7859-7877). The fungus Aspergillus ochracea, the chemical composition of which is reported only in 3, is of the type sesquiterpene having RAW 264.7 macrophage inhibitory activity, the merososesterpenoids against influenza viruses, the alpha-pyran derivatives having anti-inflammatory activity (Wang J, he W, kong F, tian X, wang P, zhou X, liu Y. J Nat Prod,2017,80 (6): 1725-1733 Wang J, wei X, qin X, tian X, liao L, li K, zhou X, yang X, wang F, zhang T, tu Z, chen B, liu Y. J Nat Prod,2016,79 (1): 59-65 Liu JT, wu W, cao M-J, yang F, lin H-W. Nat Prod Res,2018, 1732 (1715): 59-1715.
Apoptosis is a Caspase-independent mode of cell death mediated by death receptors. Programmed cell necrosis IS associated with a variety of inflammations and diseases, such as inflammatory bowel disease, acute pancreatitis, ischemic cardiomyopathy, ischemic stroke, alzheimer' S disease, and atherosclerosis, among others (Robinson N, mcComb S, mulligan R, dudani R, krishnan L, sad S.Nat Immunol.2012,13 (10): 954-962; caccamo A, branca C, piras IS, ferreira E, hunterman MJ, liang WS, readhead B, dudley JT, spangenberg EE, green KN, belfiore R, winslow W, oddo S.Nat Neurosci.2017,20 (9): 1236-1246). Therefore, the identification and discovery of the inhibitor of programmed cell necrosis are of great significance for the clinical treatment of diseases related to programmed cell necrosis.
The marine natural product has various and novel structures and is an important source of active substances. At present, no report on marine natural small molecules and derivatives with anti-programmed cell necrosis activity is found.
Disclosure of Invention
The sesquiterpene nitrobenzoate is extracted and separated from fermentation liquor of Aspergillus ochracea epizoon of sponge east-Sha moss (Tedania sp.) of south China sea, and the compound and partial derivatives thereof have good programmed cell necrosis inhibition activity and new application in preparing medicines for preventing and treating diseases related to programmed cell necrosis.
Further research finds that the sesquiterpene compounds containing the same mother nucleus and having the following structural formula also have the new application of the programmed cell necrosis inhibiting activity, and on the basis, one of the purposes of the invention is to disclose the application of the sesquiterpene compounds in preparing the medicines for preventing and treating the diseases related to the programmed cell necrosis;
Figure BDA0002536461480000021
wherein R is 4 Selected from the group consisting of hydrogen, hydroxy, halogen, hydrocarbyl, hydrocarbyloxy, hydrocarbylacyloxy, hydrocarbyloxyacyl;
R 5 selected from the group consisting of hydrogen, hydroxy, halogen, hydrocarbyl, hydrocarbyloxy, hydrocarbylacyloxy, hydrocarbylacyl, hydrocarbyloxyacyl;
R 6 selected from the group consisting of hydrogen, hydroxy, halogen, hydrocarbyl, hydrocarbyloxy, hydrocarbylacyloxy, hydrocarbylacyl, hydrocarbyloxyacyl;
R 7 and R 8 Independently selected from hydrogen, hydroxy, halogen, hydrocarbyl, hydrocarbyloxy, hydrocarbylacyloxy, hydrocarbylacyl, hydrocarbyloxyacyl; alternatively, the first and second electrodes may be,
R 7 is-O-, R 8 is-CO-R 8 And R 7 form-O-CO-.
In the above structure, the hydrocarbon group (which means the hydrocarbon group, and the hydrocarbon group in the hydrocarbyloxy group, hydrocarbylacyloxy group, hydrocarbylacyl group, and hydrocarbyloxyacyl group) includes substituted and unsubstituted alkane, alkene, alkyne, and arene groups.
In the above structure, the dotted double bond means that the bond may be a double bond or a single bond.
The programmed cell necrosis-related diseases include, but are not limited to, one or more of alzheimer's disease, ischemic cardiomyopathy, ischemic stroke, atherosclerosis, acute pancreatitis, inflammatory bowel disease in children, sepsis, salmonella infection, listeria infection, and vaccinia virus infection.
In some preferred sesquiterpene compounds for use according to the invention, R 5 Selected from the group consisting of aryloyloxy; r 7 is-O-, R 8 is-CO-R 8 And R 7 form-O-CO-.
Further, the structural formula of the preferred sesquiterpenoids in the application is as follows:
Figure BDA0002536461480000031
wherein R is 1 Selected from, but not limited to, hydrogen, alkyl, and acyl;
R 2 selected from, but not limited to, nitro, amino, N-substituted amino, alkyl, halogen, acyl, and aryl.
More preferably, the sesquiterpene compound is selected from the following compounds 1-12.
Figure BDA0002536461480000032
The second purpose of the invention is to disclose a new sesquiterpene compound which has programmed cell necrosis inhibition activity and the structural formula of which is as follows:
Figure BDA0002536461480000041
wherein R is 1 Selected from, but not limited to, hydrogen, alkyl, and acyl;
R 2 selected from the group consisting of, but not limited to, nitro, amino, N-substituted amino, alkyl, halogen, acyl, and aryl;
R 1 when it is hydrogen or acetyl, R 2 Not the nitro group in the 4-position.
With respect to R 1 ，
R 1 When alkyl, it may be substituted or unsubstituted and is selected from, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl;
R 1 when acyl, it is selected from, but not limited to, alkyl formyl, alkenyl formyl, alkynyl formyl, aryl formyl and cycloalkyl formyl;
in a further aspect of the present invention,
the alkyl formyl groups include, but are not limited to, acetyl, propionyl, and butyryl;
the alkynylcarbonyl groups include, but are not limited to, 4-pentynoyl and 6-heptynoyl;
the arylformyl group includes, but is not limited to, benzoyl and picolinoyl;
the cycloalkylformyl group includes, but is not limited to, cyclohexylformyl, cyclopentylcarbonyl, and cyclopropylformyl.
With respect to R 2 ，
R 2 When N-substituted amino, is selected from, but not limited to, N-substituted acylamino, alkylamino, alkenylamino, alkynylamino, arylamino, and cycloalkylamino; preferably N-acetylamino;
R 2 when alkyl, it may be substituted or unsubstituted and is selected from, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl;
R 2 when it is halogen, it is selected from F, cl and Br;
R 2 when acyl, it is selected from, but not limited to, alkyl formyl, alkenyl formyl, alkynyl formyl, aromatic formyl and cycloalkyl formyl. Further selected from acetyl, propionyl, butyryl, 4-pentynoyl and 6-heptynoyl, benzoyl, picolinoyl, cyclohexylformyl, cyclopentylcarbonyl and cyclopropylformyl;
R 2 aryl, when substituted, may be substituted or unsubstituted and is selected from, but not limited to, phenyl, pyridyl.
In some preferred sesquiterpene compounds of the invention,
R 1 is hydrogen, acetyl, propionyl, 4-pentynoyl, 6-heptynoyl, benzoyl, picolinoyl, cyclohexylformyl, cyclopentylcarbonyl or cyclopropylformyl;
R 2 is nitro, amino or N-acetylamino.
The following list of 10 sesquiterpene compounds preferred according to the invention, i.e. compounds 1 to 10.
Figure BDA0002536461480000051
The invention also aims to provide a preparation method of the sesquiterpenoids, which comprises the following steps:
step (a) the following compound 11 was isolated from the fermentation broth of Aspergillus ochracea,
Figure BDA0002536461480000061
or the method comprises:
and (b) taking the compound 11 as a raw material, and carrying out one-step or multi-step reaction to prepare the target compound. The compound 11 can be obtained by extracting from natural materials in the above step (a) or by chemical synthesis.
Preferably, in the step (a),
the fermentation broth is prepared by inoculating a strain of an Aspergillus ochracea strain separated from a Toshiba sponge Tedania sp. in south China to an agar culture medium of a biological malt extract for fermentation;
the extraction and separation process comprises the following steps: carrying out ultrasonic extraction on the fermentation liquor by using ethyl acetate, and then carrying out reduced pressure concentration to obtain a total crude extract; separating the total crude extract by normal phase silica gel chromatography, and eluting with CH 2 Cl 2 : meOH =100:1 → 1:1, collecting the fraction containing the compound 11, concentrating, and recrystallizing with methanol to obtain the compound 11.
Step (b) may be performed for the preparation of said sesquiterpene compounds other than compound 11, preferably, said one or more steps include, but are not limited to, acylation, nitro-reduction, alkylation and other reactions. The compounds 1 to 10 and 12 of the present invention can be prepared by the above-mentioned several reactions or combinations thereof, and the details of the following embodiments can be specifically referred to.
The invention has the beneficial effects that:
the sesquiterpene nitrobenzoate is extracted and separated from fermentation liquor of Aspergillus ochracea epizoon of sponge east-Sha moss (Tedania sp.) of south China sea, and partial derivatives of the sesquiterpene nitrobenzoate are obtained by modifying the chemical structure of the compound. The invention provides a lead compound and a new active skeleton for the development of medicaments for preventing and treating diseases related to programmed cell necrosis, and is beneficial to the development and utilization of marine medicinal resources.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below in connection with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. All raw materials without any reference to the synthesis method are purchased from manufacturers such as exploration platforms, aladdin, sigma-Aldrich and the like, and are analytically pure.
EXAMPLE 1 preparation of sesquiterpene nitrobenzoate 11
1. Examples origin and identification of the strains used: the fungus is isolated from Spongilla (Tedania sp.) Spongilla tissue collected from 15 m deep sea region of east sand Islands of south China sea in 2015 12 months, and identified as Aspergillus ochracea by rDNA gene spacer sequence (ITS) analysis.
2. Preparing strain fermentation liquor: the strains were inoculated into bio malt extract (biomult) agar (agar) medium (3% biomult, 2% agar) and fermented at 28 ℃ for 28 days.
3. Preparation of Total crude extract
Carrying out ultrasonic extraction on 12L of strain fermentation liquor by using conventional ethyl acetate, and concentrating an extracting solution under reduced pressure to obtain 18g of total crude extract.
4. Separating and purifying
Separating the total crude extract by normal phase silica gel chromatography (200-300 meshes), and using CH 2 Cl 2 : meOH =100:1 → 1:1 eluent was subjected to gradient elution, and the crude fraction containing compound 11 was collected according to thin layer plate monitoring; concentrating the crude fraction under reduced pressure, performing normal phase silica gel column chromatography, and collecting the extractThe fractions were concentrated and recrystallized from methanol to give Compound 11 (94.0 mg).
Structural identification
[α]25D＝-215.12(c 0.32,CHCl 3 )； 1 H NMR(400MHz,MeOD)δ:8.44–8.29(m,2H,H-4’/H-6’),8.23(dd,J＝9.0,2.2Hz,2H,H-3’/H-7’),6.77(d,J＝4.0Hz,1H,H-7),6.12(t,J＝4.3Hz,1H,H-6),4.55(d,J＝9.8Hz,1H,H-11a),4.26(d,J＝9.9Hz,1H,H-11b),4.12(d,J＝11.0Hz,1H,H-14a),3.52(dd,J＝11.2,1.2Hz,1H,H-14b),2.47(d,J＝4.5Hz,1H,H-5),2.29–2.07(m,1H,H-1a/H-3a),1.79–1.63(m,1H,H-2a),1.60–1.48(m,1H,H-2b),1.34(s,3H,15-Me),1.10(s,3H,13-Me),0.99(m,1H,H-3b)； 13 C NMR(100MHz,MeOD)δ:170.95(C-12),165.09(C-1’),152.36(C-5’),136.36(C-2’),134.86(C-8),133.20(C-7),132.06(C-3’/C-7’),124.92(C-4’/C-6’),77.77(C-9),76.30(C-11),68.90(C-6),65.36(C-14),47.98(C-5),40.48(C-4),36.88(C-3),33.27(C-1),27.40(C-13),21.86(C-15),18.61(C-2).
The structure of compound 11 was identified as follows:
Figure BDA0002536461480000081
EXAMPLE 2 preparation of sesquiterpene nitrobenzoate derivatives 1
Synthetic route
Figure BDA0002536461480000082
Experimental procedure
To a reaction tube were added Compound 11 (4.3mg, 10. Mu. Mol) and DAMP (0.12mg, 1. Mu. Mol), N 2 Protection, addition of 1mL pyridine followed by ice bath, dropwise addition of benzoyl chloride (4.2 mg, 30. Mu. Mol), warming to room temperature, stirring for 12h, quenching the reaction, extraction three times with ethyl acetate, combining the organic layers, brine washing, drying, spin drying, and HPLC to afford compound 1 as an amorphous solid (2.2 mg, 41% yield). 1 H NMR(600MHz,CDCl 3 )δ8.29(d,J＝9.0Hz,2H),8.17(d,J＝9.0Hz,2H),7.88(dd,J＝8.4,1.3Hz,2H),7.53(t,J＝7.4Hz,1H),7.39(t,J＝7.8Hz,2H),6.94(d,J＝4.0Hz,1H),6.17(t,J＝4.3Hz,1H),4.87(d,J＝11.3Hz,1H),4.54(d,J＝10.1Hz,1H),4.40(d,J＝11.2Hz,1H),4.35(d,J＝10.1Hz,1H),2.58(d,J＝4.5Hz,1H),2.20–2.23(m,1H),2.18–2.13(m,1H),1.66–1.64(m,2H),1.43–1.37(m,4H),1.31–1.28(m,4H). 13 C NMR(151MHz,CDCl 3 )δ168.6,166.4,163.7,150.9,134.4,133.5,133.1,131.0,130.0,129.4,128.4,123.9,75.1,67.6,67.6,46.8,39.2,37.9,37.3,31.8,27.3,21.1,17.5.
EXAMPLE 3 preparation of sesquiterpene nitrobenzoate derivatives 2
Synthetic route
Figure BDA0002536461480000091
Experimental procedure
Compound 11 (4.3 mg,10 μmol), isonicotinic acid (1.23mg, 10 μmol), DAMP (1.2mg, 10 μmol), dichloromethane (1 mL) were added, after stirring at room temperature for 10min, EDCI was added, then stirred overnight, spun dry, HPLC preparation gave amorphous solid (4.2mg, 30 μmol), warmed to room temperature and stirred for 12h, the reaction was quenched, extracted three times with ethyl acetate, the organic layers were combined, washed with salt, dried, spun dry, HPLC preparation conditions: flow rate: 2mL/min; mobile phase: acetonitrile and water (0-2min, 50%, 2-20min,10%, 20-30min, 10%); the peak time: 17.5min. Compound 2 was obtained as an amorphous solid (4.0 mg, 76% yield). 1 H NMR(600MHz,CDCl 3 )δ8.73(s,2H),8.32(d,J＝9.0Hz,2H),8.18(d,J＝9.0Hz,2H),7.71(d,J＝5.8Hz,2H),6.94(d,J＝4.0Hz,1H),6.17(t,J＝4.3Hz,1H),4.90(d,J＝11.3Hz,1H),4.54(d,J＝10.1Hz,1H),4.46(d,J＝11.1Hz,1H),4.36(d,J＝10.1Hz,1H),2.61(d,J＝4.6Hz,1H),2.32–2.25(m,1H),2.13(d,J＝13.4Hz,1H),1.68–1.61(m,2H),1.44–1.36(m,4H),1.29–1.27(m,4H). 13 C NMR(151MHz,CDCl 3 )δ168.5,164.8,163.6,151.0,150.4,137.3,134.4,133.2,131.0,130.0,123.9,122.8,75.1,68.3,67.6,46.8,39.2,37.9,37.0,31.7,27.2,21.2,17.4.
EXAMPLE 4 preparation of sesquiterpene nitrobenzoate derivatives 3
Figure BDA0002536461480000092
Referring to the preparation method of example 3, isonicotinic acid was changed to nicotinic acid. The HPLC preparation method comprises the following steps: flow rate: 2mL/min; mobile phase: acetonitrile and water (0-2min, 50%, 2-20min,10%, 20-30min, 10%); the peak time: 17.2min. Compound 3 was finally obtained as an amorphous solid (4.2 mg, 78% yield). 1 H NMR(600MHz,CDCl 3 )δ9.07(s,1H),8.73(s,1H),8.31(d,J＝8.9Hz,2H),8.24–8.12(m,3H),7.37(dd,J＝7.9,4.9Hz,1H),6.92(d,J＝3.9Hz,1H),6.17(t,J＝4.3Hz,1H),4.92(d,J＝11.2Hz,1H),4.54(d,J＝10.0Hz,1H),4.46(d,J＝11.1Hz,1H),4.36(d,J＝10.1Hz,1H),2.64(d,J＝4.6Hz,1H),2.30(td,J＝13.2,5.9Hz,1H),2.14(d,J＝13.9Hz,1H),1.73–1.65(m,2H),1.41–1.35(m,4H),1.30–1.27(s,4H). 13 C NMR(151MHz,CDCl 3 )δ168.8,165.0,163.6,153.3,151.0,150.4,137.2,134.4,133.3,133.2,131.0,126.1,123.9,123.5,76.6,75.3,67.9,67.7,46.8,39.2,37.9,37.0,31.7,27.3,21.1,17.5.
EXAMPLE 5 preparation of sesquiterpene nitrobenzoate derivatives 4
Figure BDA0002536461480000101
Referring to the preparation method of example 3, isonicotinic acid was changed to cyclohexanecarboxylic acid. Compound 4 was finally obtained as an amorphous solid (3.0 mg, 55% yield). 1 H NMR(600MHz,CDCl 3 )δ8.33(d,J＝9.0Hz,2H),8.19(d,J＝9.0Hz,2H),6.92(d,J＝3.9Hz,1H),6.11(t,J＝4.3Hz,1H),4.68(d,J＝11.1Hz,1H),4.51(d,J＝10.1Hz,1H),4.32(d,J＝10.1Hz,1H),4.09(d,J＝11.0Hz,1H),2.49(d,J＝4.5Hz,1H),2.24–2.15(m,2H),2.05(d,J＝13.2Hz,1H),1.83(d,J＝12.5Hz,1H),1.77(d,J＝12.9Hz,1H),1.71–1.66(m,2H),1.63–1.61(m,4H),1.34–1.32(m,4H),1.28–1.24(m,2H),1.23–1.21(m,1H),1.20–1.18(m,1H),1.17–1.13(m,4H). 13 C NMR(151MHz,CDCl 3 )δ175.9,168.5,163.6,150.9,134.5,133.5,133.0,131.0,123.9,75.1,67.6,66.3,46.8,43.3,39.1,37.8,36.5,31.8,29.0,28.9,27.2,25.7,25.4,25.4,21.1,17.4.
EXAMPLE 6 preparation of sesquiterpene nitrobenzoate derivatives 5
Figure BDA0002536461480000111
Referring to the preparation method of example 3, isonicotinic acid was changed to cyclopropanecarboxylic acid. The HPLC preparation method comprises the following steps: flow rate: 2mL/min; mobile phase: acetonitrile and water (0-2min, 50%, 2-20min,10%, 20-30min, 10%); the peak time: 20.5min. Compound 5 was finally obtained as an amorphous solid (2.5 mg, 55% yield). 1 H NMR(600MHz,CDCl 3 )δ8.32(d,J＝8.9Hz,2H),8.18(d,J＝9.0Hz,2H),6.90(d,J＝3.7Hz,1H),6.11(t,J＝4.3Hz,1H),4.65(d,J＝11.2Hz,1H),4.50(d,J＝10.0Hz,1H),4.32(d,J＝10.1Hz,1H),4.12(d,J＝11.0Hz,1H),2.51(d,J＝4.4Hz,1H),2.23–2.18(m,1H),2.05–2.01(m,1H),1.64–1.60(m,2H),1.51–1.45(m,1H),1.34–1.30(m,4H),1.19–1.14(m,4H),0.92–0.85(m,2H),0.84–0.78(m,2H). 13 C NMR(151MHz,CDCl 3 )δ174.7,168.7,163.7,150.9,134.5,133.4,133.1,131.0,123.9,75.1,67.6,66.9,46.7,39.1,37.7,36.8,31.8,27.2,21.1,17.4,12.8,8.4,8.3.
EXAMPLE 7 preparation of sesquiterpene nitrobenzoate derivatives 6
Figure BDA0002536461480000112
Referring to the preparation method of example 3, isonicotinic acid was changed to 4-pentynoic acid. Compound 6 was finally obtained as an amorphous solid (2.6 mg, 51% yield). 1 H NMR(600MHz,CDCl 3 )δ 1 H 8.33(d,J＝8.9Hz,1H),8.19(d,J＝9.0Hz,2H),6.89(s,1H),6.11(t,J＝4.2Hz,1H),4.72(d,J＝11.1Hz,1H),4.51(d,J＝10.1Hz,1H),4.33(d,J＝10.1Hz,1H),4.16(d,J＝11.1Hz,1H),2.53(d,J＝4.3Hz,1H),2.49–2.38(m,4H),2.26–2.18(m,1H),2.04(d,J＝14.2Hz,1H),1.61(s,2H),1.35(d,J＝13.8Hz,1H),1.37–1.33(m,3H),1.19–1.12(m,4H). 13 C NMR(151MHz,CDCl 3 )δ171.6,168.8,163.6,151.0,134.5,133.4,133.1,131.0,123.9,82.3,75.2,69.1,67.7,67.1,46.8,39.1,37.7,36.5,33.4,31.7,27.1,21.1,17.4,14.4.
EXAMPLE 8 preparation of sesquiterpene nitrobenzoate derivatives 7
Figure BDA0002536461480000121
Referring to the preparation method of example 3, isonicotinic acid was replaced by 6-heptynoic acid. HPLC preparation conditions: flow rate: 2mL/min; mobile phase: acetonitrile and water (0-2min, 35%;2-20min,10%;20-30min, 10%); the peak time: and (5) 17min. Compound 7 was finally obtained as an amorphous solid (2.6 mg, 50% yield). 1 H NMR(600MHz,CDCl 3 )δ8.38–8.30(m,2H),8.21–8.17(m,2H),6.90(d,J＝3.9Hz,1H),6.11(t,J＝4.3Hz,1H),4.68(d,J＝11.1Hz,1H),4.51(d,J＝10.1Hz,1H),4.33(d,J＝10.1Hz,1H),4.13(d,J＝11.1Hz,1H),2.51(d,J＝4.6Hz,1H),2.25–2.19(m,3H),2.16(td,J＝7.0,2.6Hz,2H),2.05–2.01(m,1H),1.68–1.65(m,2H),1.63–1.60(m,2H),1.51–1.45(m,2H),1.38–1.34(m,1H),1.32(s,3H),1.19–1.13(m,4H). 13 C NMR(151MHz,CDCl 3 )δ173.3,168.7,163.6,151.0,134.5,133.4,133.1,131.0,123.9,83.8,75.2,68.7,67.6,66.7,46.7,39.1,37.7,36.6,33.7,31.8,27.8,27.2,23.9,21.1,18.1,17.4.
EXAMPLE 9 preparation of sesquiterpene nitrobenzoate derivatives 8
Synthetic route
Figure BDA0002536461480000122
Experimental procedure
Compound 11 (4.3mg, 10. Mu. Mol), fe powder (2.7mg, 50. Mu. Mol) and NH were charged into a reaction tube 4 Cl (1.1mg, 20. Mu. Mol), 18 drops of ethanol and 2 drops of water, after heating under reflux for 2.5h, the Fe powder was removed by filtration, the filtrate was spin-dried, and the HPLC preparation conditions: flow rate: 2mL/min; mobile phase: acetonitrile and water (0-2min, 90%;2-20min, 30%; and/or more)(ii) a 20-30min, 10%), time to peak: and 20min. Compound 8 was finally obtained as an amorphous solid i.e. (1.5 mg, 37% yield). HRMS [ M + H] + 491.2039,[M+Na] + 496.1587. 1 H NMR(300MHz,DMSO)δ7.60(d,J＝8.4Hz,2H),6.58(d,J＝8.4Hz,2H),6.51(d,J＝3.8Hz,1H),6.08(s,2H),5.84(t,J＝4.1Hz,1H),5.74(s,1H),4.46(d,J＝9.7Hz,1H),4.28(t,J＝5.2Hz,1H),4.15(d,J＝9.7Hz,1H),3.89(dd,J＝10.9,5.3Hz,1H),3.31(dd,J＝11.0,5.3Hz,1H),2.50(s,2H),2.31(d,J＝4.4Hz,1H),2.05(dd,J＝31.0,9.1Hz,3H),1.22(s,3H),1.17(s,3H),0.96(s,3H). 13 C NMR(75MHz,DMSO)δ169.3,165.2,154.4,133.1,132.7,131.9,115.6,113.2,76.5,75.1,65.3,63.2,46.3,35.7,32.3,27.4,21.4,17.7.
EXAMPLE 10 preparation of sesquiterpene nitrobenzoate derivatives 9
Figure BDA0002536461480000131
Referring to the preparation method of example 9, compound 11 was changed to compound 12. Compound 9 was finally obtained as an amorphous solid (1.8 mg, 40% yield). 1 H NMR(600MHz,CD 3 CN)δ7.39(d,J＝8.7Hz,2H),6.35(d,J＝4.0Hz,1H),6.30(d,J＝8.7Hz,2H),5.65(t,J＝4.4Hz,1H),4.29(d,J＝11.3Hz,1H),4.14(d,J＝9.9Hz,1H),3.86(d,J＝9.9Hz,1H),3.81(d,J＝11.3Hz,1H),2.02(d,J＝4.7Hz,1H),1.80–1.76(m,2H),1.71–1.66(m,2H),1.55(s,3H),0.95–0.94(m,4H),0.76–0.70(m,4H). 13 C NMR(151MHz,CD 3 CN)δ170.6,168.8,165.1,153.3,133.0,132.5,131.8,129.8,113.2,76.8,74.7,66.4,65.2,46.6,38.9,37.5,36.5,31.7,26.4,20.6,19.9,17.3.
EXAMPLE 11 preparation of sesquiterpene nitrobenzoate derivatives 10
Figure BDA0002536461480000132
Compound 8 (4.1mg, 10. Mu. Mol), N, was added to the reaction tube 2 Protecting, adding 1mL of pyridine, dropwise adding 0.5mL of acetic anhydride under ice bath, stirring at room temperature for 3h, and carrying out ice bathThen adding water to quench the reaction, extracting with ethyl acetate for three times, combining organic layers, washing with salt, drying and spin-drying. HPLC preparation finally afforded compound 10 as an amorphous solid (2.4 mg, 50% yield). 1 H NMR(600MHz,CDCl 3 )δ7.93(d,J＝8.7Hz,2H),7.59(d,J＝8.4Hz,2H),6.88(s,1H),6.03(t,J＝4.3Hz,1H),4.68(d,J＝11.2Hz,1H),4.49(d,J＝9.9Hz,1H),4.31(d,J＝10.0Hz,1H),4.14(d,J＝11.3Hz,1H),2.46(d,J＝4.7Hz,1H),2.22–2.19(m,1H),2.16(s,3H),1.98–1.94(m,1H),1.92(s,3H),1.64–1.57(m,2H),1.31–1.29(m,4H),1.16–1.10(m,4H)。 13 C NMR(151MHz,CDCl 3 )δ171.3,169.1,169.0,164.8,143.0,134.3,132.4,131.1,124.3,119.0,75.2,67.2,66.2,46.7,39.1,37.5,36.7,31.8,27.1,21.1,20.9,17.5.
EXAMPLE 12 preparation of sesquiterpene nitrobenzoate derivatives 12
Figure BDA0002536461480000141
Referring to the preparation method of example 11, compound 8 was changed to compound 11. The HPLC preparation method comprises the following steps: flow rate: 1.5mL/min; mobile phase: acetonitrile and water (0-2min, 60%, 2-20min,10%, 20-30min, 10%); the peak time: and 20min. Compound 12 was finally obtained as an amorphous solid (2.9 mg, 62% yield). 1 H NMR(600MHz,CDCl 3 )δ8.39–8.31(m,2H),8.27–8.16(m,2H),6.92(d,J＝4.0Hz,1H),6.13(t,J＝4.3Hz,1H),4.66(d,J＝11.1Hz,1H),4.53(d,J＝10.1Hz,1H),4.34(d,J＝10.1Hz,1H),4.17(d,J＝11.1Hz,1H),2.52(d,J＝4.7Hz,1H),2.29–2.18(m,1H),2.04(d,J＝13.6Hz,1H),1.95(s,3H),1.66–1.62(s,2H),1.37(d,J＝13.4Hz,1H),1.33(s,3H),1.21–1.13(m,4H). 13 C NMR(151MHz,CDCl 3 )δ171.1,168.7,163.6,151.0,134.5,133.5,133.0,131.0,123.9,75.2,67.6,66.8,46.7,39.1,37.6,36.5,31.7,27.1,21.1,20.8,17.4.
Example 13 anti-apoptosis assay
Tumor cell necrosis was induced by the addition of TNF-. Alpha.20 ng/ml after 30min pretreatment with z-VAD-fmk (20. Mu.M) and Smac mimic (10 nM). The sesquiterpene nitrobenzoate esters and derivatives of the invention, the comparative positive compound TAK-632, were incubated with the cells of the above combination for 16 hours. Cell activity was tested using the CellTiter-Glo luminescent cell viability assay kit (Promega). The cell viability of the DMSO group without the necrosis-inducing agent was defined as 100%. The results are shown in Table 1.
Programmed cell necrosis inhibitory Activity of the Compounds of Table 1 at 50. Mu.M
Compound (I) Cell viability (%)
1 <30
2 70.0±12.90
3 75.3±13.60
4 <30
5 51.1±2.93
6 <30
7 <30
8 134.0±2.92
9 194±9.5
10 164±11.03
11 142.96±11.02
12 102.30±13.50
TAK-632(10μM) 145.96±11.01
The above experimental results show that most compounds of the present invention can inhibit programmed cell necrosis, especially compounds 8-12 can effectively inhibit programmed cell necrosis, and the activity of compounds 9 and 10 is obviously superior to that of parent compound 11. The above compounds can be used for preparing medicines for treating inflammation or infection related diseases such as Alzheimer disease, ischemic cardiomyopathy, ischemic stroke, atherosclerosis, acute pancreatitis, children inflammatory bowel disease, sepsis, salmonella infection, listeria infection, and vaccinia virus infection. The invention provides a lead compound and a new active skeleton for developing new medicaments for preventing and treating diseases related to programmed cell necrosis, and is beneficial to developing and utilizing marine medicinal resources.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent should be subject to the appended claims.

Claims (14)

1. The application of the sesquiterpene compound in preparing the medicine for preventing and treating the diseases related to programmed cell necrosis is characterized in that the sesquiterpene compound has the following structural formula:
Figure FDA0002536461470000011
wherein R is 4 Selected from the group consisting of hydrogen, hydroxy, halogen, hydrocarbyl, hydrocarbyloxy, hydrocarbylacyloxy, hydrocarbyloxyacyl;
R 5 selected from the group consisting of hydrogen, hydroxy, halogen, hydrocarbyl, hydrocarbyloxy, hydrocarbylacyloxy, hydrocarbylacyl, hydrocarbyloxyacyl;
R 6 selected from the group consisting of hydrogen, hydroxy, halogen, hydrocarbyl, hydrocarbyloxy, hydrocarbylacyloxy, hydrocarbyloxyacyl;
R 7 and R 8 Independently selected from the group consisting of hydrogen, hydroxy, halogen, hydrocarbyl, hydrocarbyloxy, hydrocarbylacyloxy, hydrocarbyloxyacyl; alternatively, the first and second electrodes may be,
R 7 is-O-, R 8 is-CO-R 8 And R 7 form-O-CO-.
2. Use according to claim 1, wherein R of the sesquiterpene compound is 5 Selected from the group consisting of aryloyloxy; r 7 is-O-, R 8 is-CO-R 8 And R 7 form-O-CO-.
3. The use of claim 2, wherein the sesquiterpene compound has the formula:
Figure FDA0002536461470000012
wherein R is 1 Is selected from hydrogenAlkyl and acyl;
R 2 selected from nitro, amino, N-substituted amino, alkyl, halogen, acyl and aryl.
4. The use according to claim 3, wherein the sesquiterpene compound is selected from the group consisting of compounds 1 to 12,
Figure FDA0002536461470000021
5. the use of claim 1, wherein the programmed cell necrosis-associated disease is one or more of Alzheimer's disease, ischemic cardiomyopathy, ischemic stroke, atherosclerosis, acute pancreatitis, inflammatory bowel disease in children, sepsis, salmonella infection, listeria infection, and vaccinia virus infection.
6. A sesquiterpene compound, which has a structural formula:
Figure FDA0002536461470000022
wherein R is 1 Selected from hydrogen, alkyl and acyl;
R 2 selected from nitro, amino, N-substituted amino, alkyl, halogen, acyl and aryl;
R 1 when it is hydrogen or acetyl, R 2 Not the nitro group in the 4-position.
7. The sesquiterpene compound of claim 6, wherein the acyl group comprises an alkyl-formyl, alkenyl-formyl, alkynyl-formyl, aryl-formyl and cycloalkyl-formyl group.
8. Sesquiterpene compound of claim 7,
the alkyl formyl group comprises acetyl, propionyl and butyryl;
the alkynoyl group comprises 4-pentynoyl and 6-heptynoyl;
the arylformyl group includes benzoyl and picolinoyl;
the cycloalkylformyl group includes cyclohexylformyl group, cyclopentylcarbonyl group and cyclopropylformyl group.
9. The sesquiterpene compound of claim 6, wherein the N-substituted amino group comprises N-substituted acylamino, alkylamino, alkenylamino, alkynylamino, arylamino and cycloalkylamino groups.
10. The sesquiterpene compound of claim 6,
R 1 selected from the group consisting of acetyl, propionyl, 4-pentynoyl, 6-heptynoyl, benzoyl, picolinoyl, cyclohexylformyl, cyclopentylcarbonyl and cyclopropylformyl;
R 2 selected from nitro, amino, N-acetylamino.
11. The sesquiterpene compound of claim 6, which is one of the following compounds 1-10,
Figure FDA0002536461470000031
12. a method of making a sesquiterpene compound having the structural formula:
Figure FDA0002536461470000041
wherein R is 1 Selected from hydrogen, alkyl and acyl;
R 2 selected from nitro, amino, N-substituted amino, alkyl, halogen, acyl and aryl;
the method comprises the following steps:
step (a) the following compound 11 was isolated from the fermentation broth of Aspergillus ochracea,
Figure FDA0002536461470000042
or the method comprises:
and (b) taking the compound 11 as a raw material, and carrying out one-step or multi-step reaction to prepare the target compound.
13. The method of claim 12, wherein in step (a),
the fermentation broth is prepared by inoculating strains of Aspergillus ochracea epiphysis separated from east sand moss sponge Tedania sp. in south China sea into an agar culture medium of biological malt extract for fermentation;
the extraction and separation process comprises the following steps: carrying out ultrasonic extraction on the fermentation liquor by using ethyl acetate, and then carrying out reduced pressure concentration to obtain a total crude extract; separating the total crude extract by normal phase silica gel chromatography, and eluting with CH 2 Cl 2 : meOH =100:1 → 1:1, collecting the fraction containing compound 11, concentrating, and recrystallizing with methanol to obtain compound 11.
14. The method of claim 12, wherein in step (b),
the one-step or multi-step reaction comprises one or two or more than two of acylation reaction, nitro reduction reaction and alkylation reaction.
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