Sulfonamide dehydrocurvulgarin derivative as well as preparation method and application thereof
By introducing sulfonamide groups into dehydrocurvulariacin compounds, highly efficient ACLY inhibitors were developed, solving the problems of insufficient bioavailability and antitumor activity of DCV and achieving effective inhibition of various cancers.
Patent Information
- Application Number
- CN202511329687.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-17
- Publication Date
- 2026-01-13
AI Technical Summary
The existing dehydrocurvulariacin compound DCV has limitations in bioavailability and antitumor activity, which restricts its development for clinical application.
By introducing sulfonamide groups to modify dehydrocurvulariacin, a series of sulfonamide ACLY inhibitors were developed to enhance their biological activity and selectivity, and anti-tumor drugs were prepared.
The compound's antitumor activity was enhanced, particularly its inhibitory effect on various cancers such as breast cancer, liver cancer, lung cancer, and colorectal cancer. The IC50 value was significantly reduced, demonstrating good potential for clinical application.
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Figure CN121318907A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the fields of natural products and medicinal chemistry, specifically to a sulfonamide-based ACLY inhibitor based on dehydrocurvulariacin, its preparation method, and its uses. Background Technology
[0002] ATP-citrate lyase (ACLY) is a cytoplasmic homotetramer enzyme, a key bridge in the acetylation of glucose, lipids, and histones, and participates in various cellular metabolic processes. Multiple studies have shown that ACLY activity is significantly upregulated in the pathological processes of various diseases, including cancer, cardiovascular disease, and metabolic disorders. Due to the unlimited proliferative nature of tumors, high ACLY expression can promote the production of acetyl-CoA, providing essential lipid precursors and energy support for rapid tumor proliferation; therefore, targeting ACLY holds promise for the development of novel anti-tumor drugs.
[0003] 10,11-Dehydrocurvularin (DCV, structural formula shown below), as a representative compound of the dihydroxybenzeneacetic acid lactones (DALs), has attracted much attention from the natural product chemistry community due to its unique structural features and wide range of biological sources. This molecule was first discovered in 1967 by Musgrave's research team from *Curvularia* fungi (…). Curvularia The compound DCV was successfully isolated and identified from secondary metabolites of *C. sp.*, exhibiting broad-spectrum antibacterial, anti-inflammatory, and antitumor activities. Our previous research group discovered that compound DCV possesses good ACLY inhibitory activity using chemical proteomics techniques, with an enzyme inhibitory activity of 0.93 μM. However, its low bioavailability and moderate antitumor activity limit its clinical application. Therefore, conducting target-based structural optimization of DCV to develop novel ACLY inhibitors is of great significance.
[0004]
[0005] In recent years, significant progress has been made in the research of sulfonamide compounds as ACLY inhibitors. In 2020, Nimbus Therapeutics reported a series of sulfonamide-based ACLY inhibitors, all of which retain the central sulfonamide skeleton. Among them, compound NDI-091143 exhibited excellent inhibitory activity, with an IC50 value of 0.5% for ACLY enzyme activity. 50The effective concentration reached 2.1 nM. Unfortunately, the insufficient in vitro and in vivo inhibitory activity of compound NDI-091143 against tumor cells limited its further development and application. Therefore, this patent uses 10,11-dehydrocurvulariacin as the core and introduces a sulfonamide group to develop a novel, highly effective, and highly selective ACLY inhibitor, aiming to overcome the limitations of existing inhibitors and provide more promising candidate compounds for the development of ACLY-targeted drugs. Summary of the Invention
[0006] This invention addresses the problems existing in the prior art by providing a sulfonamide-based ACLY inhibitor based on dehydrocurvulariacin. This type of compound has good antitumor activity and can be used as a potential new anticancer drug.
[0007] The present invention also provides a method for preparing and applying the aforementioned sulfonamide ACLY inhibitor based on dehydrocurvulariacin.
[0008] Based on this, the present invention provides a dehydrocurvulariacin sulfonamide derivative having the structure shown in general formula (I):
[0009] General Formula (I) R is selected from any one of benzene ring, substituted benzene ring, heterocycle, substituted heterocycle, alkane, and substituted alkane; The substituents in the substituted benzene ring include any one of methyl, ethyl, methoxy, ethoxy, halogen, nitro, cyano, and phenyl, and the substituents can be monosubstituted or polysubstituted; The substituents in the substituted heterocycle include any one of methyl, ethyl, methoxy, ethoxy, halogen, nitro, cyano, and phenyl, and the substituents can be monosubstituted or polysubstituted; The heterocycle includes any one of naphthalene ring, pyridine, indole, and morpholine; The alkanes mentioned include any one of straight-chain alkanes, branched-chain alkanes, and cyclic alkanes.
[0010] In some preferred embodiments, in the structure shown in general formula (I), R is selected from a benzene ring or a benzene ring mono- or poly-substituted with methyl, ethyl, methoxy, ethoxy, halogen, nitro, cyano, or phenyl; a naphthyl ring or a naphthyl ring mono- or poly-substituted with methyl, ethyl, methoxy, ethoxy, halogen, nitro, cyano, or phenyl; pyridine, 2-chloropyridine, 4-chloropyridine, 6-methylpyridine, 6-methoxypyridine, indole, 1-methylindoline, morpholine, 2,6-dimethylmorpholine, butane, pentane, heptane, dipropane, dimethylpentane, cyclopropane, cyclobutane, and cyclohexane.
[0011] In some preferred embodiments, the dehydrocurvulariacin sulfonamide derivative is selected from any one of the following compounds:
[0012] The preparation of the dehydrocurvulariacin-based sulfonamide ACLY inhibitor of the present invention can be carried out according to the following synthetic route. The specific synthetic route and steps of the compound can be referred to the examples.
[0013]
[0014] Synthesis of Compound 2: Compound 2 was obtained by condensation reaction of p-aminoacetophenone and sulfonyl chloride as starting materials. The solvents used included, but were not limited to, dichloromethane, tetrahydrofuran, acetonitrile, acetone, dichloroethane, chloroform, dioxane, ethanol, isopropanol, N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), and 1,4-dioxane, with dichloromethane and tetrahydrofuran being preferred. The reaction temperature was 0°C to room temperature, and the reaction time was 1 hour to 12 hours.
[0015] Synthesis of Compound 3: Compound 2 is brominated at the α-position of the ketone carbonyl group by the brominating reagent phenyltrimethylammonium tribromide to obtain Compound 3. The solvents used include, but are not limited to, acetonitrile, tetrahydrofuran, and ethanol, with tetrahydrofuran being preferred. The reaction temperature is from 0 ℃ to 60 ℃, preferably room temperature (25 ℃). The reaction time is from 15 minutes to 12 hours, preferably from 30 minutes to 2 hours.
[0016] Synthesis of compound 4: Compound 4 is obtained by reacting compound 3 with DCV under alkaline conditions. The solvent used includes, but is not limited to, acetonitrile, ethanol, and DMF, preferably DMF; the alkaline reagent includes, but is not limited to, sodium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate, preferably cesium carbonate; the reaction temperature is preferably room temperature, and the reaction time is 10 minutes to 1 hour, preferably 20 minutes.
[0017] The purpose of this invention is to provide a series of sulfonamide ACLY inhibitors based on dehydrocurvulariacin, which can improve the bioactivity of dehydrocurvulariacin, increase its bioavailability, and increase the possibility of clinical application of dehydrocurvulariacin.
[0018] Another object of the present invention is to provide a method for its preparation and its application in the preparation of ACLY inhibitor drugs.
[0019] An antitumor drug, wherein the antitumor compound is selected from the aforementioned dehydrocurvulariacin sulfonamide derivative.
[0020] Application of dehydrocurvulariacin sulfonamide derivatives in the preparation of antitumor lead compounds.
[0021] The anti-tumor properties described are anti-tumor effects against any one or more of the following cancers: breast cancer, liver cancer, lung cancer, colorectal cancer, and pancreatic cancer.
[0022] The present invention also provides an antitumor pharmaceutical composition comprising the aforementioned dehydrocurvulariacin sulfonamide derivative.
[0023] To achieve the objectives of this invention, dehydrocurvulariacin was reacted with sulfonamide groups of different substitutions to obtain a series of sulfonamide-based ACLY inhibitors based on dehydrocurvulariacin. These compounds exhibit good ACLY inhibitory activity and can be used to prepare ACLY inhibitor drugs for clinical treatment of various diseases, showing promising development prospects. Attached Figure Description
[0024] Figure 1 This is the proton NMR spectrum of compound III-5.
[0025] Figure 2 This is the carbon spectrum of compound III-5.
[0026] Figure 3 This is a diagram showing the apoptosis induced by compound III-5. Detailed Implementation
[0027] The invention is further illustrated by the following specific examples, but it should be noted that the scope of the invention is not limited by these embodiments.
[0028] Example 1 Synthesis Route
[0029] Synthesis of intermediate 2 Weigh 100 mg (739 μmol) of p-aminoacetophenone, dissolve it in analytical grade dichloromethane, add pyridine (239.3 μL, 2.96 mmol), and slowly add 3,5-difluorobenzenesulfonyl chloride (188.7 mg, 887.8 μmol) under ice bath conditions. After the addition is complete, the reaction is brought to room temperature. The reaction is monitored by thin-layer chromatography and quenched with dilute hydrochloric acid. Extraction is performed with 20 mL of dichloromethane, followed by washing with dilute hydrochloric acid solution (15 mL × 3). The aqueous layers are combined and back-extracted once with dichloromethane. The organic phases are then combined. The organic phase is evaporated under vacuum, and the crude product is purified by column chromatography to give compound 2 (110 mg), with a yield of 48%.
[0030] Synthesis of intermediate 3 Compound 2 (55 mg, 176.7 μmol) was dissolved in tetrahydrofuran, and then phenyltrimethylammonium tribromide (67.6 mg, 212 μmol) was added. The reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the organic phase was evaporated under vacuum and purified by column chromatography to obtain compound 3 (32 mg), with a yield of 46%.
[0031] Synthesis of target product III-1
[0032] Compound 3 (32 mg, 86.1 μmol), DCV (25 mg, 86.1 μmol), and cesium carbonate (28 mg, 86.1 μmol) were weighed and dissolved in analytical grade DMF. A trace amount of potassium iodide was then added, and the reaction was carried out at room temperature for 10-20 minutes. After the reaction was monitored by thin-layer chromatography, 20 mL of ethyl acetate was added for extraction, followed by washing with saturated NaCl aqueous solution. The aqueous layers were combined and back-extracted once with ethyl acetate. The organic phases were then combined. The ethyl acetate phase was evaporated under vacuum, and the crude product was purified by column chromatography to obtain the target compound III-1. 1 HNMR (400 MHz, CDCl3) δ 12.76 (s, 1H), 8.12 (s, 1H), 7.86 (d, J = 8.5 Hz, 2H),7.43 – 7.38 (m, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.03 (dq, J = 8.1, 5.8, 4.4 Hz,1H), 6.72 – 6.65 (m, 2H), 6.45 (d, J = 2.6 Hz, 1H), 6.26 (d, J = 2.5 Hz, 1H), 5.26 (s, 2H), 4.92 (dd, J = 14.9, 7.8 Hz, 1H), 4.11 (d, J = 17.5 Hz, 1H), 3.61(d, J = 18.2 Hz, 1H), 2.52 (d, J = 15.2 Hz, 1H), 2.37 (q, J = 7.3, 6.8 Hz, 1H), 2.05 (d, J = 18.2 Hz, 2H), 1.75 – 1.70 (m, 2H), 1.29 (d, 3H). 13C NMR (101 MHz, CDCl3) δ 196.27, 191.64, 171.12, 166.18, 165.50, 162.34, 157.81, 148.74,142.61, 137.77, 134.25, 132.96, 131.25, 129.87, 129.68, 129.50, 118.72,114.89, 113.65, 104.71, 101.12, 99.58, 56.39, 55.74, 38.91, 29.70, 28.99,22.97, 19.98. Example III-2
[0033] Following the method of Example 1, 3,5-difluorobenzenesulfonyl chloride was replaced with 3,5-ditrifluoromethylbenzenesulfonyl chloride to prepare the target compound III-2. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (s, 1H), 10.12 (s, 1H), 8.54 (s, 1H), 8.42 (d, J = 1.6 Hz, 2H), 7.96 – 7.93 (m, 2H), 7.32 (d, J = 2.1 Hz,2H), 6.42 – 6.35 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 16.1 Hz, 1H), 5.45 (s, 2H), 4.76 (ddt, J = 8.4, 6.3, 3.6 Hz, 1H), 2.28 (dq, J = 15.3, 6.9, 5.4Hz, 1H), 2.17 (tdd, J = 13.3, 8.9, 2.8 Hz, 1H), 1.88 – 1.76 (m, 2H), 1.48 –1.39 (m, 2H), 1.06 (d, J = 6.3 Hz, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 198.00,193.20, 170.48, 159.51, 156.90, 155.28, 138.69, 133.81, 132.91, 130.12,129.88, 122.13, 120.71, 118.53, 108.86, 101.15, 72.74, 70.32, 33.78, 33.33,24.31, 20.45. Example III-3
[0034] Following the method of Example 1, 3,5-difluorobenzenesulfonyl chloride was replaced with p-tert-butylbenzenesulfonyl chloride to prepare the target compound III-3. 1 H NMR (400 MHz, CDCl3) δ 12.71 (s, 1H), 8.31 (s, 1H), 7.81 (tt, J =9.1, 2.1 Hz, 4H), 7.52 – 7.46 (m, 2H), 7.22 – 7.15 (m, 2H), 6.68 (q, J = 2.2Hz, 2H), 6.43 (d, J = 2.6 Hz, 1H), 6.30 (d, J = 2.6 Hz, 1H), 5.25 (s, 2H), 4.93 –4.84 (m, 1H), 4.07 (d, J = 17.9 Hz, 1H), 3.63 – 3.54 (m, 1H), 2.55 – 2.44 (m,1H), 2.36 (q, J = 3.3, 2.9 Hz, 1H), 2.05 – 1.90 (m, 2H), 1.68 (p, J = 6.1 Hz, 2H), 1.31 (s, 9H), 1.26 (d, J = 6.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 196.25,191.80, 171.61, 166.22, 162.38, 157.25, 149.01, 142.73, 137.69, 136.08,131.22, 129.70, 129.44, 127.01, 126.32, 118.40, 114.80, 113.76, 101.10,72.95, 70.01, 44.02, 36.69, 35.21, 34.05, 32.70, 31.61, 31.01, 24.19, 20.00. Example III-4
[0035] Following the method of Example 1, 3,5-difluorobenzenesulfonyl chloride was replaced with p-trifluoromethoxybenzenethioyl chloride to prepare the target compound III-4. 1 H NMR (400 MHz, DMSO- d 6) δ 11.13 (s, 1H), 10.10 (s, 1H), 8.03– 7.98 (m, 2H), 7.95 – 7.91 (m, 2H), 7.63 – 7.59 (m, 2H), 7.29 – 7.24 (m, 2H), 6.45 – 6.33 (m, 2H), 6.31 – 6.22 (m, 2H), 5.47 – 5.43 (m, 2H), 4.79 –4.72 (m, 1H), 2.29 (d, J = 8.7 Hz, 1H), 2.23 – 2.11 (m, 1H), 1.78 (dt, J = 24.5,10.1 Hz, 2H), 1.47 – 1.38 (m, 2H), 1.07 (d, J = 6.3 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 198.02, 193.25, 170.50, 159.58, 156.94, 155.29, 144.12, 133.83,132.93, 130.20, 129.26, 120.71, 117.66, 108.94, 101.15, 72.76, 58.27, 48.83,48.19, 42.52, 26.69, 25.10, 20.48, 19.78. Example III-5
[0036] Following the method of Example 1, 3,5-difluorobenzenesulfonyl chloride was replaced with 2,4-dimethoxybenzenesulfonyl chloride to prepare the target compound III-5. 1 H NMR (400 MHz, CDCl3) δ 12.69 (s, 1H), 8.09 (s, 2H), 7.86 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.57 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 4.8 Hz, 2H), 6.42 (dd, J = 11.2, 2.4 Hz, 1H), 6.27 (d, J = 2.6 Hz,1H), 5.19 (s, 2H), 4.83 (t, J = 6.6 Hz, 1H), 4.03 (d, J = 17.8 Hz, 1H), 3.94 (s,3H), 3.81 (s, 3H), 3.54 (d, J = 18.0 Hz, 1H), 2.47 (dd, J = 15.5, 7.3 Hz, 1H),2.38 – 2.34 (m, 1H), 2.00 – 1.90 (m, 2H), 1.74 – 1.69 (m, 2H), 1.26 (d, J =12.1 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 198.01, 193.26, 170.50, 159.56, 156.94, 155.28, 144.14, 133.83, 132.93, 130.11, 129.96, 129.42, 120.73, 118.35,108.93, 101.15, 72.77, 70.37, 33.79, 33.34, 30.61, 24.32, 20.48. Example III-6
[0037] Following the method of Example 1, 3,5-difluorobenzenesulfonyl chloride was replaced with 4-cyanobenzenesulfonyl chloride to prepare the target compound III-7. 1 H NMR (400 MHz, CDCl3) δ 12.77 (s, 1H), 8.35 (s, 1H), 7.95 (d, J = 8.3Hz, 2H), 7.80 (dd, J = 15.0, 8.3 Hz, 4H), 7.13 (d, J = 8.4 Hz, 2H), 6.71 (d, J =4.7 Hz, 2H), 6.45 (d, J = 2.6 Hz, 1H), 6.23 (d, J = 2.6 Hz, 1H), 5.26 (s, 2H), 4.91 (t, J = 6.5 Hz, 1H), 4.12 (d, J = 18.0 Hz, 1H), 3.66 – 3.57 (m, 1H), 2.52(dd, J = 15.7, 7.4 Hz, 1H), 2.37 (dt, J = 13.7, 6.8 Hz, 1H), 2.06 – 1.91 (m, 2H), 1.72 (s, 2H), 1.28 (d, J = 4.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 196.17,191.78, 172.02, 166.34, 162.35, 149.15, 143.21, 141.60, 137.66, 133.09,131.11, 129.80, 127.77, 119.31, 117.05, 113.94, 100.94, 73.26, 70.07, 44.12,32.68, 29.70, 24.23, 20.04. Example III-7
[0038] Following the method of Example 1, 3,5-difluorobenzenesulfonyl chloride was replaced with 5-(dimethylamino)naphthalene-1-sulfonyl chloride to prepare the target compound III-8. 1 H NMR (400 MHz, CDCl3) δ 12.64 (s, 1H), 8.56 (d,J = 8.4 Hz,1H), 8.34 – 8.30 (m, 2H), 8.12 (s, 2H), 7.81 – 7.75 (m, 2H), 7.20 (d, J = 7.6Hz, 1H), 7.13 – 7.08 (m, 2H), 6.68 – 6.63 (m, 2H), 6.41 (d, J = 2.6 Hz, 1H), 6.29 (d, J = 2.6 Hz, 1H), 5.17 (s, 2H), 4.87 (t, J = 6.9 Hz, 1H), 4.35 – 4.23 (m,1H), 4.05 – 3.95 (m, 1H), 2.88 (s, 6H), 2.50 (dd, J = 15.9, 8.2 Hz, 1H), 2.36(s, 1H), 2.03 (dd, J = 19.0, 11.4 Hz, 2H), 1.75 (p, J = 6.2 Hz, 2H), 1.30 (d,3H).13C NMR (101 MHz, CDCl3) δ 198.24, 193.60, 172.02, 163.14, 161.46,151.96, 151.10, 138.34, 136.52, 136.17, 135.03, 132.93, 130.65, 129.73,129.17, 128.68, 127.58, 126.06, 123.27, 121.88, 121.15, 119.04, 116.60,110.85, 102.49, 73.28, 71.20, 45.63, 42.02, 34.63, 33.28, 24.82, 20.48. Example III-8
[0039] Following the method of Example 1, 3,5-difluorobenzenesulfonyl chloride was replaced with propylsulfonyl chloride to prepare the target compound III-9. 1 H NMR (400 MHz, CDCl3) δ 12.74 (s, 1H), 8.11 (s, 1H), 7.97 – 7.91 (m,2H), 7.28 – 7.23 (m, 2H), 6.68 (d, J= 3.2 Hz, 2H), 6.48 (d, J = 2.6 Hz, 1H), 6.33 (d, J = 2.6 Hz, 1H), 5.30 (s, 2H), 4.91 – 4.84 (m, 1H), 4.09 (d, J = 17.8Hz, 1H), 3.60 (d, J = 18.0 Hz, 1H), 3.20 – 3.12 (m, 2H), 2.56 – 2.46 (m, 1H), 2.40 – 2.33 (m, 2H), 2.08 – 1.88 (m, 4H), 1.69 (t, J = 3.5 Hz, 2H), 1.26 (d,3H), 1.05 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 196.23, 191.77, 171.63,166.33, 162.41, 148.99, 142.91, 137.74, 131.19, 130.07, 129.51, 117.92,114.78, 113.84, 101.08, 72.99, 70.13, 54.03, 38.89, 32.70, 30.56, 22.98,20.01, 17.24, 14.08. Example III-9
[0040] Following the method of Example 1, 3,5-difluorobenzenesulfonyl chloride was replaced with cyclopropylsulfonyl chloride to prepare the target compound III-9. 1 H NMR (400 MHz, DMSO- d 6) δ 10.41 (s, 1H), 10.13 (s, 1H), 8.03 – 7.97(m, 2H), 7.40 – 7.34 (m, 2H), 6.47 – 6.21 (m, 4H), 5.49 (s, 2H), 4.81 – 4.73(m, 1H), 2.79 (tt, J = 7.8, 5.1 Hz, 1H), 2.29 (dd, J= 11.8, 5.5 Hz, 1H), 2.23 – 2.12 (m, 1H), 1.84 – 1.72 (m, 2H), 1.55 – 1.26 (m, 6H), 1.09 (d, J = 6.4 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 197.99, 193.32, 170.45, 159.51, 156.96, 155.26, 142.29, 142.07, 133.84, 132.89, 132.27, 131.93, 130.71, 130.20, 128.07, 127.79, 124.22, 121.50, 120.74, 119.46, 108.81, 101.23, 72.72, 70.37, 33.77, 33.32, 24.30, 20.41. Example III-10
[0041] 1 H NMR (400 MHz, DMSO- d 6) δ 10.49 (s, 1H), 10.08 (s, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 6.43 – 6.17 (m, 4H), 5.46 (s, 2H), 4.76 – 4.69 (m, 1H), 3.46 (d, J = 15.0 Hz, 1H), 3.09 (d, J = 15.0 Hz, 1H), 2.36 – 2.23 (m, 3H), 2.17 – 2.10 (m, 1H), 2.03 (t, J = 4.6 Hz, 1H), 1.97 – 1.89 (m, 2H), 1.82 – 1.67 (m, 2H), 1.54 (dd, J = 13.6, 4.5 Hz, 2H), 1.44 – 1.31 (m, 4H), 1.05 (d, J = 6.3 Hz, 3H), 0.97 (s, 3H), 0.74 (s, 3H). 13C NMR (101 MHz, CDCl3) δ196.17, 191.81, 171.94, 166.34, 162.32, 149.03, 141.47, 137.61, 131.15,129.82, 129.51, 119.30, 113.87, 111.00, 110.72, 101.02, 73.16, 70.06, 44.08,38.91, 38.74, 29.71, 29.37, 28.99, 24.22, 22.97, 22.70, 20.02. The following is an evaluation of the antitumor activity of the preferred compounds of this invention, mainly including triple-negative breast cancer MDA-MB-231 and liver cancer HepG2.
[0042] Experimental methods Logarithmically growing cells were collected, and all test compounds were dissolved in sterile DMSO to prepare a 10 mM stock solution. The stock solution was serially diluted, with the highest concentration being 10 μM. The compound activity was evaluated using the ACLY-overexpressing triple-negative breast cancer cell line MDA-MB-231 and the liver cancer cell line HepG2. During the experiment, test cells were collected and resuspended in an appropriate amount of complete culture medium to prepare a cell suspension. The cell suspension was seeded into 96-well plates using a multichannel pipette, adjusting the cell density to approximately 4000-5000 cells per well. The well edges of the 96-well plates were filled with PBS solution to reduce evaporation. The seeded cell plates were incubated in a 5% CO2 incubator for 24 hours to allow for full cell adhesion. Subsequently, serially diluted compound solutions (a total of 8 concentrations) were added to the corresponding wells, with 3 replicates for each concentration. After drug addition, the cell plates were returned to the incubator and cultured for another 48 hours. After incubation, CCK-8 reagent was added to each well, and the mixture was incubated for another 4 hours in the dark. Finally, the absorbance of each well was measured at 450 nm using a microplate reader. The obtained data were fitted using SPSS software to calculate the half-maximal inhibitory concentration (IC50) of the compound. 50 The values are shown in Table 1.
[0043] Table 1. Antitumor activity of DCV derivatives n = 3, ± s
[0044] DCV exhibits good cytotoxic activity against MDA-MB-231 and HepG2 cells in vitro (IC50). 50The concentrations were 5.4 and 6.8 μM, respectively. The introduction of the N-benzenesulfonamide backbone, a dominant active fragment of ACLY inhibitors, into the DCV backbone significantly affected its antitumor activity. The volume and charge of the R1 group had a significant impact; smaller aliphatic sulfonamides with R1 had less effect on activity (e.g., III-8 and III-9), possibly due to weaker π-π interactions near their protein pockets. In contrast, the introduction of electron-withdrawing groups into aromatic benzenesulfonamides (e.g., III-2, 4, and 6) was detrimental to enhancing their antitumor activity, while electron-donating groups (e.g., III-3 methyl, III-5 methoxy) were beneficial. The 2,4-dimethoxy compound III-5 showed the best activity, with IC50 values of 1.9 and 3.2 μM against MDA-MB-231 and HepG2 cells, respectively, demonstrating strong in vitro tumor cell inhibitory activity, superior to the cytotoxic activity of the positive control DCV, warranting further investigation.
Claims
1. A dehydrocurvulariacin sulfonamide derivative, characterized in that, It has the structure shown in general formula (I): General Formula (I) R is selected from any one of benzene ring, substituted benzene ring, heterocycle, substituted heterocycle, alkane, and substituted alkane; The substituents in the substituted benzene ring include any one of methyl, ethyl, methoxy, ethoxy, halogen, nitro, cyano, and phenyl, and the substituents can be monosubstituted or polysubstituted; The substituents in the substituted heterocycle include any one of methyl, ethyl, methoxy, ethoxy, halogen, nitro, cyano, and phenyl, and the substituents can be monosubstituted or polysubstituted; The heterocycle includes any one of naphthalene ring, pyridine, indole, and morpholine; The alkanes mentioned include any one of straight-chain alkanes, branched-chain alkanes, and cyclic alkanes.
2. The dehydrocurvulariacin sulfonamide derivative according to claim 1, characterized in that, In the structure shown in general formula (I), R is selected from a benzene ring or a benzene ring mono- or poly-substituted with methyl, ethyl, methoxy, ethoxy, halogen, nitro, cyano, or phenyl; a naphthyl ring or a naphthyl ring mono- or poly-substituted with methyl, ethyl, methoxy, ethoxy, halogen, nitro, cyano, or phenyl; pyridine; 2-chloropyridine; 4-chloropyridine; 6-methylpyridine; 6-methoxypyridine; indole; 1-methylindoline; morpholine; 2,6-dimethylmorpholine; butane; pentane; heptane; dipropane; dimethylpentane; cyclopropane; cyclobutane; and cyclohexane.
3. The dehydrocurvulariacin sulfonamide derivative according to claim 2, characterized in that, The dehydrocurvulariacin sulfonamide derivative is selected from any one of the following compounds: 。 4. A method for preparing a dehydrocurvulariacin sulfonamide derivative as described in any one of claims 1-3, characterized in that, Includes the following steps: (1) Compound 2 was obtained by condensation reaction using p-aminoacetophenone and sulfonyl chloride as starting materials; (2) Compound 2 was brominated at the α-position of the ketone carbonyl group by the action of the brominating reagent phenyltrimethyltribromide to obtain compound 3; (3) Compound 4 was obtained by reacting compound 3 with DCV under alkaline conditions; The reaction formula is as follows: ； The R is selected from any one of benzene ring, substituted benzene ring, heterocycle, substituted heterocycle, alkane, and substituted alkane; The substituents in the substituted benzene ring include any one of methyl, ethyl, methoxy, ethoxy, halogen, nitro, cyano, and phenyl, and the substituents can be monosubstituted or polysubstituted; The substituents in the substituted heterocycle include any one of methyl, ethyl, methoxy, ethoxy, halogen, nitro, cyano, and phenyl, and the substituents can be monosubstituted or polysubstituted; The heterocycle includes any one of naphthalene ring, pyridine, indole, and morpholine; The alkanes mentioned include any one of straight-chain alkanes, branched-chain alkanes, and cyclic alkanes.
5. The method for preparing dehydrocurvulariacin sulfonamide derivatives according to claim 4, characterized in that, The solvents used in step (1) during the reaction process include any one or more combinations of dichloromethane, tetrahydrofuran, acetonitrile, acetone, dichloroethane, chloroform, dioxane, ethanol, isopropanol, N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), and 1,4-dioxane; the reaction temperature is 0 ℃ to room temperature; and the reaction time is 1 hour to 12 hours.
6. The method for preparing dehydrocurvulariacin sulfonamide derivatives according to claim 4, characterized in that, The solvents used in the reaction process in step (1) include, but are not limited to, acetonitrile, tetrahydrofuran, and ethanol, with tetrahydrofuran being preferred; the reaction temperature is 0 ℃ to 60 ℃, preferably room temperature (25 ℃); the reaction time is 15 minutes to 12 hours, preferably 30 minutes to 2 hours.
7. The method for preparing dehydrocurvulariacin sulfonamide derivatives according to claim 4, characterized in that, The solvents used in the reaction process in step (1) include, but are not limited to, acetonitrile, ethanol, and DMF, preferably DMF; the alkaline reagents include, but are not limited to, sodium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate, preferably cesium carbonate; the reaction temperature is preferably room temperature, and the reaction time is 10 minutes to 1 hour, preferably 20 minutes.
8. A sulfonamide-based ACLY inhibitor based on dehydrocurvulariacin, characterized in that, The inhibitor is selected from the dehydrocurvulariacin sulfonamide derivatives according to any one of claims 1-3.
9. An antitumor drug, characterized in that, The antitumor compound is selected from the dehydrocurvulariacin sulfonamide derivatives according to any one of claims 1-3.
10. An antitumor pharmaceutical composition, characterized in that, Includes the dehydrocurvulariacin sulfonamide derivative as described in any one of claims 1-3.