CN111689977A - Camptothecin 20-position modified sulfonylurea compound and preparation method and application thereof - Google Patents
Camptothecin 20-position modified sulfonylurea compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a camptothecin 20-position modified sulfonylurea compound shown in formula (I), a preparation method of the compound and application of the compound in preparing antitumor drugs. The chemical general formula of the compound is shown as a structural formula (I). The compound in the formula (I) is prepared by reacting different 20-amino acid-camptothecin trifluoroacetate with different substituted ethyl sulfonylcarbamates. Cytotoxic activity tests prove that the compound has better cytotoxic activity, the antitumor activity of most of the compounds is higher than that of irinotecan serving as a clinical contrast medicament, and the antitumor activity of part of the compounds is equivalent to that of topotecan serving as a clinical contrast medicament, so that the compound can be used for preparing antitumor medicaments. The invention has simple preparation process, cheap and easily obtained raw materials and high product purity.
Description
Technical Field
The invention relates to a new camptothecin 20-position modified sulfonylurea compound, a preparation method of the compound and application of the compound in preparing antitumor drugs. Belongs to the field of medicine technology.
Background
Camptothecin (CPT) is a quinoline alkaloid with significant cytotoxic activity, which is firstly extracted from camptotheca acuminata of davidiaceae in 1966 by american chemists Wall M.E and waii M.C (j.am.chem.soc.1966,88, 3888-. The camptothecin has good inhibition effect on various malignant tumors such as bone cancer, liver cancer, bladder cancer, leukemia and the like, but the camptothecin is clinically used for treating serious side effects such as vomit, myelosuppression, diarrhea and the like (Current Medicinal Chemistry-Anticancer Agents,2005,5(1):1-13.), and meanwhile, the unmodified natural camptothecin has extremely poor water solubility, so the water-soluble sodium salt of the camptothecin is clinically used in early stage. However, open-ring forms of camptothecin are very prone to binding to human serum albumin (HAS), greatly reducing anticancer activity. More seriously, the ring-opened sodium salt has great toxic and side effects on the digestive system and the urinary system after being metabolized by the kidney, which leads to clinical interruption of the phase II. In order to further improve the water solubility and reduce the toxic and side effects, in recent years, scholars at home and abroad use camptothecin as a guide to carry out systematic modification and derivative synthesis to obtain a plurality of active compounds which are approved to be on the market by FDA or are in clinical research stage, such as irinotecan, topotecan, 9-aminocamptothecin, 9-nitrocamptothecin, DX-8951f, GG211, BNP-1350, ST-1481, CKD-602 and the like (((r. bioorg. Med. chem.2004,12, 1585. sup.), (r. phytochem.2004,65, 2735. sup.). 2749). According to the research on the camptothecin-anti-tumor structure-activity relationship (SAR research), the in-vivo stability of the camptothecin lactone ring is an important factor influencing the anti-tumor activity, and the alpha-hydroxyl lactone ring is easy to hydrolyze and open the ring to generate water-soluble sodium salt, so that the anti-tumor activity is reduced. Therefore, modification and modification of the 20(S) -position to increase the ratio of lactone ring in human blood is expected to improve the activity and reduce the toxicity of the compounds, and is one of the hot spots for studying camptothecin. The literature reports show that the sulfonylurea compound generally has the characteristics of high biological activity and low toxicity in structure, and has wide application in the fields of medicines and pesticides. The sulfonylurea compound LY186641 is a drug having antitumor activity which has been used in clinical trials, and has excellent antiproliferative effects on lung cancer, breast cancer, colon cancer, ovarian cancer, pancreatic cancer, kidney cancer and stomach cancer (J.Med.chem.1992,35, 3012-. Unlike other types of antitumor drugs, sulfonylurea drugs can produce antitumor activity by inhibiting NADH oxidase (Biochimica et Biophysica Acta 1324,1997, 171-181), and therefore, sulfonylurea structures are widely used in the design of antitumor drugs.
Therefore, under the inspiration of the structure-activity relationship of camptothecin-anti-tumor, the modification and reconstruction of 20(S) -position of camptothecin can possibly improve the activity and enhance the stability of lactone ring, thereby obtaining camptothecin derivatives with higher activity and lower toxicity. The invention prepares a series of 20(S) -sulfonylurea camptothecin compounds, and seeks higher-activity camptothecin derivatives.
Disclosure of Invention
The invention aims to provide a novel camptothecin sulfonylurea compound, and simultaneously, the invention also aims to provide a preparation method of the novel camptothecin sulfonylurea compound and application of the novel camptothecin sulfonylurea compound in antitumor drugs.
The camptothecin compound of the invention is a compound shown as the following general formula (I):
wherein R in the formula (I)1Hydrogen, methyl, isopropyl, 2- (methylthio) ethyl. R2Is methyl, n-butyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-chlorophenyl, 2-thienyl.
The preparation method of the camptothecin compound is carried out according to the following chemical reaction formula I:
camptothecin is used as a reaction raw material, condensation reaction is carried out on the camptothecin and a plurality of different substituted N-Boc-amino acids to obtain intermediates 1a-d, Boc groups are removed from a 50% trifluoroacetic acid/dichloromethane solution to obtain intermediates 2a-d, and finally the camptothecin sulfonamide compounds 1-16 are obtained through reaction with different substituted sulfonyl ethyl carbamates.
The preparation method of the compound comprises the steps of dissolving the 20-amino acid-camptothecin trifluoroacetate 2a-d (0.2mmol) with different substitutions in toluene, dropwise adding a proper amount of triethylamine, and stirring until the solution is clear. Dissolving corresponding ethyl sulfonylcarbamate (0.4mmol) in toluene, dropwise adding into the reaction solution, heating and refluxing for 3-4 h, detecting by TLC, cooling to room temperature after the reaction is finished, removing the solvent under reduced pressure, and performing column chromatography to obtain the target compound.
The in vitro anti-tumor activity screening result shows that the compound shown in the formula I has stronger inhibitory activity on human lung adenocarcinoma cells (A-549), human breast cancer cell strains (MDA-MB-231), human oral epidermoid cancer cells (KB) and human oral epidermoid cancer cell drug-resistant strains (KBvin), most of the compound is higher than that of irinotecan which is a current clinical drug, and the activity of part of the compound is equivalent to that of topotecan which is a current clinical drug, so that the compound disclosed by the invention can be used for preparing anti-tumor drugs. The camptothecin compound disclosed by the invention is novel in structure, simple in synthesis process, high in product purity, strong in inhibition effect on tumor cells and good in application prospect.
The above-described aspects of the present invention will be described in further detail with reference to specific embodiments. This is not to be construed as limiting the invention.
Detailed Description
Example 1: synthesis of target Compound 1
The synthesis of compound 1 proceeds as in the following chemical reaction scheme 2:
synthesis of intermediate 1 a: N-Boc-glycine (6mmol) was dissolved in dry dichloromethane and camptothecin (3mmol), N, N' -Diisopropylcarbodiimide (DIPC) (9mmol) and 4-N, N-Dimethylaminopyridine (DMAP) (6mmol) were added sequentially at a temperature of C. After reaction at 0 ℃ for about 0.5h, the ice bath was removed and the reaction was allowed to proceed overnight at room temperature. And detecting by TCL, filtering after the reaction is finished, washing the reaction mixed solution by using a 6% sodium bicarbonate solution, water and a saturated sodium chloride solution in sequence, then drying by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and passing through a column to obtain the yield of the intermediate compound 1 a.
Synthesis of intermediate 2 a: dissolving the synthesized intermediate 1a (3mmol) in 10mL of dry dichloromethane, slowly dropwise adding 10mL of trifluoroacetic acid, stirring at room temperature for about 1h, concentrating under reduced pressure to obtain a viscous substance, and recrystallizing with petroleum ether to obtain an intermediate compound 2 a.
Synthesis of Compound 1: camptothecin derivative 2a (0.2mmol) is dissolved in toluene, and then appropriate amount of triethylamine is added dropwise, and the mixture is stirred until the mixture is clear. Dissolving corresponding ethyl methylsulfonylcarbamate (0.4mmol) in toluene, dropwise adding into the reaction solution, heating and refluxing for 3-4 hours, detecting by TLC, cooling to room temperature after the reaction is finished, removing the solvent under reduced pressure, and carrying out column chromatography to obtain the target compound 1. The detection data of the product are as follows: yield: 56 percent; melting point: 195-197 deg.c;1H NMR(DMSO-d6,400MHz):8.71(s,1H,C7-H),8.18(d,1H,J＝8.4Hz,C9-H),8.15(d,1H,J＝8.4Hz,C12-H),7.89(t,1H,J＝6.8Hz,C10-H),7.73(t,1H,J＝7.6Hz,C11-H),7.24(s,1H,C14-H),6.81(br,1H,L-glycine-NH),5.51(s,2H,C17-H),5.31(s,2H,C5-H),4.17(dd,1H,J＝18.4,6.0Hz,C23-H),4.03(dd,1H,J＝18.0,6.0Hz,C23-H),3.18(s,3H,Ms- 3CH),2.16(m,2H,C18-H),0.93(t,3H,J＝7.2Hz,C19-H)；Anal.Calcd For C24H22N4O8S:C,54.75；H,4.21；N,10.64.Found:C,54.90；H,4.32；N,10.74.MS-ESI m/z:549.1[M+Na]+.
example 2: synthesis of target Compound 2
The experimental procedure was as in example 1, replacing ethylmethylsulfonylcarbamate with only ethyln-butylsulfonylcarbamate. The detection data of the product are as follows: yield: 38 percent; melting point: 197 ℃ and 198 DEG C；1HNMR(DMSO-d6,400MHz):10.54(s,1H,SO2NH),8.70(s,1H,C7-H),8.15(m,2H,C12-H,C9-H),7.88(t,1H,J＝6.8Hz,C10-H),7.73(t,1H,J＝7.2Hz,C11-H),7.22(s,1H,C14-H),6.92(br,1H,L-glycine-NH),5.51(s,2H,C17-H),5.31(s,2H,C5-H),4.16(dd,1H,J＝4.8,17.6Hz,C23-H),4.01(dd,1H,J＝5.2,18.0Hz,C23-H),3.17(m,2H,- 2CHCH2CH2CH3),2.09-2.15(m,2H,C18-H),1.52-1.55(m,2H,-CH2 2CHCH2CH3),1.15-1.2(m,2H,-CH2CH2 2CHCH3),0.93(t,3H,J＝7.6Hz,-CH2CH2CH2 3CH),0.68(t,3H,J＝7.2Hz,C19-H)；Anal.Calcd For C27H28N4O8S:C,57.03；H,4.96；N,9.85.Found:C,56.97；H,5.02；N,9.74.MS-ESI m/z:591.1[M+Na]+.
Example 3: synthesis of target Compound 3
The experimental procedure was as in example 1, substituting ethyl phenylsulphonylaminocarbamate for ethyl methylsulphonylaminocarbamate only. The detection data of the product are as follows: yield: 40 percent; melting point: 173-174 ℃;1H NMR(DMSO-d6,400MHz):11.08(s,1H,SO2 NH),8.71(s,1H,C7-H),8.00-8.17(m,2H,C9-H,C12-H),7.45-7.90(m,7H,C10-H,C11-H,Ph-H),7.16(s,1H,C14-H),6.96(br,1H,L-glycine-NH),5.48(s,2H,C17-H),5.31(s,2H,C5-H),4.01(m,2H,C23-H),1.98(m,2H,C18-H),0.75(m,3H,C19-H)；Anal.Calcd ForC29H24N4O8S:C,59.18；H,4.11；N,9.52.Found:C,59.12；H,4.02；N,9.44.MS-ESI m/z:611.5[M+Na]+.
example 4: synthesis of target Compound 4
Experimental procedureAs in example 1, p-fluorobenzenesulfonyl carbamate alone was used in place of methylsulfonyl carbamate. The detection data of the product are as follows: yield: 50 percent; melting point: 179-181 ℃;1H NMR(DMSO-d6,400MHz):11.14(s,1H,SO2 NH),8.71(s,1H,C7-H),8.09-8.33(m,4H,C9-H,C12-H,p-FPh-H),7.89(t,1H,J＝7.2Hz,C10-H),7.74(t,1H,J＝6.8Hz,C11-H),7.28(t,2H,J＝8.4Hz,p-FPh-H),7.17(s,1H,C14-H),6.99(br,1H,L-glycine-NH),5.49(s,2H,C17-H),5.30(s,2H,C5-H),4.07(d,1H,J＝12.8Hz,C23-H),3.93(d,1H,J＝13.6Hz,C23-H),2.00(m,2H,C18-H),0.75(m,3H,C19-H)；Anal.Calcd For C29H23FN4O8S:C,57.42；H,3.82；N,9.24.Found:C,57.56；H,4.00；N,9.34.MS-ESI m/z:629.2[M+Na]+.
example 5: synthesis of target Compound 5
The experimental procedure was as in example 1, except that ethyl p-toluenesulfonylaminoate was used in place of ethyl methylsulfonylaminoate. The detection data of the product are as follows: yield: 50 percent; melting point: 182 ℃ and 183 ℃;1H NMR(DMSO-d6,400MHz):10.96(s,1H,Ts-NH),8.71(s,1H,C7-H),8.19(d,1H,J＝8.8Hz,C9-H),8.15(d,1H,J＝8.4Hz,C12-H),7.89(t,1H,J＝7.6Hz,C10-H),7.85(d,2H,J＝8.4Hz,Ts-H),7.73(t,1H,J＝7.6Hz,C11-H),7.24(d,2H,J＝8.0Hz,Ts-H),7.15(s,1H,C14-H),6.91(t,1H,J＝5.2Hz,L-glycine-NH),5.48(s,2H,C17-H),5.30(s,2H,C5-H),4.08(dd,1H,J＝18.0,5.6Hz,C23-H),3.93(dd,1H,J＝17.6,5.2Hz,C23-H),2.26(s,3H,Ts- 3CH),2.02(m,2H,C18-H),0.78(t,3H,J＝7.2Hz,C19-H)；Anal.Calcd For C30H26N4O8S:C,59.79；H,4.35；N,9.30.Found:C,59.82；H,4.54；N,9.24.MS-ESI m/z:625.4[M+Na]+.
example 6: synthesis of target Compound 6
The experimental procedure was as in example 1, except that ethyl p-chlorobenzenesulfonylcarbamate was used in place of ethyl methylsulfonylcarbamate. The detection data of the product are as follows: yield: 51 percent; melting point: 181-183 ℃;1H NMR(DMSO-d6,400MHz):11.21(s,1H,SO2 NH),8.72(s,1H,C7-H),8.17(m,2H,C9-H,C12-H),8.01(d,2H,J＝7.2Hz,p-ClPh-H),7.90(t,1H,J＝7.2Hz,C10-H),7.74(t,1H,J＝6.8Hz,C11-H),7.51(t,2H,J＝7.6Hz,p-ClPh-H),7.15(s,1H,C14-H),6.98(br,1H,L-glycine-NH),5.48(s,2H,C17-H),5.31(s,2H,C5-H),3.90-4.08(m,2H,C23-H),2.00-2.09(m,2H,C18-H),0.85(m,3H,C19-H)；Anal.CalcdFor C29H23ClN4O8S:C,55.91；H,3.72；N,8.99.Found:C,55.99；H,3.80；N,9.04.MS-ESI m/z:661.0[M+K]+.
example 7: synthesis of target Compound 7
The experimental procedure was as in example 1, except that ethyl 2-thiophenesulfonylcarbamate was used in place of ethyl methylsulfonylcarbamate. The detection data of the product are as follows: yield: 50 percent; melting point: 205 ℃ and 207 ℃;1H NMR(DMSO-d6,400MHz):11.19(s,1H,SO2 NH),8.71(s,1H,C7-H),8.19(d,1H,J＝8.4Hz,C9-H),8.14(d,1H,J＝8.0Hz,C12-H),7.89(t,1H,J＝7.2Hz,C10-H),7.80(m,2H,thiophene-H),7.73(t,1H,J＝7.2Hz,C11-H),7.17(s,1H,C14-H),6.93(m,2H,thiophene-H,L-glycine-NH),5.49(s,2H,C17-H),5.30(s,2H,C5-H),4.10(dd,1H,J＝5.6,18.0Hz,C23-H),3.97(dd,1H,J＝5.2,18.4Hz,C23-H),2.05(m,2H,C18-H),0.84(m,3H,C19-H)；Anal.Calcd For C27H22N4O8S2:C,54.54；H,3.73；N,9.42.Found:C,54.47；H,4.02；N,9.54.MS-ESI m/z:595.2[M+H]+.
example 8: synthesis of target Compound 8
The experimental procedure was the same as in example 1, except that N-Boc-alanine was used instead of N-Boc-glycine. The detection data of the product are as follows: yield: 43 percent; melting point: 172-174 ℃;1H NMR(DMSO-d6,400MHz):10.33(s,1H,SO2NH),8.70(s,1H,C7-H),8.15(m,2H,C12-H,C9-H),7.88(t,1H,J＝8.4Hz,C10-H),7.69-7.74(m,1H,C11-H),7.20(s,1H,C14-H),7.03(d,1H,J＝6.4Hz,L-alanine-NH),5.51(s,2H,C17-H),5.30(s,2H,C5-H),4.11-4.39(m,1H,C23-H),3.40(s,3H,Ms- 3CH),2.12-2.22(m,2H,C18-H),1.43(d,3H,J＝7.6Hz,L-alanine- 3CH),0.94(m,3H,J＝6.4Hz,C19-H)；Anal.Calcd ForC25H24N4O8S:C,55.55；H,4.48；N,10.36.Found:C,55.63；H,4.32；N,10.45.MS-ESI m/z:563.1[M+Na]+.
example 9: synthesis of target Compound 9
The experimental procedure was the same as in example 1 except that N-Boc-alanine was used instead of N-Boc-glycine and ethyl p-fluorobenzenesulfonylcarbamate was used instead of ethyl methylsulfonylcarbamate. The detection data of the product are as follows: yield: 40 percent; melting point: 150 ℃ to 152 ℃;1HNMR(DMSO-d6,400MHz):10.86(s,1H,SO2NH),8.73(s,1H,C7-H),8.28(m,2H,p-FPh-H),8.18(m,2H,C12-H,C9-H),7.89(t,1H,J＝7.2Hz,C10-H),7.74(t,1H,J＝7.6Hz,C11-H),7.25(t,2H,J＝8.4Hz,p-FPh-H),7.14(s,1H,C14-H),7.02(d,1H,J＝6.0Hz,L-alanine-NH),5.48(s,2H,C17-H),5.32(s,2H,C5-H),4.11-4.24(m,1H,C23-H),1.89-2.01(m,2H,C18-H),1.36(d,3H,J＝6.8Hz,L-alanine- 3CH),0.61(t,3H,J＝7.2Hz,C19-H)；Anal.Calcd ForC30H25FN4O8S:C,58.06；H,4.06；N,9.03.Found:C,58.12；H,4.02；N,8.96.MS-ESI m/z:621.2[M+H]+.
example 10: synthesis of target Compound 10
Experimental procedure as in example 1, only N-Boc-alanine was used instead of N-Boc-glycine and ethyl p-toluenesulfonylaminocarboxylate was used instead of ethyl methylsulfonylaminocarboxylate. The detection data of the product are as follows: yield: 47%; melting point: 168-170 ℃;1H NMR(DMSO-d6,400MHz):10.67(s,1H,Ts-NH),8.74(s,1H,C7-H),8.16-8.24(m,2H,C9-H,C12-H),8.05(d,2H,J＝8.0Hz,Ts-H),7.90(t,1H,J＝7.6Hz,C10-H),7.74(t,1H,J＝7.6Hz,C11-H),7.27(d,2H,J＝8.0Hz,Ts-H),7.13(s,1H,C14-H),6.91(d,1H,J＝6.4Hz,L-alanine-NH),5.48(s,2H,C17-H),5.33(s,2H,C5-H),4.24(m,1H,C23-H),2.24(s,3H,Ts- 3CH),1.92-2.04(m,2H,C18-H),1.36(d,3H,J＝7.6Hz,L-alanine- 3CH),0.68(t,3H,J＝6.8Hz,C19-H)；Anal.Calcd For C31H28N4O9S:C,60.38；H,4.58；N,9.09.Found:C,60.30；H,4.52；N,8.99.MS-ESI m/z:617.3[M+H]+.
example 11: synthesis of target Compound 11
The experimental procedure was as in example 1, substituting only N-Boc-alanine for N-Boc-glycine and ethyl 2-thiophenesulfonylcarbamate for ethylmethylsulfonylcarbamate. The detection data of the product are as follows: yield: 51 percent; melting point: 167-169 deg.C;1HNMR(DMSO-d6,400MHz):10.98(s,1H,SO2 NH),8.74(s,1H,C7-H),8.15-8.22(m,2H,C9-H,C12-H),7.85-7.91(m,2H,C10-H,thiophene-H),7.67-7.77(m,2H,C11-H,thiophene-H),7.13(s,1H,C14-H),6.96(m,2H,L-alanine-NH,thiophene-H),5.49(s,2H,C17-H),5.31(s,2H,C5-H),4.29(m,1H,C23-H),1.96-2.08(m,2H,C18-H),1.36(m,3H,L-alanine- 3CH),0.73(t,3H,J＝7.2Hz,C19-H)；Anal.Calcd For C28H24N4O8S2:C,55.25；H,3.97；N,9.21.Found:C,55.36；H,4.02；N,9.37.MS-ESI m/z:609.3[M+H]+.
example 12: synthesis of target Compound 12
The experimental procedure was the same as in example 1, except that N-Boc-valine was used instead of N-Boc-glycine. The detection data of the product are as follows: yield: 49 percent; melting point: 198-200 ℃;1H NMR(DMSO-d6,400MHz):10.08(br,1H,Ms-NH),8.69(s,1H,C7-H),8.12-8.17(m,2H,C9-H,C12-H),7.88(t,1H,J＝6.8Hz,C10-H),7.72(t,1H,J＝7.2Hz,C11-H),7.19(s,1H,C14-H),6.83(m,1H,L-valine-NH),5.56(s,2H,C17-H),5.29(s,2H,C5-H),4.13(m,1H,C23-H),3.06(s,3H,Ms- 3CH),2.30(m,1H,L-valine-CH(CH3)2),2.18(m,2H,C18-H),0.69-1.03(m,9H,C19-H,L-valine-CH( 3CH) 2))；Anal.Calcd ForC32H29N4O8S:C,57.03；H,4.96；N,9.85.Found:C,56.95；H,5.02；N,9.89.MS-ESI m/z:569.2[M+H]+.
example 13: synthesis of target Compound 13
The experimental procedure was the same as in example 1 except that N-Boc-valine was used instead of N-Boc-glycine and ethyl p-fluorobenzenesulfonylcarbamate was used instead of ethyl methylsulfonylcarbamate. The detection data of the product are as follows: yield: 46 percent; melting point: 215-217 ℃;1HNMR(DMSO-d6,400MHz):10.66(br,1H,SO2NH),8.72(s,1H,C7-H),8.14-8.20(m,2H,C9-H,C12-H),7.88-7.97(m,2H,p-FPh-H),7.33-7.49(m,2H,p-FPh-H),7.26(t,1H,J＝8.8Hz,C10-H),7.19(t,1H,J＝8.8Hz,C11-H),7.12(s,1H,C14-H),6.80(m,1H,L-valine-NH),5.49(d,2H,J＝6.4Hz,C17-H),5.29(d,2H,J＝9.6Hz,C5-H),3.97-4.02(m,1H,C23-H),2.23-2.33(m,1H,L-valine-CH(CH3)2),1.90-2.14(m,2H,C18-H),0.79-0.94(m,9H,C19-H,L-valine-CH( 3CH) 2)；Anal.Calcd For C32H29FN4O8S:C,59.25；H,4.51；N,8.64.Found:C,59.03；H,4.44；N,8.971.MS-ESI m/z:671.4[M+Na]+.
example 14: synthesis of target Compound 14
The experimental procedure was the same as in example 1, except that N-Boc-valine was used instead of N-Boc-glycine and ethyl 2-thiophenesulfonylcarbamate was used instead of ethyl methylsulfonylcarbamate. The detection data of the product are as follows: yield: 50 percent; melting point: 217 ℃ and 218 ℃;1HNMR(DMSO-d6,400MHz):174(s,1H,SO2 NH),8.71(s,1H,C7-H),8.14-8.21(m,2H,C9-H,C12-H),7.89(m,2H,C10-H,thiophene-H),7.73(m,2H,C11-H,thiophene-H),7.08(s,1H,C14-H),6.98(t,1H,J＝4.4Hz,thiophene-H),6.76(m,1H,L-alaine-NH),5.49(s,2H,C17-H),5.31(s,2H,C5-H),4.04(q,1H,J＝7.2Hz,C23-H),2.22-2.33(m,1H,L-alaine-CH(CH3)2),1.92-2.01(m,2H,C18-H),0.75-0.95(m,9H,C19-H,L-alaine-CH( 3CH) 2)；Anal.Calcd ForC30H28N4O8S2:C,56.59；H,4.43；N,8.80.Found:C,56.47；H,4.34；N,8.91.MS-ESI m/z:659.2[M+Na]+.
example 15: synthesis of target Compound 15
The experimental procedure was as in example 1, substituting only N-Boc-methionine for N-Boc-glycine and ethyl 2-thiophenesulfonylcarbamate for ethylmethylsulfonylcarbamate. The detection data of the product are as follows: yield: 43 percent; melting point: 159 ℃ and 160 ℃;1HNMR(DMSO-d6,400MHz):11.01(s,1H,SO2 NH),8.72(s,1H,C7-H),8.14-8.22(m 2H,C9-H,C12-H),7.87(m,2H,C10-H,thiophene-H),7.74(d,1H,J＝8.8Hz,thiophene-H),7.70(t,1H,J＝4.4Hz,C11-H),7.20(s,1H,C14-H),7.11(m,1H,thiophene-H),6.97(t,1H,J＝4.8Hz,L-methionine-NH),5.50(d,2H,J＝5.6Hz,C17-H),5.31(s,2H,C5-H),4.41-4.61(m,1H,C23-H),1.96-2.33(m,6H,L-methionine- 2 2CHCHSCH3,C18-H),0.84-0.91(m,3H,L-methionine-CH2CH2S 3CH),0.75(t,3H,J＝7.2Hz,C19-H)；Anal.Calcd For C30H28N4O8S3:C,53.88；H,4.22；N,8.38.Found:C,54.98；H,4.14；N,8.25.MS-ESI m/z:691.1[M+Na]+.
example 16: synthesis of target Compound 16
The experimental procedure was the same as in example 1 except that N-Boc-methionine was used instead of N-Boc-glycine and ethyl p-fluorobenzenesulfonylcarbamate was used instead of ethyl methylsulfonylcarbamate. The detection data of the product are as follows: yield: 45 percent; melting point: 152 ℃ and 154 ℃;1HNMR(DMSO-d6,400MHz):10.86(s,1H,SO2 NH),8.72(s,1H,C7-H),8.17-8.32(m 4H,C9-H,C12-H,p-FPh-H),8.00(m,1H,C10-H),7.74(t,1H,J＝7.2Hz,C11-H),7.11-7.28(m,4H,p-FPh-H,C14-H,L-methionine-NH),5.49(d,2H,J＝7.2Hz,C17-H),5.31(d,2H,J＝7.2Hz,C5-H),4.34(m,1H,C23-H),1.92-2.33(m,9H,L-methionine- 2 2 3CHCHSCH,C18-H),0.82(t,3H,J＝6.8Hz,C19-H)；Anal.Calcd For C32H29FN4O8S2:C,56.46；H,4.29；N,8.23.Found:C,56.67；H,4.04；N,8.20.MS-ESI m/z:703.1[M+Na]+.
example 17: method for testing cytotoxic Activity of Compounds 1-16 and results
The pharmacological experiment of the invention adopts Sulforhodamine B (SRB) colorimetric method, the tumor cell culture selects RPMI-1640 culture medium of 10% Fetal Bovine Serum (FBS), the tumor cell is inoculated in 96-well plates, each well is cultured for 3-5 × 103Cells are added with solutions of the target compounds to be tested at different concentrations. After 72 hours of culture, every timeThe cells were fixed by adding a pre-cooled trichloroacetic acid solution (50%, w/v) to the wells and fixed in a refrigerator for 30 minutes. After the 96-well plate was air dried at room temperature, 0.04% (w/v) SRB dye (1% acetic acid prepared from Sigma Chemical Co.) was added to each well, and after 30min of staining, the dye was poured off, washed 4 times with acetic acid to remove unbound dye, and air dried at room temperature. The dye bound to the cell protein was dissolved in 100. mu.L of unbuffered Tris-base solution, shaken on a horizontal shaker for 20min, and the light absorption at 515nm was measured using ELx800 absorption microplate reader (manufactured by Bio-TeK, USA, operating software Gen 5). All experiments were set up in 3 parallel groups or repeated 3 times. The results of the cytotoxic activity assay for compounds 1-16 are shown in Table 1.
TABLE 1 results of cytotoxic Activity assay of Compounds 1-16
Note: (1) the screening method comprises the following steps: sulforhodamine B colorimetry; (2) acting time: 48 hours; (3) the compound numbers 1 to 16 are the products obtained in the foregoing examples 1 to 16, respectively.
The test results of in vitro cytotoxic activity of four tumor cells show that the synthesized compounds 1-16 of the invention have good inhibitory activity on tumor cells such as human lung adenocarcinoma cells (A-549), human breast cancer cell strains (MDA-MB-231), human oral epidermoid cancer cells (KB) and human oral epidermoid cancer cell drug-resistant strains (KBvin), and the like, and the in vitro cytotoxic activity of most compounds is higher than that of topotecan serving as a clinical drug, and part of compounds are equivalent to that of irinotecan serving as a clinical drug, so that the prepared compounds can be used for preparing antitumor drugs and show better application prospects.
Claims (8)
1. A camptothecin sulfonylurea compound, characterized in that the compound has the chemical structural formula shown in formula (I):
wherein R in the formula (I)1Hydrogen, methyl, isopropyl, 2- (methylthio) ethyl. R2Is methyl, n-butyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-chlorophenyl, 2-thienyl.
2. The method for preparing a camptothecin sulfonylurea compound according to claim 1, wherein after different 20-amino acid-camptothecin trifluoroacetate (0.2mmol) is dissolved in toluene, a proper amount of triethylamine is added dropwise, and the mixture is stirred until the solution is clear. Dissolving corresponding ethyl sulfonylcarbamate (0.4mmol) in toluene, dropwise adding into the reaction solution, heating and refluxing for 3-4 h, detecting by TLC, cooling to room temperature after the reaction is finished, removing the solvent under reduced pressure, and performing column chromatography to obtain the target compound.
3. The method according to claim 2, wherein the silica gel column for chromatography is 200-300 mesh silica gel for column chromatography.
4. The camptothecin sulfonylurea compound according to claim 1 is used for preparing an antitumor drug.
5. Use of a camptothecin sulfonylurea compound according to claim 1 for the preparation of a medicament for the treatment of human lung adenocarcinoma (a 549).
6. Use of a camptothecin sulfonylurea compound according to claim 1 for the preparation of a medicament for the treatment of human breast cancer (MDA-MB-231).
7. Use of a camptothecin sulfonylurea compound according to claim 1 for the preparation of a medicament for the treatment of human oral epidermoid carcinoma (KB).
8. The use of a camptothecin sulfonylurea compound according to claim 1 for the preparation of a medicament for the treatment of human oral epidermoid carcinoma resistant strain (KBvin).
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