English

• 1.   Introduction

  Cancer is the second most common cause of death in humans with a high incidence.^[1] In 2015, there were 1658370 new cancer cases and 589430 cancer deaths in the United States.^[2] The World Health Organization (WHO) has estimated that the incidence of cancer will reach 22 million every year in the next two years.^[3] Therefore, it is urgent to develop effective antitumor drugs.

  Mercaptopyrimidine derivatives have excellent coordination ability because they contain N and S atoms and they can form complexes with many metal salts. It has been reported that mercaptopyrimidines have antileukemia, antitumor, anti-inflammatory, anti-bacterial and anti-con-vulsant effects.^[4~10] At the same time, Noolvi et al.^[11] reported that compound 1 has a good antitumor activity against non-small cell lung cancer cells with IC₅₀ value of 71.8 nmol/L (Figure 1). In 2013, compound 2 was synthesized and evaluated its cytotoxicity against six human cancer cell lines. The results showed that compound 2 exerted significant inhibitory activity compared to dasatinib.^[12] It was also found that compound 3 had an antibacterial activity comparable to chloramphenicol, and compound 4 showed strong cytotoxic activity against a variety of cancer cells (MDA-MB-231, Caki-1, PANC-1, A549, MKN-45, HT29 and PC-3 cells) with an IC₅₀ value of thiazole and piperazine are two pharmacophores with anti-11~20 nmol/L.^{[13, 14]} The above data indicated that benzotumor activity. According to the combination principles of pharmacodynamic groups, it is desirable to synthesize higher efficiency antitumor inhibitors if they are introduced into the pyrimidine core.

  Figure 1

  

  Figure 1.  Antitumor agents and target compounds

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  Based on previous studies, 2-mercapto-4-hydroxy-6-trifluoromethylpyrimidine was selected as the scaffold.^{[15, 16]} Then, benzothiazole and the substituted piperazines were introduced into the macropyrimidine to synthesize a series of compounds with multiple active moieties. Finally, the antitumor activities of the target compounds were determined using thiazolyl blue (MTT) method.

  1.   Results and discussion

  1.1   Chemistry

  The synthesis of the target compounds was depicted in Scheme 1. Pyrimidine core (6) was firstly synthesized by a ring-forming reaction of commercially available thiourea with ethyl 4, 4, 4-trifluoroacetoacetate (5) under basic condition in ethanol. At the same time, 2-aminobenzenethiol (7) reacted with chloroacetyl chloride to get 2-chlorome- thylbenzothiazole (8). Next, compound 9 was synthesized from pyrimidine and 2-chloromethyl benzothiazole by nucleophilic reaction, and the chlorination reaction was followed to obtain the key intermediate compound 10. Then, the N-Boc substituted piperazine was introduced to give compound 11. Finally, the piperazine substitution reaction was carried out to obtain a series of target compounds 13a~13i after the removal of tert-butyloxycarbonyl (Boc) protecting group.

  Scheme 1

  

  Scheme 1.  Synthesis of 2, 4, 6-trisubstituted pyrimidine derivatives containing benzothiazole moiety

  Reagents and conditions: (i) H₂NCSNH₂, NaH, MeCN, 70 ℃, 3 h; (ii) BF₃^•OEt₂, CH₂Cl₂, r.t., 2.5 h; (iii) KOH, H₂O, dioxane, 60 ℃, 6 h; (iv) POCl₃, dioxane, 90 ℃, 5 h; (v) 1-Boc-piperazine, DMF, 90 ℃, 2 h; . (vi) CH₂Cl₂, CF₃COOH, 0 ℃, 8 h; (vii) DMF, 90 ℃, 3 h

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  1.2   Antitumor activity

  In order to explore the antitumor activities of the prepared compounds, compounds 9, 10, 12 and 13a~13i were evaluated against EC-109 (human esophageal cancer cells), MGC-803 (human gastric cancer cells), PC-3 (human prostate cancer cells) and HepG-2 (human liver cancer cells) using MTT assay.^{[17, 18]} 5-Fluorouracil (5-Fu) was used as a positive control. The results of evaluation of antitumor activity are shown in Table 1.

  Table 1

  

  Table 1.  In vitro antitumor activities evaluation results for compounds 9, 10, 12 and 13a~13i

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  Compd.	R	IC50a/(μmol•L-1)
  		EC-109	MGC-803	PC-3	HepG-2
  9	—	> 50	> 50	> 50	> 50
  10	—	> 50	> 50	> 50	> 50
  12	—	> 50	31.93±1.50	15.77±1.19	> 50
  13a	CH3	> 50	> 50	21.58±1.33	> 50
  13b	CH2CH3	> 50	> 50	13.33±1.12	36.71±1.58
  13c	CH2CH2CH2CH3	40.01±1.61	12.38±1.10	7.89±0.46	19.35±1.32
  13d	CH2CH2OH	> 50	25.89±1.35	12.83±1.10	> 50
  13e		> 50	> 50	> 50	> 50
  13f		> 50	44.30±1.64	28.57±1.45	> 50
  13g		> 50	48.25±1. 46	38.09±1.88	> 50
  13h		35.68±1.40	11.32±1.00	3.82±0.58	23.45±1.31
  13i		27.35±1.20	9.39±0.61	2.293±0.360	15.08±1.14
  5-Fub	—	12.23±1.08	8.24±0.75	5.54±0.74	13.12±1.34
  a Antitumor activity was assayed by exposure for 72 h to substances and expressed as concentration required to inhibit tumor cells proliferation by 50% (IC50). b Used as a positive control.

  As shown in Table 1, the antitumor activities of compounds 9 and 10 against the four tumor cells were very weak, and their IC₅₀ values were greater than 50 μmol/L. The activity of compound 12 against MGC-803 and PC-3 cell lines was significantly increased compared to compounds 9 and 10. Among the target compounds 13a~13i, compounds 13h and 13i exerted excellent antitumor activities against against PC-3 with IC₅₀ values of 3.82 and 2.29 μmol/L, respectively. It could also find that compound 13i was the most active compound against HepG-2 and MGC-803 cells with IC₅₀ values of 15.08 and 9.39 μmol/L, respectively, which were comparable to the positive control 5-Fu. Compounds 13a~13g have poor antitumor activities against four tumor cells compared to the positive control 5-Fu. Compared the activity data of compounds 13a and 13b with 13c, we concluded that as the carbon chain of the aliphatic substituent group grows, the antitumor activities of the compounds against the selected four cancer cells were also increased. When R was an aromatic substituent, the antitumor activity of compound was also significantly increased when the number of heteroatoms increased by comparing compounds 13e and 13h with 13i.

  To investigate the toxicity of the target compounds to normal cells, compounds 13h and 13i were selected to further explore their cytotoxicity against GES-1 (normal human gastric epithelial cell line) and HEEC (human normal esophageal cells). As shown in Table 2, the results indicated that compounds 13h and 13i had weak or no cytotoxicity against GES-1 and HEEC, which was significantly lower than the positive control 5-Fu.

  Table 2

  

  Table 2.  In vitro antiproliferative activities of compounds 13h and 13i against human normal cells

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  Compd.	IC50/(μmol•L－1)
  	GES-1	HEEC
  13h	89.68	> 100
  13i	> 100	> 100
  5-Fu	22.60	> 100

  2.   Conclusion

  In conclusion, a series of 2, 4, 6-trisubstituted pyrimidine derivatives containing benzothiazole moiety were designed, synthesized and evaluated for antitumor activities against EC-109, MGC-803, PC-3 and HepG-2 cells using MTT method. The antitumor activity results showed that some compounds exhibited moderate to strong antitumor activities against MGC-803 and PC-3 cells. Among them, compounds 13h and 13i displayed the most potent antitumor activities against PC-3 with IC₅₀ values of 3.82 and 2.29 μmol/L, respectively. The toxicities of compounds 13h and 13i to GES-1 cells were significantly lower than the positive control 5-Fu.

  3.   Experimental

  3.1   Materials

  ¹H NMR and ¹³C NMR spectra were measured on a Bruker 400 and 101 MHz spectrometer, respectively, and TMS as an internal standard. Melting points were determined on an X-5 micromelting apparatus. High-resolution mass spectra were measured using a Waters-Micromass Q-TofMicro High Resolution Determination of tetragonal-flight time tandem mass spectrometer. The names of the compounds were from chembiooffice 14.0. All commercially available reagents and solvents were used without further purification.

  3.2   Chemistry

  3.2.1   Preparation of compounds 6 and 8

  Compounds 6 and 8 were synthesized according to the literature. Compound 6: m.p. 247~249 ℃^[19], compound 8: m.p. 34 ℃^[20].

  3.2.2   Preparation of 2-((benzo[d]thiazol-2-yl-methyl)- thio)-6-(trifluoromethyl)pyrimidin-4-ol (9)

  Compound 6 (5.00 g, 25.49 mmol) was dissolved in KOH aqueous solution (33.14 mmol, 30 mL), and a solution of compound 8 (4.68 g, 25.49 mmol) in dioxane (18 mL) was added dropwise at room temperature. The reaction mixture was heated at 60 ℃ for 6 h, while the progress of the reaction was monitored by thin-layer chromatography (TLC). After the reaction was completed, the reaction mixture was cooled to ambient temperature, and then poured into ice-water (300 mL). Large amount of yellow solid was precipitated after the resulting aqueous mixture was adjusted to pH＝7 by adding diluted hydrochloric acid (1 mL). The suspension was filtered off via suction filtration to give compound 9 6.56 g, 74.9% yield. Yellow solid, m.p. 191.0~191.4 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 13.60 (s, 1H), 8.06 (d, J＝8.0 Hz, 1H), 7.96 (d, J＝8.1 Hz, 1H), 7.51~7.47 (m, 1H), 7.43~7.36 (m, 1H), 6.70 (s, 1H), 4.91 (d, J＝11.2 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 167.5, 164.6, 152.3, 151.2, 135.1, 126.2, 125.3, 122.4, 122.1, 121.7, 119.0, 107.5, 31.8. HRMS (ESI) calcd for C₁₃H₉F₃N₃OS₂ [M+H]⁺ 344.0139, found 344.0137.

  3.2.3   Preparation of 2-(((4-chloro-6-(trifluoromethyl)- pyrimidin-2-yl)thio)methyl)benzo[d]thiazole (10)

  To a 100 mL round bottom flask was added compound 9 (6.00 g, 17.48 mmol) in dioxane (30 mL) followed by the addition of phosphorus oxychloride (8.15 mL, 87.4 mmol). The reaction mixture was heated at 90 ℃ for 5 h. After the reaction was completed, the reaction mixture was poured into an ice-water (300 mL) after cooling to room temperature. The mixture was stirred for 3 min, filtered under reduced pressure and dried in vacuo to obtain compound 10 4.85 g, yield 46.7%. Purple red solid, m.p. 93.1~93.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.06 (d, J＝8.0 Hz, 2H), 7.97 (d, J＝8.1 Hz, 1H), 7.51 (t, J＝7.6 Hz, 1H), 7.43 (t, J＝7.6 Hz, 1H), 4.95 (s, 2H); ¹³C NMR (101 MHz, DMSO- d₆) δ: 171.7, 167.4, 162.9, 155.8, 155.4, 152.4, 135.0, 126.2, 125.3, 122.4, 122.1, 114.6, 32.7. HRMS (ESI) calcd for C₁₃H₈ClF₃N₃S₂ [M+H]⁺ 361.9800, found 361.9804.

  3.2.4   Preparation of tert-butyl 4-(2-((benzo[d]thiazol- 2-ylmethyl)thio)-6-(trifluoromethyl)pyrimidin-4-yl)pi-perazine-1-carboxylate (11)

  To a solution of compound 10 (2.00 g 5.53 mmol) in N, N-dimethylformamide (DMF) (15 mL) was added an excess of 1-Boc-piperazine (3.09 g, 16.58 mmol). The reaction mixture was heated at 90 ℃ for 2 h. After the reaction was completed, the reaction mixture was concentrated to give the crude compound 11, which was used in the next step without further characterization. LC-MS (ES⁺) [M+H]⁺ m/z 512.1.

  3.2.5   Preparation of 2-(((4-(piperazin-1-yl)-6-(trifluo- romthyl)pyrimidin-2-yl)thio)methyl)benzo[d]thiazole (12)

  A 100 mL round-bottomed flask was charged with compound 11 (1.38 g, 2.70 mmol) and dichloromethane (15 mL). Then, an excess trifluoroacetic acid (10 mL) was added and the reaction was carried out at 0 ℃ for 8 h. After the reaction was completed, the reaction mixture was transferred to a 100 mL beaker. The resulting mixture was adjusted to pH 6~7 by addition of saturated sodium carbonate solution. It was extracted with dichloromethane for 2~3 times and the organic layer was concentrated to get compound 12 0.82 g, yield 73.8%). White solid, m.p. 79.4~80.1℃. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.03 (d, J＝7.9 Hz, 1H), 7.96 (d, J＝8.1 Hz, 1H), 7.57~7.46 (m, 1H), 7.46~7.35 (m, 1H), 7.06 (s, 1H), 4.82 (s, 2H), 3.87 (s, 4H), 3.07~2.82 (m, 4H), 1.19 (d, J＝7.3 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.0, 169.3, 160.9, 153.3, 152.9, 152.4, 134.9, 126.1, 125.1, 122.2, 119.4, 96.6, 45.2, 43.0, 32.7. HRMS (ESI) calcd for C₁₇H₁₇F₃N₅S₂ [M+H]⁺ 412.0877, found 412.0869.

  3.2.6   Preparation of compounds 13a~13i

  A 50 mL round bottom flask was charged with compound 12 (1.00 mmol) and N, N-dimethylformamide (DMF) (5 mL), and different chlorine-substituted compounds (1.20 mmol) were added with stirring, respectively. The mixture was heated to 90 ℃ for 3 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature and poured into the ice-water (200 mL). The suspension was filtered off via suction filtration to give compounds 13a~13i, which were purified by chromatography (petroleum ether/ethyl acetate, V:V＝2~3:1).

  2-(((4-(4-Methylpiperazin-1-yl)-6-(trifluoromethyl)pyri-midin-2-yl)thio)methyl)benzo[d]thiazole (13a): Light brown solid, yield 82.3%. m.p. 83.2~83.7 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.01 (d, J＝7.9 Hz, 1H), 7.94 (d, J＝8.1 Hz, 1H), 7.49 (dd, J＝11.3, 4.0 Hz, 1H), 7.40 (t, J＝7.3 Hz, 1H), 7.00 (s, 1H), 4.80 (s, 2H), 3.66 (s, 4H), 2.23 (s, 4H), 2.13 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.0, 169.3, 160.9, 153.2, 152.9, 152.5, 135.0, 126.0, 125.0, 122.2, 122.0, 96.3, 53.9, 45.3, 43.7, 32.7.

  2-(((4-(4-Ethylpiperazin-1-yl)-6-(trifluoromethyl)pyri-midin-2-yl)thio)methyl)benzo[d]thiazole (13b): Light brown solid, yield 77.6%. m.p. 90.1~91.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.02 (d, J＝7.8 Hz, 1H), 7.94 (d, J＝8.0 Hz, 1H), 7.52~7.47 (m, 1H), 7.40 (t, J＝7.2 Hz, 1H), 7.00 (s, 1H), 4.79 (s, 2H), 3.65 (d, J＝28.6 Hz, 4H), 2.54~2.49 (m, 2H), 2.25 (q, J＝7.2 Hz, 4H), 0.95 (t, J＝7.2 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.2, 169.3, 160.8, 153.2, 152.8, 152.5, 134.9, 126.0, 125.0, 122.2, 122.1, 96.2, 51.6, 51.2, 32.7, 28.9, 11.7.

  2-(((4-(4-Butylpiperazin-1-yl)-6-(trifluoromethyl)pyri- midin-2-yl)thio)methyl)benzo[d]thiazole (13c): Light brown solid, yield 80.4%. m.p. 84.2~84.8 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.01 (d, J＝7.8 Hz, 1H), 7.94 (d, J＝8.1 Hz, 1H), 7.49 (t, J＝7.2 Hz, 1H), 7.40 (t, J＝7.2 Hz, 1H), 6.99 (s, 1H), 4.79 (s, 2H), 3.81~3.50 (m, 4H), 2.54~2.21 (m, 4H), 2.17 (d, J＝7.3 Hz, 2H), 1.35 (dq, J＝14.3, 6.8 Hz, 2H), 1.29~1.23 (m, 2H), 0.88 (t, J＝7.2 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.2, 169.3, 160.8, 153.2, 152.8, 152.5, 134.9, 126.0, 125.0, 122.2, 122.1, 96.2, 57.1, 52.1, 43.3, 32.7, 28.1, 19.9, 13.8. HRMS (ESI) calcd for C₂₁H₂₅F₃N₅S₂ [M+H]⁺ 468.1503, found 468.1494.

  2-(4-(2-((Benzo[d]thiazol-2-ylmethyl)thio)-6-(trifluoro-methyl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol (13d): Light brown solid, yield 73.2%. m.p. 81.3~82.4 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.02 (d, J＝7.9 Hz, 1H), 7.95 (d, J＝8.1 Hz, 1H), 7.54~7.46 (m, 1H), 7.46~7.36 (m, 1H), 7.00 (s, 1H), 4.79 (s, 2H), 4.45 (s, 1H), 3.63 (s, 4H), 3.49 (s, 2H), 2.51 (s, 2H), 2.36 (t, J＝6.0 Hz, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.1, 169.3, 160.8, 152.8, 152.5, 134.9, 126.1, 125.0, 122.2, 122.1, 119.4, 96.2, 59.8, 58.3, 52.4, 43.4, 32.7.

  2-(((4-(4-Phenylpiperazin-1-yl)-6-(trifluoromethyl)-pyrimidin-2-yl)thio)methyl)benzo[d]thiazole (13e): Light brown solid, yield 61.6%. m.p. 79.1~80.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.01 (t, J＝7.1 Hz, 2H), 7.52 (t, J＝7.7 Hz, 1H), 7.41 (t, J＝7.7 Hz, 1H), 7.22 (t, J＝7.9 Hz, 2H), 7.07 (s, 1H), 6.87~6.79 (m, 3H), 4.82 (s, 2H), 3.83 (s, 4H), 3.04 (s, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.4, 169.4, 160.9, 153.3, 152.9, 152.5, 150.4, 135.0, 128.9, 126.1, 125.0, 122.3, 122.1, 119.4, 119.2, 115.6, 96.4, 47.7, 32.8.

  2-(((4-(4-(4-Methoxyphenyl)piperazin-1-yl)-6-(trifluo-romethyl)pyrimidin-2-yl)thio)methyl)benzo[d]thiazole(13f): Light brown solid, yield 67.0%. m.p. 82.6~83.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.03~7.99 (m, 2H), 7.54~7.50 (m, 1H), 7.44~7.40 (m, 1H), 7.07 (s, 1H), 6.85~6.79 (m, 4H), 4.83 (s, 2H), 3.86 (d, J＝21.7 Hz, 4H), 3.71 (s, 3H), 2.89 (d, J＝31.5 Hz, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.3, 169.4, 160.8, 153.3, 152.9, 152.5, 144.7, 135.0, 126.1, 125.0, 122.3, 122.1, 119.4, 117.8, 114.2, 96.3, 55.1, 49.2, 43.3, 32.8.

  2-(((4-(4-(4-Methoxybenzyl)piperazin-1-yl)-6-(trifluoro-methyl)pyrimidin-2-yl)thio)methyl)benzo[d]thiazole (13g): White solid, yield 82.9%. m.p. 96.1~96.8 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.02 (d, J＝7.7 Hz, 1H), 7.90 (d, J＝8.0 Hz, 1H), 7.53~7.46 (m, 1H), 7.45~7.38 (m, 1H), 7.15 (d, J＝8.6 Hz, 2H), 6.97 (s, 1H), 6.89 (d, J＝8.6 Hz, 2H), 4.77 (s, 2H), 3.75 (s, 2H), 3.73~3.42 (m, 4H), 3.33 (s, 3H), 2.40~2.05 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.2, 169.3, 160.7, 158.3, 153.2, 152.8, 152.4, 134.9, 130.1, 129.1, 127.8, 126.1, 125.0, 122.2, 122.1, 113.5, 96.1, 60.9, 54.9, 51.6, 32.7.

  2-(((4-(4-(Pyridin-2-yl)piperazin-1-yl)-6-(trifluorome-thyl)pyrimidin-2-yl)thio)methyl)benzo[d]thiazole (13h): Light brown solid, yield 65.2%. m.p. 97.1~98.4 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.15~8.12 (m, 1H), 8.01 (t, J＝8.6 Hz, 2H), 7.58~7.49 (m, 2H), 7.43~7.38 (m, 1H), 7.05 (s, 1H), 6.77 (d, J＝8.6 Hz, 1H), 6.67 (dd, J＝6.9, 5.0 Hz, 1H), 4.83 (s, 2H), 3.80 (d, J＝30.7 Hz, 4H), 3.61~3.37 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 170.15, 169.35, 160.98, 158.43, 153.20, 152.87, 152.50, 147.54, 137.58, 135.00, 126.15, 125.09, 122.34, 122.16, 113.25, 107.07, 96.41, 59.71, 43.81, 32.74. HRMS (ESI) calcd for C₂₂H₂₀F₃N₆S₂ [M+H]⁺ 489.1143, found 489.1128.

  2-(((4-(4-(Pyrimidin-2-yl)piperazin-1-yl)-6-(trifluoro-methyl)pyrimidin-2-yl)thio)methyl)benzo[d]thiazole (13i): Light brown solid, yield 68.1%. m.p. 96.7~97.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.37 (d, J＝4.7 Hz, 2H), 7.96 (dd, J＝12.3, 8.0 Hz, 2 H), 7.50~7.43 (m, 1H), 7.41~7.34 (m, 1H), 7.03 (s, 1H), 6.63 (t, J＝4.7 Hz, 1H), 4.82 (s, 2H), 3.76 (s, 8H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 169.8, 169.4, 161.0, 160.9, 157.8, 152.9, 152.4, 135.0, 126.0, 125.0, 122.2, 122.0, 119.4, 110.4, 96.4, 59.7, 42.5, 32.6. HRMS (ESI) calcd for C₂₁H₁₉F₃N₇S₂ [M+H]⁺ 490.1095, found 49.1080.

  Supporting Information The ¹H NMR and ¹³C NMR spectra of compounds 12 and 13a~13i. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

  
  
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  Figure 1  Antitumor agents and target compounds

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  Scheme 1  Synthesis of 2, 4, 6-trisubstituted pyrimidine derivatives containing benzothiazole moiety

  Reagents and conditions: (i) H₂NCSNH₂, NaH, MeCN, 70 ℃, 3 h; (ii) BF₃^•OEt₂, CH₂Cl₂, r.t., 2.5 h; (iii) KOH, H₂O, dioxane, 60 ℃, 6 h; (iv) POCl₃, dioxane, 90 ℃, 5 h; (v) 1-Boc-piperazine, DMF, 90 ℃, 2 h; . (vi) CH₂Cl₂, CF₃COOH, 0 ℃, 8 h; (vii) DMF, 90 ℃, 3 h

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  Table 1.  In vitro antitumor activities evaluation results for compounds 9, 10, 12 and 13a~13i

  Compd.	R	IC50a/(μmol•L-1)
  		EC-109	MGC-803	PC-3	HepG-2
  9	—	> 50	> 50	> 50	> 50
  10	—	> 50	> 50	> 50	> 50
  12	—	> 50	31.93±1.50	15.77±1.19	> 50
  13a	CH3	> 50	> 50	21.58±1.33	> 50
  13b	CH2CH3	> 50	> 50	13.33±1.12	36.71±1.58
  13c	CH2CH2CH2CH3	40.01±1.61	12.38±1.10	7.89±0.46	19.35±1.32
  13d	CH2CH2OH	> 50	25.89±1.35	12.83±1.10	> 50
  13e		> 50	> 50	> 50	> 50
  13f		> 50	44.30±1.64	28.57±1.45	> 50
  13g		> 50	48.25±1. 46	38.09±1.88	> 50
  13h		35.68±1.40	11.32±1.00	3.82±0.58	23.45±1.31
  13i		27.35±1.20	9.39±0.61	2.293±0.360	15.08±1.14
  5-Fub	—	12.23±1.08	8.24±0.75	5.54±0.74	13.12±1.34
  a Antitumor activity was assayed by exposure for 72 h to substances and expressed as concentration required to inhibit tumor cells proliferation by 50% (IC50). b Used as a positive control.

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  Table 2.  In vitro antiproliferative activities of compounds 13h and 13i against human normal cells

  Compd.	IC50/(μmol•L－1)
  	GES-1	HEEC
  13h	89.68	> 100
  13i	> 100	> 100
  5-Fu	22.60	> 100

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