Synthesis and Biological Evaluation of KRIBB3 Analogues on a Proliferation of HCT-116 Colorectal Cancer Cells

Sang-Ku Lee, Jae-Nyoung Kim, Ji-Hye Min, Kab-Seog Yoon, Ki-Deok Shin, Byoung-Mog Kwon, Dong-Cho Han
2010 Bulletin of the Korean Chemical Society (Print)  
3 4 5 2 1b i, ii 1c R 1 = Me, R 2 = Me R 1 = Me, R 2 = Bn R 1 = Me, R 2 = H R 1 = H, R 2 = H 1e 1d iii, iv v vii viii Scheme 1. Reagents and conditions: (i) POCl3, DMF, 10 o C to rt, 1 hr; (ii) CH3I, K2CO3, DMF, rt; (iii) 4-methoxybenzyl magnesium chloride, 0 o C to rt, 1 hr; (iv) tetrapropylammonium perruthenate, 4-methylmorpholine N-oxide, 4Å molecular sieves, CH2Cl2, rt, 30 min; (v) DMFDMA, toluene, reflux; (vi) NH2OH-HCl, MeOH, AcOH, Na2CO3, 115 o C, (vii) BBr3, CH2Cl2, -10 o C, 2 h O N H 3
more » ... 10 o C, 2 h O N H 3 CO H 3 CO Et OH Figure 1. Structure of KRIBB3 (1a). Even though target-specific cancer therapies have some progress, only 5% of such therapy show efficacy in the clinic. 1 Therefore, the development of cancer therapy targeted to cytotoxicity is still important. Cell cycle control is the major regulatory mechanism of cell growth. Small chemicals that inhibit cell cycle progression have attracted much attention for cancer therapy because they can block tumor growth. Drug-mediated mitotic-checkpoint-dependent-arrest is often followed by cell death. 2 In previous studies, we reported a diaryl oxazole compound, KRIBB3 (1a) that displayed strong anti-mitotic activity against cancer cells. 3 KRIBB3 showed inhibition of proliferation of HCT-116 colorectal cancer cells with GI 50 value of 0.1 μM and showed 6 times stronger inhibitory activity than nocodazol. Nocodazole is a well known anti-mitotic chemical and we used it as a control compound. In an effort to further develop this promising compound 1a toward a potent anti-cancer agent, we have focused on examining structure-activity relationships for KRIBB3. We synthesized a series of diaryl isoxazole derivatives by modifying alkoxy and hydroxyl group in the aryl moiety of KRIBB3 (1a), and evaluated their antiproliferative activity on the proliferation of HCT-116 colorectal cancer cells. Herein, we describe the synthesis and biological evaluation of KRIBB3 analogues 1. The synthesis of diaryl isoxazole derivative 1b was achieved through the route in Scheme 1. The formylation 4 of 4-ethylresorcinol (2) with DMF and POCl 3 gave 5-ethyl-2-hydroxy-4-methoxybenzaldehyde which was dimethylated utilizing methyl iodide and potassium carbonate to furnish compound 3. Reaction of aldehyde 3 with 4-methoxybenzylmagnesium chloride and the subsequent oxidation of the resulting secondary alcohol with TPAP and NMO afforded ketone 4. 5 Condensation of compound 4 with dimethylformamide dimethylacetal (DMFDMA) in refluxing toluene gave enaminoketone 5, 6 which was cyclized in refluxing methanolic AcOH in the presence of Na 2 CO 3 to provide isoxazole 1b. 6b Compound 1c and 1f were prepared from 2-benzyloxy-4-methoxy-5-ethylbenzaldehyde and 3,5-dimethyl-4-hydroxybenzaldehyde, respectively, in same fashion as described for synthesis of 1b. Compound 1d and 1e were prepared by demethylation of 1c using BBr3 in 45% and 30% yields, repectively. Compound 1g was synthesized by debenzylation of compound 1f using hydrogen (60 psi) and 10% Pd/C. Inhibitory activity of diaryl isoxazole derivatives against proliferaction of HCT-116 colorectal cancer cells was evaluated by measurement of the amount of WST-1 formazan formed by adding cell proliferation reagent WST-1. The GI 50 values of these compounds were presented in Table 1 . The extent of inhibiting proliferaction of HCT-116 colorectal cancer cells was greater in methoxy group (1a, 1b and 1c) of B-aryl moiety than in hydroxyl group (1d and 1e) . The presence of free hydroxyl hydrogen in the B-aryl moiety of KRIBB3 analogues decreased the efficiency of antiproliferative activity. Large benzyloxy substituent (1c) at 2-position of A-aryl moiety showed a weak inhibitory activity in comparision with relatively small sized methoxy (1b) or hydroxy (1a) substituent. Change of substituents in A-aryl moiety of KRIBB3 analogues (1f and 1g) did not enhance antiproliferative activity. Among the evaluated compounds, compound 1b exhibited the strongest antiproliferative effects and showed 6 times more potent activity than nocodazole as a positive control. The structure-activity analysis indicated
doi:10.5012/bkcs.2010.31.12.3800 fatcat:qham2b27jnh2za5iltnnhesl74