Among the multiple heterocyclic moieties of biological and pharmacological interest,the oxazole ring has gained considerable attention in past decades ^[1]. In particular,2,5-disubstituted oxazoles are important substructures in various natural products ^[2] and show activity against inflammation ^[3],diabetes ^[4], bacterial infection ^[5],cardiovascular disease ^[6],and cancer ^[7]. Accordingly,many strategies have been developed for their synthesis ^[8]. Robinson-Gabriel oxazole synthesis is a widely used method,but the reaction needs hazardous reagents such as H₂SO₄,PCl₅ or POCl₃ ^[9]. In addition,α-diazoketones,the starting materials of the reaction,are dangerous and not readily commercially available. Gold-mediated homogeneous catalysts,because of their unique properties,have now become one of the hot topics in the organic chemistry ^[10]. Among various types of gold catalysis, the research of α-oxo gold carbene intermediates has contributed significantly to the diversity and versatility of gold chemistry. Gold carbene intermediates generated via gold-catalyzed activation of C-C multiple bonds and subsequently attacked by a nucleophilic reagent such as imine and alkoxy,has proven to be an exceptionally powerful method to construct new C-C and C-N bonds ^[11]. Recently,the first efficient intermolecular reaction of gold carbene intermediates,using nitriles as both the reacting partner and the reaction solvent,was reported,offering a generally efficient synthesis of 2,5-disubstituted oxazoles ^[12]. To the best of our knowledge,research on the synthesis and applications of gold- catalyzed oxazoles has beenvirtually nonexistent inpharmaceutical literature. Herein,we report the gold-catalyzed synthesis of a number of 5-aryl-2-methyloxazoles and their cytotoxic effects against MCF-7,A549 and Hela cancer cell lines in vitro.

The alkynes 2b-2g,2i were prepared according to the strategy described in Scheme 1 by a modified literature method ^[13]. In general,reactions of halides 5,the starting materials,with 1.3 equiv. of trimethylsilylacetylene using catalytic quantities of bis(triphenylphosphine) palladium(II) chloride and copper iodide in diisopropyl-amine afforded protected alkynes 3. Hydrolysis of 3 in methanol using anhydrous potassium carbonate led to the formation of the products alkynes 2b-2g,2i,yield 78%-91% after two steps. Ferrocenylacetylene 2h was prepared as shown in Scheme 2 ^[14]. In the initial step,(2-formy-1-chlorovinyl) ferrocene 6 was synthesized via the reaction of acetylferrocene with Vielsmeier complex prepared from phosphorus oxychloride and DMF in an ice bath. Then the treatment of the alkene 6 with sodium hydroxide solution afforded the corresponding ferroceny- lacetylene 2h.

Scheme 1

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Scheme 1. Reagents and condition: (a) Pd(PPh3)2Cl2,CuI,(i-Pr)2NH,TMSacetylene; (b) K2CO3,MeOH.

Scheme 2

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Scheme 2. Reagents and condition: (a) POCl3,DMF; (b) NaOH,dioxane,reflux.

Oxazoles 1 were prepared from alkynes under the reaction conditions of Table 1 and the progress of the reaction was monitored by TLC. Compounds 1 were purified by column chromatography on silica gel in 68%-94% yield. All of them were confirmed by ₁H NMR and HRMS spectra ^[15]. The presence of nitrogen or sulfur in heteroaryl substituents would reduce the activity of gold catalyst.

Table 1

Table 1 Gold-catalyzed synthesis of oxazoles 1<.b>.a

Table 1 Gold-catalyzed synthesis of oxazoles 1<.b>.a

Based on Zhang’s work ^[12],we further screened the reaction conditions,using phenylacetylene as the substrate. Compared to ambient temperature,the reaction proceeded faster at 60 ℃ (Table 2,entries 1 and 2).

Table 1

Table 2 Screening of reaction conditions.a

Table 2 Screening of reaction conditions.a

Different quinoline N-oxides were tested (Table 2,entries 2-5), 8-ethylquinoline N-oxide (4c) was the best among the oxidants examined. As the use of LAuCl/AgX is becoming more widespread in gold chemistry ^[16],we envisioned the possibility of increasing the chemical yield of the reaction sequence by examining the roles of the ligand and counterion (Table 2,entries 6-14). Though other gold catalysts (e.g.,Ph₃PAuCl/AgNTf₂,BrettPhosAuCl/AgNTf₂) worked equally well,we chose Ph₃PAuCl/AgSbF₆ as the catalyst for economic reasons.

In the screening assay studies,a series of compounds 1a-1i were evaluated against three cell lines: MCF-7 (Human breast carcinoma),A-549 (Human lung carcinoma) and Hela (Human cervical carcinoma). Cis-dichlorodiamineplatinum(II) (cis-DDP) was used as the reference substance. As shown in Table 3, compounds 1b,1c,1d,1f and 1g are the active molecules against various cell lines. The compound 1b exhibited excellent inhibitory activity against all the cancer cell lines and the IC₅₀ values even compared well with cis-DDP.

Table 3

Table 3 Cytotoxicity of oxazoles 1a-1i against MCF-7,A549 and Hela cancer cell.

Table 3 Cytotoxicity of oxazoles 1a-1i against MCF-7,A549 and Hela cancer cell.

Introduction of a benzene group increased biological activity,as demonstrated by the IC₅₀ value difference between the pairs 1c and 1d and 1e-1f. It is interesting to note that the compounds with nitrogen heterocyclic groups as the substituents exhibited higher activities than thosewith sulfur heterocyclic groups. The compound 1d with quinoline showed the best selective cytotoxicity against MCF-7cell lineswiththe IC₅₀ values of 2.2 μmol/L,andthe valuewas slightly better than cis-DDP serving as a positive control. Except for 1b,the products exhibited poor activity against Hela and A549 cell lines (more than 30 μmol/L).Usually,ferrocene groups elicit a broad range of biological activities,such as anti-inflammatory,anti- malaria,antimicrobial,anticancer properties ^[17]. Unfortunately, the compound 1h with a ferrocene group did not exhibit good activity as expected.

A series of 5-aryl-2-methyloxazoles were prepared and studied for their cytotoxicity against various cancer cell lines. Of the synthesized oxazoles,compound 1b was found to be most cytotoxic against cancer cell lines. In addition,compound 1c and 1d were highly selective against MCF7 cancer cell lines. The structure-activity relationship study showed that naphthalen-2-yl and quinolin-3-yl at the C-5 position of the oxazole ring are important for the activity and selectivity of 5-aryl-2-methylox- azoles.

This work was supported by NSFC (No. 21276068),Department of Science and Technology Foundation of Hunan Province (No. 2010SK2001) and Hunan Natural Science Foundation (No. 11JJ5008).