Microwave-assisted synthesis, molecular docking and antiproliferative activity of (3/5-aryl-1,2,4-oxadiazole-5/3-yl)(3,4,5-trimethoxyphenyl)methanone oxime derivatives

Abstract

A series of (3/5-aryl-1,2,4-oxadiazole-5/3-yl)(3,4,5-trimethoxyphenyl)methanone oxime derivatives were synthesized via a rapid and facile microwave-assisted synthesis method of building 1,2,4-oxadiazole skeleton using mandelic acid as the starting material. Twenty four target compounds were evaluated for their in vitro antiproliferative activities against three human cancer cell lines (SGC-7901, A549 and HT-1080). Among them, 16b exhibited the most potency against different tumour cell lines, especially A549 cell lines (IC 50 = 87 nM). Structure-activity relationship (SAR) studies revealed the aryl substituent at C-5 position on 1,2,4-oxadiazole ring is superior to that at C-3 position. Oxime as a connector can obviously increase the potency, contrary to that in SMART derivatives. Moreover, 16b significantly induced cell cycle arrest in the G2/M phase and caused microtubule destabilization. Molecular docking studies provide a theoretical binding mode of 16b at the colchicine site in the tubulin dimer. Our work laid the foundation for further structure-guided design of novel tubulin polymerization inhibitors.

Synthesis and bioevaluation of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors with potent antiproliferative activity

“…Furthermore, a set of oxadiazole CBSIs with an oxime linker between the A-ring and the B-ring was previously reported by our group ( 9 , Fig 1A) [18]. The structures of these CBSIs feature three aromatic rings (A-, B- and C- rings) and an sp 2 hybridized linker between the A-ring and B-ring (Fig 1A).…”

“…Furthermore, CBSIs containing an sp 3 amino linker have also been reported [20]. In our continued research into novel CBSIs [18, 21, 22], we hypothesized that the sp 2 linker between the A- and B-rings could be replaced by a sp 3 amino linker and that the substitutions on the A- and C-rings could be different groups. As expected from calculations using the Gaussian 09 software, the skeletal structure of target compounds superimposed well with that of SMART (Fig 1B).…”

Metal-Involving Synthesis and Reactions of Oximes

“…After that, C-functionalization via palladium-catalyzed arylation of aldoximes and silver-or cobaltcatalyzed functionalization of sulfonyl oximes yielding ketoximes (section 3.3, c), metal-mediated dehydration of aldoximes (section 3.4, d), and reduction of oximes (section 3.5, e) will be considered. 152,153,158,159 allyl, 156−158 or propargyl 154,155 substituents at the O atom. In the presence of a metal center, the scope of alkylating reagents extends to alkenes and ethers.…”

Design, synthesis and biological evaluation of 1-Aryl-5-(4-arylpiperazine-1-carbonyl)-1H-tetrazols as novel microtubule destabilizers

“…Under conventional heating conduction, the reaction of 8 with PPh 3 in CCl 4 to generate (E)-ethyl 2-chloro-2-(arylimino)acetates (9) suffered from long reaction time and low yields (Table 1, entries 1-5). Microwave irradiation offered many advantages, such as rate enhancements and higher yields, over conventional heating and had become a popular technique that was widely used in organic synthesis today [15][16][17][18] . When microwave irradiation was incorporated into synthesis of 9-8, we found that the reaction rate was greatly improved.…”