Second generation β-elemene nitric oxide derivatives with reasonable linkers: potential hybrids against malignant brain glioma

Abstract

Elemene is a second-line broad-spectrum anti-tumour drug that has been used in China for more than two decades. However, its main anti-tumour ingredient, β-elemene, has disadvantages, including excessive lipophilicity and relatively weak anti-tumour efficacy. To improve the anti-tumour activity of β-elemene, based on its minor molecular weight character, we introduced furoxan nitric oxide (NO) donors into the β-elemene structure and designed six series of new generation β-elemene NO donor hybrids. The synthesised compounds could effectively release NO in vitro , displayed significant anti-proliferative effects on U87MG, NCI-H520, and SW620 cell lines. In the orthotopic glioma model, compound Id significantly and continuously suppressed the growth of gliomas in nude mice, and the brain glioma of the treatment group was markedly inhibited (>90%). In short, the structural fusion design of NO donor and β-elemene is a feasible strategy to improve the in vivo anti-tumour activity of β-elemene.

Recent progress in synthesis and application of furoxan

“…Hybridization of b-elemene with furoxan as the NO-donating moiety was reported, and showed improvements in the anticancer properties in relation to those of the parent b-elemene molecule. 68,69 Six series of hybrids were synthesized and, when evaluated biologically, displayed signicant anti-proliferative effects against malignant brain glioma cells. Hybrid 68 signicantly and continuously suppressed the growth of gliomas in mice, with the brain glioma of the treatment group inhibited by more than 90%.…”

Nickel-catalyzed cross-electrophile allylation of vinyl bromides and the modification of anti-tumour natural medicine β-elemene

“…As shown in Fig. 2, a wide range of b-arylsubstituted (E)-alkenyl bromides bearing electron-decient substituents such as ester, triuoromethyl and cyano (17-20) or electron-rich substituents such as methyl, N,N-dimethyl, Bpin and methoxy (21)(22)(23)(24)(25)(26)(27) on the arene afforded the desired products smoothly. The electronic properties of alkenyl halides did not show an obvious effect on the efficiency of this transformation.…”

“…The electronic properties of alkenyl halides did not show an obvious effect on the efficiency of this transformation. Among the methoxy-substituted products (1,(24)(25), the paraone was the most effective. Signally, the b-aryl-substituted (E)alkenyl bromides bearing multi-substituents on the aromatic ring (26-27) underwent this allylation smoothly with high levels of transformation.…”

“…With the b-elemene vinylated compounds in hand, we subsequently investigated the in vitro anti-tumour activities of these compounds towards HCT116 (colon cancer cells) and A549 (lung cancer cells) tumour cell lines. 24 Aer the rst preliminary screening at a concentration of 50 mM, compound 55 was selected to further test its IC50 values against these two tumour cell lines. For the HCT116 cell line, compound 55 is over 15-fold more active than b-elemene (IC50: 50.9 mM and 781.9 Next, we investigated whether the allylation strategy was possible to achieve enantioselectivity for the coupling of vinyl bromide 1a with (E)-4-phenylbut-3-en-2-yl acetate using a chiral tridentate pybox ligand L4.…”

Novel hydroxyl carboximates derived from β-elemene: design, synthesis and anti-tumour activities evaluation

“…Based on the characteristics of functional groups, β -elemene derivatives could be divided into the following classes: amines, esters, amino acid derivatives, ethers, alcohols, glycosides and organometallic compounds, etc 18 , as shown in Figure 2 . In recent years, the dimer derivatives 19 , 20 ( Figure 2 , Ii ) and NO donor derivatives 21 , 22 ( Figure 2 , Ij ) of β -elemene were investigated and showed promising biological activities. However, the hybrid drugs derived from β -elemene and histone deacetylase inhibitors (HDACi) were rarely studied and reported.…”