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.

Keywords: NO donor; anti-tumour; malignant glioma; natural product; β-Elemene.

Figure 1.

The structure of β-elemene and its clinical preparations.

Figure 2.

(A) The allylicchlorination reaction of β-elemene and the corresponding reaction products 2–4. (B) The designing strategy of β-elemene NO donor hybrids.

Figure 3.

In vivo metabolizion of 13-β-elemenol ester NO donor derivatives may result in producing toxic 13-β-elemenal.

Scheme 1.

Reagents and conditions: DIPEA, DMF, 60 °C.

Scheme 2.

Reagents and conditions: (a) THF, NaOH (4:1, v/v), r.t.; (b) DMAP, DCM, r.t.

Scheme 3.

Reagents and conditions: EDCI, DMAP, DCM, r.t.

Figure 4.

The anti-tumour activity of β-elemene and compound Id against brain malignant glioma (n = 5). (A) Body weight (model group as 100%). (B) Brain weight. (C) Boluminescence signal intensity of brain tumour. (D) Inhibitory rates of β-elemene and compound Id from week 1 to week 3. (E) Representative brain glioma images of the model, β-elemene, and compound Id groups. (F) Histological analysis of the brain glioma tumour tissue (**P < 0.01 vs. model group; ^##P < 0.01 vs. β-elemene group).