Abstract
Harmine is a natural β-carboline compound showing several biological activities, including antiproliferative properties, but this soluble natural molecule lacks selectivity. Harmine derivatives were reported to overcome this problem, but they are usually poorly soluble. Here, we designed and synthesized a new 2, 7, 9-trisubstituted molecule (1-methyl-7-(3-methylbutoxy)-9-propyl-2-[(pyridin-2-yl)methyl]-9H-pyrido[3,4-b]indol-2-ium bromide) with a solubility of 1.87 ± 0.07 mg/mL in a simulated injection vehicle. This compound is stable for at least 72 h in acidic and physiological conditions (pH 1.1 and 7.4) as well as in a simulated injection vehicle (physiological liquid + 0.1% Tween80®). Solubility in those media is 1.06 ± 0.08 mg/mL and 1.62 ± 0.13 mg/mL at pH 7.4 and 1. The synthesized molecule displays a significant activity on five different cancer cell lines (IC50 range from 0.2 to 2 µM on A549, MDA-MB-231, PANC-1, T98G and Hs683 cell lines). This compound is also more active on cancer cells (MDA-MB-231) than on normal cells (MCF-10a) at IC50 concentrations. Due to its high activity at low concentration, such solubility values should be sufficient for further in vivo antitumoral activity evaluation via intravenous injection.
Highlights
Harmine is a natural β-carboline alkaloid compound (Figure 1) extracted from Peganum Harmala seeds and displaying several biological activities
Harmine leads to in vitro apoptosis in stomach cancer cells by decreasing the cyclooxygenase-2 (COX-2) expression while increasing Bax protein expression [10] or by inhibiting the Akt phosphorylation, which is essential for cell survival [11]
Compound 2 has been synthesized by an original route implying mechanochemistry for the last synthesis step
Summary
Harmine is a natural β-carboline alkaloid compound (Figure 1) extracted from Peganum Harmala seeds and displaying several biological activities. Antitumoral activities of harmine were largely studied because it is reported to interact with DNA and to inhibit topoisomerase I, leading to cell death [5,6]. This natural molecule was reported as an apoptotic pathway activator in hepatocarcinoma because it decreases Bcl-2 protein level without any modification of Bax pro-apoptotic expression [7,8,9]. Harmine on itself exhibits poor selectivity, which may cause undesirable effects. Using derivatives of this natural compound might help overcome this issue. Ianntoirpdreorlitfoeriamtipvreoavcetihvaitrimesi,nceydcleordiveaxttirviness scoolmubpilleitxyatwiohnilheams abienetnaianlirnegadthyepirearfnotripmreodlifienraotuivr egraocutipviatineds, cthyicslofodremxturliantsiocnolmedplteoxaattwioon-fhoalsd binecerneaaslereiandsyolpuebrifliotrymatepdhiynsoioulor ggircoaul ppHan[2d2]t.hDisefsoprimteuthlaotsieonstuleddietso, atotwthoe-fobledstincorfeaosuerinksnoolwubleilditgye,atopnhlyyspioalroegnitcearlapl Hin[j2e2ct]i.oDn esispitreeftehroresde sftourdihesa,rmtointhee dbeersitvoaftiovuesr kadnmowinleisdtgraet,ioonnl.y parenteral injection is referred for harmine derivatives administration
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