Design and synthesis of a new soluble natural β-carboline derivative for preclinical study by intravenous injection

Harmine is a naturalβ-carboline compound showing several biological activities,including antiproliferative properties, but this soluble natural molecule lacks selectivity. Harminederivatives were reported to overcome this problem, but they are usually poorly soluble. Here, wedesigned 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 of1.87±0.07 mg/mL in a simulated injection vehicle. This compound is stable for at least 72 h in acidicand physiological conditions (pH 1.1 and 7.4) as well as in a simulated injection vehicle (physiologicalliquid + 0.1% Tween80®). Solubility in those media is 1.06±0.08 mg/mL and 1.62±0.13 mg/mLat pH 7.4 and 1. The synthesized molecule displays a significant activity on five different cancercell lines (IC50range from 0.2 to 2μM 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) atIC50concentrations. Due to its high activity at low concentration, such solubility values should besufficient for further in vivo antitumoral activity evaluation via intravenous injection.