Structurally Simple Phenanthridine Analogues Based on Nitidine and Their Antitumor Activities

Abstract

A series of novel structurally simple analogues based on nitidine was designed and synthesized in search of potent anticancer agents. The antitumor activity against human cancer cell lines (HepG2, A549, NCI-H460, and CNE1) was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro. The results showed that some of them had good anticancer activities, especially derivatives with a [(dimethylamino)ethyl]amino side chain in the C-6 position. Planar conjugated compounds 15a, 15b, and 15c, with IC₅₀ values of 1.20 μM, 1.87 μM, and 1.19 μM against CNE1 cells, respectively, were more active than nitidine chloride. Compound 15b and compound 15c with IC₅₀ values of 1.19 μM and 1.37 μM against HepG2 cells and A549 cells demonstrated superior activities to nitidine. Besides, compound 5e which had a phenanthridinone core displayed extraordinary cytotoxicity against all test cells, particularly against CNE1 cells with the IC₅₀ value of 1.13 μM.

Keywords: antitumor activity; nitidine; phenanthridine; phenanthridinone.

Scheme 1

Reagents and conditions: (a) SOCl₂, ⁱPrNEt, DCM, reflux, 78–91%; (b) NaH, DMF, PMBCl or MOMCl, rt, 92–98%; (c) Pd(oAc), P(o-tol)₃, K₂CO₃, DMF, 155 °C, 78–90%; (d) TFA, 75 °C, 54–78%; (e) LiAlH₄, dry THF, 0 °C-rt, 45–55%.

Scheme 1

Reagents and conditions: (a) SOCl₂, ⁱPrNEt, DCM, reflux, 78–91%; (b) NaH, DMF, PMBCl or MOMCl, rt, 92–98%; (c) Pd(oAc), P(o-tol)₃, K₂CO₃, DMF, 155 °C, 78–90%; (d) TFA, 75 °C, 54–78%; (e) LiAlH₄, dry THF, 0 °C-rt, 45–55%.

Scheme 2

Reagents and conditions: (a) ethyl bromoacetate or ethyl 4-bromobutyrate, Cs₂CO₃, TBAI, DMF, 90 °C, 76–95%; (b) MeOH, H₂O, 10N NaOH, rt, 93–98%; (c) triethylamine, THF, CH₂Cl₂, isobutyl chloroformate, dimethylamine, 0 °C-rt, 82–85%.

Scheme 3

Reagents and conditions: (a) POCl₃, 105 °C, 83–85%; (b) Me₂N(CH₂)₂NH₂, reflux, 59–78%. (c) MeI, toluene, 80 °C, 75–84%.