Synthesis and Biological Evaluation of 1‐Phenyl‐1,2,3,4‐dihydroisoquinoline Compounds as Tubulin Polymerization Inhibitors

Abstract

A series of 1-phenyl-3,4-dihydroisoquinoline derivatives and several 1-phenyl-1,2,3,4-tetrahydroisoquinoline, 1-phenyl-isoquinoline analogues were synthesized, and their cytotoxicity and tubulin polymerization inhibitory activity were evaluated. The 1-phenyl-3,4-dihydroisoquinoline compounds were found to be potential tubulin polymerization inhibitors. Compound 5n, bearing a 3'-OH and 4'-OCH(3) substituted 1-phenyl B-ring, was shown to confer optimal bioactivity. The single-crystal structure of 5n was further determined by X-ray diffraction, and the binding mode of 5n to tubulin was obtained by molecular docking, which can explain the structure-activity relationships. The studies presented here provide a new structural type for the development of novel antitumor agents.

Quantum Chemistry Calculation-Aided Structural Optimization of Combretastatin A-4-like Tubulin Polymerization Inhibitors: Improved Stability and Biological Activity

“…Compounds were tested in triplicate in at least three independent assays, and the average median inhibitory concentration (IC50) values were reported. 14,[34][35][36] Assay for Tubulin Polymerization Inhibition. Bovine brain tubulin (Cytoskeleton, Inc., USA) (>99% pure, 3 mg/mL) in 100 μL of general tubulin buffer at 0 °C was placed in a half-area 96-well plate prewarmed at 37 °C in the presence of the tested compounds at varying concentrations.…”

“…The mass of polymer formed was monitored by turbidimetry at 340 nm every 1 min for 60 min with a multifunction microplate reader (Biotek Synergy 4, USA). 14,[34][35][36] Assay for in vivo antitumor activity. BALB/c nude female mice (18−20 g) were obtained from Shanghai SLAC Laboratory Animal Co., Ltd. (Shanghai, China).…”

Biological evaluation of octahydropyrazin[2,1-a:5,4-a′]diisoquinoline derivatives as potent anticancer agents

“…The 3,4-dihydroisoquinoline compounds seemed to be potential tubulin polymerization inhibitors. 15 The promising results from in vitro and in vivo studies give a basis for searching novel isoquinoline alkaloid derivatives.…”

Dihydroisoquinoline copper(ii) complexes: crystal structures, cytotoxicity, and action mechanism

“…This compound is known for its efficacy against diarrhea, hepatitis, skin infections and cancer 32 and is widely applied in the design of new antitumor agents. [33][34][35] Recently, we utilized 3,4-dihydroisoquinoline as a leading compound in the design and synthesis of one isoquinoline derivative, 4,5-methylenedioxy-1pyridinedihydroisoquinoline (MPDQ), which contains a DNA intercalation moiety and a pyridine ring and can act as a chelating ligand (Scheme 1); the antitumor activity of Zn(II)/ Ni(II) complexes has also been reported for the MPDQ ligand. 36 As a part of our research for new metal-based anticancer agents, herein, we report the synthesis, crystal structure and in vitro antitumor activity of three copper(II) complexes with MPDQ as a chelating ligand; the mechanism of their cytotoxicity as well as their interactions with the potential target DNA were also investigated.…”