N-Benzoylated Phenoxazines and Phenothiazines: Synthesis, Antiproliferative Activity, and Inhibition of Tubulin Polymerization

Abstract

A total of 53 N-benzoylated phenoxazines and phenothiazines, including their S-oxidized analogues, were synthesized and evaluated for antiproliferative activity, interaction with tubulin, and cell cycle effects. Potent inhibitors of multiple cancer cell lines emerged with the 10-(4-methoxybenzoyl)-10H-phenoxazine-3-carbonitrile (33b, IC(50) values in the range of 2-15 nM) and the isovanillic analogue 33c. Seventeen compounds strongly inhibited tubulin polymerization with activities higher than or comparable to those of the reference compounds such as colchicine. Concentration-dependent flow cytometric studies revealed that inhibition of K562 cell growth was associated with an arrest in the G2/M phases of the cell cycle, indicative of mitotic blockade. Structure-activity relationship studies showed that best potencies were obtained with agents bearing a methoxy group placed para at the terminal phenyl ring and a 3-cyano group in the phenoxazine. A series of analogues highlight not only the phenoxazine but also the phenothiazine structural scaffold as valuable pharmacophores for potent tubulin polymerization inhibitors, worthy of further investigation.

(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone inhibits tubulin polymerization, induces G2/M arrest, and triggers apoptosis in human leukemia HL-60 cells

“…The ability of PHT to arrest cancer cells in G 2 /M phases is consistent with cytotoxic agents that act by binding to tubulin. The compounds that damage mitotic spindles inhibit the tumor cell proliferation and block cells at metaphase phase (Cocca et al, 2009;Prinz et al, 2003Prinz et al, , 2011Rycker et al, 2009;Schneider et al, 2003). The hypothesis that arrest of the cell cycle at mitosis is following by apoptosis has been largely accepted.…”

Cancer and the Dopamine D2Receptor: A Pharmacological Perspective

“…Indeed, novel phenothiazine derivatives have been shown to have many potential anticancer activities aside from the established activities with respect to calmodulin, dopamine receptors, and other known psychiatrically relevant targets. These include antioxidant ability, inhibition of tubulin polymerization, and inhibition of farnesyl transferase (Prinz et al, 2011;Baciu-Atudosie et al, 2012;Engwa et al, 2016;Ghinet et al, 2016). We recognize how our hypothesis, which runs counter to a voluminous literature, could be interpreted, but we believe it would be useful if this generates controversy that leads to hypothesis-driven studies using orthogonal approaches and varying structural series of D 2 R antagonists.…”

Docking, CoMFA and CoMSIA Studies of a Series of N-Benzoylated Phenoxazines and Phenothiazines Derivatives as Antiproliferative Agents

“…A collection of 39 compounds was reported recently by H. Prinz and co-workers, 27 as a new class of antiproliferative agents, was used for docking and 3D-QSAR analysis. The activity (IC 50 ) values of some molecules had been reported qualitative (i.e.…”