Phenothiazines Modified with the Pyridine Ring as Promising Anticancer Agents

Beata Morak-Młodawska,Krystian Pluta,Małgorzata Jeleń

doi:10.3390/life11030206

Abstract

Azaphenothiazines are the largest and most perspective group of modified phenothiazines, and they exhibit variety of biological activities. The review sums up the current knowledge on the anticancer activity of isomeric pyridobenzothiazines and dipyridothiazines, which are modified azaphenothiazines with one and two pyridine rings, respectively, against 10 types of cancer cell lines. Some 10-substituted dipyridothiazines and even 10-unsubstituted parent compounds, such as 10H-1,9-diazaphenothiazine and 10H-3,6-diazaphenothiazine, exhibited very potent action with the IC50 values less than 1 µg/mL and 1 µM against selected cancer cell lines. The strength of the anticancer action depends both on the tricyclic ring scaffolds and the substituents at the thiazine nitrogen atom. The review discusses the kind of the substituents, nature of tricyclic ring scaffolds with the location of the azine nitrogen atoms, the types of the cancer cell lines, and the mechanism of action.

Highlights

Phenothiazines are a very important class of heterocyclic compounds possessing a tricyclic dibenzo-[1,4]-thiazine ring system
The review summarizes the current knowledge on the anticancer activity of isomeric pyridobenzothiazines and dipyridothiazines, the modified azaphenothiazines with one and two pyridine rings against 10 types of cancer cell lines
Whereas pyridobenzothiazines were synthesized as modified successors of the classical neuroleptic phenothiazines and their anticancer activity was found only recently, dipyridothiazines were mostly obtained with the aim at the anticancer activity

Summary

Introduction

Phenothiazines are a very important class of heterocyclic compounds possessing a tricyclic dibenzo-[1,4]-thiazine ring system. He with his research groups started extensive studies on the anticancer activity of new phenothiazines which were the inspiration to other research groups They synthesized modified tricyclic phenothiazines with amidoalkyl, sulfonamidoalkyl, and chloroethylureidoalkyl substituents in position 10 and replaced the benzene ring with naphthalene. These phenothiazines exhibited cytotoxic activities against ten different human tumor cell lines: leukemia, melanoma, small cell lung, colon, central nervous system, renal, breast, ovarian, and prostate tumors. The aim of this review is to present comprehensively anticancer activities of those azaphenothiazines

Pyridobenzothiazines

Dipyridothiazines

Findings

Conclusions