Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Abstract

Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as convenient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Although the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and GADD44. Other proteins such as cdc2 were also expressed at a higher level. Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

4-furanylvinylquinoline derivative as a new scaffold for the design of oxidative stress initiator and glucose transporters inhibitor drugs

“…In addition, subsequent experiments proved the induction of cell death through the apoptotic pathway. According to the general observations, arrest in the G2/M phase often leads to apoptosis [71]. Subsequently, the uorescence tests that were performed showed changes in the level of generated ROS and exhibited a signi cant disruption of the oxidoreductive system of the cancer cells.…”

In Vitro and in Silico Studies of 3‐Hydroxyflavone‐Based Sulfonate Esters: Potent Acetylcholinesterase, Carbonic Anhydrase and α‐Glycosidase Inhibitors

“…Sulfonate esters appear as suitable starting compounds in the activation of the hydroxy group, [23,24] in many coupling reactions, [25][26][27] in the production of sulfonamides [27][28][29][30] which are synthetic antibiotics used as antibacterial agents. Along with this versatile use, it is of great interest to researchers to develop many new methods for the production of sulfonate esters, [21,28,[35][36][37][38][39] which possess important biological activity such as anticancer, [19,40] antibacterial, [18,35,41] some enzyme inhibitory, [20,42,43] anti-viral, [21] insecticidal activities. [22] Along with all these, the possible DNA effects of sulfonate esters should not be ignored.…”

Chemistry towards Biology—Instruct: Snapshot

“…Chelating metal ions can be a promising approach to designing novel and effective anticancer drugs. In our recent work, several scaffolds were evaluated for their potency as biologically active chelating and ionophoric agents, including quinolones [ 59 , 60 , 61 ], quinazolines [ 62 , 63 , 64 ], and thiosemicarbazones [ 65 , 66 , 67 , 68 ]. More recently, we have investigated terpyridines (Tpy) that possess strong chelating activity and potential for development [ 69 ].…”