New benzenesulfonamide scaffold-based cytotoxic agents: Design, synthesis, cell viability, apoptotic activity and radioactive tracing studies
Nissan, Y.M; Arafa, R.K.; Maher, A; Motaleb, M.A.; Sakr, T.M.; Sharaky, M.M.; Ibrahim, D.M; Ahmed, W.A.; Mohamed, K.O
Date issued:
2020-03
Publisher:
Academic Press Inc.
Series Info:
Bioorganic Chemistry;Volume 96, March 2020, Article number 103577
Type:
Article
Keywords:
EMTREE medical terms: A-549 cell lineanimal tissueArticlecell cycle arrestcell cycle regulationcell viabilitycontrolled studydrug cytotoxicitydrug designdrug screeningdrug synthesisHCT 116 cell lineHep-G2 cell linehumanhuman cellIC50isotope labelingmaleMCF-7 cell linemousenonhumanpriority journalproapoptotic activityproton nuclear magnetic resonanceradioactivity
,
EMTREE drug terms: 2 chloro n (4 sulfamoylphenyl)acetamide4 (2 imino 6 oxo 6,7 dihydro 1,3,5 dithiazepin 4 ylamino)benzenesulfonamide4 (4 oxo 4,5 dihydrothiazol 2 ylamino)benzenesulfonamide4 (4 oxo 5,6 dihydro 4h 1,3 thiazin 2 ylamino)benzenesulfonamide4 (5 benzylidene 4 oxo 4,5 dihydrothiazol 2 ylamino)4 (5 benzylidene 4 oxo 5,6 dihydro 4h 1,3 thiazin 2 ylamino)benzenesulfonamide4 (7 benzylidene 2 imino 6 oxo 6,7 dihydro 1,3,5 dithiazepin 4 ylamino)benzenesulfonamide4 [2 imino 7 (4 methoxybenzylidene) 6 oxo 6,7 dihydro 1,3,5 dithiazepin 4 ylamino]benzenesulfonamide4 [5 (4 bromobenzylidene) 4 oxo 4,5 dihydrothiazol 2 ylamino]benzenesulfonamide4 [5 (4 bromobenzylidene) 4 oxo 5,6 dihydro 4h 1,3 thiazin 2 ylamino]benzenesulfonamide4 [5 (4 chlorobenzylidene) 4 oxo 4,5 dihydrothiazol 2 ylamino]benzenesulfonamide4 [5 (4 chlorobenzylidene) 4 oxo 5,6 dihydro 4h 1,3 thiazin 2 ylamino]benzenesulfonamide4 [5 (4 fluorobenzylidene) 4 oxo 4,5 dihydrothiazol 2 ylamino]benzenesulfonamide4 [5 (4 fluorobenzylidene) 4 oxo 5,6 dihydro 4h 1,3 thiazin 2 ylamino]benzenesulfonamide4 [5 (4 hydroxybenzylidene) 4 oxo 4,5 dihydrothiazol 2 ylamino]benzenesulfonamide4 [5 (4 hydroxybenzylidene) 4 oxo 5,6 dihydro 4h 1,3 thiazin 2 ylamino]benzenesulfonamide4 [5 (4 methoxybenzylidene) 4 oxo 4,5 dihydrothiazol 2 ylamino]benzenesulfonamide4 [5 (4 methoxybenzylidene) 4 oxo 5,6 dihydro 4h 1,3 thiazin 2 ylamino]benzenesulfonamide4 [5 [4 (bimethylamino)benzylidene] 4 oxo 4,5 dihydrothiazol 2 ylamino]benzenesulfonamide4 [5 [4 (dimethylamino)benzylidene] 4 oxo 5,6 dihydro 4h 1,3 thiazin 2 ylamino]benzenesulfonamide4 [7 (4 bromobenzylidene) 2 imino 6 oxo 6,7 dihydro 1,3,5 dithiazepin 4 ylamino]benzenesulfonamide4 [7 (4 chlorobenzylidene) 2 imino 6 oxo 6,7 dihydro 1,3,5 dithiazepin 4 ylamino]benzenesulfonamide4 [7 (4 fluorobenzylidene) 2 imino 6 oxo 6,7 dihydro 1,3,5 dithiazepin 4 ylamino]benzenesulfonamide4 [7 (4 hydroxybenzylidene) 2 imino 6 oxo 6,7 dihydro 1,3,5 dithiazepin 4 ylamino]benzenesulfonamide4 [7 [4 (dimethylamino)benzylidene] 2 imino 6 oxo 6,7 dihydro 1,3,5 dithiazepin 4 ylamino]benzenesulfonamidebenzenesulfonamide derivativecytotoxic agentdoxorubicinfluorouracilunclassified drugunindexed drug
,
Cytotoxicity
,
Cell cycle phase distribution analysis
,
Caspase 8 and 9 levels
,
Benzenesulfonamide scaffold-based derivatives
Abstract:
A new series of thiazolidinone (5a-g), thiazinone (9a-g) and dithiazepinone (9a-g) heterocycles bearing a benzenesulfonamide scaffold was synthesized. Cytotoxicity of these derivatives was assessed against MCF-7, HepG2, HCT-116 and A549 cancer cell lines and activity was compared to the known cytotoxic agents doxorubicin and 5-FU where the most active compounds displayed better to nearly similar IC50 values to the reference compounds. For assessing selectivity, the most active derivatives against MCF-7, 5b, 5c and 5e, were also assessed against the normal breast cell line MCF-10 A where they demonstrated high selective cytotoxicity to cancerous cells over that to normal cells. Further, the effect of the most active compounds 5b-e on MCF-7 and HepG2 cell cycle phase distribution was assessed and the tested sulfonamide derivatives were found to induce accumulation of cells in the <2n phase. To further confirm apoptosis induction, caspase 8 and 9 levels in MCF-7 and HepG2 were evaluated before and after treatment with compounds 5b-e and were found to be significantly higher after exposure to the test agents. Since 5c was the most active, its effect on the cell cycle regulation was confirmed where it showed inhibition of the CDK2/cyclin E1. Finally, in vivo biodistribution study using radioiodinated-5c revealed a significant uptake and targeting ability into solid tumor in a xenograft mouse model. © 2020 Elsevier Inc.
Description:
MSA Google Scholar
SCOPUS
Show full item record