Synthesis and biological evaluations of mono‐ and bis‐ferrocene uracil derivatives. (13th October 2020)

• Record Type: Journal Article
• Authors: Djaković, Senka; Glavaš‐Obrovac, Ljubica; Lapić, Jasmina; Maračić, Silvija; Kirchofer, Juraj; Knežević, Marija; Jukić, Marijana; Raić‐Malić, Silvana
• Is Part Of: Applied organometallic chemistry. Volume 35:Number 1(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-10-13
• Subjects: antiproliferative activity -- apoptosis -- bis‐ferrocene conjugated nucleobases -- mitochondrial dysfunction -- ROS accumulation; Organometallic chemistry -- Periodicals; Organometallic compounds -- Periodicals; 547.05
• DOI: 10.1002/aoc.6052
• Languages: English
• ISSNs: 0268-2605

Abstract

Abstract : Mono‐ (3a –3e and 4a –4e ) and bis‐ferrocene (5a –5e and 6a –6e ) conjugated 5‐substituted uracil derivatives that are bridged by 1, 2, 3‐triazole linker were synthesized. The impact of ferrocene unit and spacer between ferrocene and triazole on radical scavenging potency was observed. Bis‐ferrocenyl uracil derivatives exhibited better antiproliferative activities than their mono‐ferrocenyl analogs. Bis‐ferrocenyl methyl‐ (5b ) and halogen‐substituted (5e, 6c, and 6d ) uracil derivatives showed pronounced and selective cytostatic activities on colon adenocarcinoma (CaCo‐2) and Burkitt lymphoma (Raji) cells, with higher potency and selectivity than the reference drug 5‐fluorouracil. Generation of reactive oxygen species (ROS) in CaCo‐2 and Raji cells when treated with compounds 5b, 5e, and 6d was observed. Bis‐ferrocenyl 5‐chlorouracil 6c induced significant disruption in mitochondrial membrane potential that is accompanied by activation of apoptosis in CaCo‐2, Raji, and acute lymphoblastic leukemia (CCRF‐CEM) cells, while 6d caused mitochondrial dysfunction and apoptosis induction in CaCo‐2 and Raji cells. Potent antiproliferative activity of 6c and 6d could be associated with mitochondrial membrane potential disruption accompanied by apoptosis induction. Our findings highlighted 6c and 6d with potent and selective antiproliferative activity on CaCo‐2, Raji, and CCRF‐CEM cells that may be associated with targeting cancer cell mitochondria, as a molecular target. Abstract : Mono‐ and bis‐ferrocene conjugated pyrimidine nucleobases bridged via 1, 2, 3‐triazole linker were synthesized, and their antiproliferative activity, ROS intracellular accumulation, mitochondrial membrane potential dysfunction, and apoptosis induction in tumor cells were explored.