Colchicine metallocenyl bioconjugates showing high antiproliferative activities against cancer cell lines

Abstract

A series of ferrocenyl and ruthenocenyl conjugates with colchicine bearing a 1,2,3-triazole moiety were synthesized and their anticancer properties were evaluated. We found that the most potent metallocenyl derivatives Rc4 and Rc5 are 6-7 times more cytotoxic toward HepG2 cells, while Fc4 and Fc5 are two times more cytotoxic toward HCT116 cells as colchicine. We also found that compounds Fc4, Fc5, Rc1 and Rc3-Rc5 are able to induce apoptosis, while compound Fc2 arrests mitosis.

Has Ferrocene Really Delivered Its Role in Accentuating the Bioactivity of Organic Scaffolds?

“…Kowalczyk and co-workers synthesized ferrocene/ruthenocene analogues ( 84 – 85 ) of colchicine, an antimitotic compound responsible for apoptosis and cell apoptosis death (Figure ). The compounds were tested for their cytotoxic potencies against a panel of human cancer (Colo205, HCT116, HepG2, MCF-7, and A549) cell lines. It is a compelling case where the metallocene-type (ruthenocene/ferrocene) significantly impacted the cell line specificity.…”

Synthesis and Biological Activity of Ferrocenyl and Ruthenocenyl Analogues of Etoposide: Discovery of a Novel Dual Inhibitor of Topoisomerase II Activity and Tubulin Polymerization

“…The 1,2,3‐triazolyl conjugates T1 – 8 were synthesized in Cu‐catalyzed 1,3‐dipolar cycloaddition of azide 5 and ω‐metalocenylacetylenes 7 – 14 according to Scheme 2 by applying a reported procedure [29f] . The required ω‐metallocenylalkynes 8 – 14 were prepared in Friedel–Crafts acylation of ferrocene or ruthenocene with acyl trifluoroacetates generated in situ in the presence of trifluoromethanesulfonic acid according to a reported procedure [29b, 37] . Next, azide 5 reacts with acetylenes 7 – 14 at RT for 3 days in a mixture of tert ‐butanol and water in the presence of Cu I complex with TTTA as a catalyst (freshly prepared form copper(II) sulfate, sodium ascorbate and TTTA [38] ) to give 1,2,3‐triazoles T1 – 8 in 19–79 % yields, isolated by column chromatography on silica.…”

“…The cytotoxic activity of metallocenyl derivatives often correlates with their ability to induce reactive oxygen species (ROS) production within the cells [49] . Therefore, we studied the pro‐oxidative potential of the investigated compounds using dihydrorhodamine 123 (DHR123) oxidation assay as described previously [29b] (Figure 6). Neither etoposide nor amino conjugates significantly altered intracellular ROS level compared to control.…”

“…Anhydrous solvents were prepared according to reported procedures:, dichloromethane (DCM) and 1,2‐dichloroethane (DCE) were distilled from calcium hydride, tetrahydrofuran (THF) was distilled from sodium/benzophenone. The 4′‐ O ‐demethylepipodophyllotoxin 4 , [35] 4β‐azido‐4′‐ O ‐demethyl‐4‐deoxypodophyllotoxin 5 , [35] and 4β‐amino‐4′‐ O ‐demethyl‐4‐deoxypodophyllotoxin 6 , [36] ω‐alkynoylferrocenes 8 – 10 , [37] ω‐alkynoylruthenocenes 11 – 14 , [29b] 4‐ferrocenylbutyric acid 15 , [39b] 5‐ferrocenylpentanoic acid 16 , [39a] 6‐ferrocenylhexanoic acid 17 , [29f] 4‐ruthenocenylbutyric acid 25 , and 3‐ruthenocenoylpropanoic acid 28 [42] were synthesized according to reported procedures. 1 H and 13 C{ 1 H} NMR spectra were recorded with a Bruker ARX 600 MHz (spectrometer frequency 600.3 MHz for 1 H and 150.9 MHz for 13 C).…”

Complement System as a Target for Therapies to Control Liver Regeneration/Damage in Acute Liver Failure Induced by Viral Hepatitis

“…Negative proliferation percentage using CFSE-FITC was quantified by flow cytometry. Positive control of the absence of cell proliferation was carried out using colchicine at 10 μ M [ 26 ]. Negative control was performed adding RPMI1640 with 10% fetal bovine serum (FBS) heat-inactivated (57°C, 30 min) in HepG2 culture.…”