Synthesis, Cytotoxicity, and COMPARE Analysis of Ferrocene and [3]Ferrocenophane Tetrasubstituted Olefin Derivatives against Human Cancer Cells

Abstract

Herein we report the antiproliferative effects of a series of 28 compounds against the MDA-MB-231 breast cancer cell line, including the synthesis of seven new [3]ferrocenophanyl and four new ferrocenyl compounds. For each p-R-phenyl substitution pattern investigated, the [3]ferrocenophanyl derivatives were more cytotoxic than the corresponding ferrocenyl derivative, with the highest activity found for compounds with protic substituents. Theoretical calculations of the HOMO-LUMO gap for the molecules in the Fe³(+) oxidation state suggest a higher reactivity for the [3]ferrocenophanyl derivatives. A lead compound from each series, a [3]ferrocenophanyl and a ferrocenyl compound, possessing two phenol groups, were screened against the NCI/DTP 60-cell-line panel. The mean activity over all cell lines was better than cisplatin for both compounds, and both compounds showed subpanel selectivity for leukemia, CNS cancer, and renal cancer. Low systemic toxicity and lack of interaction with DNA (when in the reduced form), suggest that the compounds may act as prodrugs.

Side‐Chain Effects on the 1‐(Bis‐aryl‐methylidene)‐[3]ferrocenophane Skeleton: Antiproliferative Activity against TNBC Cancer Cells and Comparison with the Acyclic Ferrocifen Series

“…Treatment of 20 with dimethylamine provides an alternative route to 7, but in this case the overall yield was low (13 % Complexes 12, 13, 15, and 16 were prepared in two-step reactions starting from 17, [19] 22, [20] 23, [17] and 24 [21] (Scheme 4). The amino function was first transformed into a chloro-amido chain by reaction with 3-chloropropionyl chloride in the presence of pyridine as base; in these cases, the acyl chloride reacted exclusively with the amino function.…”

“…At present, therefore, molecule 12 is one of the three most efficacious of all the ferrocenyl derivatives that we have prepared. [17] For comparison, we have also included the IC 50 values for molecules 29 and 30, which were synthesized previously; [23] these compounds are less effective than compounds 12 and 13. The lengthening of the amido chain may be the cause of their diminished activity.…”

“…The activity profiles of these compounds also show that 3 and 4 probably do not share the same mechanism of action either with each other or with the 171 reference molecules in the database, and in particular that they do not act, like cisplatin, by alkylation of DNA. [17] The diphenol 4 possesses, like 3, a moderate level of affinity for the estradiol receptor. As a result, both show a proliferative effect at low concentrations (10 -8 M) on hormone-dependent MCF-7 cells, which partially offsets the cytotoxic effect caused by the oxidation of the ferrocene.…”

Aryl Butenes Active against K562 Cells and Lacking Tyrosinase Inhibitory Activity as New Leads in the Treatment of Leukemia

“…A particular analogue of tamoxifen possessing a para-aniline group (compound 20, Figure 1) was shown selective for leukemia, CNS (central nervous system) cancer, and renal cancer [2]. Tested on a full panel of 60 human tumor cell lines (NCI/DPT), this compound was particularly active against ACHN and SF-539, but also against UACC-62 melanoma, HL-60 (TB), and SR leukemia cell lines with GI50 (growth inhibitory activity) values below 0.2 µM [2].…”

“…A particular analogue of tamoxifen possessing a para-aniline group (compound 20, Figure 1) was shown selective for leukemia, CNS (central nervous system) cancer, and renal cancer [2]. Tested on a full panel of 60 human tumor cell lines (NCI/DPT), this compound was particularly active against ACHN and SF-539, but also against UACC-62 melanoma, HL-60 (TB), and SR leukemia cell lines with GI50 (growth inhibitory activity) values below 0.2 µM [2]. In another study, the antiproliferative effects of a series of ferrocene-tamoxifen derivatives (compounds 2, 20, 15, 16, 3, 5, 13, and 14) were evaluated against HL-60 (human promyelocytic leukemia) cells, with IC50 range of 0.66-8.4 µM [3].…”