Synthesis and Characterization of New Organometallic Benzo[b]thiophene Derivatives with Potential Antitumor Properties

Abstract

The incorporation of organometallic moieties into the structure of known active drugs to improve their therapeutic properties has gained considerable interest in recent years. The benzo- [b]thiophene derivative raloxifene is a selective estrogen receptor modulator (SERM) that has been found to decrease breast cancer risk in postmenopausal women compared to placebo. The current data suggest that, in the postmenopausal setting, raloxifene may have the benefits of the widely used tamoxifen with fewer side effects. As part of a program designed toward the synthesis and biological screening of organometallic benzo[b]thiophene derivatives inspired by the structure of raloxifene, we have prepared a series of 2-benzoyl-3-ferrocenylbenzo[b]thiophenes where the benzoyl sub- stituent contains terminal tertiary alkylamino groups, expected to ensure affinity to the estrogen receptor. The synthetic strategy and full characterization (NMR, MS, X-ray diffraction, cyclic voltammetry) of the new ferrocenylbenzo[b]thiophenes is reported herein. Moreover, the new 2- benzoyl-3-ferrocenylbenzo[b]thiophene derivatives were tested for their cytotoxic properties against several human tumor cell lines. All the test compounds showed considerable cytotoxic activity; among these, [3-ferrocenyl-6-methoxybenzo[b]thiophen-2-yl][4-(piperazin-1-yl)methyl- phenyl]methanone (compound 13) is of note, showing IC50 values in the low-micromolar range and more than 1 order of magnitude lower than those of the reference compound, cisplatin. In addition, chemosensitivity tests on resistant phenotypes indicated that compound 13 elicited no cross-resistance with cisplatin, besides not being a potential multidrug-resistant (MDR) substrate. Moreover, caspase-3 activation analyses revealed that 13 induced a caspase-3-dependent apoptotic cell-death mechanism. Taken together, these data suggest that the new 2-benzoyl-3- ferrocenylbenzo[b]thiophenes, in particular compound 13, have potentially useful antitumor properties

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

“…Another class demonstrates the enthusiasm researchers have for grafting metallocenes and metal carbonyls to a variety of biomolecules to modify their biological effects. [12] These therapeutic bioconjugates include steroidal [13][14][15] and nonsteroidal [16][17][18][19][20][21][22][23] endocrine modulators, natural products, [24][25][26][27] and others. [28][29][30][31][32][33][34] In these cases, the often covalently grafted organometallic unit is usually inert to ligand substitution, but potentiates the activity of the biomolecule via modification of the pharmacokinetic profile or acts as a structural mimic.…”

A tandem mass spectrometric investigation of N‐(3‐ferrocenyl‐2‐naphthoyl) dipeptide ethyl esters and N‐(6‐ferrocenyl‐2‐naphthoyl) dipeptide ethyl esters

“…The N-(3-ferrocenyl-2-naphthoyl) dipeptide ethyl esters 1-4 and the N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters 5-8 shown in Fig. 1 were synthesized as previously reported and spectroscopically characterized by a combination of 1 H NMR, 13 C NMR, DEPT-135 and 1 H-13 C COSY (HMQC) spectroscopy and tandem mass spectrometry. [22] The dipeptide ethyl esters used were GlyGly(OEt) (1,5), AlaGly(OEt) (2,6), GlyPhe(OEt) (3,7) and GlyLeu(OEt) (4,8).…”

“…[4] In addition, ferrocene has been incorporated into several different classes of drugs such as antibiotics, anti-malarials and anti-cancer agents. [5][6][7][8][9][10][11][12][13] We have reported the synthesis and structural characterization of N-ferrocenoyl and N-ferrocenyl amino acid and peptide derivatives. [14][15][16][17][18] Preliminary in vitro bioassay results showed that the N-ferrocenyl amino acid and peptide derivatives are cytotoxic against the highly invasive H1299 lung cancer cells.…”

Synthesis and cytotoxicity of fused thiophene and pyrazole derivatives derived from 2-N-acetyl-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene

“…Furthermore, the tetrahydrobenzo[b]thiophene nucleus was adopted as a scaffold for many antimicrobial (Refat and Fadda, 2013), antiviral (Dewal et al, 2012), antiarrhythmic, (Amr et al, 2010), and antitumor (Abbas et al, 2013) activities. A structure activity relationship was established for the heterocyclic compounds derived from benzo[b]thiophene series with antitumor properties were prepared (Ferreirra et al, 2009), as well as a series of N-(2-(5-fluoro-2-(4-fluorophenylthio)benzo [b]thiophen-3-yl)ethyl) acylamides, which were evaluated for their binding affinity and intrinsic activity at melatonin receptors (Mésangeau et al, 2011). Also, benzothiophenes offer interest to pharma industry as scaffolds for synthesis of raloxifene and relevant structural analogs of selective estrogen receptor modulators (SERM) (Dadiboyena, 2012).…”