Synthesis and Antiproliferative Effects of [3]Ferrocenophane Transposition Products and Pinacols Obtained from McMurry Cross-Coupling Reactions

Abstract

We here report the synthesis and antiproliferative activities of two new series of ferrocenophanes obtained from McMurry cross-coupling reactions of [3]ferrocenophan-1-one with benzophenone, 4-hydroxybenzophenone, 4,4′-dihydroxybenzophenone, and 4,4′-diacetylaminobenzophenone. In addition to the main formation of olefins at reflux, tetrahedral transposition products, resulting from a pinacolic rearrangement, were also isolated in about 10% yields. Lowering the temperature of the reaction to 0 °C allowed the isolation of pinacols, which could be transformed into transposition compounds in good yields. Three ferrocenophane compounds have been characterized by X-ray crystallography: 1-(p-hydroxyphenyl)-1-phenyl-2-oxo[4]ferrocenophane (7b), 1,1-diphenyl-2-oxo[4]ferrocenophane (7c), and 1-hydroxy-1-[1-hydroxy-1-[3]ferrocenophanyl][3]ferrocenophane (12) crystallize in monoclinic P21/n, triclinic P1̅, and monoclinic P21/c space groups, respectively. The antiproliferative effects on hormone-independent breast cancer cells (MDA-MB-231) of the transposition compounds are generally lower than those of their corresponding butene analogues (IC50 values in micromolar versus nanomolar range). In contrast and quite surprisingly, the pinacol complexes are significantly cytotoxic (IC50 in the nanomolar range), among the most cytotoxic ferrocene compounds prepared so far. This antiproliferative activity may be linked to their oxidative cleavage.

Organometallic Antitumor Compounds: Ferrocifens as Precursors to Quinone Methides

“…This radical oxidation parallels ap revious report on [3]-ferrocenophane derivatives. [11] Thec ytotoxicity of 3b-QM against MDA-MB-231 cells was consistent with its chemical derivatives 3b-A and 3b-B (IC 50 values of 2.03 and 4.14 mm,r espectively). Compounds 3b-QM, 3b-A, 3b-B, 3b-C,a nd 3b-D were the major products during the chemical oxidation and subsequent decomposition of 3b.T he cytotoxicity values obtained from the precursor 3b strongly suggest that, when incubated with live cancer cells, 3bshould generate aremarkable intrinsically electrophilic metabolite that is probably native 3b-QM.T he evolution of 3b proposed above occurred through chemical methods without the involvement of other nucleophiles.I t provides some clues that prodrug 3b could generate several possible carbenium ions in vivo that could be captured by nucleophiles,such as thiols or selenols,inside the cells.…”

“…Another pathwaythat could be relevant to the cytotoxicityi so xidative cleavage of pinacol-type analogues. [11] In summary,modification of the alkyl chain in the original acyclicderivatives yielded 3b,which bears aterminal hydroxyalkyl group and exhibits exceptional antiproliferative activity against liver hepatocellular carcinoma cells (HepG2) and ERÀ breast cancer cells (MDA-MB-231), with IC 50 values of 0.07 and 0.11 mm,r espectively.C hemical oxidation of 3b yielded an unprecedented tetrahydrofuran-substituted QM via internal cyclization of the alkyl chain, which was identified as ap ossible key primary metabolite.T he ferrocenyl group not only plays the role of intramolecular reversible redox "antenna" but also acts as as tabilized carbenium ion "modulator". Resulting from these structural changes, 3b-QM exhibits moderate stability and au nique chemical oxidation profile,w hich reveals crucial clues that may help us decipher its mechanism of action in vivo.Future work will focus on gaining insight into the mechanism of action of these novel species,e specially in the presence of healthy cells and .…”

“…Secondly,apinacol rearrangement can give compound 3b-B. [11] Finally,the carbenium ion can react with traces of water to give apinacol-type intermediate that gives 3b-C and 3b-D on further oxidation. This radical oxidation parallels ap revious report on [3]-ferrocenophane derivatives.…”

Organometallic Antitumor Compounds: Ferrocifens as Precursors to Quinone Methides

“…Finally, the carbenium ion can react with traces of water to give a pinacol‐type intermediate that gives 3 b‐C and 3 b‐D on further oxidation. This radical oxidation parallels a previous report on [3]‐ferrocenophane derivatives 11…”

“…The first is ring expansion by migration of the adjacent oxygen, which places the carbocation adjacent to the ferrocenyl group, and subsequent proton loss to yield 3 b‐A . Secondly, a pinacol rearrangement can give compound 3 b‐B 11. Finally, the carbenium ion can react with traces of water to give a pinacol‐type intermediate that gives 3 b‐C and 3 b‐D on further oxidation.…”