Synthesis, substitution kinetics, electrochemistry and phase studies of long-chain alkylated ferrocene-containing rhodium(I) complexes with biomedical applications

Abstract

English: New alkylferrocene-containing β-diketones of the type (Cp-R)-Fe-(Cp-COCH2COCH3), where R = C9H19, C10H21, C12H25, C14H29 and C18H37 as well as (Cp)-Fe-(R-Cp-COCH2COCH3), (Cp-R)-Fe- (R-Cp-COCH2COCH3) and (Cp-R)-Fe-(Cp-COCH2CO-Cp)-Fe-(Cp-R) with R = C10H21 or C12H25 were prepared by Claisen condensation of acetyl-alkylferrocene derivatives and the appropriate ester under the influence of lithium diisopropylamide. Complexation of all the β-diketones with [RhCl2(cod)2] in DMF gave the [Rh(β-diketonato)(cod)] complexes. The pKa / values of the new β- diketone derivatives were determined spectroscopically in water containing 10 % acetonitrile (v/v). The keto-enol isomerization kinetics of all new β-diketones was studied in CDCl3 by 1H NMR spectroscopy. Electrochemical studies revealed that all the β-diketones exhibited an electrochemically and chemically reversible one-electron transfer process for the Fc/Fc+ couple. The redox active centre of all the β-diketones exhibited Eo/ values that are independent of the alkyl chain length of the ferrocene-containing β-diketones due to the lack of conjugation between the ferrocenyl group and the alkyl R groups. Cyclic voltammetry results of all the rhodium complexes showed that the RhI nucleus exhibited an electrochemically quasi reversible process. Substitution reactions of the β-diketonato ligand from [Rh(β-diketonato)(cod)] with 1,10- phenanthroline exhibited saturation kinetics. Second-order rate constants, k2, were determined from the linear plots of 1/kobs against 1/[1,10-phenanthroline]. The large negative activation entropy values suggested an association mechanism. All substitution reactions had no observable mechanistic solvent pathway. Phase studies showed that the ferrocenyl derivatives and free β-diketones exhibited solid state phase changes while the rhodium(I) complexes showed no pronounced melting or crystallization peaks due to very slow crystallization kinetics. Cytotoxic properties in terms of potential anticancer applications of selected β-diketones and their rhodium complexes are described. Cytotoxicity of these complexes was probed with respect to human colorectal (CoLo) and human cervix epitheloid (HeLa) cancer cell lines. All the drugs that were investigated in this study had lower IC50 values than the rhodium complexes without long chain alkyl substituents.

Afrikaans: Nuwe alkielferroseen-bevattende β-diketone van die tipe (Cp-R)-Fe-(Cp-COCH2COCH3), waar R = C9H19, C10H21, C12H25, C14H29 en C18H37 sowel as (Cp)-Fe-(R-Cp-COCH2COCH3), (Cp-R)-Fe-(RCp- COCH2COCH3) en (Cp-R)-Fe-(Cp-COCH2CO-Cp)-Fe-(Cp-R) met R = C10H21 of C12H25 is berei deur Claisen kondensasie van asetiel-alkielferroseenderivate en die toepaslike ester onder die invloed van litiumdiisopropielamied. [Rh(β-diketonato)(cod)] komplekse is verkry deur kompleksering van al die β-diketone met [RhCl2(cod)2] in DMF. Die pKa / waardes van die nuwe β- diketoonderivate is spektroskopies in water met 10 % asetonitriel (v/v) bepaal. Die keto-enol isomerisasiekinetika van alle nuwe β-diketone is met 1H KMR spektroskopie in CDCl3 bestudeer. Elektrochemiese studies het gewys dat al die β-diketone 'n elektrochemies- en chemies omkeerbare enkelelektronoordragsproses vir die Fc/Fc+ koppel vertoon. Die redoksaktiewe sentra van al die β- diketone het Eo/ waardes getoon wat onafhanklik is van die alkielkettinglengte van die ferroseenbevattende β-diketone weens die gebrek aan konjugasie tussen die ferrosenielgroep en die alkiel R groepe. Sikliese voltammetrie resultate van al die rodiumkomplekse het gewys dat die RhI sentrum 'n elektrochemies kwasi-omkeerbare proses vertoon. Substitusiereaksies van die β-diketonatoligand van [Rh(β-diketonato)(cod)] met 1,10-fenantrolien het versadigingskinetika getoon. Tweede-orde tempokonstantes, k2, is bepaal vanaf die lineêre grafieke van 1/kwg teen 1/[1,10-fenantrolien]. Die groot negatiewe aktiveringsentropiewaardes dui op 'n assosiatiewe meganisme. Tydens al die substitusiereaksies is geen meganistiese oplosmiddelroete waargeneem nie. Fasestudies het daarop gedui dat die ferrosenielderivate en vrye β-diketone vastetoestand faseveranderinge ondergaan, terwyl die rodium(I)komplekse weens uiters stadige kristallisasiekinetika geen noemenswaardige smeltings- of kristallisasiepieke vertoon het nie. Sitotoksiese eienskappe, in terme van potensiële antikanker toepassings, van sekere β-diketone en hul rodiumkomplekse word beskryf. Sitotoksisiteit van hierdie komplekse ten opsigte van menslike kolorektale- (CoLo) en menslike servikale epiteloïede (HeLa) kankerseltipes is ondersoek. Al die geneesmiddels wat tydens hierdie studie ondersoek is, het laer IC50 waardes as die rodiumkomplekse sonder langketting alkielsubstituente gehad.