Synthesis and biological evaluation of enantiopure substituted titanocene complexes

Cini, Melchior (2015) Synthesis and biological evaluation of enantiopure substituted titanocene complexes. PhD thesis, University of Nottingham.

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Tolerated by normal tissues, implementation of anti-cancer therapies based on titanium compounds is limited by low efficacy/selectivity, lack of understanding of their mode(s) of action and access to the most active chiral variants. This thesis reports the synthesis, characterization and biological evaluation of a novel class of chiral substituted titanocenes from novel chiral cyclopentadienyl ligands, themselves accessible from substituted pentafulvenes.

After an introductory chapter, the second chapter describes the synthesis and biological evaluation of substituted (rac/meso)-mixtures of TiCl2{η- C5H4CHEt(phenyl)}2 (abbreviated CpR2TiCl2). Addition of a substituted pentafulvene to alkyl/branched-alkyl/phenyl Grignard solutions with catalytic copper catalyst resulted in the formation of novel racemic/tautomeric cyclopentadienyl ligands in yields of up to 92%. The deprotonation of the racemic substituted cyclopentadienyl ligands with n-butyllithium and subsequent transmetallation with titanium(IV) tetrachloride resulted in the formation of novel substituted titanocene complexes in yields up to 81%. The antiproliferative activities of the (rac/meso)- mixtures of titanocenes in comparison to the simple benzyl-substituted titanocene analogue, titanocene dichloride and cisplatin were then evaluated in vitro against HCT-116, MiaPaCa-2 and MDA-MB-468 carcinoma cell lines, which represented intractable cancers from three different organ sites. All chiral substituted titanocenes were micromolar active against all the studied cancer cell lines. Finally, cyclic voltammetry studies using chiral substituted titanocenes were carried which confirmed a close to optimal fit of the chiral substituted ethyl titanocene.

The third chapter reports the synthesis and biological evaluation of single enantiomers of TiCl2{η-C5H4CHEt(2-MeOPh)}2 (abbreviated CpR2TiCl2), attained through unprecedented asymmetric copper-catalysed addition of ZnEt2 to the C=C bond of substituted pentafulvenes C5H4(=CHAr) (Ar = 2-MeOPh and related species). Such enantioselective reaction resulted in enantiomerically enriched (up to 93:7 e.r.) cyclopentadienyl ligands. Copper catalyst promotion with both chiral phosphoramidite ligands and a phosphate additive was vital in realizing both acceptable enantioselectivies and reaction rates. Chloride hydrolysis of the enantiopure titanocene to [CpR2Ti(OH]+ can be detected by NMR, GCMS and LCMS in vitro under near therapeutic conditions. The anti-cancer potency of (S,S)- CpR2TiCl2 was twice that of other stereoisomers, selective for cancer cells, and the kinetics of formation of the soluble hydroxy species correlate with the latter being the biologically active species. Extensive cytoplasmic vacuolization, endoplasmic reticulum (ER) swelling and activation of MAPKinase signal transduction were consistent with ligand-induced paraptosis (type III cell death), which is morphologically distinct from, and independent of, caspase-mediated apoptosis in MDA-MB-468 and HCT-116 cells.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Woodward, S.
Bradshaw, T.D.
Lygo, B.
Keywords: asymmetric catalysis; carbometalation; diethylzinc; paraptosis; titanocene; chirality
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 30485
Depositing User: Cini, Melchior
Date Deposited: 13 Jan 2016 13:15
Last Modified: 13 Dec 2017 06:37

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