Abstract
From the carbolithiation of 6--dimethylamino fulvene (3) and 2,4[bis(-dimethylamino)methyl]--methylpyrrolyl lithium (2a), -(-dimethylaminomethyl)benzimidazolyl lithium (2b), or -(-dimethylamino)methylphenyl lithium (2c), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4' resulting in -dimethylamino-functionalised titanocenes 5a–c. When these titanocenes were tested against a pig kidney epithelial cell line (LLC-PK), the values obtained were of 23, and 52 M for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene in this paper, 5c with an value of 13 M, was found to be approximately two times less cytotoxic than its analogue Titanocene C ( M) and almost four times less cytotoxic than cisplatin, which showed an value of 3.3 M when tested on the LLC-PK cell line.
Highlights
Titanium-based reagents have significant potential against solid tumors
These in vitro and ex vivo experiments showed that prostate, cervix, and renal cell cancers are prime targets for these novel classes of titanocenes, whereas the IC50 values for the breast cancer cell lines were very promising as well
We present a new series of chiral titanocenes, their synthesis, and preliminary cytotoxicity studies
Summary
Titanium-based reagents have significant potential against solid tumors. Budotitane ([cis-diethoxybis(1-phenylbutane1,3-dionato)titanium(IV)]) looked very promising during its preclinical evaluation, but did not go beyond Phase I clinical trials, a Cremophor EL-based formulation was found for this rapidly hydrolysing molecule [1]. The antiproliferative activity of Titanocene Y has been studied in 36 human tumor cell lines [21] and in explanted human tumors [22] These in vitro and ex vivo experiments showed that prostate, cervix, and renal cell cancers are prime targets for these novel classes of titanocenes, whereas the IC50 values for the breast cancer cell lines were very promising as well. Our most cytotoxic titanocene, Titanocene C (bis(N, N-dimethylamino-2(N-methylpyrrolyl)methylcyclo pentadienyl) titanium (IV) dichloride, was obtained through carbolithiation of fulvenes, which has been published recently [26] It has an IC50 value of 5.5 μM when tested on the LLC-PK cell line. This meant significant progress, since Cp2TiCl2 exhibits an IC50 value of only 2000 μM against LLC-PK, which explains partly the failed Phase II clinical trials against renal cell carcinoma. We present a new series of chiral titanocenes, their synthesis, and preliminary cytotoxicity studies
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