titanocene and fulvene

6-Substituted fulvenes are interesting and easily accessible starting materials for the synthesis of novel substituted titanocenes via reductive dimerisation, carbolithiation or hydridolithiation reactions, which are followed by a transmetallation reaction with titanium tetrachloride in the latter two cases. Depending on the substitution pattern, these titanocenes prove to be bioorganometallic anti-cancer drugs, which have significant potential against advanced or metastatic renal-cell cancer. Patients bearing these stages of kidney cancer have a poor prognosis so far and therefore real progress in the area of metal-based anti-cancer drugs may come from this simple and effective synthetic approach. This tutorial review provides an insight into the synthesis of fulvene-derived titanocenes and their activity in preclinical experiments.

Topics: Animals; Antineoplastic Agents; Cell Survival; Cyclopentanes; Drug Screening Assays, Antitumor; Inhibitory Concentration 50; Kidney Neoplasms; LLC-PK1 Cells; Molecular Structure; Organometallic Compounds; Swine

From the carbolithiation of 6-bis-N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl(4) resulting in bis-N,N-dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC(50)-values obtained were of 240, and 270 microM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper, 5a with an IC(50)-value of 36 microM was found to be approximately six times less cytotoxic than its mono-N,N-dimethylamino substituted analogue Titanocene C (IC(50) = 5.5 microM) and almost ten times less cytotoxic than cisplatin, which showed an IC(50)-value of 3.3 microM, when tested on the LLC-PK cell line.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cyclopentanes; Drug Evaluation, Preclinical; Heterocyclic Compounds; Humans; Inhibitory Concentration 50; Molecular Conformation; Molecular Structure; Neoplasms; Organometallic Compounds

From the carbolithiation of 6-morpholino fulvene (3) and different lithiated nitrogen containing heterocycles (2-N-methylimidazolyl, 2-N-(N,N-dimethylamino)methyl-imidazolyl, and 2-N-methylindolyl), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl(4) resulting in morpholino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC(50) values obtained were of 24, 36, and 41 microM respectively. The most cytotoxic titanocene in this paper (5a) with an IC(50) value of 24 microM is found to be almost ten times less cytotoxic than cis-platin, which showed an IC(50) value of 3.3 microM when tested on the epithelial pig kidney LLC-PK cell line, and approximately 2 times less cytotoxic than its dimethylamino-functionalised analogue. Encouragingly however, the IC(50) value obtained for titanocene 5a is approximately 100 times better than titanocene dichloride itself.

Topics: Animals; Antineoplastic Agents; Cyclopentanes; Inhibitory Concentration 50; LLC-PK1 Cells; Morpholines; Organometallic Compounds; Structure-Activity Relationship; Swine