Determination of New Antitumor Organotitanium Complexes with a Pendant Biologically Active Diazo Group, Participating in Bioorthogonal Click Reactions

This chapter highlights new antitumor organotitanium complexes with a pendant biologically active diazo group, participating in bioorthogonal click reactions. Organotitanium complexes are expected to play a pivotal role in the worldwide effort to conquer cancer, due to the human body's high tolerance of the metal and titanium's ability to coordinate with biologically active and proven anticancer ligands. The overall mechanism of the cytotoxic action of organotitanium complexes extensively studied so far, like titanocene dichloride Cp2TiCl2, budotitane, titanocene Y, is incomplete in most cases and not well understood, unlike other metallodrugs, compare with cis-platin. Special emphasis is given to the stability of some newly proposed organotitanium complexes in the physiological aqueous environment, where they are expected to survive before reaching their cell-targeted application. A strategy to monitor the mode of cytotoxic action of candidate antitumor complexes is by tagging them with bioactive side chains like a diazo group, for in-cell site- specific labeling. In this paper we propose for the first time several methods for the preparation of potential antitumor organotitanium complexes with a pendant diazo group, aiming at better understanding their mode of cytotoxic action. In certain instances, Strain-Promoted Azide Cycloaddition (SPAAC) reactions may be employed for bio-imaging through fluorescence or other monitoring purposes. The possibility of engaging any of the three types of organotitanium complexes mentioned above, along with an expanded choice of small molecules, for insertion reactions into the active Ti-C o-bond, aiming at controlling the stability and aqueous solubility of the antitumor candidates, gives rise to a great number of possible effective cytotoxic complexes. A number of the complexes may participate in established “click” reactions of their pendant diazo group with other unsaturated synthons, nitriles, alkynes, alkenes, etc. Several of the established interactions of diazo groups in chemical biology, applied to a number of our complexes carrying the diazo group, may open up new avenues for our understanding of the mechanism of their cytotoxic action and efficacy.