Cesar M. Manna

Cytotoxic salan-titanium(IV) complexes: high activity toward a range of sensitive and drug-resistant cell lines, and mechanistic insights.

The cytotoxicities of highly efficient salan–TiIV complexes toward a range of cell lines, including drug‐resistant cells, are reported along with preliminary mechanistic insights. Five salan–TiIV complexes were investigated toward eight different human and murine cancer‐derived cell lines, including colon, ovarian, lung, cervical, pancreatic, leukemic, skin, and breast. The salan complexes are more active toward the cells analyzed than cisplatin and the known titanium compound (bzac)2Ti(OiPr)2, and no cell line resistant to the salan complexes was identified. Moreover, the salan–TiIV complexes are highly active toward both cisplatin‐sensitive (A2780) and cisplatin‐resistant (A2780CisR) human ovarian cancer cell lines. Similarly, the salan complexes are cytotoxic toward multi‐drug‐resistant (ABCB1‐expressing) mouse lymphoma cell lines HU‐1 and HU‐2. Importantly, minimal or no activity was observed toward primary murine cells (bone marrow, heart, liver, kidney, spleen, and lung), supporting selectivity for cancer cells. Additionally, the salan complexes maintain high cytotoxicity for up to 24 h following exposure to cell culture medium, whereas reference complexes (bzac)2Ti(OiPr)2 and Cp2TiCl2 rapidly lose much of their activity upon exposure to medium, within ∼1 h. The upregulation of p53 followed by cell‐cycle arrest in G1 phase is likely one mechanism of action of the salan complexes. Taken together, the results indicate that these compounds are selectively toxic to cancer cells and are able to circumvent two independent mechanisms of drug resistance, thus expanding the scope of their potential medicinal utility.

New insights on the active species and mechanism of cytotoxicity of salan-Ti(IV) complexes: a stereochemical study.

Following the discovery of cisplatin, much effort has been devoted to the exploration of transition metal complexes as cytotoxic agents. We have recently introduced the highly efficient C(2)-symmetrical salan-Ti(IV) family of complexes, demonstrating high cytotoxicity toward colon and ovarian cells and enhanced hydrolytic stability in mixed organic/water solutions. The effect of stereochemistry is hereby reported, by comparing the cytotoxic activity and hydrolysis of pure enantiomers and their racemic mixture for four complexes of this family with different aromatic substitutions: para-Me, para-Cl, ortho-Cl, and ortho-OMe. These complexes include the trans-diaminocyclohexyl bridge, which enables ligand-to-metal chiral induction to give solely the Δ isomer when starting from the R,R ligand and vice versa. Different activity is obtained for the different stereochemical forms (Δ, Λ, and rac) in two of the four complexes, where for the other two either all forms are inactive or all are highly active. Additionally, where not all are of similar activity, the racemic mixture is the least active of the three. We therefore conclude that the salan ligand is essential for the fruitful biological interaction, which probably involves a chiral cellular target. The activity of the racemate differing from that expected from a simple mixture of enantiomers operating separately may be explained by the involvement of a polynuclear active species, where different metal centers might be of different configurations. This is particularly supported by the different polynuclear products of hydrolysis obtained from an optically pure complex and from the racemic one, as analyzed crystallographically. The former is an all-R,R chiral C(1)-symmetrical homodimer, while the latter is an achiral R,R-S,SC(i)-symmetrical heterodimer obtained through chiral recognition.

Unexpected Influence of Stereochemistry on the Cytotoxicity of Highly Efficient TiIV Salan Complexes: New Mechanistic Insights

The effect of stereochemistry on the cytotoxicity of highly active and hydrolytically stable N-methylated Ti(IV) salan complexes is reported. Four bis(isopropoxo) complexes incorporating N-methylated salan ligands with different aromatic substitution patterns have been prepared in racemic and optically active forms for the first time by ligand-to-metal chiral induction from trans-diaminocyclohexyl-based chiral ligands. The configuration of the metal center that derives from that of the ligand has an enormous influence on cytotoxicity, with the racemic mixture mostly being more active than the single enantiomers that are of either similar or different activity. This implies that the active species is a salan-bound heterochiral polynuclear compound, interacting with a chiral target. Four additional complexes of achiral salan and chiral labile sec-butoxo ligands, analyzed as racemic and as homochiral, revealed no influence of stereochemistry, supporting early dissociation of the labile ligands to give the polynuclear products.

Stereoselective Catalysis Achieved through in Situ Desymmetrization of an Achiral Iron Catalyst Precursor

Stereoselective catalysis is described that proceeds with catalyst control but without the need to synthesize preformed chiral catalysts or ligands. Iron-based catalysts were discovered to effect the stereoselective polymerization of lactides starting from a single achiral precursor and the proper choice of an achiral silanol additive. Spectroscopic analysis of the polymer revealed that the stereoselectivity originates from an enantiomorphic site rather than a chain end stereocontrol mechanism. Iron intermediates that are stereogenic at iron are proposed to form in situ as a result of desymmetrization that occurs from a change in the metal coordination number. The proposed mechanism is supported by a combination of spectroscopic measurements, model complexes, kinetic measurements, and DFT calculations.

Abstract 1762: Highly potent anti-cancer ‘salan’ Titanium(IV) complexes: Structure - function relationship

Cisplatin is a widely used platinum-based metallo-chemotherapeutic drug that is considered an efficient treatment mainly for testicular and ovarian cancers. However, its narrow activity range and severe side effects trigger studies of other potent transition metal complexes. Two titanium(IV) anti-cancer agents that have been previously studied extensively as cisplatin alternatives are titanocene dichloride and budotitane. Despite their high activity, these complexes failed clinical trials mainly due to their poor water stability and formation of unidentified aggregates in water solutions. Our research group focuses on development of new, better-suited families of anti-tumor Ti(IV) complexes lacking Cp or diketonato ligands, and their investigation as anti-tumor agents. We recently reported the synthesis, characterization, and cytotoxicity of “salan” type Ti(IV) complexes [1]. The well defined hydrolytic behaviour, high stability, and high cytotoxicity of these compounds are strongly correlated to their particular structure. This enables fine tuning of complex properties by structural modifications. Herein we elaborate on the investigation of these salan titanium(IV) compounds. The correlation between the complex properties: structure, hydrolytic stability and cytotoxicity will be discussed, revealing insights on the biological mechanism of their cytotoxicity, suggesting an apoptotic cell death pathway.Additionally, further biological evaluation is presented, evincing that these compounds are markedly more active than cisplatin towards human and murine cancer-derived cell lines, including colon, ovarian, lung, cervix, pancreas, leukaemia, skin and breast, with activity also against cisplatin-resistant and multi-drug-resistant cells, and with minor effect on primary murine cells. In vivo experiments are now under way to determine both safety, as well as the anti-cancer activity of these complexes. [1] D. Peri, S. Meker, C. M. Manna, E. Y. Tshuva, Inorg. Chem., 2011, 50, 1030. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1762. doi:1538-7445.AM2012-1762