Synthesis, structure, and antitumor activity of a novel tetranuclear titanium complex

The coordination complex cyclo-tetrakis[bis( 1-phenyl-3-methyl-4-benzoylpyr azolon-5-ato)mu-oxotitanium(IV)] has been synthesized and characterized wit h IR and NMR spectroscopies and X-ray diffraction. The core of this species consists of an eight-membered Ti-mu-oxo ring with alternate short-long Ti- O bond lengths. Besides these two O ligands, each metal is bound octahedral ly to four O atoms from two chelating 1-phenyl-3-methyl-4-benzoylpyrazolon- 5-ato anions. Several sets of Ti-O bond lengths are present: the shortest a re the two Ti-O(oxo) (which are cis to each other), the longest are the two Ti-O(acyl) (cis to each other), and the two Ti-O(pyrazolonato) (trans to e ach other) are intermediate. The beta-diketonate ligand asymmetry, a featur e considered essential in other antitumor Ti compounds, induces the short-l ong Ti-O(oxo) sequence of bond lengths. The antitumor activity of this comp ound, encapsulated in a dipalmitoylphosphatidylcholine liposome, has been s tudied in vitro using TA-S(mouse mammary adenocarcinoma), HEP-2 (human epit helial larynx carcinoma), and VERO (African green monkey kidney) cell lines and in vivo in CF-1 and AJ female mice ip inoculated with TA-3. In vitro c ytotoxicity is greater for TA-3 than for HEP-8 and null for VERO cell lines . In vivo results show a marked increase in survival time (T/C = 293% for A J and 208% for CF-1), whereas tumor weight decrease was observed for CF-1-t reated mice. These results suggest the Ti complex-liposome system may be pr omising as an antitumor drug.