Synthesis, structure, and antitumor activity of a novel tetranuclear titanium complex.
The coordination complex cyclo-tetrakis[bis(1-phenyl-3-methyl-4-benzoylpyrazolon-5-ato++ +)mu-o xotitanium(IV)] has been synthesized and characterized with 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 octahedrally 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 are 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 each other) are intermediate. The beta-diketonate ligand asymmetry, a feature considered essential in other antitumor Ti compounds, induces the short-long Ti-O(oxo) sequence of bond lengths. The antitumor activity of this compound, encapsulated in a dipalmitoylphosphatidylcholine liposome, has been studied in vitro using TA-3 (mouse mammary adenocarcinoma), HEP-2 (human epithelial 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 cytotoxicity is greater for TA-3 than for HEP-2 and null for VERO cell lines. In vivo results show a marked increase in survival time (T/C = 293% for AJ and 208% for CF-1), whereas tumor weight decrease was observed for CF-1-treated mice. These results suggest the Ti complex-liposome system may be promising as an antitumor drug.
Caruso
F
F
Istituto di Strutturistica Chimica "G. Giacomello", Consiglio Nazionale delle Ricerche (CNR), Box 10, 00016 Monterotondo Stazione, Rome, Italy.
Rossi
M
M
Tanski
J
J
Sartori
R
R
Sariego
R
R
Moya
S
S
Diez
S
S
Navarrete
E
E
Cingolani
A
A
Marchetti
F
F
Pettinari
C
C
D015060:1,2-Dipalmitoylphosphatidylcholine; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D008081:Liposomes; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013045:Species Specificity; D013055:Spectrophotometry, Infrared; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D008081:Liposomes; D009942:Organometallic Compounds; C415157:cyclo-tetrakis(bis(1-phenyl-3-methyl-4-benzoylpyrazolon-5-ato)mu-oxotitanium(IV)); D015060:1,2-Dipalmitoylphosphatidylcholine