Synthesis, characterization, and antitumor activity of new platinum(IV) trans-carboxylate complexes: crystal structure of [Pt(cis-1,4-DACH)trans-(acetate)2Cl2].
A series of novel platinum(IV) cisplatin analogues of the type [Pt(cis-1,4-DACH)trans-(L)2Cl2] (where cis-1,4-DACH = cis-1,4-diaminocyclohexane and L = acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, nonanoate, or decanoate) was synthesized and characterized by elemental analysis, IR, 13C-NMR, and 195Pt-NMR spectroscopy. The structure of [Pt(cis-1,4-DACH)trans-(acetate)2Cl2] (1) was determined by X-ray crystallography. The crystals were monoclinic, space group P2(1)/n (no. 14) with a = 10.193(2), b = 10.687(2), c = 14.265(3) A, beta = 99.67(3) degrees, Z = 4. The total reflections collected were 2556. The structure refinement converged to R1 = 0.0539 and wR2 = 0.1531. In this complex, platinum has distorted octahedral geometry, and cis-1,4-DACH is in a unique twist-boat configuration. cis-1,4-DACH forms a seven-member chelating ring with platinum, leading to considerable strain in bidentate DACH binding. The strain is evidenced by a large 126.5(9) degrees C-N-Pt angle. The N-Pt-N angle is expanded to 97.4(5) degrees owing to geometric constraints of the cis-1,4-DACH geometry. Three lower homologs of the cis-1,4-DACH-Pt(IV) series were tested in the murine L1210/0 leukemia model for antitumor activity. The results indicate that activity decreases in ascending the homologous series, and that the activity of two of the complexes is substantially better than that of cisplatin with respect to increase in life span and cures.
Shamsuddin
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S
Department of Clinical Investigation, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.
Santillan
C C
CC
Stark
J L
JL
Whitmire
K H
KH
Siddik
Z H
ZH
Khokhar
A R
AR
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008956:Models, Chemical; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C115135:bis(acetato)(1,4-diaminocyclohexane)dichloroplatinum(IV)