Selective platination of biologically relevant polyamines. Linear coordinating spermidine and spermine as amplifying linkers in dinuclear platinum complexes

被引:96
作者
Rauter, H
DiDomenico, R
Menta, E
Oliva, A
Qu, Y
Farrell, N
机构
[1] VIRGINIA COMMONWEALTH UNIV, DEPT CHEM, RICHMOND, VA 23284 USA
[2] BOEHRINGER MANNHEIM ITALIA, RES CTR, DEPT CHEM, I-20052 MONZA, ITALY
关键词
D O I
10.1021/ic9701827
中图分类号
O61 [无机化学];
学科分类号
070301 ; 081704 ;
摘要
A new approach to the synthesis of novel bifunctional dinuclear platinum complexes with linear coordinating spermidine and spermine is reported. The synthetic pathway involves first the three-step selective protection of the polyamines, giving bis(trifluoroacetyl)polyamines (1, 4), (tert-butoxycarbonyl)bis(trifluoroacetyl) (2, 5), and (tert-butoxycarbonyl)polyamines (3, 6), respectively. The platination at desired sites with activated species of cis-or trans-[PtCl2(NH3)(2)] (CDDP or TDDP,respectively) produces the BOG-protected dinuclear species [{cis-or trans-PtCl(NH3)2)(2)}(2)(mu-L)]X (7, L = BOC-spermidine, X = (NO3)(0.75)Cl-1.25; 9, L = (BOC)(2)-spermine, X = Cl-2; cis spermine species not isolated). Through final deprotection, three different complexes were obtained and further investigated: [{trans-PtCl(NH3)(2)}(2){mu-spermidine-N-1,N-8}]Cl-3 (8), [{trans-PtCl(NH3)(2)}(2)- {mu-spermine-N-1,N-12}]Cl-4 (10), and [{cis-PtCl(NH3)(2)}(2){mu-spermine-N-1,N-12}]Cl-4 (11). One-and two-dimensional NMR solution studies provided evidence that 11, at physiological pH, forms an inert bis((tetraamine)platinum) species in which each Pt is chelated by a central and a terminal amino group. In contrast, complexes 8 and 10 retain their reactivity, showing only reversible formation of hydroxo bridges. The comparison of in vitro cytotoxicity data for 8, 10, and 11 with data for previously described bifunctional dinuclear complexes shows the enhanced activity particularly of complex 8 in the CDDP-resistant L1210 cell line. The binding of 8 and 10 to poly(dG-dC).poly(dG-dC) is further increased and also reflected by B --> Z conformational changes at lower doses.
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页码:3919 / 3927
页数:9
相关论文
共 40 条
[21]   MONO-PROTECTED DIAMINES - N-TERT-BUTOXYCARBONYL-ALPHA,OMEGA-ALKANEDIAMINES FROM ALPHA,OMEGA-ALKANEDIAMINES [J].
KRAPCHO, AP ;
KUELL, CS .
SYNTHETIC COMMUNICATIONS, 1990, 20 (16) :2559-2564
[22]   NATURE OF CIS AMINE PD(II) AND ANTITUMOR CIS AMINE PT(II) COMPLEXES IN AQUEOUS-SOLUTIONS [J].
LIM, MC ;
MARTIN, RB .
JOURNAL OF INORGANIC & NUCLEAR CHEMISTRY, 1976, 38 (10) :1911-1914
[23]  
MARTIN RB, 1983, ACS SYM SER, V209, P231
[24]   PALLADIUM(II) COMPOUNDS OF PUTRESCINE AND SPERMINE - SYNTHESIS, CHARACTERIZATION, AND DNA-BINDING AND ANTITUMOR PROPERTIES [J].
NAVARRORANNINGER, C ;
PEREZ, JM ;
ZAMORA, F ;
GONZALEZ, VM ;
MASAGUER, JR ;
ALONSO, C .
JOURNAL OF INORGANIC BIOCHEMISTRY, 1993, 52 (01) :37-49
[25]   PALLADIUM(II) SALT AND COMPLEXES OF SPERMIDINE WITH A 6-MEMBER CHELATE RING - SYNTHESIS, CHARACTERIZATION, AND INITIAL DNA-BINDING AND ANTITUMOR STUDIES [J].
NAVARRORANNINGER, C ;
ZAMORA, F ;
PEREZ, JM ;
LOPEZSOLERA, I ;
MARTINEZCARRERA, S ;
MASAGUER, JR ;
ALONSO, C .
JOURNAL OF INORGANIC BIOCHEMISTRY, 1992, 46 (04) :267-279
[26]   PLATINUM(II) AND PLATINUM(IV) SPERMIDINE COMPLEXES - SYNTHESIS, CHARACTERIZATION, AND BIOLOGICAL STUDIES [J].
NAVARRORANNINGER, C ;
OCHOA, PA ;
PEREZ, JM ;
GONZALEZ, VM ;
MASAGUER, JR ;
ALONSO, C .
JOURNAL OF INORGANIC BIOCHEMISTRY, 1994, 53 (03) :177-190
[27]   A ONE-STEP PROCEDURE FOR THE SELECTIVE TRIFLUOROACETYLATION OF PRIMARY AMINO-GROUPS OF POLYAMINES [J].
OSULLIVAN, MC ;
DALRYMPLE, DM .
TETRAHEDRON LETTERS, 1995, 36 (20) :3451-3452
[28]   RECENT ADVANCES IN THE BIOCHEMISTRY OF POLYAMINES IN EUKARYOTES [J].
PEGG, AE .
BIOCHEMICAL JOURNAL, 1986, 234 (02) :249-262
[29]  
PEGG AE, 1988, CANCER RES, V48, P759
[30]   Dinuclear platinum complexes form a novel intrastrand adduct with d(GpG), an anti-syn conformation of the macrochelate as observed by NMR and molecular modeling [J].
Qu, Y ;
Bloemink, MJ ;
Reedijk, J ;
Hambley, TW ;
Farrell, N .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1996, 118 (39) :9307-9313