Serum-protein interactions with anticancer Ru(III) complexes KP1019 and KP418 characterized by EPR.
The compounds imidazolium [trans-[RuCl(4)(1H-imidazole)(2)] (KP418) and indazolium [trans-RuCl(4)(1H-indazole)(2)] (KP1019) both show significant anticancer activity, with the latter recently having completed phase I clinical trials. An important component of this success has been associated with targeted delivery of the complexes to cancer cells by serum proteins. In this study, electron paramagnetic resonance (EPR) measurements, combined with incubation under physiological conditions, and separation of protein-bound fractions, have been used to characterize the interactions of these complexes with human serum albumin (hsA), human serum transferrin (hsTf) apoprotein, and whole human serum. The strong EPR signals observed in these experiments demonstrate that both complexes are primarily retained in the 3+ oxidation state in the presence of serum components. Rapid, noncovalent binding of KP1019 was observed in the presence of both hsA and serum, indicating that the predominant interactions occur within the hydrophobic binding sites of hsA. This sequestering process correlates with the low levels of side effects observed in clinical trials of the complex. At longer incubation times, the noncovalently bound complexes are converted slowly to a protein-coordinated form. Noncovalent interactions are not observed in the presence apo-hsTf, where only slow binding of KP1019 via ligand exchange with the protein occurs. By contrast, hydrophobic interactions of KP418 with hsA only occur with the aquated products of the complex, a process that also dominates in serum. In the presence of apo-hsTf, KP418 interacts directly with the protein through exchange of ligands, as observed with KP1019.
Cetinbas
Naniye
N
Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
Webb
Michael I
MI
Dubland
Joshua A
JA
Walsby
Charles J
CJ
D000970:Antineoplastic Agents / Q000737:chemistry*; D001059:Apoproteins / Q000737:chemistry*; D001665:Binding Sites; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D007191:Indazoles / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D017975:Ruthenium Compounds / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001059:Apoproteins; D007191:Indazoles; D008024:Ligands; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; D012709:Serum Albumin; C521720:imidazolium tetrachlorobis(1H-imidazole)ruthenate(III); C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III))
Biochim Biophys Acta. 1997 Mar 14;1331(1):1-40
9325434
J Biol Chem. 1994 Jan 28;269(4):2581-8
8300587
Anal Biochem. 2005 Jun 15;341(2):326-33
15907879
Semin Oncol. 1992 Apr;19(2 Suppl 3):73-81
1373006
Arzneimittelforschung. 1992 Jun;42(6):821-4
1418038
J Inorg Biochem. 2000 Mar;78(4):341-6
10857915
Cancer Chemother Pharmacol. 2004 Jul;54(1):71-8
15034754
J Inorg Biochem. 2004 May;98(5):903-16
15134936
Br J Cancer. 2002 May 20;86(10):1652-7
12085218
Mol Pharmacol. 1975 Nov;11(6):824-32
1207674
J Inorg Biochem. 2008 May-Jun;102(5-6):1060-5
18222004
Eur J Cancer. 1997 Dec;33(14):2404-10
9616290
Met Based Drugs. 1996;3(1):15-23
18472789
J Inorg Biochem. 2004 Feb;98(2):402-12
14729322
Anticancer Drugs. 2009 Feb;20(2):97-103
19209025
J Biol Inorg Chem. 2008 Aug;13(6):909-18
18438690
Dalton Trans. 2004 Aug 7;(15):2347-51
15278129
Eur J Cancer. 2002 Feb;38(3):427-35
11818210
J Biol Inorg Chem. 2001 Apr;6(4):435-45
11372202
Met Based Drugs. 1996;3(5):243-60
18472901
Hepatology. 2005 Jun;41(6):1211-9
15915465
Biochem Pharmacol. 1987 Aug 15;36(16):2661-6
3111487
Invest New Drugs. 2003 Nov;21(4):401-11
14586207
J Chromatogr B Biomed Sci Appl. 2001 Aug 5;759(1):81-9
11499632
J Appl Toxicol. 1998 Mar-Apr;18(2):93-101
9570691
J Cancer Res Clin Oncol. 2005 Feb;131(2):101-10
15503135
Inorg Chem. 2005 Jan 10;44(1):122-32
15627368
Biochem Pharmacol. 1993 Jun 22;45(12):2411-6
8328979
Inorg Chem. 2005 Jul 11;44(14):4897-9
15998012
Chem Rev. 2006 Jun;106(6):2224-48
16771448
Inorg Chem. 2004 Nov 1;43(22):7083-93
15500346
Met Based Drugs. 1994;1(2-3):169-73
18476228
Biochim Biophys Acta. 1973 Oct 18;322(2):195-203
4358082
J Inorg Biochem. 2006 May;100(5-6):891-904
16603249
Dalton Trans. 2006 Apr 28;(16):1929-33
16609762
Curr Top Med Chem. 2004;4(15):1525-35
15579094
J Biol Inorg Chem. 2001 Mar;6(3):292-9
11315565
Mol Pharmacol. 1976 Nov;12(6):1052-61
1004490
J Inorg Biochem. 2004 Jun;98(6):1135-42
15149825
BMC Struct Biol. 2003 Jul 7;3:6
12846933
Chem Rev. 1999 Sep 8;99(9):2511-34
11749489
J Med Chem. 2005 Apr 21;48(8):2831-7
15828821
Biochemistry. 2005 Jun 7;44(22):8013-21
15924420
J Med Chem. 2007 May 3;50(9):2185-93
17402720
J Inorg Biochem. 1999 Mar;73(3):123-8
10331241
Electrophoresis. 2008 May;29(10):2224-32
18512673
Curr Pharm Des. 2003;9(25):2078-89
14529417
Dalton Trans. 2006 Apr 14;(14):1796-802
16568190
Curr Med Chem. 2006;13(9):1085-107
16611086
Met Based Drugs. 2000;7(4):225-32
18475949
Blood. 1979 Jun;53(6):1058-65
444649
Inorg Chem. 2008 Jul 21;47(14):6513-23
18553904
Inorg Chem. 1996 Aug 14;35(17):4896-4903
11666690
Adv Protein Chem. 1985;37:161-245
3904348
J Inorg Biochem. 2008 Feb;102(2):347-58
18022241
Cancer Lett. 2005 Aug 26;226(2):115-21
16039951