Current status of platinum-based antitumor drugs.

The influence of structure on the activity and toxicity of Pt anti-cancer drugs

Over the past two decades, platinum-based drugs (cis-platin and, latterly, the less toxic analogue carboplatin) have conferred significant therapeutic benefit to a large number of cancer suffers. However, there remains scope for substantial improvement in the clinical utility of metal coordination complexes through the discovery of additional platinum-based complexes (or possibly alternative metals). Future drug discovery strategies should focus on tumor resistance and its circumvention. To date, only one series of compounds, those containing a 1,2-diaminocyclohexane carrier ligand (e.g., oxaliplatin, tetraplatin), has entered clinical trial based on their circumvention of acquired cisplatin resistance in some (mainly murine) preclinical tumor models. At present these agents are in early clinical trial and thus their true clinical utility in cisplatin/carboplatin refractory disease is not yet determinable (and may not be due to dose-limiting neurotoxicity). Over the past few years, our understanding of mechanisms of resistance to cisplatin and its interaction with DNA has vastly increased. This new information will undoubtedly guide the development of new strategies aimed at the circumvention of intrinsic and acquired tumor resistance to cisplatin. Approaches to circumvent resistance will probably involve not only the rational development of a new generation of platinum-based drugs (e.g., compounds designed to overcome reduced cisplatin accumulation or enhanced removal of cisplatin-induced DNA adducts) but also non-platinum drugs which are capable of modulating resistance (e.g., modulators of signal transduction pathways, ras and myc oncogene expression and glutathione biosynthesis). One may look forward with a great deal of optimism that these promising new approaches will result in clinical benefit by the end of the century. Nevertheless, cis-platin and carboplatin remain the standard anticancer drugs to which novel platinum-based complexes must be compared.

New platinum antitumor complexes

To obtain insight into the structure−activity relationships of new antitumor active platinum compounds the X-ray structure of the antitumor active Pt compound [Pt(bmic)Cl2] (bmic = bis-(N-methylimidazol-2-yl)carbinol) (1) and its interaction with short DNA fragments has been investigated using NMR spectroscopy. For comparison also the structurally related compound [Pt(bmi)Cl2] (bmi = N1,N1‘-dimethyl-2,2‘-biimidazole) (2), which is not antitumor active, has been studied. The structure of the compound [Pt(bmic)Cl2] (1) was characterized by single-crystal X-ray structure determination. Compound 1 crystallizes in the monoclinic space group P21/n, with a = 10.055(3) A, b = 11.802(3) A, c = 10.620(3) A, β = 103.78(2)°, V = 1224.0(6) A3 and Z = 4. Convergence was reached at wR2 = 0.1148 (all data) and R1 = 0.0476 (I > 2 (I)) for 2433 independent reflections and 156 adjustable parameters. The platinum atom is coordinated by two nitrogen and two chlorine atoms, resulting in a square planar PtN2Cl2 coordination sph...

Synthesis, Crystal Structure, Antitumor Activity, and DNA-Binding Properties of the New Active Platinum Compound (Bis(N-methylimidazol-2-yl)carbinol)dichloroplatinum(II), Lacking a NH Moiety, and of the Inactive Analog Dichloro(N1,N1‘-dimethyl-2,2‘-biimidazole)platinum(II)

Syntheses, antitumor activity, and molecular mechanics studies of cis-PtCl2(pzH)2 (pzH=pyrazole) and related complexes. Crystal structure of a novel Magnus-type double-salt [Pt(pzH)4][PtCl4][cis-PtCl2(pzH)2]2 involving two perpendicularly aligned 1D chains

The platinum(II) organoamides [Pt(NRCH2)2L2] (L = pyridine (py), R = p-HC6F4, C6F5,p-IC6F4,p-CIC6F4,p-C6F5C6F4; L = 4-methylpyridine, R = p-HC6F4) and [Pt(NRCH2CH2NR')(py)2] (R = p-HC6F4, R' = C6F5, p-BrC6F4, or p-MeC6F4) inhibit the growth of murine L1210 leukemia cells in culture with ID50 values for continuous exposure in the range 0.6-2.7 microM. Representative complexes are also active against L1210 cells in 2-h pulse exposures, as well as against the cisplatin-resistant variant L1210/DDP and human colonic carcinoma cell lines HT 29 and BE. Three complexes [Pt(NRCH2)2L2] (R = p-HC6F4, C6F5, or p-IC6F4) have good activity (T/C greater than or equal to 180%) against P388 leukemia in mice, and all other compounds tested are active except when R = p-C6F5C6F4, L = py. Although the molecular basis of the biological activity of these complexes is not known, the observation of good activity for amineplatinum(II) compounds with no hydrogen substituents on the nitrogen donor atoms introduces a new factor in the anticancer behavior of platinum(II) complexes.

cis-bis(pyridine)platinum(II) organoamides with unexpected growth inhibition properties and antitumor activity.

The complexes Pt[N(p-HC6F4)CH2CH2NMe2]X(L) (L = py , X = Cl or Br; L = 2- methylpyridine or 4-methylpyridine, X = Cl ) have been prepared by decarboxylation reactions between PtX2( dmen ) ( dmen = N,N- dimethylethane - 1,2-diamine) and thallous pentafluorobenzoate in the appropriate hot pyridine. Other organoamidoplatinum (II) complexes, Pt[N(R)CH2CH2NMe2] X( py ) (R = p-HC6F4, X = I; R = C6F5, X = Cl , Br or I; R = p-MeC6F4, X = Cl ; R = p-ClC6F4 or p-BrC6F4, X = I) and Pt[N(R)CH2CH2NMe2] Cl ( dmpy ) (R = p-HC6F4; dmpy = 2,5-dimethylpyridine), have been prepared by analogous decarboxylations between PtX2( dmen ), thallous 2,3,5,6- tetrafluorobenzoate, and the corresponding polyfluorobenzene, RF. The mixed halogen complex Pt[N(C6F5)CH2CH2NMe2]I0.63Cl0.37( py ) has been prepared similarly and the crystal structure determined. This shows square-planar stereochemistry with the halogen and pyridine trans to NC6F5 and NMe2 respectively. Comparison of spectroscopic data suggests the other complexes have similar stereochemistry.

Organoamidometallics. II. Decarboxylation Syntheses and Structures of [N,N-Dimethyl-N'-(Polyfluorophenyl)Ethane-1,2-Diaminato(1-)]Platinum(II) Complexes

Reaction of PtCl2(en) (en = ethane-1,2-diamine) with thallous pentafluorobenzoate in hot pyridine ( py ) or 4-methylpyridine ( mepy ) yields the [N,N′- bis (2,3,5,6-tetrafluorophenyl)ethane-1,2-diaminato(2-)]platinum(II) complexes, Pt[N(p-HC6F4)CH2]2( py )2 (1a) and Pt[N(p- HC6F4)CH2]2( mepy )2 (1b). The route to (1a) is considered to involve formation of [Pt(en)( py )2](O2CC6F5)2 (2), decarboxylation of (2) into Pt(NHCH2)2( py )2 (1c) and pentafluorobenzene, and nucleophilic attack of (1c) on C6F5H. Complex (1a) has also been prepared by decarboxylation of (2), reaction of PtI2(en) and TlO2CC6F5, and reaction of PtCl2(en), C6F5H, and TlO2CC6F4H-p in boiling pyridine. From reaction of PtCl2(en), TlO2CC6F4H-p, and the appropriate polyfluorobenzene (RF) in boiling pyridine or 4-methylpyridine, the organoamidoplatinum compounds Pt(NRCH2)2L2(R = C6F5, p-MeC6F4, p-ClC6F4, p-BrC6F4, p-IC6F4, 2,3,5-F3C6H2, or p-C6F5C6F4, L = py and R = C6F5, L = mepy ) have been prepared. Analogous reactions of PtCl2( pn )( pn = propane-1,3-diamine) give the complexes Pt[NR(CH2)3NR]( py )2 (R = C6F5 or p-HC6F4). Spectroscopic evidence for the structures is discussed. The polyfluorophenyl groups confer stability to water on ethane-1,2-diaminato(2-)platinum(II) complexes, and this is attributable to delocalization of non-bonded lone pairs from the amido nitrogens into the polyfluorophenyl rings.

Organoamidometallics. I. Syntheses of [N,N′-Bis(Polyfluorophenyl)Ethane-1,2-Diaminato(2-)]Platinum(II) Complexes by Decarboxylation

Organoamidometallics. Part 2. Decarboxylation Syntheses and Structures of (N,N-Dimethyl-N′-(polyfluorophenyl)ethane-1,2-diaminato(1-))platinum(II) Complexes.

David P. Buxton

Papers

cis-bis(pyridine)platinum(II) organoamides with unexpected growth inhibition properties and antitumor activity.

Organoamidometallics. II. Decarboxylation Syntheses and Structures of [N,N-Dimethyl-N'-(Polyfluorophenyl)Ethane-1,2-Diaminato(1-)]Platinum(II) Complexes

Organoamidometallics. I. Syntheses of [N,N′-Bis(Polyfluorophenyl)Ethane-1,2-Diaminato(2-)]Platinum(II) Complexes by Decarboxylation

Organoamidometallics. Part 2. Decarboxylation Syntheses and Structures of (N,N-Dimethyl-N′-(polyfluorophenyl)ethane-1,2-diaminato(1-))platinum(II) Complexes.