Salaam Al-Baker

Synthesis and antitumor activity of ammine/amine platinum(II) and (IV) complexes

Dimeric platinum complexes, [Pt(RNH2)I2]2 (where R = H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), have been synthesized by reactions of diiodoplatinum compounds with perchloric acid in water/ethanol solutions. The dimerization varies from several hours to a few days depending upon the length of the carbon chain in the alkylamines and the process can be conveniently monitored by 195Pt NMR spectroscopy. All these dimers exhibit two closely separated resonances around -4000 ppm (vs K2PtCl4 at -1620 ppm) in dimethylformamide. Reactions of [Pt(NH3)I2]2 with alkylamines do not yield the desired mixed ammine/amine complexes, which are obtained subsequently by treatment of the alkylamine dimer [Pt(RNH2)I2]2 with ammonium hydroxide in water. By using this latter procedure, a novel class of ammine/amine platinum complexes of the type PtII(NH3)(RNH2)Cl2, PtIV(NH3)(RNH2)X2A2, and PtIV(NH3)(RNH2)(CBDCA)A2.H2O, where X2 = chloro or 1,1-cyclobutanedicarboxylato (CBDCA), A = OH, Cl, or OCOCH3, have been synthesized and characterized by elemental analysis, infrared, and 195Pt NMR spectroscopic techniques. The alicyclic ammine/amine Pt(II) complexes, where R is C3-C6 were selected as representative of the class to undergo antitumor evaluations. The compounds had excellent activity against murine leukemic L1210/0 cells with cyclobutylamine-, cyclopentylamine- and cyclohexylamine-containing complexes demonstrating cytotoxicity superior to that of the clinically established cisplatin.

Lipophilic platinum complexes entrapped in liposomes: improved stability and preserved antitumor activity with complexes containing linear alkyl carboxylato leaving groups

Lipophilic diaminocyclohexane (DACH) platinum complexes have shown significant promise in preclinical studies. One of these compounds,cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) (NDDP), which contains two branched leaving groups of 10 carbons, showed a favorable toxicity profile in a liposomal formulation in early clinical trials. However, like many other DACH platinum compounds with branched leaving groups, it is unstable within the liposomes, thus preventing its widespread clinical evaluation. We studied the effect of the configuration of leaving groups on intraliposomal complex stability by studying a series of DACH platinum complexes containing linear alkyl carboxylato leaving groups of 5–18 carbons. The entrapment efficiency was greater than 90% for all liposomal preparations of the complexes and was independent of lipid composition and length of the leaving group. The drug leakage from the liposomes was minimal, but was directly related to the length of the leaving group. Intraliposomal stability was inversely related to the length of the leaving group and the content of DMPG (dimyristoyl phosphatidylglycerol) in the liposomes. The effect of length of leaving group on intraliposomal stability was minimal in compounds with leaving groups smaller than 10 carbons, but very pronounced in compounds with longer leaving groups. Stable liposomal formulations of selected compounds with leaving groups of 6 and 10 carbons had significant in vivo antitumor activity against both L1210/S and L1210/PDD leukemias. The results indicate (1) that compounds with linear leaving groups are much more stable within DMPG-containing liposomes than compounds with branched leaving groups and (2) that DMPG is required for in vivo antitumor activity. Stable and active liposomal formulations of selected compounds with linear leaving groups have been identified. These formulations are candidates for clinical development.

X-ray crystal structure of tetrachloro(trans-d,l-1,2-diaminocyclohexane) platinum(IV) complex: A potential anticancer agent

Tetrachloro(trans-d,l-1,2-diaminocyclohexane)platinum(IV) complex (tetraplatin or ormaplatin) has been recognized as a potential anticancer agent. We have determined the crystal structure of this compound by x-ray single crystal diffraction. It has a unique space group and rare molecular packing. Parameters are as follows: space group R3c (rhombohedral), a = 26.425(4) A, alpha = 54.50(1) degrees; V = 11375A3, Z = 36. The coordination about Pt atoms is a slightly distorted octahedron owing to the presence of the geometrically strained five-membered ring (avg. N-Pt-N angle = 82.9 degrees). An intricate network of intermolecular hydrogen bonds holds the crystal lattice together. Three independent ormaplatin molecules surround each water molecule, forming the three shortest A...B contacts and thus the three strongest hydrogen bonds.

The X-ray crystal structure of the trans-dl-1,2-diaminocyclohexane-(N-methyliminodiacetato)platinum(II) complex

Abstract The crystal structure of the trans-dl-1,2-diaminocyclohexane(N-methyliminodiacetato)platinum(II) complex has been determined by X-ray diffraction. It has the following parameters: space group P21/c (monoclinic), a=11.272(5), b=14.034(7), c=10.163(5) A, β=116.13(3)°, Z=4. The slightly distorted square plane of the Pt includes two nitrogens of the diamine in cis positions and one oxygen and one nitrogen from N-methyliminodiacetate ion. The PtN and PtO distances average 2.038 and 2.013 A, respectively. An intricate system of hydrogen bonds which involves every hydrogen atom not attached to carbon was observed. The molecule is a zwitterion and the charge density on the unbound carboxylate is probably stabilized through this series of strong hydrogen bonds.

Synthesis and antitumor activity of 1,2-diaminocyclohexane platinum(IV) complexes

The synthesis, characterization, and antitumor activity of a series of platinum(IV) complexes of the type DACH-PtIV(X)2Y (where DACH = trans-dl, or trans-l-1,2-diaminocyclohexane, X = OH or Cl, and Y = oxalato, malonato, methylmalonato, tartronato, ketomalonato, 1,1-cyclopropanedicarboxylato, or 1,1-cyclobutanedicarboxylato, are described. These complexes have been characterized by elemental analysis, HPLC, and infrared and 195Pt NMR spectroscopic techniques. The complexes had good in vitro cytotoxic activity (IC50 = 0.14-7.6 micrograms/ml) and were highly active in vivo against leukemia L1210 cells (%T/C = 152- > 600, cisplatin = 218). In addition, excellent in vivo antitumor activities against B16 melanoma (%T/C = 309), M5076 reticulosarcoma (100% cures) and cisplatin-resistant L1210/DDP (%T/C = 217) cell lines were also exhibited by an analog selected for further evaluation.

Differential antitumor activity and toxicity of isomeric 1,2-diaminocyclohexane platinum (II) complexes

Acquired resistance is a main drawback of using cisplatin in cancer chemotherapy; however, analogs containing the 1,2-diaminocyclohexane (DACH) ligand can overcome this resistance. Because DACH can exist as thetrans-1R,2R, trans-1S,2S orcis isomer, the antitumor activity and toxicity of individual isomers of both DACH(sulfato)Pt(II) and DACH(1,1-cyclobutanedicarboxylato)Pt(II) complexes have been examined. At optimal doses, differences in antitumor activities among the three isomers were moderately dependent on the in vivo tumor models (L1210/0, L1210/DDP, B16 and M5076). However, differences in efficacy among these isomers were greatly modulated by the sulfate or 1,1-cyclobutanedicarboxylate (CBDCA) leaving ligands. Thus, thetrans isomers (R,R and/orS,S) of the sulfate complex generally had greater activities than the correspondingcis form, while thecis configuration appeared to be superior in the complex containing the CBDCA ligand. The isomers were also compared for their potential to elicit myelosuppression and kidney toxicity. Of the six isomers investigated,cis-DACH(CBDCA)Pt(II) was myelosuppressive, and the correspondingR,R andS,S isomers were mildly nephrotoxic. No such toxicities were apparent with any of the sulfate complexes. From these studies, particularly with the cisplatin-resistant L1210/DDP cell line, theR,R isomers are evidently the most interesting. However, it is possible that other leaving ligands or tumor models may indicate eitherS,S- orcis-DACH as the isomer worthy of greater interest.

SYNTHESIS AND CHARACTERIZATION OF NEW ANTITUMOR TRANS-R,R-, TRANS-S,S- AND CIS-1,2-DIAMINOCYCLOHEXANE PLATINUM (IV) COMPLEXES

Abstract A series of isomeric 1, 2-diaminocyclohexane platinum (IV) complexes of the type DACH-PtIV-trans(X)2 cis(Y) (where DACH = trans-R,R-, trans-S,S- or cis-1,2-diaminocyclohexane, X = chloro, bromo, acetato, or trifluoroacetato, and Y = dichloro, dibromo, 1,1-cyclobutanedicarboxylato, tartronato, ketomalonato, or methylmalonato) has been synthesized. The isomeric DACH-PtIV-trans(X)2 cis(Y) complexes were prepared by first oxidizing the corresponding DACH-dihaloplatinum(II) or DACH-dicarboxylato-platinum(II) [DACH-PtIIY] with hydrogen peroxide to DACH-PtIV-trans(OH)2Y, and then replacing the axial hydroxo groups with chloro, bromo, or monocarboxylato ligands. These complexes were characterized by elemental analysis, and infrared and nuclear magnetic resonance (195Pt{1H}) spectroscopic techniques.

Antitumor activity of isomeric 1,2-diaminocyclohexane platinum(IV) complexes

Acquired drug resistance is a major drawback of using cisplatin in the treatment of cancer; however, analogs containing the 1,2-diaminocyclohexane (DACH) ligand can overcome this resistance. DACH can exist as thetrans-1R,2R, trans-1S,2S orcis isomer, and we have examined whether specific isomers coordinated to a platinum(IV) center can modulate antitumor activities in murine tumor models in vivo. Ten isomeric series of DACH-Pt(IV) complexes were synthesized, each series containing a different combination of axial and equatorial ligands and varying only by the isomeric form of the DACH ligand. Among the ten series, seven clearly indicated superiority of the (R,R)-DACH-Pt(IV) complex against leukemia L1210/0 cells, while in three theR,R andS,S configurations gave similar efficacies which were better than that of the correspondingcis analog. In three out of the ten series, the antitumor activities of theS,S andcis complexes were similar, in six thecis analogs were the least effective, and in the remaining one thecis analog was superior toS,S. One series of complexes with axial chloro ligands and an equatorial 1,1-cyclobutanedicarboxylato group, which had produced the efficacy rankingR,R>cis>S,S in the L1210/0 model, gaveS,S>R,R>cis against cisplatin-resistant L1210/DDP cells,R,R=S,S>cis against B16 melanoma cells, andR,R=S,S=cis against M5076 reticulosarcoma cells. The results demonstrate that profound variation can occur in antitumor activities among isomeric forms of the DACH-Pt(IV) complex. However, the (R,R)-DACH-Pt(IV) complexes appear to be of greater interest overall.

SYNTHESIS AND CHARACTERIZATION OF A SERIES OF HYDROPHOBIC ANTITUMOR BIS(CARBOXYLATO) (1,2-DIAMINOCYCLOHEXANE) PLATINUM(II) COMPLEXES

Abstract A series of hydrophobic platinum(II) complexes of the type (DACH)PtX2 (where DACH = various isomeric forms of 1,2-diaminocyclohexane and X = pentanoato, hexanoato, heptanoato, octanoato, nonanoato, decanoato, unidecanoato, laurato, tridecanoato, myristato, pentadecanoato, palmitato, heptadecanoato, or stearato) has been synthesized and characterized using elemental analysis, infrared spectra and nuclear magnetic resonance (13C{1H} and 195Pt{1H}). The complexes have been prepared as potential antitumor agents for liposome entrapment.

Synthesis and biological studies of new lipid-soluble cisplatin analogues entrapped in liposomes.

A series of highly lipophilic platinum(II) complexes of the type cis-[(RNH2)2PtX2] have been synthesized, where R = ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclopentyl, or neopentyl and X = either long-chain carboxylate, such as decanoate (C10), laurate (C12), myristate (C14), heptadecanoate (C17), stearate (C18), nonadecanoate (C19), or 2,2,3,3-tetramethylcyclopropylcarboxylate, or branched-chain carboxylate, such as neopentanoate, neohexanoate, neoheptanoate, neononanoate, or neodecanoate. These complexes have been characterized by elemental analysis, IR, and 13C and 195Pt NMR spectroscopic techniques. The platinum complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a 7:3 molar ratio and tested for antitumor activity. The entrapment efficiency of liposomal platinum (L-Pt) complexes ranged from 60 to 100%. The percentage of T/C obtained after a single i.p. injection of the optimal dose of L-Pt complexes tested against L1210 leukemia ranged from 90 to 125%. These L-Pt preparations did not show significant antitumor activity in mice.