Barry A. Murrer

Carboxylation of Kinetically Inert Platinum(IV) Hydroxy Complexes. An Entr.acte.ee into Orally Active Platinum(IV) Antitumor Agents

Carboxylation of hydroxide coordinated to Pt(1V) by anhydrides, pyrocarbonates, and isocyanates to form the corresponding Pt(1V) carboxylates, carbonates, and carbamates is described. For example, the acylation with acetic anhydride of (OC-6-33)-amminedichloro(cyclohexanamine)dihydroxyplatinum(IV) leads to formation of (OC-6-43)-bis(acetato-O)amminedichloro(cyclohexanamine)platinum(IV) (JM-216) in 60% yield. This compound is currently in worldwide clinical trials as an orally active antitumor agent. Pt(1V) dicarbonates and dicarbamates are prepared similarly by reaction of a Pt(1V) hydroxide with a pyrocarbonate or isocyanate. The carboxylation reaction can be used to prepare molecules containing ligands with pendant functional groups that would be difficult to introduce by substitution reactions. Thus (OC-6-43)-amminedic~oro(cyclohexanamine)bis((methylthio)acetatoO)platinum(IV) was prepared, which was oxidized to the corresponding sulfoxide (OC-6-43)-amminedichloro(cyclohexanamine)bis( methylsulfiiy1)acetato-O)platinum(IV). Finally, unsymmetrical carboxylate complexes may be obtained by reaction of a binary mixture of two electrophiles with a Pt(IV) hydroxide followed by chromatographic separation of the carboxylation products. A simplified synthesis of the K[PtnC13NH3] in 55% yield from cisplatin is also reported. This improves tHe availability of molecules of the general formula cis-PtnC12AA’ (A, A’ = ammine, amine) which are critical intermediates in the multistep synthesis of the Pt(IV) carboxylates having antitumor activity.

Ruthenium complexes as nitric oxide scavengers: a potential therapeutic approach to nitric oxide-mediated diseases

1 Ruthenium(III) reacts with nitric oxide (NO) to form stable ruthenium(II) mononitrosyls. Several Ru(III) complexes were synthesized and a study made of their ability to bind NO, in vitro and also in several biological systems following expression of the inducible isoform of nitric oxide synthase (iNOS). Here we report on the properties of two, related polyaminocarboxylate‐ruthenium complexes: potassium chloro[hydrogen(ethylenedinitrilo)tetraacetato]ruthenate (=JM1226; CAS no.14741‐19‐6) and aqua[hydrogen(ethylenedinitrilo)tetraacetato]ruthenium (=JM6245; CAS no.15282‐93‐6). 2 Binding of authentic NO by aqueous solutions of JM1226 yielded a product with an infrared (IR) spectrum characteristic of an Ru(II)‐NO adduct. A compound with a similar IR spectrum was obtained after reacting JM1226 with S‐nitroso‐N‐acetylpenicillamine (SNAP). 3 The effect of JM1226 or JM6245 on nitrite (NO2−) accumulation in cultures of macrophages (RAW 264 line) 18 h after stimulating cells with lipolysaccharide (LPS) and interferon‐γ (IFNγ) was studied. Activation of RAW264 cells increased NO2− levels in the growth medium from (mean±1 s.e.mean) 4.9±0.5  μM to 20.9±0.4 μM. This was blocked by actinomycin D (10 μM) or cycloheximide (5 μM). The addition of JM1226 or JM6245 (both 100 μM) to activated RAW264 cells reduced NO2− levels to 7.6±0.2 μM and 8.8±0.6 μM, respectively. NG‐methyl‐L‐arginine (L‐NMMA; 250 μM) similarly reduced NO2− levels, to 6.1±0.2 μM. 4 The effect of JM1226 or JM6245 on NO‐mediated tumour cell killing by LPS+IFNγ‐activated macrophages (RAW 264) was studied in a co‐culture system, using a non‐adherent murine mastocytoma (P815) line as the ‘target’ cell. Addition of JM1226 or JM6245 (both 100 μM) to the culture medium afforded some protection from macrophage‐mediated cell killing: target cell viability increased from 54.5±3.3% to 93.2±7.1% and 80.0±4.6%, respectively (n=6). 5 Vasodilator responses of isolated, perfused, pre‐contracted rat tail arteries elicited by bolus injections (10 μl) of SNAP were attenuated by the addition of JM1226 or JM6245 (10−4 M) to the perfusate: the ED50 increased from 6.0 μM (Krebs only) to 1.8 mM (Krebs+JM6245) and from 7 μM (Krebs only) to 132 μM (Krebs+JM1226). Oxyhaemoglobin (5 μM) increased the ED50 value for SNAP from 8 μM to 200 μM. 6 Male Wistar rats were injected with bacterial LPS (4 mg kg−1; i.p.) to induce endotoxaemia. JM1226 and JM6245 (both 100 μM) fully reversed the hyporesponsiveness to phenylephrine of tail arteries isolated from animals previously (24 h earlier) injected with LPS. Blood pressure recordings were made in conscious LPS‐treated rats using a tail cuff apparatus. A single injection of JM1226 (100 mg kg−1, i.p.) administered 20 h after LPS (4 mg kg−1, i.p.) reversed the hypotension associated with endotoxaemia. 7 The results show that JM1226 and JM6245 are able to scavenge NO in biological systems and suggest a role for these compounds in novel therapeutic strategies aimed at alleviating NO‐mediated disease states.

A phase I and pharmacology study of an oral platinum complex, JM216: dose-dependent pharmacokinetics with single-dose administration

JM216 [bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV)] is an oral platinum complex with in vivo activity against murine and human tumor models and a lack of nephro- and neurotoxicity in rodents. During a phase I study of a single-dose schedule, JM216 was given in dry-filled hard gelatin capsules by mouth without hydration or diuresis. In all, 37 patients were given a total of 88 courses at doses ranging from 60 to 700 mg/m2. The study was stopped before the MTD was reached because of nonlinear pharmacokinetics. Myelosuppression was manifest by leucopenia or thrombocytopenia and showed marked variability at 420–700 mg/m2. Vomiting was mild and controllable by antiemetics in approximately 50% of courses. The onset of vomiting was delayed to 4 h after during ingestion. There was no nephro-, oto- or neurotoxicity. A partial response was recorded in a patient with recurrent ovarian cancer, and significant falls in plasma tumour markers (CA125) were seen in two further cases. Plasma pharmacokinetics were linear and showed moderate interpatient variability at dose levels of ≤120 mg/m2. At dose levels of ≥200 mg/m2, Cmax and AUC increased less than proportionally to dose. This was associated with greater interpatient pharmacokinetic variability and reduced urinary platinum recovery. A significant sigmoidal relationship existed between ultrafilterable plasma AUC and the percentage of reduction in platelet count (r2=0.78). Nonlinear absorption was a limitation to this single-dose schedule of oral NM216; however, little nonhaematological toxicity was seen at doses associated with myelosuppression and antitumour activity. Clinical studies of divided dose schedules using doses within the range of pharmacokinetic linearity (≤120 mg/m2) are now being investigated.

Biotransformation of the platinum drug JM216 following oral administration to cancer patients

Abstract This study evaluates the metabolic profile of JM216 [bis(acetato)ammine-dichloro(cyclohexylamine) platinum(IV)], the first orally administrable platinum complex, in plasma ultrafiltrates of 12 patients (n=2–4 time points per patient) following different doses of drug (120, 200, 340, 420, 560 mg/m2). The biotransformation profile was evaluated by high-performance liquid chromatography (HPLC) followed by atomic absorption spectrophotometry (AA). The AA profiles were compared with those previously identified by HPLC on line with mass spectrometry (HPLC-MS) in plasma incubated with JM216. A total of six platinum peaks (Rt=5.5, 7.2, 10.6, 12.4, 15.6, and 21.6 min, respectively) were observed in patients’ plasma ultrafiltrate samples, of which only four appeared during the first 6 h post-treatment. Four of these coeluted with those observed and identified previously in plasma incubation medium. No parent JM216 was detected. The major metabolite seen in patients was the Pt II complex JM118 [cis-amminedichloro-(cyclohexylamine)platinum (II)] and was observed in all the patients. Interestingly, the second metabolite was shown to coelute with the Pt IV species JM383 [bis-acetatoammine(cyclohexylamine)dihydroxoplatinum (IV)]. Both JM118 and JM383 were identified by HPLC-MS in a clinical sample. Peak C, which was a minor product (less than 5% of the free platinum), coeluted with JM559 [bis-acetatoammine-chloro(cyclohexylalamine)hydroxoplatinum (IV)]. The cytotoxicity profile of all three metabolites in a panel of cisplatin-sensitive and -resistant human ovarian carcinoma cell lines was very close to that of the parent drug. In addition, the concentrations of JM118 reached in patients’ plasma ultrafiltrate were comparable with the cytotoxic levels of the compound determined in the ovarian carcinoma panel of cell lines. Two metabolites were seen in patients but not in the in vitro incubation medium, suggesting the involvement of a possible enzyatic reaction. Thus, the biotransformation profile following oral administration of JM216 shows a variety of Pt(IV) and Pt(II) metabolites in plasma that differ significantly from other systemically applied platinum drugs.

Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer.

PURPOSE We aimed to determine the maximum-tolerated dose (MTD) clinical toxicities, pharmacokinetics, and pharmacodynamics of oral JM216 given once daily for 5 days to cancer patients. PATIENTS AND METHODS Patients who fulfilled standard phase I trial criteria were enrolled. Oral JM216 was given at doses based on patient body-surface area, on an empty stomach, once daily for 5 consecutive days, as 10-, 50-, and 200-mg hard gelatin capsules and with oral antiemetics. The pharmacokinetics of platinum were studied on days 1 and 5 of the first treatment course using atomic absorption spectrophotometry (AAS). RESULTS Thirty-two patients received 94 courses of oral JM216 at doses that ranged from 30 to 140 mg/m2 body-surface area for 5 consecutive days. The MTD was 140 mg/m2/d. The dose-limiting toxicities were thrombocytopenia and neutropenia. Hematotoxicity was reversible (nadir, 17 to 21 days; recovery, 28 days), noncumulative, and dependent on the dose and history of previous therapy. There were two instances of neutropenic sepsis. Two-thirds of patients experienced mild nausea, vomiting, or diarrhea. There was no ototoxicity, neurotoxicity, nephrotoxicity, or objective tumor responses. There was a significant correlation between JM216 dose and the day 1 and 5 plasma ultrafiltrate area under the concentration-time curve (AUC; r = .78), which indicates linear pharmacokinetics. There was considerable intersubject pharmacokinetic and pharmacodynamic variability, but a significant sigmoidal relationship between the plasma ultrafiltrate AUC and severity of thrombocytopenia (R2 = .83). CONCLUSION We recommend JM216 doses of 100 and 120 mg/m2/d x 5 for previously treated and untreated patients, respectively, for phase II trials.

Efficient near IR sensitization of nanocrystalline TiO2 films by ruthenium phthalocyanines

Bis(3,4-dicarboxypyridine)(1,4,8,11,15,18,22,25-octamethyl- phthalocyaninato)ruthenium(II) (JM3306) anchored to nanocrystalline TiO2 films through the axial pyridine 3,4-dicarboxylic acid ligands is an efficient near IR sensitizer for photovoltaic injection cells based on nanocrystalline TiO2 films.

Metabolic studies of an orally active platinum anticancer drug by liquid chromatography-electrospray ionization mass spectrometry

Bis(acetato)amminedichloro(cyclohexylamine) platinum(IV) (JM216) is a new orally administered platinum complex with antitumor properties, and is currently undergoing phase II clinical trials. When JM216 was incubated with human plasma ultrafiltrate, 93% of the platinum species were protein-bound and 7% were unbound. The unbound platinum complexes in the ultrafiltrates of human plasma were analysed using a liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method. Apart from the parent drug, four metabolites were identified and characterised. These include JM118 [amminedichloro(cyclohexylamine) platinum(II)], JM383 [bis(acetato)ammine(cyclohexylamine)dihydroxo platinum(IV)] and the two isomers JM559 and JM518 [bis(acetato)amminechloro(cyclohexylamine) hydroxo platinum(IV)]. Their elemental compositions were determined by accurate mass measurement during the LC analysis, to confirm their identities. Quantitation of these metabolites by off-line LC atomic absorption spectroscopy demonstrated that JM118 is the major metabolite in plasma from patients receiving JM216 treatment.

Use of luminescent gold compounds in the design of thin-film oxygen sensors

The use of two gold compounds incorporated into thin plastic films as luminescence quenching oxygen sensors is described. The films are sensitive both to gaseous oxygen and to oxygen dissolved in nonaqueous media such as ethanol. The luminescence quenching of these sensors by oxygen obeys the Stern−Volmer equation and Stern−Volmer constants of 5.35 × 10-3 and 0.9 × 10-3 Torr-1 are found, respectively, for the two dyes in a polystyrene polymer matrix. The sensitivity of the films is strongly influenced by the nature of the polymer matrix, and greatest sensitivity was found in systems based on the polymers polystyrene or cellulose acetate butyrate. Sensitivity was not found to be temperature dependent though raising the temperature from 15 to 50 °C did result in a slight decrease in emission intensity and a hypsochromic shift in the emission wavelength. The rate of response and recovery of the sensors can be increased either by decreasing film thickness or by increasing the operating temperature. The operat...

Synthesis and Reactions of a New Class of Orally Active Pt(IV) Antitumor Complexes

The advent of cisplatin was a breakthrough in the chemotherapy of certain cancers. Its success, in spite of adverse effects such as nephrotoxicity, nausea and vomiting, ototoxicity and myelosuppression, attests to its efficacy1. Still, the cost of treatment, in terms of patient quality of life, underscores the need for an efficacious drug with milder side effects. Carboplatin is an example of an agent specifically developed to reduce side effects while retaining the antitumor activity of cisplatin2. Its tremendous success, following its introduction in Europe and the US, attests to the importance of addressing patient quality of life. Although, oral chemotherapeutic agents are not presently a significant factor in cancer treatment, a properly designed agent could offer significant advantages in terms of a patients’ comfort and convenience, and anticipates the possibility of outpatient chemotherapy. At Johnson Matthey, in conjunction with the Institute of Cancer Research and Bristol-Myers Squibb, a portion of our platinum antitumor drug discovery program is devoted to the design and development of an orally active platinum antitumor drug. This paper describes the synthesis, reactions, and a few of the biological properties of a new class of antitumor agents that possess many characteristics required of an orally active antitumor agent.

Reversal of chirality induced by ortho-methoxyl substitution of arylphosphine ligands in rhodium-catalysed asymmetric hydrogenation

Abstract o-Methoxyl substitution in DIOP(2) causes a reversal of configuration in asymmetric homogeneous hydrogenation of enamides.