Iris H. Hall

Tricarbonylrhenium(I) complexes of phosphine-derivatized amines, amino acids and a model peptide: structures, solution behavior and cytotoxicity

Abstract Modified Mannich reactions of amines, amino acids and a model peptide with Ph2PH and CH2O gave bis(diphenylphosphinomethyl)amines (Ph2PCH2)2NR [R=Ph (1), CH2CH2OH (2), CH2COOCH2Ph (3), CH2CONHCH2COOCH2Ph (4), CH2COOH (5)] and (Ph2PCH2)2NCH2CH2N(CH2PPh2)2 (6). Reaction with [ReBr3(CO)3]2− under mild conditions led to [ReBr(CO)3]{(Ph2PCH2)2NR} [R=Ph (7), CH2CH2OH (8), CH2COOCH2Ph (9), CH2CONHCH2COOCH2Ph (10), CH2COOH (11)] and [ReBr(CO)3(Ph2PCH2)2NCH2]2 (12). All new complexes have been characterized by NMR and IR spectroscopy and for 7, 9 and 10, single-crystal X-ray diffraction analyses. Electrospray mass spectrometric studies show that the rhenium–phosphine chelates are very stable, especially in neutral methanolic solution. Hydrolysis of the ester and amide linkages slowly occur in acidic and basic solutions over several weeks; displacement of the bromide ligand also occurs in basic medium. Cytotoxicity testing of 7–10 and 12 showed that all the complexes are active against specific tumor cell lines, especially MCF-7 breast cancer and HeLa-S3 suspended uterine carcinoma.

Investigations on the Mechanism of Action of the Novel Antitumor Agents 2‐Benzothiazolyl, 2‐Benzoxazolyl, and 2‐Benzimidazolyl Hydrazones Derived from 2‐Acetylpyridine

2‐Acetylpyridine hydrazone derivatives of benzothiazole, benzoxazole, and benzimidazole were found to exhibit potent cytotoxic activity against the growth of suspended leukemia and lymphomas. They were also active in a number of solid tumor screens, e.g. HeLa uterine carcinoma, SOS bone osteosarcoma, lung MB9812, lung A549, Mcf‐7 breast growth. In L1210 lymphoid leukemia cells the compounds preferentially inhibited RNA synthesis followed by DNA synthesis at 100 μM after 60 min. The reduction of de novo purine synthesis by the compounds at the regulatory sites PRPP‐amido transferase, IMP dehydrogenase and dihydrofolate reductase was responsible for the suppression of nucleic synthesis. Other minor sites where the agents have metabolic effects were thymidylate synthetase and thymidine kinase which would be additive with the overall inhibition of cell growth. The ct‐DNA studies suggest that the compounds also interacted with the DNA molecule itself, probably affecting template activity.

Substituted cyclic imides as potential anti-gout agents

N-substituted cyclic imides of phthalimide, 2,3-dihydrohalazine-1,4-dione, and diphenimide were shown to reduce the serum uric acid levels in normal and hyperuric mice at 20 mg/kg/day I.P. for 14 days. The agents were potent inhibitors of commercial xanthine dehydrogenase and xanthine oxidase enzyme activities with IC50 values from 10(-7) to 10(-8) M concentrations of drug.

Lasiodiplodin, a potent antileukemic macrolide from Euphorbia splendens

Abstract In vivo P-388 assay-directed fractionation of an active extract from Euphorbia splendens has led to the isolation of lasiodiplodin, a potent antileukemic macrolide, the structure of which was established from spectral data and a single-crystal X-ray analysis.

The cytotoxicity of copper(II) complexes of heterocyclic thiosemicarbazones and 2-substituted pyridine N-oxides.

Thiosemicarbazone complexes of copper(II) were shown to be potent cytotoxic/antineoplastic agents against the growth of murine and human tumor cells. Selectivity of some agents was demonstrated against specific solid tumor growth. In L1210 lymphoid leukemia cells the copper complexes preferentially inhibited DNA synthesis with their major effects on the purine de novo pathway at PRPP amido transferase, IMP dehydrogenase and dihydrofolate reductase. The reductions of purines correlated positively with inhibition of DNA synthesis and cytotoxicity of the agents tested. DNA itself was fragmented after incubation with the drug; however, no binding of the agent to nucleotide bases or intercalation between base pairs was evident.

Boron analogues of amino acids VI. Synthesis and characterization of di- and tripeptide analogues as antineoplastic, anti-inflammatory and hypolipidemic agents

Abstract A number of boron-containing dipeptides with the general formulation Me 3 NBH 2 C(O)NHCH(R)COOR′ and a tripeptide, Me 3 NBH 2 C(O)NHCH 2 C(O)NHCH 2 COOEt were synthesized by condensation of Me 3 NBH 2 COOH with the corresponding NH 2 CH(R)COOR′ (NH 2 CH 2 C(O)NHCH 2 COOEt in case of tripeptide) in the presence of PPh 3 and CCl 4 . Further reaction with liquid NH 3 afforded NH 3 BH 2 C(O)NHCH(R)CONH 2 (NH 3 BH 2 C(O)NHCH 2 C(O)NHCH 2 C(O)NH 2 in the case of tripeptide) or NH 3 BH 2 C(O)NHCH(R)COOMe. These peptides proved to have antineoplastic, anti-inflammatory and hypolipidemic activity in mice. The antineoplastic activity was weak. The anti-inflammatory activity was similar to that of phenylbutazone, although at a lower dosage, ie 8 mg/kg × 2 was required for activity. IC 50 values were in the range of 7.0–29.0 mg/kg × 2. The compounds were most effective as hypolipidemic agents, significantly lowering both serum cholesterol and triglyceride levels at a dose of 8 mg/kg per day. After 16 days administration, this activity was far superior to known clinical therapeutic agents used to treat atherosclerosis.

The cytotoxicity of heterocyclic thiosemicarbazones and their metal complexes on human and murine tissue culture cells.

Heterocyclic thiosemicarbazones, thioureas and 2-substituted pyridine N-oxides as well as representative nickel, cobalt and copper complexes were shown to be potent antineoplastic/cytotoxic agents. The cytotoxicity was demonstrated against single cell leukemia as well as cell lines derived from solid tissue (colon adenocarcinoma, HeLa, KB, skin, bronchogenic lung, bone osteosarcoma and glioma). In L1210 cells, DNA synthesis and subsequently RNA synthesis were particularly inhibited by the agents. IMP dehydrogenase activity and thus purine de novo synthesis was reduced significantly by the agents. Dihydrofolate reductase, ribonucleoside reductase, nucleoside kinase and DNA polymerase alpha activities were inhibited by the agents. d(NTP) pool levels were reduced by most of the agents. DNA strand scission was present with all of the derivatives; however, there was no evidence of intercalation, cross linking or alkylation/binding to bases of DNA. This new group of compounds may offer novel exploratory derivatives for future investigations in the treatment of cancer.

The Hypolipidemic Activity of Heterocyclic Thiosemicarbazones,Thioureas and Their Metal Complexes in Sprague Dawley Male Rats

Heterocyclic thiosemicarbazones, thioureas and their copper, nickel, and cobalt complexes were shown to be potent hypolipidemic agents in male Sprague Dawley rats at 8 mg/kg/day, orally. These agents lowered the activity of rat hepatic rate limiting enzymes for the synthesis of cholesterol and triglycerides. The effects of these agnets on cytoplasmic ATP-dependent citrate lyase, acetyl CoA synthetase and HMG-CoA reductase activities were reduced by a magnitude to explain the reduction of serum cholesterol levels afforded by the compounds. The reduction of acetyl CoA carboxylase, sn-glycerol-3-phosphate synthetase and phosphotidylate phosphohydrolase activities caused by the derivatives is of sufficient magnitude to explain the observed reduction in serum triglycerides after administration of the agents.

Synthesis, X-ray structures, and cytotoxicity of rhenium(I) carbonyl 2-(dimethylamino)ethoxide complexes

Abstract The complexes [Re(η2-Me2NCH2CH2O)(CO)3(μ-OH)Re(η2-Me2NCH2CH2OH)(CO)3] (1) and [Re3(μ3-OH)(μ-OH)2(μ-OCH2CH2NMe2H)(CO)9] (2) have been synthesised and characterised by single-crystal X-ray diffraction analysis. Complex 1 exists as hydrogen-bonded dimers in the solid state and in solution. Proton NMR, 1H–1H COSY and NOESY spectroscopic studies showed that the structure of 1 is static in solution, and that only one of the many possible geometric isomers of 1 exists. The hydrogen atom on the ammonio nitrogen of 2 is involved in intramolecular NH⋯O hydrogen-bonding with a bridging OH group. Complexes 1 and 2 were shown to be potent in suspended tumour cell lines in suppressing growth but were more selective in inhibiting the growth of cultures from solid tumours. The compounds [NBun4][ReO4] and [NEt4]2[ReBr3(CO)3] were also very active against the suspended cell lines and selective against solid tumours. All the compounds tested are inactive against normal cells.

Cytotoxicity of Metallic Complexes of Furan Oximes in Murine and Human Tissue Cultured Cell Lines

The copper complexes of 2-furaldehyde and furan oximes have previously demonstrated potent cytotoxicity, L1210 DNA synthesis inhibition, DNA topoisomerase II inhibition and DNA fragmentation. Currently a series of cobalt metal complexes of 2-furaldehyde oximes were compared with copper complexes of furan oximes to determine whether the type of metal is important to the cytotoxicity and mode of action of the complexes. The cobalt complexes of furan oximes, like the copper complexes, were shown to be cytotoxic to suspended tumor cell lines, e.g. leukemias, lymphomas, acute monocytic leukemia and HeLa-S3 uterine carcinoma. The cobalt complexes did not demonstrate dramatic cytotoxicity against the growth of tumors derived from solid human tumor lines. The cobalt complexes preferentially inhibited L1210 DNA synthesis, followed by inhibition of RNA and protein synthesis from 25 to 100 µM over 60 min. These agents, like the copper complexes of 2-furaldehyde and furan oximes, were inhibitors of DNA polymerase α activity and de novo purine synthesis with marginal inhibition of ribonucleoside reductase and dihydrofolate reductase activities with DNA fragmentation. Unlike the copper complexes, the cobalt complexes did not inhibit L1210 DNA topoisomerase II activity but did reduce thymidylate synthetase activity. Thus, varying the type of metal within the complexes of 2-furaldehyde and furan oximes produces differences in both cytotoxicity and mode of action. Copyright