Synthesis,characterization and antitumor activity of a series of N-substituted iminodiacetato(diammine) platinum(II) complexes

A series of water-soluble N-substituted iminodiacetato (diammine)platinum(II) complexes [Pt(NRIDA)(NH₃)₂] have been synthesized and characterized by measurement of physical properties (conductivity and pH) and by various spectroscopic techniques (infrared, ¹H and ¹³C{¹H} nuclear magnetic resonance). The iminodiacetate ligand is coordinated to platinum through an O,N linkage. The results obtained suggest that these complexes are relatively stable for more than 24 h in aqueous solution. Preliminary in vitro and in vivo screening test for antitumor activity of these complexes against L1210 murine leukemia were performed. Many of complexes had acceptable in vitro cytotoxicity, but none displayed a significant level of in vivo antitumor efficacy.     

Synthesis and antitumor activity of a series of 1,2-diaminocyclohexanepalladium(II) dicarboxylate complexes

A series of complexes of the type [Pd(O O(DACH)] (O O = dicarboxylate ligand, DACH = 1,2-diaminocyclohexane) has been prepared. These complexes have been characterized by elemental analysis and infrared spectroscopy. The complexes have been screened in vivo for antitumor activity against the L1210 leukemia cell line. These palladium complexes lack antitumor activity, which may be due to (1) lack of solubility and/or (2) lack of stability of the complexes in solution.     

Synthesis,antineoplastic and cytotoxic activities of some mononuclear Ru(II) complexes

A series of mononuclear Ru(II) complexes of the type [Ru(S)₂(K)]²⁺, where S = 1,10-phenanthroline/2,2′-bipyridine and K = 4-OH-btsz, 4-CH₃-btsz, 3,4-di-OCH₃-btsz, 4-OH-binh, 4-CH₃-binh, 3,4-di-OCH₃-binh, were prepared and characterized by elemental analysis, FTIR, ¹H-NMR, and mass spectroscopy. The complexes displayed metal–ligand charge transfer (MLCT) transitions in the visible region. These ligands formed bidentate octahedral ruthenium complexes. The title complexes were evaluated for their in vivo anticancer activity against a transplantable murine tumor cell line, Ehrlisch’s ascites carcinoma (EAC), and in vitro cytotoxic activity against human cancer cell lines Molt 4/C₈ and CEM and murine tumor cell line L1210. The ruthenium complexes showed promising biological activity especially in decreasing tumor volume and viable ascites cell counts. Treatment with these complexes prolonged the life span of mice bearing EAC tumors by 10–52%. In vitro evaluation of these ruthenium complexes revealed cytotoxic activity from 0.21 to 24 μM against Molt 4/C₈, 0.16 to 19 μM aginst CEM, and 0.75 to 32 μM against L1210.     

Synthesis, characterization, and antitumor activity of 1,2-bis(diphenylphosphino) ethane platinum(II) and palladium(II) complexes

A number of 1,2-bis(diphenylphosphino)ethane monomeric platinum(II) and palladium(II) complexes have been synthesized in light of their potential antitumor activity. The metal center is coordinated with a number of carboxylate anions in the cis-configuration. These complexes have been characterized by elemental analysis, conductivity measurement, and various spectroscopic techniques [IR and 195Pt NMR]. In vivo screening tests for activity of these complexes were performed against the L1210/0 murine leukemia cancer model, but none displayed a significant level of antitumor activity.     

Synthesis of Bis(Aziridinyl) Phosphinic Amide Derivatives of Thymidine as Potential Anticancer Agents

Abstract

3′- and 5′-Bis(aziridinyl)phosphinic amide derivatives of thymidine have been synthesized as potential anticancer agents from 3′-amino-3′-deoxythymidine and 5′-amino-5′-deoxythymidine, respectively. The aziridine-containing compounds were tested for their cytotoxic action in vitro against the L1210 leukemia; the 3′-bis(aziridinyl)phosphinic amide derivative was found to be about 11-times more active than its 5′-counterpart in inhibiting the replication of these leukemic cells, with ED₅₀ values of 0.6 and 7 μM, respectively, being obtained.     

Preparation, characterization, and antitumor activity of water-soluble aminoalkanol platinum(II) complexes

A new series of highly water-soluble aminoalkanol platinum(II) complexes have been synthesized and characterized by elemental analysis, conductance, IR, and 195Pt NMR. Preliminary in vitro and in vivo screening tests for antitumor activities of these complexes against L1210 murine leukemia were performed. In general, these compounds were far less cytotoxic than cisplatin and possessed only a moderate degree of antitumor activity.     

Antitumor activity and metal complexes of the first transition series. Trans-bis(salicylaldoximato)copper(II) and related copper(II) complexes,a novel group of potential antitumor agents

The antitumor activity of forty nine different metal complexes of the first transition series against mouse leukemia L 1210 cells and of two of the complexes against Ehrlich ascites carcinoma have been tested in vitro by the method described in this paper. Eight complexes showed a 50% inhibition of tumor cell division at concentration level 5–6 μg/ml of the complex for the former and two most effective complexes also for the latter. The trans-bis-(salicylaldoximato)copper(II) and trans-bis(resorcylaldoximato)copper(II) complexes were found to possess the highest antitumor activity.     

Synthesis, characterization, and antitumor activity of new chloroethylamine platinum complexes.

A series of cis-bis-(2-chloroethylamine)platinum(II) and platinum(IV) complexes were synthesized and characterized by elemental analysis, IR, and 1H and 195Pt NMR spectroscopic techniques. Complexes were tested in vitro against murine L1210 leukemia and human ovarian A2780 cell lines and in vivo against the L1210 leukemia model. Some of these complexes showed excellent antitumor activity in both systems. However, all were inactive against cisplatin-resistant A2780/CP cells.     

Targeting of the antiviral protein from Phytolaccaamericana with an antibody

The antiviral protein (PAP) of $\text{Phytolacca}\text{americana}$ was conjugated with the Fab' fragment of IgG from a rabbit antiserum against murine leukemia L1210 cells via a disulfide bond employing $\text{N}$-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) as the coupling agent. The conjugate showed a potent $\text{in}\text{vitro}$ cytotoxicity against L1210 cells which was competitively blocked by F(ab′)₂ directed against L1210 cells. PAP itself did not exhibit the cytotoxicity at the concentration corresponding to the PAP content in the conjugate concurrently tested.     

Palladium(II) complexes with N,N'-dialkyl-1,10-phenanthroline-2,9-dimathanamine: synthesis, characterization and cytotoxic activity

Five new tetradentate ligands and their corresponding palladium complexes, [Pd(L)]Cl2 (L = N,N'-dimethyl-1,10-phenanthroline-2,9-dimathanamine, N,N'-diethyl-1,10-phenanthroline-2,9-dimathanamine, N,N'-dipropyl-1,10-phenanthroline-2,9-dimathanamine, N,N'-ditert-butyl-1,10-phenanthroline-2,9-dimathanamine, N,N'-dicyclohexyl-1,10-phenanthroline-2,9-dimathanamine) have been synthesized. The ligands and their complexes have been characterized by elemental analysis, IR, and 1H NMR. The complexes have been assayed for antitumor activity in vitro against the mouse leukemia L1210 and the mouse liver carcinoma Bel7402 cell lines. The results showed that the activities of these complexes are significantly dependent on the nature of the alkyl groups on the coordinated amine moieties, and three of these palladium complexes showed lower ID50 values against the two cell lines than cisplatin.     

Antitumor complexes of platinum with carrier molecules. 2 [1]. Mixed complexes of amino acids and tert-butylamine

In the search for a fine modulation of cisplatin analogues we have synthesized complexes with two different inert ligands bound to platinum in the cis- position. This paper reports on compounds of formula cis-[PtCl₂(aaH)(tba)] (aaH, amino acid; tba, tert-butylamine). These complexes have been synthesized with the aim of obtaining liposoluble cisplatin analogues bound to natural carrier groups. The derivatives of glycine, D-alanine, L-threonine, and L-serine were found to be moderately active against murine P388 and L1210 leukemia models. The compound K[PtCl₃(tba)] was also found to be active against the same tumor models. Their activity and potency was, however, much lower than that of cisplatin.     

Synthesis and first in vitro cytotoxicity studies of bis(2-chloroethyl) amino group containing polymers. Pharmacologically active polymers: 22

Monomers containing the cytotoxic bis(2-chloroethyl)amino group (nor-nitrogen mustard), linked in deactivated form via urethane and O-acylated hydroxamic acid bonds to polymerizable methacrylic acid derivatives, have been prepared. Besides the homopolymerization, these monomers were copolymerized with hydrophilic comonomers to obtain water-soluble polymers. The linkages used are expected to undergo intracellular enzymatic or hydrolytic cleavage, releasing the cytotoxic bis(2-chloroethyl)amino moiety from the polymeric carrier. Preliminary in vitro cytotoxicity data for the polymers against three rat and mouse experimental tumour lines (Walker 256 carcinosarcoma, L1210 murine leukaemia and ADJ/PC6A plasma cell tumour) are reported. An approximately 10² fold difference in cytotoxic potency was found, depending on the type of the cleavable spacer group.     

Daunomycin-polypeptide conjugates with antitumor activity

We have developed a group of water-soluble drug conjugates in which daunomycin (Dau) is coupled to cationic, amphoteric or anionic branched polypeptides and a new conjugate containing a cationic polypeptide carrier modified with a cell penetrating octaarginine. We investigated in vitro physiological activity of these conjugates in several aspects: in vitro cytotoxicity and cytostatic effect, adhesion and cellular uptake were examined on murine (J774 and L1210) and human (MonoMac6 and HL-60) leukemia cell lines and on murine bone marrow derived macrophages. We found that these processes are dependent on the properties of the carrier, on experimental conditions like concentration and incubation time. We found that attachment of polypeptide and cell penetrating peptide to the bioactive agent, depending on the cell line, could significantly improve the antitumor activity of the drug.     

Novel,quinone-thiosemicarbazone hybrid (QTSCHY) non-platinum antitumor agents: inhibition of DNA biosynthesis in P388 lymphocytic cells by coordinatively unsaturated copper(II) and iron(III) complexes of naphthoquinone thiosemicarbazones

Coordinately unsaturated Cu(II) and Fe(III) complexes of the stoichiometry [Cu(L)Cl] and [Fe(L)Cl₂], where L=tridentate anion of 2-hydroxy-1,4-naphthoquinone 1-thiosemicarbazone (2HNQTSC) and its 3-methyl derivative (3M2HNQTSC), were screenedin vitro against P388 lymphocytic leukemia cells. Copper complexes were found to be more effective inhibitors of DNA synthesis than analogous Fe(III) compounds. The inhibitory activities are suggested to be related to Cu(II)–Cu(I) redox couple or nitrogen adduct formation.     

Structure-antitumour activity relationships for new platinum complexes

Fourteen platinum (Pt) coordination complexes with different ligands, which include both Pt(II) and Pt(IV) complexes, were prepared, characterized and tested for their in vitro cytotoxic effects on KB cells and for their antitumour activity against some tumour systems (L1210 and P388 leukaemia, ADJ/PC6A plasma cell tumour and Yoshida sarcoma).The majority of the ligands were derivatives of aniline or pyridine, but complexes with tranylcypromine, guanethidine and octodrine were also synthetized.Depending on cytotoxicity the Pt-compounds could be divided into 3 groups. The compounds with a high cytotoxicity (ED₅₀ = 0.1–1 μg/ml) were also active against L1210 and P-388 leukaemia; a correlation between cytotoxicity and antitumour activity was not always observed.In these complexes the oxidation state of the Pt appears to be critical for their activity.     

Tetrameric 1:1 and monomeric 1:3 complexes of silver(I) halides with tri(p-tolyl)-phosphine: A structural and biological study

Silver(I) halides react with tri(p-tolyl)phosphine (tptp, C₂₁H₂₁P) in MeOH/MeCN solutions in 1:1 or 1:3 molar ratios to give complexes of formulae {[AgCl(tptp)]₄} (1) or [AgX(tptp)₃] (X = Cl (2), Br (3), I (4)), respectively. The complexes were characterized by elemental analyses, and FT-IR far-IR, FT-Raman, TG and ¹H, ¹³C, ³¹P NMR spectroscopic techniques. Crystal structures of complexes 2-4 were determined by X-ray diffraction at room temperature (rt). The crystal structure of 1 and 4 was also determined at 100(1) and 140(2) K (lt), respectively. In complex 1 four μ3-Cl ions are bonded with four Ag(I) ions forming a cubane while the coordination sphere of silver(I) ions is completed by one P atom from a terminal tri(p-tolyl)phosphine ligand. In complexes 2-3 one terminal halogen and three P atoms from phosphine ligands form a tetrahedral arrangement around the metal ion. Complexes 1-4 were tested for in vitro cytostatic activity against sarcoma cancer cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (PAH, benzo[a]pyrene) carcinogenesis and against murine leukemia (L1210) and human T-lymphocyte (Molt4/C8 and CEM) cells. The silver(I) complexes 1-4 show strong activity.     

Synthesis, antitumor activity and structure-activity relationships of a series of Ru(II) complexes

A series of octahedral Ru(II) polypyridyl complexes, [Ru(phen)(2)L](2+) (L=R-PIP and PIP=2-phenylimidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized by elementary analysis, (1)H NMR and ES-MS, as well as UV-visible spectra and emission spectra. The antitumor activities of these complexes and their corresponding ligands were investigated against mouse leukemia L1210 cells, human oral epidermoid carcinoma KB cells, human promyelocytic leukemia cells (HL-60) and Bel-7402 liver cancer cells by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. It was found that the complexes [Ru(phen)(2)L](2+) (L=R-PIP) exert rather potent activities against all of these cell lines, especially for the KB cells (IC(50)=4.7+/-1.3 microM). The binding affinities of these Ru(II) complexes to CT-DNA (calf thymus DNA), as well as the DNA-unwinding properties on supercoiled pBR322 DNA were also investigated. The results showed that these Ru(II) polypyridyl complexes not only had an excellent DNA-binding property but also possessed a highly effective DNA-photocleavage ability. The structure-activity relationships and antitumor mechanism were also carefully discussed.     

Synthesis and antitumor activity of platinum complexes of protonated diamines

Complexes of the formula cis-[Pt(H$\text{N}\text{+}$^～N)(L)Cl₂], where (H$\text{N}\text{+}$^～N) are the protonated diamines including 3-aminoquinuclidine, N-aminopiperidine, piperazine, N-methylpiperazine, 1,1,4-trimethylpiperazine, and N-methyl-1,4-diazabicyclo [2,2,2] octane (N-methyl-dabco) and L = SCN^?, NO₂^?, Br^?, and F^?, were synthesized from the protonated diamine complexes, [Pt(H$\text{N}\text{+}$^～N)Cl₃]. The antitumor activities of the complexes were evaluated in vitro against L1210 murine leukemia cells, and ID₅₀ values for the L-substituted complexes were compared to values of the parent complexes. In each case it was found that replacement of a chloride ion by SCN^?, NO₂^?, Br^?, or F^?, either reduced or completely eliminated antitumor activity. This effect is explained in terms of the trans-directing ability of the ligand, L, compared to chloride. The NO₂-substituted complex of 3- aminoquinuclidine was tested in vivo and found to exhibit little or no antitumor activity.     

Shikimic acid complexes of platinum. Preparation, reactivity, and antitumor activity of (R,R-1,2-diaminocyclohexane) bis(shikimato) platinum(II). Evidence for a novel rearrangement involving platinum-carbon bond formation

The complex (R,R-1,2-diaminocyclohexane)bis(shikimato)platinum(II) (shikimato = the anion of 3R,4S,5R-trihydroxy-1-cyclohexene-1-carboxylic acid), I, has been synthesized and purified by high performance liquid chromatography (HPLC). The complex is only moderately stable in aqueous solution. Its major hydrolysis product, also purified by HPLC, is proposed to be a unique complex type in which a single shikimate group is coordinated through both the carboxylate oxygen and the C(2) vinylic carbon of the shikimate moiety [Pt(R,R-dach)(O,C-shikimato)], II. In vitro, complex I is active against L1210 leukemia and against an L1210 cell line with acquired resistance to cisplatin. In vivo, the complex is active against L1210, P388, and B16 melanoma; this activity is highly schedule-dependent. Complex II is also active against L1210 leukemia.     

Evaluation of antioxidant and antiproliferative activities of 1,2‐bis (p‐amino‐phenoxy) ethane derivative Schiff bases and metal complexes

In this study, the effects of the two Schiff base derivatives and their metal complexes were tested for MDA concentration, which is an indicator of lipid peroxidation, antioxidant vitamin A, vitamin E, and vitamin C levels in cell culture. A comparison was performed among the groups and it was observed that MDA, vitamin A, vitamin E, and vitamin C concentrations were statistically changed. According to the results, all compounds caused a significant oxidative stress without Zn complexes. Moreover, Mn(II), Cu(II), Zn(II), and Ni(II) complexes of Schiff bases derived from a condensation of 1,2‐bis (p‐aminophenoxy) ethane with naphthaldehydes and 4‐methoxy benzaldehyde were examined in terms of antitumor activity against MCF‐7 human breast cancer and L1210 murine leukemia cells. Furthermore, the derivatives were tested for antioxidative and prooxidative effects on MCF‐7 breast cancer cells. The compounds which were tested revealed that there was an antitumor activity for MCF‐7 and L 1210 cancer cells. Also, some of the compounds induced oxidative harmful.