Osvaldo Cox

Synthesis and characterization of new platinum(II) complexes containing thiazole and imidazole donors III. Dichlorobis(styrylbenzazole)platinum(II) complexes

Platinum(II) complexes of the type cis-[Pt(L)2Cl2], where L is a styrylbenzazole, have been prepared. The benzazoles included derivatives of imidazole, thiazole and oxazole. The ligands and the complexes were characterized by their melting points, elemental analyses, NMR, UV-Vis and IR spectra. The benzazole ligands are all coordinated to the Pt through N. The assignment of cis geometry for the complexes was based on the method of synthesis, comparison with a styrylbenzazole complex of known geometry, and far-IR spectral data.

Dna binding-independent anti-proliferative action of benzazolo[3,2-α]quinolinium DNA intercalators

The proposed mechanism of action of the antineoplastic drug 3-nitrobenzothiazolo[3,2-& agr;]quinolinium chloride (NBQ-2) involves its interaction with DNA by intercalation and inhibition of topoisomerase II activity by arresting the enzyme in a covalent cleavage complex. In an attempt to identify some structural determinants for activity and develop a molecular structure/cytotoxicity correlation, four new structural analogs of the antitumor NBQ-2 were prepared and their cytotoxic activity and DNA binding properties were investigated. The cytotoxic activity was evaluated against six different human tumor cell lines: U937, K-562, HL-60, HT-29, HeLa, and A431. The results showed that these new drugs elicit pronounced cytotoxic effects against U937, K-562, HL-60 and A431 while HeLa and HT-29 were less sensitive to the new drugs. This apparent selectivity was different to that of m-AMSA, a drug currently used for cancer treatment. Since the interaction of NBQ-2 to DNA by intercalation has been proposed as the initial step leading to its antineoplastic activity, DNA binding and changes in DNA contour length induced by the new NBQ-2 structural analogs were also investigated using calf thymus and human DNA. The drug, 7-(1-propenyl)-3-nitrobenzimidazolo[3,2-& agr;]quinolinium chloride (NBQ-59) was the most cytotoxic agent of the analog series (IC50 = 16 & mgr;M for HL-60 cells), however, it demonstrated the weakest binding to DNA (Kint = 0.9 × 105 M-1 for calf thymus DNA). NBQ-59 was also found to be a poor intercalator into the DNA double helix. Therefore, our results suggest that DNA binding is not the primary mechanism of drug action for this family of compounds. In addition structural determinants important for cytotoxicity of the benzazolo quinolinium chlorides were suggested by our results. In particular, the nitro group in the 3 position does not seem to be necessary for bioactivity, while substitutions in the benzazolo moiety have striking effects on the biological activity of the drugs.

Reductive activation of benzazolo[3,2-a]-quinolinium chlorides

Initial ferricytochrome c (Cyt(III)c) reduction rates occurring in aerobic or anaerobic solutions containing either 3-nitrobenzothiazolo[3,2-a]-(NBQCl), 1-ethyl-3-nitrobenzimidazolo[3,2-a]-(ENBIQCl), 7-ethylbenzimidazolo[3,2-a]quinolinium chloride (EHBIQCL), or nitrofurantoin (NFT) and xanthine/xanthine oxidase were measured. Maximum rates in nitrogen-saturated solutions follow the order NFT > NBQCL > ENBIQCL > EHBIQCL. These rates correlate linearly with the half-wave reduction potentials (E1/2) of these compounds. With the exception of EHBIQCl, smaller rates of Cyt(III)c reduction were obtained in air-saturated than in nitrogen-saturated solutions at the quinolinium salt concentrations used. Larger concentrations of superoxide dismutase (SOD) are needed for 50% inhibition of the Cyt(III)c reduction reaction for heterocyclic compounds with larger E1/2 values. Thus, measurement of the portion of the Cyt(III)c reduction rate under air that is inhibited by SOD does not account solely for the production of superoxide. These observations suggest that NBQCL, ENBIQCl, and less probably EHBIQCl may interfere with mitochondrial energy metabolism or induce DNA damage through reduced intermediates.

Crystal and molecular structure of 2-(2'-chloro-5'-nitrostyryl)benzoselenazole

The title compound C15H9ClN2O2Se (nsbse) is orthorhombic, witha=6.823(2),b=7.860(2),c=26.349(5) Å,Z=4,Dx=1.709,μ(MoKα)=28.3 cm−1,F(000)=720,T=298K in space groupP212121. The structure was solved by heavy atom and Fourier methods and refined toR=0.045 for 1095 unique observed reflections. The molecule is almost planar, with a dihedral angle of 4.8(2)° between the benzoselenazole and phenyl rings. The C-Se-C angle in the selenazole ring is very small, 84.6(4)°, while the C-N-C angle in that ring is 113.7(7)°.

New Synthesis of Bicyclo [3.1.0] Hex-3-en-2-one

Abstract As part of our research efforts we had to prepare quantities of bicyclo[3.1.0] hex-3-en-2-one (1). Attempts to follow the previously described procedure for the synthesis of 1 1 produced unsatisfactory yields, consequently we decided to explore other synthetic approaches to 1. The method described herein envolves fewer steps and the yields for each step are quite satisfactory.

Structure of a complex of platinum(II) with 2-(2-chloro-5-nitrostyryl)benzothiazole

Tetraethylammonium tribromo[2-(2-chloroseveral derivatives of the styrylbenzothiazoles (Cox, 5-nitrostyryl)benzothiazole]platinate(II), [(C2Hs)4N][PtBra(C 15H9C1N2028)], M r = 881.8, monoclinic, P2,/c, a=9 .454(4) , b=20.137(10), c = 15.071 (7)A, f l=99.25 (3) ° , V= 2831.9 A 3, Dx= 2.07 Mg m -3, Z = 4, 2(Mo Ka) = 0.71073 A, /~(Mo Ks) = 9.39 mm -~, F(000) = 1680, T = 169 K, final R = 0.050 for 2286 observed reflections. The [PtBra(nsb)]unit has square-planar geometry about the Pt, with the nsb coordinated to the Pt through the N of the thiazole ring. The ligand is non-planar, with a dihedral angle of 60.1 (4) ° between the benzothiazole and the nitrobenzene rings. Introduction. Platinum(II) complexes with imidazole, thiazole and other N-donor heterocyclic ligands have been studied for their potential antitumor properties (Dehand & Jordanov, 1975, 1976; Van Kralingen & Reedijk, 1978; Van Kralingen, Reedijk & De Ridder, 1979). Some Schiff bases derived from thiazoles and benzothiazoles (Dash, Patra & Praharaj, 1980) and 0108-2701/87/071258-04501.50 Jackson, Vargas, Baez, Colon, Gonzalez & de Leon, 1982) have also shown biological activity. The complex [PtBr3(nsb)]where nsb is 2-(2-chloro-5-nitrostyryl)benzothiazole, is of particular interest because of the possible synergism between the nsb ligand, shown below, and the metal ion.

Structure of a styrylbenzothiazole platinum(II) complex: [NEt4][PtBr3(asb)].

Tetraethylammonium tribromo[2-(2- acetoxystyryl)benzothiazole]platinate(II), [(C2H5)4N]-[PtBr3(C17H13NO2S)], Mr = 860.4 monoclinic, P21/c, a = 11.230 (9), b = 19.333 (4), c = 13.685 (6) A, beta = 101.06 (4) degrees, V = 2916 (4) A3, Z = 4, D chi = 1.96 g cm-3, lambda(Mo K alpha) = 0.71073 A, mu = 90.3 cm-1, F(000) = 1648, T = 296 K, final R = 0.047 for 3384 unique observed reflections. The [PtBr3(asb)]- unit has square-planar geometry about the Pt, with the asb coordinated to the Pt through the N of the thiazole ring and a Pt-N bond distance of 2.010 (8) A. The average Pt-Br distance is 2.426 (7) A. The ligand is non-planar with a dihedral angle of 22.4 (7) degrees between the benzothiazole and the acetoxybenzene rings. The dihedral angles between the platinum coordination plane and the benzothiazole and benzene rings are 85.7 (1) and 71.3 (3) degrees respectively.

Structure of a styrylbenzoxazole derivative

Chloro-5-nitrostyryl)benzoxazole (nsbo), C15H9C1N203, Mr = 300.70, monoclinic, P2./c, a = 7.030 (3), b = 13.55 ~!i c = 15.40 (1) A,/3 = 114.77 (3) °, V= 1332 (3) Z = 4, Dx = 1.498 g cm -3, A(Mo Ka) = 0.71073 ~, /x = 2.94 cm-l, F(000) = 616, T = 298 K, final R = 0.043

Structure of cis-Pt(asb)2Cl2, a platinum(II) complex with a styrylbenzothiazole ligand

cis-Bis[2-(2-acetoxystyryl)benzothiazole]dichloroplatinum(II), [PtCl2(C17H13NO2S)2], Mr = 856.7, triclinic, P1, a = 12.145 (6), b = 12.859 (4), c = 11.021 (5) A, alpha = 105.88 (3), beta = 90.64 (4), gamma = 87.64 (4) degrees, V = 1654 (2) A3, Z = 2, D chi = 1.72 g cm-3, lambda(Mo K alpha) = 0.71073 A, mu = 46.1 cm-1, F(000) = 840, T = 296 K, final R = 0.029 for 6121 unique observed reflections. The [PtCl2(asb)2] complex has square-planar geometry about the Pt, with the asb coordinated to the Pt through the N of the thiazole ring. The average Pt-N and Pt-Cl bond distances are 2.035 (1) and 2.287 (5) A. The ligand is non-planar with an average dihedral angle of 36 (3) degrees between the benzothiazole and the benzene rings. The dihedral angles between the platinum coordination plane and the benzothiazole and benzene rings are 78 (4) and 69 (7) degrees respectively. The acetoxybenzene rings in the two ligands have different orientations with respect to the olefin C atoms.