Interaction of binuclear xylylthiolato(2,2',2"-terpyridine)platinum(II) complexes with DNA

The new binuclear platinum(II) complexes, (1,3-benzenedimethanethiolate-S)di(2,2',2"-terpyridine)diplatinum(II) chloride tetrahydrate, 5, and (1,4-benzenedimethanethiolate-S)di(2,2',2"-terpyridine)diplatinum(II) chloride tetrahydrate, 6, were synthesized in order to investigate the binding of platinum(II) complex with calf thymus DNA, which was examined by UV and CD spectroscopies. Complex 5 interacted strongly with DNA by intercalation compared to 6.     

2,4-Diaryl-5,6-dihydro-1,10-phenanthroline and 2,4-diaryl-5,6-dihydrothieno[2,3-h] quinoline derivatives for topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship study

Designed and synthesized thirty-two 2,4-diaryl-5,6-dihydro-1,10-phenanthroline and 2,4-diaryl-5,6-dihydrothieno[2,3-h] quinoline derivatives as rigid analogs of 2,4,6-trisubstituted pyridines were evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Structure-activity relationship study showed that [2,2';6',2"]-terpyridine skeleton is important for the cytotoxicity against several human cancer cell lines.     

Metabolism of 2,2'-dihydroxybiphenyl by Pseudomonas sp. strain HBP1: production and consumption of 2,2',3-trihydroxybiphenyl.

Cells of Pseudomonas sp. strain HBP1 grown on 2-hydroxy- or 2,2'-dihydroxybiphenyl contain NADH-dependent monooxygenase activity that hydroxylates 2,2'-dihydroxybiphenyl. The product of this reaction was identified as 2,2',3-trihydroxybiphenyl by 1H nuclear magnetic resonance and mass spectrometry. Furthermore, the monooxygenase activity also hydroxylates 2,2',3-trihydroxybiphenyl at the C-3' position, yielding 2,2',3,3'-tetrahydroxybiphenyl as a product. An estradiol ring cleavage dioxygenase activity that acts on both 2,2',3-tri- and 2,2',3,3'-tetrahydroxybiphenyl was partially purified. Both substrates yielded yellow meta-cleavage compounds that were identified as 2-hydroxy-6-(2-hydroxyphenyl)-6-oxo-2,4-hexadienoic acid and 2-hydroxy-6-(2,3-dihydroxyphenyl)-6-oxo-2,4-hexadienoic acid, respectively, by gas chromatography-mass spectrometry analysis of their respective trimethylsilyl derivatives. The meta-cleavage products were not stable in aqueous incubation mixtures but gave rise to their cyclization products, 3-(chroman-4-on-2-yl)pyruvate and 3-(8-hydroxychroman-4-on-2-yl)pyruvate, respectively. In contrast to the meta-cleavage compounds, which were turned over to salicylic acid and 2,3-dihydroxybenzoic acid, the cyclization products are not substrates to the meta-cleavage product hydrolase activity. NADH-dependent salicylate monooxygenase activity catalyzed the conversions of salicylic acid and 2,3-dihydroxybenzoic acid to catechol and pyrogallol, respectively. The partially purified estradiol ring cleavage dioxygenase activity that acted on the hydroxybiphenyls also produced 2-hydroxymuconic semialdehyde and 2-hydroxymuconic acid from catechol and pyrogallol, respectively.     

Synthesis and DNA binding properties of a cationic 2,2':6',2"-terpyridine cobalt(II) complex containing an oligopeptide

The first example of DNA metallointercalator containing an oligopeptide moiety is presented. The ternary cobalt(II) complex [(DOTA)Co(II)(TPY)](ClO(4))(2) (DOTA=1,4,7,10-tetraaza-cyclododecane-2,9-dione, TPY=2, 2':6',2"-terpyridine) was found to be efficient in binding ct-DNA. The binding constant was determined by spectrophotometric titration. In vitro antitumor studies shows that this complex has significant antitumor activity. The single-crystal of a six coordinated oligopeptide cobalt(II) complex [Co(II)(DOTA)(2)](ClO(4))(2) is also reported. The stabilities and species distributions of Co(II)-DOTA (1:1) and DOTA-Co(II)-TPY (1:1:1) systems were investigated by potentiometry titration.     

New chiral oligopyridines-4,4'-bis(disaccharide)-functionalised 2,2'-bipyridines and 4'-(disaccharide)-functionalised 2,2':6',2'-terpyridines

A new class of oligopyridine ligands bearing disaccharides linked to the 4- and 4'-positions of a 2,2'-bipyridine or the 4'-position of a 2,2':6',2'-terpyridine metal-binding domain are described. Representative ligands with furanosylfuranose and pyranosylpyranose (cellobiose) substituents have been prepared.     

Effects of molecular substitution patterns on the cytochrome P-450-dependent metabolism of 2,2',3,5,5',6- and 2,2',3,4,4',6-hexachlorobiphenyl by rat liver microsomal monooxygenases

The metabolism by rat hepatic microsomal cytochrome P-450-dependent monooxygenases of several model substrates that are specific for individual isoforms of cytochrome P-450 and the metabolism by these monooxygenases of two structurally related isomers of hexachlorobiphenyl was studied. The most striking result was that 2,2',3,5,5',6-hexachlorobiphenyl was metabolised in vitro at the rate of 4.5 pmol/mg microsomal protein per min, whereas the other isomer 2,2',3,4,4',6-hexachlorobiphenyl was not metabolised at detectable rates. This finding provides strong evidence for a regioselective oxidative attack by cytochrome P-450-dependent monooxygenase with preferential insertion of oxygen at meta-para unsubstituted carbon atoms. Investigations into the mechanism of this oxidative attack suggest that the ortho hydrogen atom at carbon atom C-6' of 2,2',3,4,4',6-hexachlorobiphenyl was associated with a lower charge (0.075 e) compared with the meta or para hydrogen atoms at carbon atom C-3' and C-4' of 2,2',3,5,5',6-hexachlorobiphenyl (0.086 e). In addition, measurement of the main C-C bond length using MOPAC calculations and X-ray crystalographic data suggests significant differences in the bond-length distance, with the main bond lengths of 1.390, 1.385 and 1.374 A, respectively, for bridgehead to ortho (C1-C2), for ortho to meta (C2-C3), and for meta to para bonds. These results provide evidence that the preferential meta-para oxidative attack is linked to a shorter carbon-carbon bond length and a more positive charge distribution of the corresponding hydrogen atoms.     

Chloro(2,2':6',2"-terpyridine) platinum inhibition of the renal Na+,K+-ATPase

Chloro(2,2':6',2"-terpyridine)platinum, a bulky, hydrophilic reagent, inhibited the renal sodium pumpwith a single exponential time course. K⁺ increased therate constant of the reaction by about twofold; the K⁺concentration dependence was monotonic, with a half-maximal effect observed at 1 mM, consistent with K⁺ acting at a transportsite. Na⁺, Mg²⁺, eosin, and vanadate did notsignificantly alter the rate of reaction. The results of proteolysisand mass spectrometer analysis were consistent with terpyridineplatinum labeling of Cys452, Cys456, or Cys457. Because phenylarsineoxide reacts with vicinal cysteines and did not prevent terpyridineplatinum modification, terpyridine platinum most likely modifiesCys452. This modification prevents ADP binding; interestingly, theanalogous residue in sarco(endo)plasmic reticulumCa²⁺-ATPase (SERCA) is on the exterior of thenucleotide-binding pocket. Thus it appears that the terpyridineplatinum residue is more accessible in the presence of K⁺than in its absence and that terpyridine platinum modification preventsnucleotide binding.

     

New synthesis of (S)-dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethenedioxy-biphenyl-2,2'-dicarboxylate by configuration transform

(R/S)-4,4'-Dimethoxy-5,6,5',6'-dimethenedioxy-2,2'-di-(4(S)-methyl-oxazoline-1)-biphenyl has been synthesized from dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethenedioxy-biphenyl-2,2'-dicarboxylate, and then the diastereoisomer mixture was almost fully converted to a single diastereoisomer with S-configuration ((S)-3) through the key configuration transform promoted by CuI, which was confirmed by CD, HPLC and (13)C NMR. The C(2)-symmetric biphenyl, (S)-dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethenedioxy-biphenyl-2,2'-dicarboxylate was prepared easily via the hydrolysis and ester exchange of (S)-3.     

Chiral overcrowded alkenes; asymmetric synthesis of (3S,3'S)-(M, M)-(E)-(+)-1,1',2,2',3,3',4,4'-octahydro-3,3',7,7'-tetramethyl-4, 4'-biphenanthrylidenes

An asymmetric synthesis route towards (3S,3'S)-(M,M)-(E)-(+)-1,1',2, 2',3,3',4,4'-octahydro-3,3',7,7'-tetramethyl-4,4'-biphenanthrylidene was developed using the Evans procedure as a key step. The absolute configurations of the title compound and of its parent ketone were determined by CD spectroscopy and could be correlated with the stereochemical results of the asymmetric alkylation. Furthermore, a comparison was made with the known (3R,3'R)-(P,P)-(E)-(-)-1,1',2,2', 3,3',4,4'-octahydro-3,3',7,7'-dimethyl-4,4'-biphenanthrylidene. Finally, the X-ray crystallographic analysis of (3S,3'S)-(M, M)-(E)-(+)-1,1',2,2',3,3',4,4'-octahydro-3,3',7,7'-tetramethyl-4, 4'-biphenanthrylidene is presented.     

Synthesis of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives and evaluation of their topoisomerase I and II inhibitory activity,cytotoxicity, and structure–activity relationship

A series of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives were designed, synthesized, and evaluated for their topoisomerase I and II inhibition and cytotoxic activity against several human cancer cell lines. Compounds 10–19 showed moderate topoisomerase I and II inhibitory activity and 20–29 showed significant topoisomerase II inhibitory activity. Structure–activity relationship study revealed that 4-(5-chlorofuran-2-yl)-2-(thiophen-3-yl) moiety has an important role in displaying topoisomerase II inhibition.     

Crystal structure of the novel neutral octahedral complex [(4′-(4-tbutylphenyl)-2,2′:6′,2″-terpyridine)Rh(Br)(acetonyl)2]

The synthesis and the crystal and molecular structure of a unique Rh(III) complex, [Rh^III(Br)(acetonyl)₂(4′-(4-tbutylphenyl)-2,2′:6′,2″-terpyridine)] (1) are described. The yellow crystals separate from the acetone solution of the starting complex [Rh(Br)(COD)]₂ and the ligand 4′-(4-tbutylphenyl)-2,2′:6′,2″-terpyridine after standing at room temperature for a prolonged period of time. The crystals are almost insoluble in all common organic solvents. The single-crystal X-ray structure determination shows that compound 1 is the first Rh-complex with a terdentate nitrogen ligand and two axially oriented, σ-bound acetonyl groups. DFT-calculations on a model complex without the substituent on the terpyridine ligand were carried out and agree very well with the X-ray results, confirming the constitution and geometry of the molecule.     

Synthesis and reactivities of 2,2'-anhydro-1-(3'-deoxy-3'-iodo-5'-O-trityl- beta-D-arabinofuranosyl)thymine.

2,2'-Anhydro-1-(3'-deoxy-3'-iodo-5'-O-trityl-beta-D-arabinofuranosyl) thymine (2) was synthesized from 2',3'-didehydro-3'-deoxythymidine (DHT). Compound 2 was readily converted into the 2',3'-anhydrolyxofuranosyl derivatives 4-6. Treatment of 4a with some nucleophiles (N3-, OMe-, Cl-) gave the corresponding 3'-substituted arabinosyl nucleosides (7a,c,e) together with the minor xylosyl isomers (8a,c,d). 7a,c,e were deprotected to 7b,d,f, respectively.     

2,2',6,6'-Tetrachlorobiphenyl is estrogenic in vitro and in vivo

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants whose effects on biological systems depend on the number of and the positions of the chlorine substitutions. In the present study we examined the estrogenicity of the fully ortho-substituted PCB, 2,2',6,6'-tetrachlorobiphenyl (2,2',6,6'-TeCB). This PCB was chosen as the prototypical ortho-substituted PCB to test the hypothesis that ortho-substitution of a PCB with no para- or meta-chlorine-substitutions results in enhanced estrogenic activity. The results indicate that 2,2',6,6'-TeCB is estrogenic both in vitro, in the MCF-7 cell focus assay, and in vivo, in the rat uterotropic assay. The estrogenic activity elicited by the addition of 5 microM 2,2',6,6'-TeCB to the medium of MCF-7 cultures was inhibited by the estrogen receptor (ER) antagonist, LY156758, suggesting that 2,2',6,6'-TeCB or a metabolite is acting through an ER-dependent mechanism. Results from competitive binding assays using recombinant human (rh) ER indicate that 2,2',6,6'-TeCB does not bind rhERalpha or rhERbeta. A metabolite of 2,2',6,6'-TeCB, 2,2',6,6'-tetrachloro-4-biphenylol (4-OH-2,6,2',6'-TCB), does bind rhERalpha and rhERbeta and is also 10-fold more estrogenic than 2,2',6,6'-TeCB in the MCF-7 focus assay; however, this metabolite is not detected in the medium of MCF-7 cultures exposed to 2,2',6,6'-TeCB. Taken together, the results suggest that the estrogenicity observed in human breast cancer cells and the rat uterus may be due to 1) an undetected metabolite of 2,2',6,6'-TeCB binding to the ER, 2) 2,2',6,6'-TeCB binding directly to a novel form of the ER, or 3) an unknown mechanism involving the ER.     

A simple and efficient synthesis of puromycin, 2,2'-anhydro-pyrimidine nucleosides, cytidines and 2',3'-anhydroadenosine from 3',5'-O-sulfinyl xylo-nucleosides

Synthesis of antibiotics, puromycin and 3'-amino-3'-deoxy-N6,N6-dimethyladenosine 11 was achieved by utilizing the cyclic sulfite 6a of the xylo-3',5'-dihydroxy group as a new protective group. The key synthetic step is the deprotection of the sulfite moiety through the intramolecular cyclization of 2-alpha-carbamate 7. In a similar manner 2,2'-anhydro-pyrimidine nucleosides 15, ribo-cytidines 17 and 2',3'-anhydroadenosine 14 were prepared in high yields from the corresponding sulfites 4, 5, and 6b, respectively.     

DNA-binding behavior of ruthenium(II) complexes containing both group 15 donors and 2,2':6',2''-terpyridine

Tetrafluoroborate salts of cationic ruthenium complexes [Ru(kappa(3)-tpy)(EPh(3))(2)Cl](+) (tpy=2,2':6',2'-terpyridine; E=P, 1 or As, 2) containing both the group 15 donor ligands and tpy and their representative substitution products are reported. Weak interaction {C-H...X (X=Cl, F and pi) and pi-pi interaction} studies revealed the presence of a double helical motif in complex 1, while the complex 2 assumes a single helical motif. Intercalative mode of interaction of the complexes 1 and 2 with calf thymus DNA (ctDNA) has been supported by absorption titration studies.     

Synthesis and evaluation of 2',4',6'-trihydroxychalcones as a new class of tyrosinase inhibitors

In this study, we synthesized a series of hydroxychalcones and examined their tyrosinase inhibitory activity. The results showed that 2',4',6'-trihydroxychalcone (1), 2,2',3,4',6'-pentahydroxychalcone (4), 2',3,4,4',5,6'-hexahydroxychalcone (5), 2',4',6'-trihydroxy- 3,4-dimethoxychalcone (9) and 2,2',4,4',6'-pentahydroxychalcone (15) exhibited high inhibitory effects on tyrosinase with respect to l-tyrosine as a substrate. By the structure-activity relationship study, it was suggested that the 2',4',6'-trihydroxyl substructure in the chalcone skeleton were efficacious for the inhibition of tyrosinase activity. And also, the catechol structure on B-ring of chalcones was not advantageous for the inhibitory potency. Furthermore, 15 (IC(50)=1microM) was found to show the highest activity out of a set of 15 hydroxychalcones, even better than both 2,2',4,4'-tetrahydroxychalcone (13, IC(50)=5microM) and kojic acid (16, IC(50)=12microM), which were known as potent tyrosinase inhibitors. Kinetic study revealed that 15 acts as a competitive inhibitor of tyrosinase with K(i) value of 3.1microM.     

Synthesis and stability studies of 2',3',5'-tri-O-acetyl-2-amino(-N6-cyclopentyl)-1-deazaadenosines

In this article, we report on the synthesis of 2',3',5'-tri-O-acetyl-2-amino-1-deazaadenosine and of 2',3',5'-tri-O-acetyl-2-amino-N(6)-cyclopentyl-1-deazaadenosine, which are very versatile intermediates for the preparation of 2-substituted 1-deazaadenosine derivatives. The two synthesized compounds showed to be quite unstable, with the N(6)-substituted derivatives being less stable than the N(6)-unsubstituted counterpart, according to the calculated HOMO-LUMO energy gap. Stability studies were performed through HPLC-MS analysis.     

Photooxidation of d(TpG) by riboflavin and methylene blue. Isolation and characterization of thymidylyl-(3',5')-2-amino-5-[(2-deoxy-beta-D- erythro-pentofuranosyl)amino]-4H-imidazol-4-one and its primary decomposition product thymidylyl-(3',5')-2,2-diamino-4-[(2-deoxy-beta-D- erythro-pentofuranosyl)amino]-5(2H)-oxazolone.

The major initial product of riboflavin- and methylene blue-mediated photosensitization of 2'-deoxyguanosine (dG) in oxygen-saturated aqueous solution has previously been identified as 2-amino-5-[(2-deoxy-beta-D-erythro-pentofuranosyl)amino] 4H-imidazol-4-one (dlz). At room temperature in aqueous solution dlz decomposes quantitatively to 2,2-diamino-4-[(2-deoxy-beta-D-erythro- pentofuranosyl)amino]-5(2H)-oxazolone (dZ). The data presented here show that the same guanine photooxidation products are generated following riboflavin- and methylene blue-mediated photosensitization of thymidylyl-(3',5')-2'-deoxyguanosine [d(TpG)]. As observed for the monomers, the initial product, thymidylyl-(3',5')-2-amino-5-[(2-deoxy- beta-D-erythro-pentofuranosyl)amino]-4H-imidazol-4-one [d(Tplz)], decomposes in aqueous solution at room temperature to thymidylyl-(3',5')-2,2-diamino-4- [(2-deoxy-beta-D-erythro-pentofuranosyl)amino]-5(2H)-oxazolone [d(TpZ)]. Both modified dinucleoside monophosphates have been isolated by HPLC and characterized by proton NMR spectrometry, fast atom bombardment mass spectrometry, chemical analyses and enzymatic digestions. Among the chemical and enzymatic properties of these modified dinucleoside monophosphates are: (i) d(Tplz) and d(TpZ) are alkali-labile; (ii) d(Tplz) reacts with methoxyamine, while d(TpZ) is unreactive; (iii) d(Tplz) is digested by snake venom phosphodiesterase, while d(TpZ) is unaffected; (iv) relative to d(TpG), d(TpZ) and d(Tplz) are slowly digested by spleen phosphodiesterase; (v) d(Tplz) and d(TpZ) can be 5'-phosphorylated by T4 polynucleotide kinase. The first observation suggests that dlz and dZ may be responsible for some of the strand breaks detected following hot piperidine treatment of DNA exposed to photosensitizers.     

Revisiting the regiospecificity of Burkholderia xenovorans LB400 biphenyl dioxygenase toward 2,2'-dichlorobiphenyl and 2,3,2',3'-tetrachlorobiphenyl

2,2'-Dichlorobiphenyl (CB) is transformed by the biphenyl dioxygenase of Burkholderia xenovorans LB400 (LB400 BPDO) into two metabolites (1 and 2). The most abundant metabolite, 1, was previously identified as 2,3-dihydroxy-2'-chlorobiphenyl and was presumed to originate from the initial attack by the oxygenase on the chlorine-bearing ortho carbon and on its adjacent meta carbon of one phenyl ring. 2,3,2',3'-Tetrachlorobiphenyl is transformed by LB400 BPDO into two metabolites that had never been fully characterized structurally. We determined the precise identity of the metabolites produced by LB400 BPDO from 2,2'-CB and 2,3,2',3'-CB, thus providing new insights on the mechanism by which 2,2'-CB is dehalogenated to generate 2,3-dihydroxy-2'-chlorobiphenyl. We reacted 2,2'-CB with the BPDO variant p4, which produces a larger proportion of metabolite 2. The structure of this compound was determined as cis-3,4-dihydro-3,4-dihydroxy-2,2'-dichlorobiphenyl by NMR. Metabolite 1 obtained from 2,2'-CB-d(8) was determined to be a dihydroxychlorobiphenyl-d(7) by gas chromatographic-mass spectrometric analysis, and the observed loss of only one deuterium clearly shows that the oxygenase attack occurs on carbons 2 and 3. An alternative attack at the 5 and 6 carbons followed by a rearrangement leading to the loss of the ortho chlorine would have caused the loss of more than one deuterium. The major metabolite produced from catalytic oxygenation of 2,3,2',3'-CB by LB400 BPDO was identified by NMR as cis-4,5-dihydro-4,5-dihydroxy-2,3,2',3'-tetrachlorobiphenyl. These findings show that LB400 BPDO oxygenates 2,2'-CB principally on carbons 2 and 3 and that BPDO regiospecificity toward 2,2'-CB and 2,3,2,',3'-CB disfavors the dioxygenation of the chlorine-free ortho-meta carbons 5 and 6 for both congeners.