Trans Adducts Research Articles

Density functional study on the ClCO + NO2 reaction

Various reaction pathways on the potential energy surface for the ClCO+NO2, radicals which are both known to be upper atmosphere pollutants, were investigated at the B3LYP level of theory using the 6-311G(d) and 6-311+G(3df) basis sets. The energetics were refined with G3//B3LYP and CBS-QB3 calculations. The following reaction channels between the two are the most probable: (i) the formation of ClNO+CO2 or ClON+CO2 via cis–trans ClC(O)ONO or cis–cis ClC(O)ONO intermediates, respectively, and (ii) the formation of the low-lying adduct trans–trans ClC(O)ONO. The other adduct ClC(O)NO2 is calculated to lie about 20kcalmol−1 higher in energy than trans–trans ClC(O)ONO. Thus, trans–trans ClC(O)ONO can be considered to be a sink for ClCO radical on the ground-state surface.

Robust Incision of Benoz[a]pyrene-7,8-dihyrodiol-9,10-epoxide−DNA Adducts by a Recombinant Thermoresistant Interspecies Combination UvrABC Endonuclease System

Prokaryotic DNA repair nucleases are useful reagents for detecting DNA lesions. UvrABC endonuclease, encoded by the UvrA, UvrB, and UvrC genes can incise DNA containing bulky nucleotide adducts and intrastrand cross-links. UvrA, UvrB, and UvrC were cloned from Bacillus caldotenax (Bca)and UvrC from Thermatoga maritima (Tma), and recombinant proteins were overexpressed in and purified from Escherichia coli. Incision activities of UvrABC composed of all Bca-derived subunits (UvrABC(Bca)) and an interspecies combination UvrABC composed of Bca-derived UvrA and UvrB and Tma-derived UvrC (UvrABC(Tma)) were compared on benoz[a]pyrene-7,8-dihyrodiol-9,10-epoxide (BPDE)-adducted substrates. Both UvrABC(Bca) and UvrABC(Tma) specifically incised both BPDE-adducted plasmid DNAs and site-specifically modified 50-bp oligonucleotides containing a single (+)-trans- or (+)-cis-BPDE adduct. Incision activity was maximal at 55-60 degrees C. However, UvrABC(Tma) was more robust than UvrABC(Bca) with 4-fold greater incision activity on BPDE-adducted oligonucleotides and 1.5-fold greater on [(3)H]BPDE-adducted plasmid DNAs. Remarkably, UvrABC(Bca) incised only at the eighth phosphodiester bond 5' to the BPDE-modified guanosine. In contrast, UvrABC(Tma) performed dual incision, cutting at both the fifth phosphodiester bond 3' and eighth phosphodiester bond 5' from BPDE-modified guanosine. BPDE adduct stereochemistry influenced incision activity, and cis adducts on oligonucleotide substrates were incised more efficiently than trans adducts by both UvrABC(Bca) and UvrABC(Tma). UvrAB-DNA complex formation was similar with (+)-trans- and (+)-cis-BPDE-adducted substrates, suggesting that UvrAB binds both adducts equally and that adduct configuration modifies UvrC recognition of the UvrAB-DNA complex. The dual incision capabilities and higher incision activity of UvrABC(Tma) make it a robust tool for DNA adduct studies.

Inhibition of Werner Syndrome Helicase Activity by Benzo[a]pyrene Diol Epoxide Adducts Can Be Overcome by Replication Protein A

RecQ helicases are believed to function in repairing replication forks stalled by DNA damage and may also play a role in the intra-S-phase checkpoint, which delays the replication of damaged DNA, thus permitting repair to occur. Since little is known regarding the effects of DNA damage on RecQ helicases, and because the replication and recombination defects in Werner syndrome cells may reflect abnormal processing of damaged DNA associated with the replication fork, we examined the effects of specific bulky, covalent adducts at N(6) of deoxyadenosine (dA) or N(2) of deoxyguanosine (dG) on Werner (WRN) syndrome helicase activity. The adducts are derived from the optically active 7,8-diol 9,10-epoxide (DE) metabolites of the carcinogen benzo[a]pyrene (BaP). The results demonstrate that WRN helicase activity is inhibited in a strand-specific manner by BaP DE-dG adducts only when on the translocating strand. These adducts either occupy the minor groove without significant perturbation of DNA structure (trans adducts) or cause base displacement at the adduct site (cis adducts). In contrast, helicase activity is only mildly affected by intercalating BaP DE-dA adducts that locally perturb DNA double helical structure. This differs from our previous observation that intercalating dA adducts derived from benzo[c]phenanthrene (BcPh) DEs inhibit WRN activity in a strand- and stereospecific manner. Partial unwinding of the DNA helix at BaP DE-dA adduct sites may make such adducted DNAs more susceptible to the action of helicase than DNA containing the corresponding BcPh DE-dA adducts, which cause little or no destabilization of duplex DNA. The single-stranded DNA binding protein RPA, an auxiliary factor for WRN helicase, enabled the DNA unwinding enzyme to overcome inhibition by either the trans-R or cis-R BaP DE-dG adduct, suggesting that WRN and RPA may function together to unwind duplex DNA harboring specific covalent adducts that otherwise block WRN helicase acting alone.

A Novel Chiral Ferrocene-Based Amidine/Amidinato Ligand and Its Rhodium Complexes

The N,N‘-bisferrocenyl-substituted chiral formamidine 1 (N,N‘-bis[(S)-2-{(1R)-1-(diphenylphosphino)ethyl}ferrocen-1-yl]formamidine) was prepared from commercially available {(1R)-1-(dimethylamino)ethyl}ferrocene by a multistep procedure in an overall yield of 29%. Deprotonation of 1 followed by addition of [Rh2Cl2(COD)2] yielded the (formamidinato)rhodium(I) complex 2 [(N,N‘-bis[(S)-2-{(1R)-1-(diphenylphosphino)ethyl}ferrocen-1-yl]formamidinato)rhodium(I)]. Direct reaction of formamidine 1 with [Rh2Cl2(COD)2] led to complex 10 [(κ-N,P-bis[(S)-2-{(1R)-1-(diphenylphosphino)ethyl}ferrocen-1-yl]formamidine)(chloro)(η4-1,5-cyclooctadiene)rhodium(I)], which was converted to 2 upon addition of base. Oxidative addition of methyl chloride or methyl iodide to 2 yielded the trans adducts 11 [(N,N‘-bis[(S)-2-{(1R)-1-(diphenylphosphino)ethyl}ferrocen-1-yl]formamidinato)(chloro)(methyl)rhodium(III)] and 12 [(N,N‘-bis[(S)-2-{(1R)-1-(diphenylphosphino)ethyl}ferrocen-1-yl]formamidinato)(iodo)(methyl)rhodium(III)], the configurations of which were determined by means of NMR and, in the case of the Rh(III) methyl chloride adduct 11, by X-ray analysis.

Structure of a High Fidelity DNA Polymerase Bound to a Benzo[a]pyrene Adduct That Blocks Replication

Of the carcinogens to which humans are most frequently exposed, the polycyclic aromatic hydrocarbon benzo[a]pyrene (BP) is one of the most ubiquitous. BP is a byproduct of grilled foods and tobacco and fuel combustion and has long been linked to various human cancers, particularly lung and skin. BP is metabolized to diol epoxides that covalently modify DNA bases to form bulky adducts that block DNA synthesis by replicative or high fidelity DNA polymerases. Here we present the structure of a high fidelity polymerase from a thermostable strain of Bacillus stearothermophilus (Bacillus fragment) bound to the most common BP-derived N2-guanine adduct base-paired with cytosine. The BP adduct adopts a conformation that places the polycyclic BP moiety in the nascent DNA minor groove and is the first structure of a minor groove adduct bound to a polymerase. Orientation of the BP moiety into the nascent DNA minor groove results in extensive disruption to the interactions between the adducted DNA duplex and the polymerase. The disruptions revealed by the structure of Bacillus fragment bound to a BP adduct provide a molecular basis for rationalizing the potent blocking effect on replication exerted by BP adducts.

Synthesis of the B-ring of FR182877. Investigation of the reactions of 6-fumaryl 1,3,8-nonatrienes

Investigation of the intramolecular Diels–Alder reactions of 6-fumaryl 1,3,8-nonatrienes, substituted at the C5 by a vinyl group, to afford the B-ring of FR182877 are reported. The synthesis of the required 1,3,8-nonatriene was achieved quickly and in high yield. 6-Fumaryl 1,3,8-nonatrienes substituted at the C5 by a vinyl group were found to undergo competing tandem sigmatropic rearrangement/Diels–Alder cyclisation when heated under standard Diels–Alder cyclisation conditions. This rearrangement became the exclusive pathway when the reaction was performed in the presence of a Lewis acid. As expected from modeling studies, the major intramolecular Diels–Alder cyclisation product was the desired exo- trans adduct, which was required for the synthesis of FR182877. Intrigued by the rearrangements, a number of alterations were made to the 1,3,8-nonatriene. Replacement of the fumaryl group by an acetyl group resulted in the diminished reactivity of the 1,3,8-nonatriene with neither rearrangements nor cycloadditions observed. Variation of the C5 substituent was found to be very important in determining the π-diastereoselectivity of the Diels–Alder cyclisation.

Structural characterization of isomeric 2,3,5‐substituted tetrahydropyrrolo[3,4‐d]isoxazole‐4,6‐diones prepared by cycloaddition of N‐methyl‐C‐arylnitrones to N‐phenyl‐ or N‐methylmaleimide

Abstract1,3‐Dipolar cycloaddition reactions of N‐methyl‐C‐arylnitrones with N‐phenyl‐ or N‐methylmaleimide were studied. The reaction of p‐dimethylamino‐, 4‐benzyloxy‐3‐methoxy‐, p‐nitro‐ and p‐chloro‐substituted phenylnitrones with N‐phenylmaleimide gave cis and trans cycloadducts but that of the corresponding phenylnitrones with N‐methylmaleimides only the cis adducts in the case of p‐dimethylamino and 4‐benzyloxy‐3‐methoxy substitution. All cis adducts attain a biased conformation whereas the trans forms are shown (by 1H NMR at 233 K and 13C NMR at 208 K) to be mixtures of two invertomers, namely o‐(N‐lone pair antiperiplanar to 3H; minor) and i‐conformations (3H‐C‐C‐3aH dihedral angle close to 90°; major). PM3 and DFT calculations at the B3LYP/6–31G(d) level of theory prove qualitatively that these two conformers of the trans adduct are of comparable stability and represent energy minima.

Disulfidation of Alkynes and Alkenes with Gallium Trichloride.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Addition of lithiated 5-hydroxymethyl-1,3-dithiane to benzaldehyde: HMPA-controlled trans stereoselectivity.

Addition of 5-substituted dithianyl anions to carbonyl compounds normally produces trans adducts. The presence of a nucleophilic hydroxymethyl group in position 5 dramatically decreases the trans stereoselectivity of the reaction in THF. The trans/cis ratio shows a bell curve dependence on HMPA, fitted to a quantitative model involving a series of equilibrated ion pairs, of which an intermediate contact ion pair possessing three (effective) HMPA molecules yields the trans adduct with much higher stereoselectivity. [structure: see text]

Benzo[a]pyrene diol epoxide forms covalent adducts with deoxycytidylic acid by alkylation at both exocyclic amino N(4) and ring imino N-3 positions.

The carcinogen 7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) alkylates DNA at dGuo, dAdo, and dCyd. dCyd adducts, formed in small amounts, elute near the more abundant dGuo adducts. We isolated the dCyd adducts formed with dCMP. Each BPDE enantiomer forms three major adducts with dCMP, two cis and one trans. The trans adduct and one of the cis adducts form by alkylation at exocyclic N(4), while the second cis adduct is a dUrd adduct formed by alkylation at ring N-3 followed by deamination. Epoxide ring-opening geometries were assigned on the basis of halide and temperature effects on adduct yield, the sign of the major CD band, and benzo ring proton NMR coupling constants. One of each set of cis adducts is fluorescent (FL), and the other is nonfluorescent (NF). The trans and FL cis adducts have fluorescence quantum yields 40-50% of that of the BPDE hydrolysis product. The long wavelength UV maxima of the FL and NF cis adducts are red-shifted 1 and 3 nm relative to the trans adduct. (1)H NMR deuterium exchange experiments indicate that in the trans and FL cis adducts N(4)-H is coupled to C10-H. Adduct formation experiments with methyl-protected Cyd derivatives show that NF cis adducts result from alkylation at N-3. MS results, pK(a) measurements, and dUrd alkylation experiments indicate that the N-3 dCyd adducts spontaneously deaminate to dUrd adducts. NMR coupling constants show that in the NF cis adduct the C7 and C8 substituents are quasi equatorial and the C9 substituent is quasi axial, unlike in other cis BPDE adducts. (1)H NOESY spectra of the (-)-BPDE NF cis adduct reveal that it exists in two conformers. Molecular modeling shows that the conformers result from two low-energy conformations of very similar energies with the pyrimidine in opposite orientations, separated by significant barriers to rotation of the uracil moiety.

Thermodynamic and kinetic data for adduct formation, cis-trans isomerization and redox reactions of ML4 complexes: a case study with rhodium- and iridium-tropp complexes in d8, d9 and d10 valence electron configurations (tropp=dibenzotropylidene phosphanes).

The formation of adducts of the square-planar 16-electron complexes trans-[M(tropp(ph))(2)](+) and cis-[M(tropp(ph))(2)](+) (M=Rh, Ir; tropp(Ph)=5-diphenylphosphanyldibenzo[a,d]cycloheptene) with acetonitrile (acn) and Cl(-), and the redox chemistry of these complexes was investigated by various physical methods (NMR and UV-visible spectroscopy, square-wave voltammetry), in order to obtain some fundamental thermodynamic and kinetic data for these systems. A trans/cis isomerization cannot be detected for [M(tropp(ph))(2)](+) in non-coordinating solvents. However, both isomers are connected through equilibria of the type trans-[M(tropp(ph))(2)](+)+L<==>[ML(tropp(ph))(2)](n)<==>cis-[M(tropp(ph))(2)](+)+L, involving five-coordinate intermediates [ML(tropp(ph))(2)](n) (L=acn, n=+1; L=Cl(-), n=0). Values for K(d) (K(f)), that is, the dissociation (formation) equilibrium constant, and k(d) (k(f)), that is, the dissociation (formation) rate constant, were obtained. The formation reactions are fast, especially with the trans isomers (k(f)>1x10(5) m(-1) s(-1)). The reaction with the sterically more hindered cis isomers is at least one order of magnitude slower. The stability of the five-coordinate complexes [ML(tropp(ph))(2)](n) increases with Ir>Rh and Cl(-)>acn. The dissociation reaction has a pronounced influence on the square-wave (SW) voltammograms of trans/cis-[Ir(tropp(ph))(2)](+). With the help of the thermodynamic and kinetic data independently determined by other physical means, these reactions could be simulated and allowed the setting up of a reaction sequence. Examination of the data obtained showed that the trans/cis isomerization is a process with a low activation barrier for the four-coordinate 17-electron complexes [M(tropp(ph))(2)](0) and especially that a disproportionation reaction 2 trans/cis-[M(tropp(ph))(2)](0)-->[M(tropp(ph))(2)](+)+[M(tropp(ph))(2)](-) may be sufficiently fast to mask the true reactivity of the paramagnetic species, which are probably less reactive than their diamagnetic equilibrium partners.

Supercoiled DNA Promotes Formation of Intercalated cis-N2-Deoxyguanine Adducts and Base-Stacked trans-N2-Deoxyguanine Adducts by (+)-7R,8S-Dihydrodiol-9S,10R-epoxy-7,8,9,10-tetra- hydrobenzo[a]pyrene

The highly reactive and mutagenic benzo[a]pyrene metabolite, (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), forms predominantly N2-deoxyguanine DNA adducts in two stereoisomeric configurations (cis and trans). In previous in vitro assays using oligonucleotide substrates site specifically modified with cis- and trans-BPDE adducts, the nucleotide excision repair (NER) systems of eukaryotes and prokaryotes incise cis-BPDE adducts more efficiently than trans-BPDE adducts [Hess, et al. (1997) Mol. Cell Biol 17, 7069; Zou, et al. (2001) Biochemistry 40, 2923). We investigated the influence of DNA secondary structure on stereospecificity of BPDE adduct formation, and incision of BPDE adducts by the prokaryotic UvrABC NER endonuclease was examined. BPDE adducts formed at low density on supercoiled plasmids were incised 6-7-fold better by the thermoresistant Bacillus caldotenaxUvrABC than were BPDE adducts formed on linear DNA. Linearizing supercoiled plasmid DNAs after BPDE adduct formation did not diminish incision efficiency. These results suggested that configuration and/or conformation of adducts formed on linear and supercoiled DNAs differed. This hypothesis was confirmed by low temperature fluorescence spectroscopy of adducted supercoiled and linear DNAs. Spectroscopic results indicated that intercalated cis-BPDE adducts as well as base-stacked trans-BPDE adducts formed more abundantly in supercoiled DNA than in linear DNA. A higher cis to trans adduct ratio in supercoiled DNA was confirmed by high resolution [32P]postlabeling analyses. These results demonstrate that DNA secondary structure influences both configuration and conformation of BPDE adducts formed at low density (approximately 1 adduct/kbp) and suggests that the ratio of cis- to trans-BPDE adducts and amount of base-stacked trans adducts formed under physiological exposure conditions may be higher than inferred from high dose experiments.

Disulfidation of alkynes and alkenes with gallium trichloride.

[reaction: see text] Treatment of diphenyl disulfide and terminal alkynes with gallium trichloride afforded (E)-1,2-diphenylthio-1-alkenes selectively (E/Z > 20/1). Alkenes also underwent this reaction to form trans adducts.

Theoretical Study of the Spin Trapping of Hydroxyl Radical by Cyclic Nitrones: A Density Functional Theory Approach

The hydroxyl radical (*OH) is an important mediator of biological oxidative stress, and this has stimulated interest in its detection. 5,5-Dimethyl-1-pyrroline N-oxide (DMPO) and its alkoxycarbonyl and alkoxyphosphoryl analogues have been employed as spin traps for electron paramagnetic resonance (EPR) spectroscopic radical detection. Energies of optimized geometries of nitrones and their corresponding *OH adducts were calculated using density functional theory (DFT) at the B3LYP/6-31+G//B3LYP/6-31G level. Calculations predict that the trans adduct formation is favored in alkoxycarbonyl nitrones, while cis adducts with intramolecular H-bonding is favored for alkoxyphosphoryl nitrones. Addition of *OH to a phosphoryl-substituted nitrone is more exoergic than the carbonylated nitrones. Charge and spin densities on the nitrone spin traps were correlated with their rates of addition with *OH, and results show that the charge density on the nitronyl C, the site of *OH addition, is more positive in phosphorylated nitrones compared to DMPO and the alkoxycarbonyl nitrones. The dihedral angle between the beta-H and nitroxyl O bonds is smaller in phosphorylated nitrones, and that aspect appears to account for the longer half-lives of the spin adducts compared to those in DMPO and alkoxycarbonyl nitrones. Structures of nitrones with trifluoromethyl-, trifluoromethylcarbonyl-, methylsulfonyl-, trifluoromethylsulfonyl-, amido-, spiropentyl-, and spiroester substituents were optimized and their energies compared. Amido and spiroester nitrones were predicted to be the most suitable nitrones for spin trapping of *OH due to the similarity of their thermodynamic and electronic properties to those of alkoxyphosphoryl nitrones. Moreover, dimethoxyphosphoryl substitution at C-5 was found to be the most efficient substitution site for spin trapping of *OH, and their spin adducts are predicted to be the most stable of all of the isomeric forms.

DNA-protein cross-linking by trans-[PtCl(2)(E-iminoether)(2)]. A concept for activation of the trans geometry in platinum antitumor complexes.

The structure-pharmacological activity relationships generally accepted for antitumor platinum compounds stressed the necessity for the cis-[PtX(2)(amine)(2)] structure while the trans-[PtX(2)(amine)(2)] structure was considered inactive. However, more recently, several trans-platinum complexes have been identified which are potently toxic, antitumor-active and demonstrate activity distinct from that of conventional cisplatin (cis-[PtCl(2)(NH(3))(2)]). We have shown in the previous report that the replacement of ammine ligands by iminoether in transplatin (trans-[PtCl(2)(NH(3))(2)]) results in a marked enhancement of its cytotoxicity so that it is more cytotoxic than its cis congener and exhibits significant antitumor activity, including activity in cisplatin-resistant tumor cells. In addition, we have also shown previously that this new trans compound (trans-[PtCl(2)(E-iminoether)(2)]) forms mainly monofunctional adducts at guanine residues on DNA, which is generally accepted to be the cellular target of platinum drugs. In order to shed light on the mechanism underlying the antitumor activity of trans-[PtCl(2)(E-iminoether)(2)] we examined oligodeoxyribonucleotide duplexes containing a single, site-specific, monofunctional adduct of this transplatin analog by the methods of molecular biophysics. The results indicate that major monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] locally distort DNA, bend the DNA axis by 21 degrees toward the minor groove, are not recognized by HMGB1 proteins and are readily removed from DNA by nucleotide excision repair (NER). In addition, the monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] readily cross-link proteins, which markedly enhances the efficiency of this adduct to terminate DNA polymerization by DNA polymerases in vitro and to inhibit removal of this adduct from DNA by NER. It is suggested that DNA-protein ternary cross-links produced by trans-[PtCl(2)(E-iminoether)(2)] could persist considerably longer than the non-cross-linked monofunctional adducts, which would potentiate toxicity of this antitumor platinum compound toward tumor cells sensitive to this drug. Thus, trans-[PtCl(2)(E-iminoether)(2)] represents a quite new class of platinum antitumor drugs in which activation of trans geometry is associated with an increased efficiency to form DNA-protein ternary cross-links thereby acting by a different mechanism from 'classical' cisplatin and its analogs.

New biomimetic chemistry in water: the anomalous ‘salting-in’ of neutral compounds of natural amino acids with transition metals

The addition of simple salts [such as CaCl 2, MgCl 2 and AgNO 3] greatly enhances the solubility in water of many stable non-electrolytes [M(α) n ] where M is a transition metal ion, α represents the conjugate base of a natural amino acid Hα (operating as a bidentate chelating ligand) and n is the oxidation state of the metal ion. The complex compounds are ‘salted-in’. Both kinetically labile (Cu 2+) and inert (Co 3+, Cr 3+) ions show the effects. Some are due to local changes in the thermodynamic activity of water. The concept of a ‘spectator’ ion is questioned and ‘cybotaxis’ revived. Novel equilibria have been detected in a number of cases [with Cu(α) 2] and several solid adducts are described. The novel adducts trans-[Cu(glyO −) 2]·2AgNO 3 ( 1) and trans, trans-[Cu(glyO −) 2Cl 2][Mg(H 2O) 6]·H 2O ( 2), have been isolated from aqueous silver nitrate and magnesium chloride solutions respectively. Structural features of both are reported and in each case the glycinate ligands coordinate to the copper atoms in a trans arrangement. Structural features of other adducts are briefly reported.

DNA binding by antitumor trans-[PtCl2(NH3)(thiazole)]. Protein recognition and nucleotide excision repair of monofunctional adducts.

Antitumor effects of cis-diamminedichloroplatinum(II) (cisplatin) and the clinical inactivity of its trans isomer (transplatin) have been considered a paradigm for the classical structure-activity relationships of platinum drugs. However, several new analogues of transplatin which exhibit a different spectrum of cytostatic activity including activity in tumor cells resistant to cisplatin have been recently identified. Analogues containing the planar amine ligand of the general structure trans-[PtCl(2)(NH(3))(L)], where L = planar amine, represent an example of such compounds. DNA is believed to be the major pharmacological target of platinum compounds. To contribute to the understanding of mechanisms underlying the activation of trans geometry in transplatin analogues containing planar amine ligands, various biochemical and biophysical methods were employed in previous studies to analyze the global modifications of natural DNA by trans-[PtCl(2)(NH(3))(L)]. These initial studies have revealed some unique features of the DNA binding mode of this class of platinum drugs. As the monofunctional lesions represent a significant fraction of stable adducts formed in DNA by bifunctional antitumor trans-platinum compounds with planar ligands, we analyzed in the present work short DNA duplexes containing the single, site-specific monofunctional adduct of a representative of this class of platinum drugs, antitumor trans-[PtCl(2)(NH(3))(thiazole)]. It has been shown that, in contrast to the adducts of monodentate chlorodiethylenetriamineplatinum(II) chloride or [PtCl(NH(3))(3)]Cl, the monofunctional adduct of trans-[PtCl(2)(NH(3))(thiazole)] inhibits DNA synthesis and creates a local conformational distortion similar to that produced in DNA by the major 1,2-GG intrastrand CL of cisplatin, which is considered the lesion most responsible for its anticancer activity. In addition, the monofunctional adducts of trans-[PtCl(2)(NH(3))(thiazole)] are recognized by HMGB1 domain proteins and removed by the nucleotide excision repair system similarly as the 1,2-GG intrastrand CL of cisplatin. The results of the present work further support the view that the simple chemical modification of the structure of an inactive platinum compound alters its DNA binding mode into that of an active drug and that processing of the monofunctional DNA adducts of the trans-platinum analogues in tumor cells may be similar to that of the major bifunctional adducts of "classical" cisplatin.

Enantioselective Vicinal Bis‐acylation of Olefins.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Photoactivated hydrosilylation reaction of alkynes

The photoactivated (350 nm) hydrosilylation of alkynes by silanes catalyzed by platinum(II) bis(acetylacetonato) has been studied. Platinum(II) bis(acetylacetonato) is an efficient catalyst. High yields of adducts (>98% for terminal alkynes) can be obtained in 2–3 h after a short induction period with a catalyst–reactant molar ratio of 10 −3/1. The reaction rate depends on the choice of silane, irradiation time and the concentration of catalyst. The major product is the β- trans adduct. Minor products are the α isomer with a trace of β- cis isomer. Comparisons of hydrosilylation reactions of alkynes with hydrosilylation reactions of alkenes are reported.

Novel stereoselective control over cis vs trans opening of benzo[c]phenanthrene 3,4-diol 1,2-epoxides by the exocyclic N(2)-amino group of deoxyguanosine in the presence of hexafluoropropan-2-ol.

We describe a novel and efficient synthesis (62-84% yields) of the eight possible, diastereomerically pure, cis and trans, R and S O(6)-allyl-protected N(2)-dGuo phosphoramidite building blocks derived through cis and trans opening of (+/-)-3alpha,4beta-dihydroxy-1beta,2beta-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene [BcPh DE-1 (1)] and (+/-)-3alpha,4beta-dihydroxy-1alpha,2alpha-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene [BcPh DE-2 (2)] by hexafluoropropan-2-ol (HFP)-mediated addition of O(6)-allyl-3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine (3) at C-1 of the epoxides. Simply changing the relative amount of HFP used in the reaction mixture can achieve a wide ratio of cis/trans addition products. Thus, the observed cis/trans adduct ratio for the reaction of DE-1 (1) in the presence of 5 equiv of 3 varied from 17/83 to 91/9 over the range of 5-532 equiv of HFP. The corresponding ratios for DE-2 (2) varied from 2/98 to 61/39 under the same set of conditions. When 1 or 2 was fused with a 20-fold excess of 3 at 140 degrees C in the absence of solvent HFP, almost exclusive trans addition (>95%) was observed for the both DEs. Through the use of varying amounts of HFP in the reaction mixture as described above, each of the eight possible phosphoramidite oligonucleotide building blocks (DE-1/DE-2, cis/trans, R/S) of the BcPh DE N(2)-dGuo adducts can be prepared in an efficient fashion. To rationalize the varying cis-to-trans ratio, we propose that the addition of 3 to 1 or 2 in the absence of solvent or in the presence of small amounts of HFP proceeds primarily via an S(N)2 mechanism to produce mainly trans-opened adducts. In contrast, increasing amounts of HFP promote increased participation of an S(N)1 mechanism involving a relatively stable carbocation with two possible conformations. One of these conformations reacts with 3 to give mostly trans adduct, while the other conformation reacts with 3 to give mostly cis adduct.