Controllable Activation of Pd-G3 Palladacycle Precatalyst in the Presence of Thiosugars: Rapid Access to 1-Aminobiphenyl Thioglycoside Atropoisomers at Room Temperature.

A controllable method for the functionalization of XantPhos Pd-G3 precatalyst with thiosugars and thiols has been established. Under mild and operationally simple reaction conditions through just mixing of precatalyst and thiosugars (α- or ß-mono-, di- and poly-thiosugar derivatives) in water at 25 °C for 20 min, a series of 1-aminobiphenyl thioglycosides that are difficult to synthesize by classical methods has been synthesized in very high yields.

Oxidative radical arylation of anilines with arylhydrazines and dioxygen from air.

Substituted 2-aminobiphenyls have been prepared from arylhydrazine hydrochlorides and anilines in biphasic radical arylation reactions with dioxygen from air as a most simple and readily available oxidant. Under optimized conditions, the free amino functionality of the aniline leads to high ortho:meta regioselectivities, now even for anilines bearing a donor substituent in the para position. Finally, the mild and metal-free new access to aminobiphenyls was shown to be applicable on a gram scale.

DNA adducts of the tobacco carcinogens 2-amino-9H-pyrido[2,3-b]indole and 4-aminobiphenyl are formed at environmental exposure levels and persist in human hepatocytes.

Aromatic amines and structurally related heterocyclic aromatic amines (HAAs) are produced during the combustion of tobacco or during the high-temperature cooking of meat. Exposure to some of these chemicals may contribute to the etiology of several common types of human cancers. 2-Amino-9H-pyrido[2,3-b]indole (AαC) is the most abundant HAA formed in mainstream tobacco smoke: it arises in amounts that are 25-100 times greater than the levels of the arylamine, 4-aminobiphenyl (4-ABP), a human carcinogen. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a prevalent HAA formed in cooked meats. AαC and MeIQx are rodent carcinogens; however, their carcinogenic potency in humans is unknown. A preliminary assessment of the carcinogenic potential of these HAAs in humans was conducted by examining the capacity of primary human hepatocytes to form DNA adducts of AαC and MeIQx, in comparison to 4-ABP, followed by the kinetics of DNA adduct removal by cellular enzyme repair systems. The principal DNA adducts formed were N-(deoxyguanosin-8-yl) (dG-C8) adducts. Comparable levels of DNA adducts were formed with AαC and 4-ABP, whereas adduct formation was ∼5-fold lower for MeIQx. dG-C8-AαC and dG-C8-4-ABP were formed at comparable levels in a concentration-dependent manner in human hepatocytes treated with procarcinogens over a 10,000-fold concentration range (1 nM-10 µM). Pretreatment of hepatocytes with furafylline, a selective inhibitor of cytochrome P450 1A2, resulted in a strong diminution of DNA adducts signifying that P450 1A2 is a major P450 isoform involved in bioactivation of these procarcinogens. The kinetics of adduct removal varied for each hepatocyte donor. Approximately half of the DNA adducts were removed within 24 h of treatment; however, the remaining lesions persisted over 5 days. The high levels of AαC present in tobacco smoke and its propensity to form persistent DNA adducts in human hepatocytes suggest that AαC can contribute to DNA damage and the risk of hepatocellular cancer in smokers.

The Gomberg-Bachmann reaction for the arylation of anilines with aryl diazotates.

Simply aqueous sodium hydroxide is sufficient to exclude ionic side reactions and to prepare 2-aminobiphenyls from aryl diazotates and anilines through a new variant of the Gomberg-Bachmann reaction (see scheme). The metal-free reaction under basic conditions allows to exploit the highly radical-stabilizing effect of the aniline's free amino function for the first time, which leads to a so far unreached regioselectivity.

Rationally designing safer anilines: the challenging case of 4-aminobiphenyls.

We describe how we have been able to design 4-aminobiphenyls that are nonmutagenic (inactive in the Ames test). No such 4-aminobiphenyls were known to us, but insights provided by quantum mechanical calculations have permitted us to design and synthesize some examples. Importantly, the quantum mechanical calculations could be combined with predictions of other properties of the compounds that contained the 4-aminobiphenyls so that these remained druglike. Having found compounds that are not active, the calculations can provide insight into which factors (electronic and conformational in this case) are important. The calculations provided SAR-like information that was able guide the design of further examples of 4-aminobiphenyls that are not active in the Ames test.

Rapid nickel-catalyzed Suzuki-Miyaura cross-couplings of aryl carbamates and sulfamates utilizing microwave heating.

High-speed and scalable nickel-catalyzed cross-coupling of arylboronic acids with aryl carbamates and sulfamates is achieved by using sealed-vessel microwave processing.

Novel aminoethylbiphenyls as 5-HT7 receptor ligands.

The synthesis of a series of aminoethylbiphenyls as novel 5-HT(7) receptor ligands is described. The novel derivatives exhibit high affinity for the 5-HT(7) receptor with selectivity toward 5-HT(1A) receptor.

Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase.

Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.

Development of orally bioavailable and CNS penetrant biphenylaminocyclopropane carboxamide bradykinin B1 receptor antagonists.

A series of biphenylaminocyclopropane carboxamide based bradykinin B1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery that the replacement of the trifluoropropionamide in the lead structure with polyhaloacetamides, particularly a trifluoroacetamide, significantly reduced P-glycoprotein mediated efflux for the series proved essential. One of these novel bradykinin B1 antagonists (13b) also exhibited suitable pharmacokinetic properties and efficient ex vivo receptor occupancy for further development as a novel approach for the treatment of pain and inflammation.

Synthesis, characterization, and 32P-postlabeling of N-(deoxyguanosin)-4-aminobiphenyl 3'-phosphate adducts.

The (32)P-postlabeling assay is an extremely sensitive technique for detecting carcinogen-DNA adducts. However, for the assignment of DNA adduct structures and the accurate determination of DNA adduct levels by (32)P-postlabeling, authentic adduct standards are needed. For most (32)P-postlabeling applications, such verified synthetic standard compounds are required in the form of their deoxynucleoside 3'-phosphates because they represent substrates for the polynucleotide kinase for transfer of [(32)P]phosphate from [gamma-(32)P]ATP. Three N-(deoxyguanosin)-4-aminobiphenyl 3'-phosphate adducts were prepared and fully characterized by (1)H NMR and mass spectroscopy to serve as standards for the (32)P-postlabeling assay. Apart from the C8- and the N(2)-deoxyguanosine 3'-phosphate adducts of the mutagenic human bladder carcinogen 4-aminobiphenyl (dG3'p-C8-4-ABP and dG3'p-N(2)-4-ABP), the C8-deoxyguanosine 3'-phosphate adduct of the nonmutagenic 4'-tert-butyl-4-aminobiphenyl (dG3'p-C8-4'tBu-4-ABP) was included in the study. Both C8-deoxyguanosine 3'-phosphate adducts were prepared by the in situ formation of deoxyguanosine 3'-phosphate and its subsequent reaction with the appropriate electrophilic amination agent (N-acetoxy compound). The N(2)-deoxyguanosine 3'-phosphate adduct was obtained by a modification of a previously described procedure for the synthesis of N(2)-deoxyguanosine adducts of aromatic amines. The three adduct standards were added at different concentrations to calf thymus DNA, and adduct recoveries were determined by the (32)P-postlabeling assay under conditions routinely used in the standard methodology, enhancement by nuclease P1 digestion and enhancement by butanol extraction. The dG3'p-C8-4-ABP adduct was recovered irrespective of the concentration with approximately 30% in both the standard and the butanol extraction version of the assay. Both C8-deoxyguanosine 3'-phosphate adducts were sensitive to nuclease P1 digestion resulting in recoveries of only 1-3%. In contrast, the dG3'p-N(2)-4-ABP adduct was resistant to nuclease P1 digestion; however, recovery in all three versions was poor (1-2%) resulting in a detection limit of one adduct/10(6) nucleotides. These results demonstrate that the (32)P-postlabeling assay underestimates the level of DNA adducts formed by 4-ABP and indicates that there is a need to determine the recovery for each adduct to be analyzed by the (32)P-postlabeling technique.

Catalysis of the photo-Fries reaction: antibody-mediated stabilization of high energy states.

A conformationally constrained hapten is presented that is capable of catalyzing the first antibody-mediated photo-Fries rearrangement. In this reaction, absorption of light energy by a diphenyl ether substrate results in homolytic C-O bond cleavage followed by recombination to yield biphenyl-derived products. The most proficient antibody studied converts 4-phenoxyaniline 15 into 2-hydroxy-5-aminobiphenyl 16 under high-intensity irradiation at a rate of 8.6 microM/min. These results support a recent hypothesis stating that immunization with conformationally constrained haptens provides higher titers for the acquisition of simple binding antibodies; however, in this case, conformational constraint does not ensure the development of more efficient catalysts. Using the obtained antibodies, the presence of products resulting from escape of free radicals from the solvent cage can be suppressed, altering the excited state energy surface such that free radicals are funneled into the formation of the desired biphenyl product. However, studies also show the inactivation of the antibodies as a result of photodecay of the biphenyl product. Using an isocyanate scavenging resin, the photodecay product could be removed and the inactivation of the antibody drastically reduced. Furthermore, despite the observed photodecay, turnover of the antibody was present; this represents the first case in which true turnover of a photochemical reaction using a catalytic antibody could be observed.

Discovery of a series of (4,5-dihydroimidazol-2-yl)-biphenylamine 5-HT7 agonists.

A novel (4,5-dihydroimidazol-2-yl)-biphenylamine series of 5-HT(7) agonist compounds was developed from a structurally related lead compound 1. The newly discovered series is exemplified by compound 2 that possesses high affinity for 5-HT(7) receptors and shows intrinsic agonist activity in functional assays. This new series has significant alpha(1) and alpha(2) activities perhaps due to the presence of the 2-aminoimidazoline moiety.

Synthesis and characterization of nucleoside derivatives, n-(benzoyl)-n-(deoxyguanosin-8-yl)4-aminobiphenyl and n-(2'-deoxyguanosin-8-yl)4-aminobiphenyl via alpha-phenyl-n-(4-biphenyl)nitrone.

Lead tetraacetate (LTA) oxidation of alpha-Phenyl-N-(4-bipheny])nitrone (8) to give a new ultimate carcinogen, N-acetoxy-N-benzoyl-4-aminobiphenyl (9) which was reacted with deoxyguanosine (dG) at pH 6.9 to give nucleoside derivative, N-(benzoyl)-N-(deoxyguanosin-8-yl)-4-aminobiphenyl (10). Following debenzoylation with sodium carbonate-methanol leads to N-(2'-deoxyguanosin-8-yl)-4-aminobiphenyl (11).

A selective synthesis of 4-aminobiphenyl-N2-deoxyguanosine adducts.

A selective synthesis of N2-deoxyguanosine adducts derived from 4-aminobiphenyl (ABP) is described. The reactions of O2-trifluoromethylsulfonyl-O6-allyl-3',5'-O-bis(tert-butyldimethyl silyl)-2'- deoxyxanthosine with 3-amino-4-acetaminobiphenyl and 4-hydrazinobiphenyl, respectively, are the key steps. Successive removal of the protecting groups from the protected adducts leads to the free adducts 3-(deoxyguanosine-N2-yl)-acetyl-ABP and N-(deoxyguanosyl-N2-yl)-ABP, respectively.

A new synthetic route to nucleotide adducts derived from N-acetylated and unacetylated 4-aminobiphenyl.

The carcinogen N-acetoxy-N-2-acetylaminofluorene reacts with dG and dG-containing nucleotides to give good yields of the C-8 adducts, but the analogous 4-aminobiphenyl derivative does not. Replacement of the N-acetoxy group by 2,6-dichlorobenzoyloxy circumvents this difficulty. This reaction is shown to be generally applicable, and biphenylamido adducts with dG, d(CpG), d(GpC) and d(ApG) have been prepared. A new, useful deacetylation procedure employing the heterogeneous system sodium carbonate/methanol which leads to the corresponding biphenylamino derivative without appreciable imidazole ring opening is also reported.

Synthesis of N-glucuronides of carcinogenic N-hydroxyarylamines.

The N-glucuronides of N-hydroxy-2-aminofluorene, N-hydroxy-4-aminobiphenyl, and N-hydroxy-2-aminonaphthalene were synthesized in good yields by reacting the hydroxylamines with glucuronic acid.

New syntheses of N-(guanosin-8-yl)-4-aminobiphenyl and its 5'-monophosphate.

N-Acetoxy-4-trifluoroacetylaminobiphenyl (N-acetoxy-TFAABP) reacted readily with Guo and GMP at neutrality in a one-step fashion to yield N-(guanosin-8-yl)4-aminobiphenyl (Guo-ABP) (I) and N(guanosin-8-yl)-4-aminobiphenyl-5'-monophosphate (GMP-ABP) (II), respectively. GMP-ABP could also be formed in much lower yield from the reaction of N-acetoxy-4-formylaminobiphenyl (N-acetoxy-FABP) with GMP (pH 7.0) under more rigorous conditions. Enzymatic hydrolysis of GMP-ABP with alkaline phosphatase in Tris buffer (pH 8.0) at 37 degrees C yielded Guo-ABP. Guo-ABP showed a brilliant blue fluorescence on exposure to 366 nm UV light and its UV absorption spectrum was identical to that of Guo-ABP prepared by Kriek via a different route. Elemental analysis and nuclear magnetic resonance (NMR) data further confirmed the identity of this compound.