Structural and stereoisomer effects of model estrogen quinone-derived DNA adducts: N6-(2-hydroxyestron-6(alpha,beta)-yl)-2'-deoxyadenosine and N2-(2-hydroxyestron-6(alpha,beta)-yl)-2'-deoxyguanosine

An extensive conformational analysis has been carried out for two diastereoisomeric pairs of model estrogen quinone-derived DNA adducts, N6-(2-hydroxyestron-6(alpha,beta)-yl)-2'-deoxyadenosine (2-OHE1-6(alpha,beta)-N6-dA) and N2-(2-hydroxyestron-6(alpha,beta)-yl)-2'-deoxyguanosine (2-OHE1-6(alpha,beta)-N2-dG), in a B-DNA duplex and at a primer-template junction in a pol alpha family DNA polymerase. In vitro primer extension studies in pol alpha [Terashima, I., et al. (1998) Biochemistry 37, 13807-13815] have shown that the adenine adducts can incorporate dT, together with a small proportion of the incorrect base dC opposite the lesion, and they block less strongly than the guanine adducts. We have carried out conformational searches with energy minimization for four DNA duplexes containing 2-OHE1-6alpha-N6-dA, 2-OHE1-6beta-N6-dA, 2-OHE1-6alpha-N2-dG, or 2-OHE1-6beta-N2-dG. Our searches revealed that the four-ring nonplanar 2-hydroxyestrone (2-OHE1) moiety strongly prefers to reside in the major groove of the adenine adducts or the minor groove of the guanine adducts in a B-DNA duplex, with stereochemistry-dependent orientational differences in each case. No low energy conformations involving intercalation of the 2-OHE1 moiety were located in the searches. This stems from the largely nonplanar, nonaromatic nature of the 2-OHE1 ring system and implies that the proclivity for such bulky, nonplanar adducts to reside at the DNA helix exterior is a plausible conformational feature of other structurally similar estrogen quinone-derived DNA adducts, independent of base sequence context. In addition, the adenine adduct isomers, located in the major groove, manifest serious disturbance to the Watson-Crick base pairs at and near the lesion site, suggesting repair susceptibility. Possible structures of these adducts in a pol alpha family polymerase were also investigated through molecular modeling. The results rationalized the experimental in vitro primer extension studies. In addition, poor accommodation of the beta-stereoisomers within the polymerase was noted, suggesting that these stereoisomers would be more prone to cause blockage. Stereochemistry-dependent differences in adduct orientation could be expected to produce different biochemical effects, as has been observed in adducts derived from polycyclic aromatic hydrocarbons.     

Synthesis and pharmacological activity of 6-[(E)-2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethen-1-yl]- and 6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylic acids

6-[(E)-2-(2,6,6-Trimethyl-1-cyclohexen-1-yl)ethen-1-yl]- and 6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylic acids (4 and 8) have been synthesized and show significant activity in reversing the keratinization process in hamster tracheal organ culture and in inhibiting the induction of ornithine decarboxylase in mouse skin by 12-O-tetradecanoylphorbol-13-acetate, two assays used to measure retinoid activity. The 2-naphthalenecarboxylic acid 8 was more active than 4.     

1-苄基-2-(4′-甲磺酰基-1-羟基-苯乙基)-1,2,3,4-四氢异喹啉类化合物的合成及其抗心律失常活性(英文)

目的寻找具有Ⅲ/Ⅱ复合作用的新型抗心律失常药物。方法拼合1-苄基-1,2,3,4-四氢异喹啉与具有Ⅲ/Ⅱ复合作用的sotalol结构片段,设计合成1-苄基-2-(4′-甲磺酰基-1-羟基-苯乙基)-1,2,3,4-四氢异喹啉类化合物,通过离体豚鼠心肌标本不应期测定法对所合成的目标化合物进行筛选。结果合成了18个未见文献报道的新化合物(1a-1r)。体外结果表明化合物1d、1e、1i、1j具有较好的延长动作电位时程的作用。结论化合物1d、1e、1i、1j表现出Ⅲ类抗心律失常药物延长动作电位时程的特征,有关Ⅲ/Ⅱ复合作用的药理实验有待进行。     

Identification and characterization of a series of nucleoside adducts formed by the reaction of 2'-deoxyguanosine and 1,2,3,4-diepoxybutane under physiological conditions

The carcinogenicity of 1,3-butadiene (BD) has been attributed to its in vivo metabolites, 3,4-epoxy-1-butene (EB) and 1,2,3,4-diepoxybutane (DEB). In this study, DEB was demonstrated to react with 2'-deoxyguanosine (dG) under in vitro physiological conditions (pH 7.4, 37 degrees C) to yield several pairs of diastereomeric adducts, including N-(2-hydroxy-1-oxiranylethyl)-2'-deoxyguanosine (P4-1 and P4-2), 7,8-dihydroxy-3-(2-deoxy-beta-d-erythro-pentofuranosyl)-3,5,6,7,8,9-hexahydro-1,3-diazepino[1,2-a]purin-11(11H)one (P6), 1-(2-hydroxy-2-oxiranylethyl)-2'-deoxyguanosine (P8 and P9), 1-[3-chloro-2-hydroxy-1-(hydroxymethyl)propyl]-2'-deoxyguanosine (1AP9 and 2AP9), and 4,8-dihydroxy-1-(2-deoxy-beta-d-erythro-pentofuranosyl)-9-hydroxymethyl-6,7,8,9-tetrahydro-1H-pyrimido[2,1-b]purinium ion (1BP4 and 2BP4). The 7-alkylation dG adducts (P5 and P5') were not characterized directly by NMR spectrometry because of their instability. However, their formula weights were determined to be 354, and their acid hydrolysis products were characterized as 2-amino-7-(3-chloro-2,4-dihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H3), consistent with the structures of P5 and P5' being diastereomers of 6-oxo-2-amino-9-(2-deoxy-beta-d-erythro-pentofuranosyl)-7-(2-hydroxy-2-oxiranylethyl)-6,9-dihydro-1H-purinium ion. Time-course experiments indicated that alkaline pH and/or high DEB:dG molar ratios made the reactions faster without changing the adduct profile. The adducts were detected in the following chronological order: 7- (P5 and P5'), 1- (P8 and P9), N(2)- (P4-1 and P4-2), and P6. Whereas P4-1, P4-2, and P6 appeared stable during the courses of the reactions, P5, P5', P8, and P9 were labile and completely decomposed by the time dG was fully consumed. These results may contribute to a better understanding of the chemical reactivity and strong mutagenicity and carcinogenicity of DEB.     

Verbindungen mit potentiell positiv inotroper Wirkung, 2. Mitt. Synthese von 3,4-Dihydro-2-[(3-oxo-1-cyclopenten-1-yl)amino]-1(2H)-phenanthron und 3-(1,2,3,4-Tetrahydro-1-hydroxy-2-phenanthrylamino)-2-cyclopentenon

Compounds with Potentially Positive Inotropic Activity, II: Synthesis of 3,4-Dihydro-2-[(3-oxo-1-cyclopenten-1-yl)amino]-1(2H)-phenanthrone and 3-(1,2,3,4-Tetrahydro-1-hydroxy-2-phenanthrylamino)-2-cyclopentenone The synthesis of the title compounds from 1,3-cyclopentanedione and 2-amino-3,4-dihydro-1(2H)-phenanthrone and 2-amino-1,2,3,4-tetrahydro-1-phenanthrole is described.     

Synthesis and biological properties of 9-(trans-4-hydroxy-2-buten-1-yl)adenine and guanine: open-chain analogues of neplanocin A

Alkylation of adenine (5a) or 2-amino-6-chloropurine (5b) with excess trans-1,4-dichloro-2-butene (4), effected by K2CO3 in dimethyl sulfoxide or tetra-n-butylammonium fluoride in tetrahydrofuran, led in 90-95% regioselectivity to 9-alkylpurines 6a and 6b. The title compounds 2a and 2b were obtained by refluxing intermediates 6a and 6b in 0.1 M NaOH or HCl. Adenine derivative 2a is a substrate for adenosine deaminase whereas both 2a and 2b exhibit 50% inhibition of the growth of murine leukemia L 1210 cell culture at 1 mM concentration.     

1-(2-Diethylaminoethyl)-3,4-pentamethylenepyrazole and N2-substituted bornylenepyrazoles]

An unambiguous synthesis of 1-(2-diethylaminoethyl)-3,4-pentamethylenepyrazole (III) by acid cyclization of 2-(2-cycloheptanonyl)-1,3-dioxolane 2-diethylaminoethylhydrazone, and of N2-methyl and N2-(2-diethylaminoethyl)bornylenepyrazole (VIII) and (IX), by heating the hydrazones from 3-hydroxymethylene-2-bornanone and methylhydrazine or 2-diethylaminoethylhydrazine respectively, is described. (III) showed antiinflammatory activity and (VIII) an anticonvulsant action.     

Synthesis and antibacterial activity of 1-(5-aryl-4-benzoyl-3-hydroxy-2-oxo-3-pyrrolin-1-yl)-2-(3-benzoylmethylene-2-oxopiperazin-1-yl)ethanes

A series of l-(5-aryl-4-benzoyl-3-hydroxy-2-oxo-3-pyrrolin-l-yl)-2-(3-benzoylmethylene-2-oxopiperazin-1-yl)ethanes have been obtained with 35–37% yields via reactions of benzoylpyruvic acid methyl ester with a mixture of aromatic aldehyde and diethylenetriamine in a 2: 1: 1 molar ratio. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 8, pp. 5–6, August, 2006.     

5-羟基-6-甲氧基-2-苄基-3,4-二氢异喹啉-1-酮的合成

目的研究5-羟基-6-甲氧基-3,4-二氢异喹啉-1-酮衍生物的合成方法。方法以异香草酸甲酯为原料,通过烯丙基醚化、Claisen重排、氧化、西佛碱的制备、还原、分子内酯的胺解6步反应合成了5-羟基-6-甲氧基-2-苄基-3,4-二氢异喹啉-1-酮(1),总收率达55.0%。Schiff碱的制备、还原、酯的胺解3步在"一锅"内完成。结果合成了新的3,4-二氢异喹啉-1-酮衍生物,其结构经IR和1HNMR确认。结论设计的合成路线具有反应条件温和、操作简便、反应总收率高等优点。     

Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932)

Sphingosine 1-phosphate lyase (S1PL) has been characterized as a novel target for the treatment of autoimmune disorders using genetic and pharmacological methods. Medicinal chemistry efforts targeting S1PL by direct in vivo evaluation of synthetic analogues of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI, 1) led to the discovery of 2 (LX2931) and 4 (LX2932). The immunological phenotypes observed in S1PL deficient mice were recapitulated by oral administration of 2 or 4. Oral dosing of 2 or 4 yielded a dose-dependent decrease in circulating lymphocyte numbers in multiple species and showed a therapeutic effect in rodent models of rheumatoid arthritis (RA). Phase I clinical trials indicated that 2, the first clinically studied inhibitor of S1PL, produced a dose-dependent and reversible reduction of circulating lymphocytes and was well tolerated at dose levels of up to 180 mg daily. Phase II evaluation of 2 in patients with active rheumatoid arthritis is currently underway.     

6- and 8-hydroxy-3,4-dihydro-3-(dipropylamino)-2H-1-benzopyrans. Dopamine agonists with autoreceptor selectivity

The dopamine agonist profiles of 3,4-dihydro-3-(3-dipropylamino)-2H-1-benzopyran-6- and -8-ol (4 and 5, respectively) were examined. Both 4 and 5 exhibited greater relative affinity for receptors labeled with the dopamine agonist ligand [3H]propylnorapomorphine than for those labeled with the dopamine antagonist ligand [3H]haloperidol. Both compounds attenuated the stimulation of brain dopamine synthesis caused by gamma-butyrolactone (GBL) and decreased the firing rate of substantia nigra dopamine neurons in rats. This profile of activity, together with the ability of the dopamine antagonist haloperidol to reverse the inhibition of dopamine neuronal firing, indicate that both compounds are brain dopamine agonists.     

N-(双膦羧次甲基)-6-(5-氟-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基)-6-氧代-己酰胺的合成及其初步的骨靶向性研究

目的合成N-（双膦羧次甲基）-6（5-氟-2，4-二氧代3，4-二氢-2H-嘧啶-1-基）-6-氧代-己酰胺，并进行初步体外骨靶向性实验。方法以5-氟尿嘧啶为原料，经硅烷化、缩合、氢解3步合成6-（5-氟-2，4-二氧代-3，4-二氢-2H-嘧啶-1-基）-6-氧代-己酸（2），用二氯亚砜氯化后再与含氨基的偕二膦酸酯偶联，最后再用溴代三甲基硅烷特异性解离掉膦酸酯得到目标化合物L，并采用羟磷灰石晶体吸附实验考察目标物的骨靶向性。结果合成了目标物L，并利用^-1H—NMR、IR和MS进行了结构确证。结论体外骨靶向性实验结果显示目标物L有较好的骨靶向性。     

Inefficient nucleotide excision repair in human cell extracts of the N-(deoxyguanosin-8-yl)-6-aminochrysene and 5-(deoxyguanosin-N(2)-yl)-6-aminochrysene adducts derived from 6-nitrochrysene

Ubiquitous environmental agents [e.g., polynuclear aromatic hydrocarbons (PAHs) and their nitrated derivatives (NO(2)-PAHs)] that are known to induce mammary cancer in rodents are regarded as potential human risk factors for inducing analogous human cancers. Although 6-nitrochrysene (6-NC) is less abundant than other NO(2)-PAHs in the environment, it is the most potent mammary carcinogen in the rat; its carcinogenic potency is not only higher than that of the carcinogenic PAH, benzo[a]pyrene (B[a]P), but also of the well-known carcinogenic heterocylic aromatic amine, 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP). Studies in rats and in vitro assays have indicated that 6-NC can be activated by simple nitroreduction leading to the formation of 6-hydroxylaminochrysene (N-OH-6-AC); this metabolite yielded N-(deoxyguanosin-8-yl)-6-aminochrysene (N-[dG-8-yl]-6-AC) and 5-(deoxyguanosin-N(2)-yl)-6-aminochrysene (5-[dG-N(2)-yl]-6-AC. These lesions are likely to cause mutations if they are not removed by cellular defense mechanisms before DNA replication occurs. However, nothing is known about the susceptibility of these adducts to nucleotide excision repair (NER), the major cellular repair system that removes bulky adducts. In order to address this issue, we synthesized the N-(dG-8-yl)-6-AC and 5-(dG- N(2)-yl)-6-AC lesions and site-specifically inserted these lesions into 135-mer DNA duplexes. These constructs were incubated with NER-competent nuclear extracts from human HeLa cells. The efficiency of repair of these lesions was ～ 8 times less efficient than that in the case of the well-known and excellent substrate of NER, the intrastrand cross-linked cis-diaminodichloroplatinum II adduct in double-stranded DNA (cis-Pt), but similar to N(2)-dG adducts derived from the (+)-bay region diol epoxide of B[a]P [(+)-trans-B[a]P-N(2)-dG]. The results support the hypothesis that the N-(dG-8-yl)-6-AC and 5-(dG-N(2)-yl)-6-AC lesions may be slowly repaired and thus persistent in mammalian tissue which could, in part, account for the potent tumorigenic activity of 6-NC in the rat mammary gland.     

Immunomodulatory effects of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1-ethanone from Petasites hybridus and its synthesized benzoxazepine derivatives

1-(6-Hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1-ethanone (1), isolated from the roots of Petasites hybridus L., and a series of synthetic benzoxazepine derivatives of compound 1 (2–6) were evaluated for their immunomodulatory effects. The compounds were evaluated for their effects on the respiratory burst of human whole blood and isolated human polymorphonuclear leukocytes (PMNs) using luminol- and lucigenin-based chemiluminescence (CL) assays, and their effect on chemotactic migration of PMNs was assessed using the Boyden chamber technique. Compound 1 exhibited stronger inhibition than acetylsalicylic acid (ASA) on luminol-enhanced CL of PMNs. It also inhibited PMN chemotaxis with an IC₅₀ value comparable to that of ibuprofen. Of the compounds tested, 5 was the most effective in inhibiting luminol-enhanced CL and also strongly inhibited lucigenin-enhanced CL with IC₅₀ values lower than that of ASA. Compound 2 was the most active in inhibiting migration of PMNs and was five times stronger than ibuprofen. The results suggest that compound 1 and its synthesized benzoxazepine derivatives, especially compounds 2 and 5, were able to modulate the innate immune response of phagocytes at different steps, emphasizing their potential as leads for the development of new immunomodulatory agents.     

4,5-Epoxy-2(E)-decenal-induced formation of 1,N(6)-etheno-2'-deoxyadenosine and 1,N(2)-etheno-2'-deoxyguanosine adducts

trans-4,5-Epoxy-2(E)-decenal reacted with 2'-deoxyadenosine to give 1,N(6)-etheno-2'-deoxyadenosine as well as other 2'-deoxyadenosine adducts. It also reacted with 2'-deoxyguanosine to give 1,N(2)-etheno-2'-deoxyguanosine and other 2'-deoxyguanosine adducts. Synthetic trans-4,5-epoxy-2(E)-decenal was quite stable under the reaction conditions that were used. It was not contaminated with 2,3-epoxyoctanal, a potential precursor to the formation of unsubstituted etheno adducts. Furthermore, using a sensitive LC/MS assay, it was possible to show that no 2,3-epoxyoctanal was formed during prolonged incubations of trans-4,5-epoxy-2(E)-decenal. Therefore, trans-4,5-epoxy-2(E)-decenal, a primary product of lipid peroxidation, is a precursor to the formation of 1,N(6)-etheno-2'-deoxyadenosine and 1,N(2)-etheno-2'-deoxyguanosine. There is no need for an additional oxidation step such as would be required if trans,trans-2,4-decadienal or 4-hydroxy-2-nonenal were the lipid hydroperoxide decomposition products that initiated the formation of unsubstituted etheno adducts. These findings provide an important link between a primary product of lipid peroxidation and a mutagenic DNA lesion that has been detected in human tissues.