(2S,4S,5S)-3,4-二甲基-5-苯基-2-对二甲氨基苯基恶唑烷晶体结构的研究

目的：测定（２Ｓ，４Ｓ，５Ｓ）－３，４－二甲基－５－苯基－２－对二甲氨基苯基恶唑烷的光谱和晶体结构。方法：Ｘ－射线晶体衍射法。结果：晶胞参数为ａ＝６０７８３（４），ｂ＝１９００４２（３），ｃ＝１４３４２１（２），Ｖ＝１６２４３３，Ｚ＝４，Ｆｗ＝２６８２８，计算得，Ｄｃ＝１０３２ｇ／ｃｍ３，结构偏离因子为Ｒ＝００５８，Ｒｗ＝００５３。结论：标题化合物属于正交晶系，空间群为Ｐ２１２１２１。     

麻黄生物碱衍生物噁唑烷类药物水解动力学的研究

本文研究了由麻黄碱和伪麻黄碱与取代苯由醛缩合而成的恶唑烷类前药的水解动力学。测定了恶唑烷类前药的水解速度常数。发现该类物质的水解和其苯甲醛上的取代基的Hammett电性常数具有线性关系。研究了温度、pH值、离子强度和缓冲液组分浓度等对水解速度常数的影响,测定了10种药品水解开环的活化能Ea,活化焓△H~≠、活化熵△S~≠、活化自由能△G~≠,活化平衡常数K~≠。     

Physicochemical Characterization of High- and Low-Melting Phenylephrine Oxazolidines

Phenylephrine oxazolidine is a new prodrug of phenylephrine developed for improving ocular absorption and reducing systemic side effects. In the present study, high- and low-melting phenylephrine oxazolidines (HMP and LMP) were characterized in terms of their stereochemistry and crystal properties. It was found that the molecular configuration of the prodrug in the crystals of either HMP or LMP is identical (5R/2R). The two crystals were shown to have the same IR spectra and X-ray diffraction patterns but different crystal habits, thermal properties, solubilities and intrinsic dissolution rates. Single crystal X-ray structure analysis indicates that crystals of both HMP and LMP are orthorhombic and belong to the P2₁2₁2₁ space group with four molecules in a unit cell (a = 20.697 , b = 7.065 , and c = 9.304 ). The molecules in the crystal are held together by an intermolecular hydrogen bonding interaction between N(3) and O(13). The different physical properties observed for LMP result from crystal imperfections caused by the presence of trace amounts (often at levels <0.5%) of an unidentified, structurally related synthetic impurity which can be dispersed in the pro-drug. It was observed that both HMP and LMP can sustain thermal and mechanical treatment in the solid state. However, LMP was partially converted to HMP when suspended in certain solvents.     

噁唑烷衍生物的合成与结构测定

近期文献报道从麻黄植物中分离出微量的恶唑烷酮衍生物,并证明是抗炎有效成分.本文根据上述资料,从麻黄生物碱出发。合成5种 N-取代的麻黄碱衍生物,8种恶唑烷衍生物.根据元素分析、红外、核磁共振氢谱、质谱,确定了衍生物结构.经醋酸扭体法和热板法药理试验,化合物(8)有镇痛作用.     

Mode of mutagenic action for the biocide Bioban CS-1246 in mouse lymphoma cells and implications for its in vivo mutagenic potential.

The biocidal agent, BIOBAN CS-1246 (7-ethyl bicyclooxazolidine, CAS# 7747-35-5, CS-1246) induced a concentration-dependent mutagenic response in mouse lymphoma (L5178Y TK+/-) cells both with and without the addition of S9 metabolic activation. Previous data indicating the ability of CS-1246 to hydrolyze in aqueous media to generate formaldehyde (FA), led us to investigate the potential role of FA in the CS-1246-induced mutagenic response in the mouse lymphoma assay (MLA). To accomplish this, the MLA on CS-1246 was repeated in the presence of a metabolizing system (formaldehyde dehydrogenase/NAD+), which was shown to successfully inhibit the mutagenic response of formaldehyde in this assay system. Significantly, the observed mutagenicity of CS-1246 was completely abrogated when the cultures were supplemented with formaldehyde dehydrogenase/NAD+, suggesting that the positive MLA response was attributable to the generation of FA in situ. These results demonstrate that in vitro mutagenicity of CS-1246 in the MLA is most likely associated with FA. Negative results from two in vivo assays for genotoxicity were consistent with the known activity of FA in these assays. In the mouse bone marrow micronucleus (MNT), there were no significant increases in micronucleated polychromatic erythrocytes (with evaluation of 2000/animal), after treatment with 0.5, 1, and 2 g/kg/day CS-1246 (6/dose group) for 2 consecutive days and sacrifice 24 h later. Furthermore, in the unscheduled DNA synthesis (UDS) study, male F344 rats (5 /dose group), given a single oral gavage (0, 1, and 2 g/kg) and evaluated at two time points (2-4 and 14-15 h post dosing), did not elicit an UDS response, indicating a lack of DNA reactivity in vivo. Based on the negative in vivo findings, it can be inferred that the FA detoxification mechanisms that exist in intact organisms prevent the likelihood of generating FA at levels capable of causing genotoxicity following exposure to CS-1246 at low, environmentally relevant concentrations. The extensive literature on FA would therefore be of value in assessing the carcinogenic risk to humans and animals from CS-1246 exposure.     

Exploration of the structure–activity relationship and druggability of novel oxazolidinone‐based compounds as Gram‐negative antibacterial agents

To gain further knowledge of the structure–activity relationship and druggability of novel oxazolidinone‐based UDP‐3‐O‐acyl‐N‐acetylglucosamine deacetylase (LpxC) inhibitors as Gram‐negative antibacterial agents, compounds containing the hydrophobic tails with different lengths and terminal substitutions were synthesized and their antibacterial activities against standard and clinically isolated Gram‐negative strains were evaluated. We summarized their structure–activity relationships and found that oxazolidinone‐based compounds exhibited a narrower antibacterial spectrum compared with threonine‐based compounds. Furthermore, we parallelly compared the metabolic stabilities of the compounds with the classic threonine scaffold and the novel oxazolidinone scaffold in liver microsomes. The results indicated that the druggability of the oxazolidinone scaffold may be inferior to the classic threonine scaffold in the design of LpxC inhibitors.     

高效液相色谱法对麻黄碱前体药物恶唑烷水解的研究

本文用反相高效液相色谱法测定了13个麻黄碱衍生物的恶唑烷类化合物在生理条件下的水解半衰期,初步阐明了结构与稳定性的关系以及有关的取代基效应。实验结果表明,麻黄生物碱的立体构型和芳醛上取代基的种类与位置,通过空间效应或电性效应影响恶唑烷衍生物的稳定性。实验数据与Hammett电性参数呈一定规律,对研究前体药物有理论和应用价值。     

Formulation,in Vitro Dissolution,and Ocular Bioavailability of High- and Low-Melting Phenylephrine Oxazolidines

The in vitro dissolution and the relative ocular bioavailability of high- and low-melting phenylephrine oxazolidines (HMP and LMP) from a nonaqueous suspension (silicone fluid) were compared. Stability-indicating HPLC assays were developed for evaluation of the prototype formulations, in which a normal-phase HPLC method was necessary for analysis of PO, while a reverse-phase HPLC method was required for analysis of the primary degradation product, phenylephrine (PE), following its separation from the formulation using a short silica gel column. PO was formulated as an ophthalmic suspension in silicone fluid (20 cs) because of its property of undergoing rapid hydrolysis in aqueous media. An experimental test system for measuring the dissolution characteristics of a water-immiscible multiparticulate suspension was designed to obtain the dissolution profiles of suspensions of HMP and LMP. The dissolution rates, which were nearly identical for LMP and HMP, were obtained assuming a quasi-infinite reservoir. A reverse-phase HPLC assay with fluorescence detection was used for measuring the concentrations of PE in aqueous humor and corneal samples. Statistical analysis of the bioavailability data showed that suspensions containing HMP and LMP were equal in extent of absorption following a single topical application to the rabbit eye. The results correlated well with the in vitro dissolution rates of the suspensions of HMP and LMP.     

Mefloquine–Oxazolidine Derivatives: A New Class of Anticancer Agents

A series of 23 racemic mefloquine–oxazolidine derivatives, 4‐[3‐(aryl)hexahydro[1,3]oxazolo[3,4‐a]pyridin‐1‐yl]‐2,8‐bis(trifluoromethyl)quinolines, derived from (R*, S*)‐(±)‐mefloquine and arenealdehydes, have been evaluated for their activity against four cancer cell lines (HCT‐8, OVCAR‐8, HL‐60, and SF‐295). Good cytotoxicities have been determined with IC₅₀ values ranging from 0.59 to 4.79 μg/mL. In general compounds with aryl groups having strong electron‐releasing substituents, such as HO and MeO, or electron‐rich heteroaryl groups, for example imidazol‐2‐y‐l, are active. However, other factors such as steric effects may play a role. As both the active and non‐active conformations of the mefloquine–oxazolidine derivatives are similar, it is concluded that molecular conformations do not play a significant role either. This study is the first to evaluate mefloquine derivatives as antitumor agents. The mefloquine–oxazolidine derivatives are considered to be useful leads for the rational design of new antitumor agents.     

Occupational contact allergy to formaldehyde and formaldehyde releasers

Background: Formaldehyde allergy is common and usually derives from formaldehyde‐releasing biocides in cosmetic and other products. Objectives: To analyse patterns of patch test reactions to formaldehyde and formaldehyde‐releasing compounds and the sources of sensitization. Patients/Methods: At the Finnish Institute of Occupational Health, we screened the patch test files for allergic reactions to formaldehyde and 12 formaldehyde‐releasing compounds. All patients with contact allergy to any of the substances were included, and their records were reviewed. Results: Between January 2001 and May 2007, we had patch tested 81 patients with formaldehyde allergy and 18 with independent allergy to some formaldehyde releaser. Of the formaldehyde allergies, 60 were new sensitizations, 25 of which were considered to be occupational. The most common source of occupational sensitization was metalworking fluids followed by creams and related products. Exposure to formaldehyde‐releasing preservatives in liquid soaps and other rinse‐off products was common in both occupational and non‐occupational cases. Reactions to formaldehyde‐releasing compounds were seen in 79% of the formaldehyde‐allergic patients. Conclusions: Occupational formaldehyde allergy was common and occurred in metalworkers, hairdressers, masseurs, and workers using protective creams, detergents, and liquid soaps. When compared with studies on general dermatological patients, contact allergy to formaldehyde releasers without formaldehyde allergy was rare.