Sensitization of cancer cells to DNA damaging agents by imidazolines

Apoptosis, or programmed cell death, is a cellular mechanism used to regulate cell number and eliminate damaged or mutated cells. Concomitant with the initiation of the apoptotic cell signal, chemotherapeutic agents also induce anti-apoptotic factors, such as NF-kappaB, which compromise the overall efficacy of chemotherapeutic anticancer treatment. Here we describe an adjuvant therapy in which a small molecule is used to sensitize cancer cells toward apoptosis induced by chemotherapeutics. Our results indicate that the imidazoline 1d modulates the pro-survival NF-kappaB pathway and selectively sensitizes cancer cells toward DNA damaging agents, thus enhancing the overall efficacy of the treatment. Pretreatment of cancer cells with the noncytotoxic imidazoline 1d (10 nM) resulted in a significant increase in apoptosis and anticancer efficacy of the clinically significant DNA damaging agents camptothecin and cisplatin. Noncancerous cells remained unaffected during this regimen.     

Antigen targeting to M cells for enhancing the efficacy of mucosal vaccines

Vaccination is one of the most successful applications of immunology and for a long time has depended on parenteral administration protocols. However, recent studies have pointed to the promise of mucosal vaccination because of its ease, economy and efficiency in inducing an immune response not only systemically, but also in the mucosal compartment where many pathogenic infections are initiated. However, successful mucosal vaccination requires the help of an adjuvant for the efficient delivery of vaccine material into the mucosa and the breaking of the tolerogenic environment, especially in oral mucosal immunization. Given that M cells are the main gateway to take up luminal antigens and initiate antigen-specific immune responses, understanding the role and characteristics of M cells is crucial for the development of successful mucosal vaccines. Especially, particular interest has been focused on the regulation of the tolerogenic mucosal microenvironment and the introduction of the luminal antigen into the lymphoid organ by exploiting the molecules of M cells. Here, we review the characteristics of M cells and the immune regulatory factors in mucosa that can be exploited for mucosal vaccine delivery and mucosal immune regulation.     

Studies on the reaction of aziridines with nitriles and carbonyls: synthesis of imidazolines and oxazolidines

Reaction of N-tosylaziridines with nitriles and carbonyls to produce imidazolines and oxazolidines has been studied in the presence of a variety of Lewis acids. The reaction is efficient with 1 equiv of BF3.Et2O or Et3OBF4 in CH2Cl2. However, it is catalytic with metal triflates that give the best results for cycloaddition of N-tosylaziridine with nitriles under solvent free conditions. The same reaction with carbonyls proceeds best in CH2Cl2 in the presence of molecular sieves. Among various triflates, Zn(OTf)2 has been found to be the best. The cleavage of the N-Ts bond of the cyclized products has been studied in order to make it more versatile in synthesis. The mechanistic aspect of the reaction has been studied by using chiral aziridines as substrates. These formal [3+2] cycloaddition reactions of aziridines with nitriles and carbonyls proceed in a Ritter fashion.     

Radiation-sensitive diselenide block co-polymer micellar aggregates: toward the combination of radiotherapy and chemotherapy

We have developed a potential radiation-sensitive drug-delivery system using active diselenide-containing block co-polymer aggregates in aqueous solution that can load and release anticancer drugs. These aggregates were sensitive to even a low dose of γ-radiation, such as 5 Gy, which is close to the radiation dose received by patients during a single radiotherapy treatment. This line of research may open an avenue for the combination of radiotherapy and chemotherapy.     

Synthesis of conformationally constrained adamantane imidazolines with trypanocidal activity

Aiming at the development of new adamantano building blocks for treating African trypanosomiasis, we report on the synthesis of spiro adamantane 2‐imidazolines 8a‐f and 9a‐c , and their congeneric 5‐(1‐adamantyl)imidazolines 14 and 15 . The potency of these compounds against Trypanosoma brucei was compared to that of rimantadine and found, in the case of compound 14e , to be three fold higher. Together with the other active compounds, 14b and 15b , which were equipotent to rimantadine, the new molecules illustrate the synergistic effect of the lipophilic character of adamantane and the C1 amidine functionality on trypanocidal activity.     

Protein heterodimerization through ligand-bridged multivalent pre-organization: enhancing ligand binding toward both protein targets

Structure-based design of a bifunctional ligand for two protein pentamers, cholera toxin B pentamer (CTB) and human serum amyloid P component (SAP), leads to multivalent dimerization of CTB and SAP in solution. This multivalent heterodimerization of proteins significantly enhances the affinity of the bifunctional ligand toward both target proteins.     

Targeted drug delivery to chemoresistant cells: folic acid derivatization of FdUMP[10] enhances cytotoxicity toward 5-FU-resistant human colorectal tumor cells

Current chemotherapy protocols that include fluoropyrimidines, such as 5-fluorouracil (5-FU), are limited by the development of chemoresistance during the course of treatment. Our laboratory has developed a novel class of fluoropyrimidines, FdUMP[N], that are oligodeoxynucleotides (ODNs) composed of some number, N, of 5-fluoro-2'-deoxyuridine-5'-O-monphosphate (FdUMP) nucleotides. Novel synthetic procedures are described that permit conjugation of folic acid to the 5'-OH of FdUMP[10] via a phosphodiester linkage using automated synthesis. The synthetic methods developed are generally applicable for ODN conjugation with folic acid. The folic acid conjugate FA-FdUMP[10] showed improved cytotoxicity toward human colorectal tumor cells (H630), and 5-FU-resistant colorectal tumor cells (H630-10). Enhanced cytotoxicity was observed for FA-FdUMP[10] relative to nonconjugated FdUMP[10] for cells grown under folate-restricted conditions, consistent with cellular uptake being, in part, receptor-mediated. Folate receptor alpha (FRalpha) mRNA was shown by RT-PCR to be overexpressed 26.3-fold in 5-FU-resistant H630-10 cells relative to H630 cells. Thus, FA-FdUMP[N] may prove useful for the treatment of 5-FU-resistant malignancies.     

一种基于硝酸纤维素膜的新颖便捷的芯片对循环肿瘤细胞的高效捕获

开发了一种新颖便捷的循环肿瘤细胞(CTC)捕获芯片用于癌细胞的分离和检测。CTC芯片以硝酸纤维素膜为基底制备,利用其对蛋白质的超强吸附能力来结合抗体,简便高效,便于将来大规模的推广应用。以非小肺癌细胞NCI-H1650为目标靶细胞,证明了CTC芯片对癌细胞具有很高的捕获效能。向1 mL正常人血液中加入500个癌细胞模拟病人血样的分析中成功检测到了182个癌细胞,预示了CTC芯片将来在临床应用上的巨大潜力。     

Amidinyl radicals: new and useful intermediates for the synthesis of imidazolines and imidazoles

Amidinyl radicals are readily generated from amidoxime benzoates by treatment with a stannane-diazo initiator or with Ni-AcOH and captured by an internal olefin to give the corresponding imidazoline.     

胶束增敏荧光光度法测定小檗碱的含量

在pH 10的磷酸盐缓冲介质中,十二烷基苯磺酸钠(SDBS)对小檗碱的荧光有明显的增敏作用,且其荧光的增强程度与小檗碱浓度在2.0×10-9～1.0×10-3mol·L-1之间呈线性关系.此反应对小檗碱的检出限(3S/N)为1.29×10-9mol·L-1.利用此反应作为测定小檗碱的方法并应用于小檗碱片剂的分析,测得结果与药典法测定结果相符,对药片的标示量而言,测定所得回收率的平均值为99.8%,测定结果的相对标准偏差(n=5)的平均值为0.17%.     

A novel general route for the preparation of enantiopure imidazolines

A novel procedure for the preparation of enantiopure 1,4-disubstituted 2-imidazolines is reported. Enantiopure beta-amino alcohols are converted into N-hydroxyethylamides, which are reacted with excess thionyl chloride, or with thionyl chloride followed by phosphorus pentachloride to yield N-chloroethylimidoyl chlorides. These intermediates are treated with amines and anilines to produce N-chloroethylamidines, which are converted into imidazolines upon workup with aqueous hydroxide. The method is simple and efficient and has been used to prepare a wide variety of enantiopure imidazolines, in a modular fashion, from readily available amino alcohols.     

One-pot synthesis of imidazolines from aldehydes: detailed study about solvents and substrates

Imidazolines were prepared in one-pot operation from aldehydes and diamines through oxidation of aminal intermediates by NBS. This method could be applied to various aromatic and aliphatic aldehydes and N-nonsubstituted and N-monosubstituted 1,2-diamines. Furthermore, it was found that CH₂Cl₂ could be altered to TBME, a more environmentally friendly solvent, in the reaction using N-nonsubstituted 1,2-diamines. The reaction conditions were very mild and chemoselective.     

Oridonin nanosuspension enhances anti-tumor efficacy in SMMC-7721 cells and H22 tumor bearing mice

PurposeThe aim of the present study was to evaluate both the in vitro and in vivo antitumor activity of an oridonin nanosuspension (ORI-N) relative to efficacy of bulk oridonin delivery.MethodsORI-N with a particle size of 897.2 ± 14.2 nm and a zeta potential of −21.8 ± 0.8 mV was prepared by the high-pressure homogenization (HPH) technique. The in vitro cytotoxicity of ORI-N against SMMC-7721 cells was evaluated by MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, the effects of ORI-N on cell cycle and cell apoptosis was analyzed by flow cytometry; the in vivo anti-tumor activity was observed in H22 tumor bearing mice.ResultsORI-N effectively inhibited the proliferation of SMMC-7721 cells. Flow cytometric analysis demonstrated that ORI-N arrested SMMC-7721 cells in the G2/M cycle, and furthermore, that ORI-N induced a higher apoptotic rate than the bulk ORI solution. In vivo studies ORI-N also showed higher antitumor efficacy as measured by reduced tumor volume and tumor weight, as well as lower toxicity in H22 solid tumor bearing mice compared to free ORI at the same concentration.ConclusionsThese results suggest that the delivery of ORI-N as a nanosuspension is a promising approach for treating tumors.     

Efficient and one‐pot catalytic synthesis of 2‐imidazolines and bis‐imidazolines with p‐toluenesulfonic acid under solvent free conditions

A practical, efficient, and inexpensive method for the synthesis of 2‐imidazoline from the reaction of nitriles with ethylenediamine or 1,2‐propanediamine using p‐toluenesulfonic acid or pyridinium p‐toluenesulfonate under reflux conditions is reported. This catalyst can be successfully applied for the chemoselective conversion of dicyanobenzenes to corresponding mono‐ and bis‐imidazolines. The applications of these catalysts are feasible because of easy preparation, easy handling, stability, inexpensive, good activity, and eco‐friendly. J. Heterocyclic Chem., (2011).     

Synthesis of substituted imidazolines via [3+2]-cycloaddition of aziridines with nitriles

An efficient synthesis of 2,4-disubstituted 1H-imidazolines from aziridines and nitriles in the presence of BF₃-Et₂O or triethyloxonium tetrafluoroborate has been described. The reaction proceeds via a [3+2]-cycloaddition reaction. Most of the nitriles successfully underwent cycloaddition reactions with aziridines even at room temperature in a very short time.     

表面活性剂对金属-桑色素荧光反应的增敏作用

研究了表面活性剂对Zr⁴⁺、Hf⁴⁺、Al³⁺、Ga³⁺、In³⁺、及Sb(Ⅴ)与桑色素荧光反应的增敏作用。在阴离子表面活性剂十二烷基磺酸钠存在下,三元体系的灵敏度成倍增加。利用这种增敏作用,渴望建立这些元素的高灵敏度荧光分析方法。     

Molecular design of antimicrobial conjugated oligoelectrolytes with enhanced selectivity toward bacterial cells

A series of cationic conjugated oligoelectrolytes (COEs) was designed to understand how variations in molecular dimensions impact the relative activity against bacteria and mammalian cells. These COEs kept a consistent distyrylbenzene framework but differed in the length of linker between the core and the cationic site and the length of substitute on the quaternary ammonium functioned group. Their antimicrobial efficacy, mammalian cell cytotoxicity, hemolytic activity, and cell association were determined. We find that hydrophobicity is a factor that controls the degree of COE association to cells, but in vitro efficacy and cytotoxicity depend on more subtle structural features. COE2-3C-C4butyl was found to be the optimal structure with a minimum inhibitory concentration (MIC) of 4 μg mL⁻¹ against E. coli K12, low cytotoxicity against HepG2 cells and negligible hemolysis of red blood cells, even at 1024 μg mL⁻¹. A time-kill kinetics study of COE2-3C-C4butyl against E. coli K12 demonstrates bactericidal activity. These findings provide the first systematic investigation of how COEs may be modulated to achieve low mammalian cell cytotoxicity with the long-range perspective of finding candidates suitable for developing a broad-spectrum antimicrobial agent.

A series of cationic conjugated oligoelectrolytes (COEs) was designed to understand how variations in molecular dimensions impact the relative activity against bacteria and mammalian cells.