[A review on the prevention and treatment of congenital cytomegalovirus infection in mothers and infants].

Human cytomegalovirus (HCMV) has a high infection rate worldwide, and 85%-90% of congenital cytomegalovirus (CMV) infections are asymptomatic at birth, with the clinical manifestations of hearing loss, psychomotor retardation, and learning disabilities, while 10%-15% are symptomatic infections. Some preterm infants develop CMV infection after birth, which can cause sepsis-like syndrome, thrombocytopenia, neutropenia, liver injury, and lung injury. However at present, women of childbearing age have a lack of awareness of CMV. CMV education and hygiene precautions for pregnant women can prevent CMV infections in themselves and congenital CMV infections in their infants. No definite results have been obtained from the studies on the effect of CMV vaccine and high-titer immunoglobulin in preventing congenital CMV infection in fetuses. Recent studies have confirmed that the specificity and sensitivity of urinary or salivary CMV-DNA detection have reached more than 98%, which contributes to the early diagnosis of congenital CMV infection. In addition to short-term treatment with ganciclovir, long-term treatment with oral valganciclovir is safe for symptomatic congenital CMV infection and appears to have a better clinical effect than the short-term treatment. In the future, it is necessary to strengthen the health education for pregnant women, enhance the mother-to-child management of CMV infection, conduct the research on CMV vaccine, and further standardize treatment regimens.

[Effect of Qiling Decoction combined HAART on expression levels of Treg cells and Th17 in HIV/AIDS patients].

OBJECTIVE: To explore the effect of Qiling Decoction (QD) combined highly active antiretroviral treatment (HAART) on expression levels of peripheral blood Th17 and Treg cells in HIV/AIDS patients. METHODS: Totally 55 HIV/AIDS patients were randomly assigned to the treatment group (28 cases) and the combination group (27 cases). Besides, 21 HIV negative patients were recruited as the healthy control group. Those in the treatment group received HARRT alone, while those in the combination group received HAART combined QD. The observation lasted for 24 weeks. Meanwhile, according to peripheral blood CD4+ T cell counts before treatment, HIV/AIDS patients were assigned to three subgroups. For patients in subgroup 1, 1 cells/microL < CD4+ T cell counts < or = 100 cells/microL; For patients in subgroup 2, 101 cells/microL < CD4+ T cell counts < or = 200 cells/lL; For patients in subgroup 3, 201 cells/microL < CD4+ T cell counts < or = 350 cells/microL. Expression of peripheral blood Th17 and Treg cells, and number of CD4+ T cell counts were detected using flow cytometry (FCM)in HIV/AIDS patients at the pre-treatment baseline, week 4, 12, and 24, as well as those in the healthy control group. RESULTS: Compared with the healthy control group, CD4+ T cell counts and the baseline expression level of Th17 cells in the peripheral blood of HIV/AIDS patients significantly decreased, the expression level of Treg cells significantly increased P < 0.01). Compared with before treatment in the same group, CD4+ T cell counts all increased at week 4, 12, and 24 in the two treatment groups, showing statistical difference (P < 0.05, P < 0.01). There was no statistical difference in the effective rate at various CD4+ T cell levels between the two groups (P > 0.05). There was no statistical difference in expression levels of Th17 and Treg cells between the combination group and the treatment group at any time point (all P >0.05). The Th17/Treg ration significantly increased in the combination group after 24 weeks of treatment, showing statistical difference when compared with the treatment group (U = 2.135, P = 0.038). CONCLUSION: QD could improve the immune balance of Th17/Treg cells, which might be one of its mechanisms for improving HIV/AIDS patients' immunity.

[Advances in the study of structural modifications of multi-target anticancer drug sorafenib].

Sorafenib, the first oral multikinase inhibitor, can inhibit several kinases involved in tumor proliferation and angiogenesis including Raf, VEGFR, PDGFR, kit and so on. Due to the advantages of multi-mechanisms, broad-spectrum anticancer potency, and well-tolerated results in combination trials, more and more researchers have focused on the optimization of sorafenib in order to develop novel multi-targeted anticancer drugs. The present paper reviews the development of modification of sorafenib in recent years from two aspects: bio-isosterism and scaffold hopping. The structure-activity relationship (SAR) of these compounds is also summarized.

LYP, a novel bestatin derivative, inhibits cell growth and suppresses APN/CD13 activity in human ovarian carcinoma cells more potently than bestatin.

LYP is a bestatin dimethylaminoethyl ester which inhibits aminopeptidase N (APN/CD13). Our goal in this study was to evaluate LYP as a candidate compound for cancer treatment, beginning by studying its inhibitory effects on tumors and then comparing it to bestatin. Experiments were performed on human ovarian carcinoma (OVCA) ES-2 and SKOV-3 cell lines, which have high and low levels of APN/CD13 respectively. LYP effectively inhibited ES-2 cell growth as estimated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and the trypan blue dye-exclusion test. LYP significantly suppressed APN/CD13 activity on the surface of ES-2 cells as measured by quantifying the enzymatic cleavage of the substrate L-leucine-p-nitroanilide. The inhibitory effects of LYP were greater than those of bestatin at the same concentrations. In contrast, LYP was a weak inhibitor of SKOV-3 cell growth, suggesting that LYP may inhibit ES-2 cell growth via suppression of APN/CD13. Inhibition of APN/CD13 expression was also demonstrated with immunofluorescent flow cytometry and Western blot analysis. Inhibitory effects of LYP were confirmed by using a mouse model in which LYP delayed the growth of ES-2 xenografts in mice after 2 weeks of LYP injections. Inhibition of APN/CD13 expression was demonstrated in the ES-2 xenografts using Western blot analysis. The inhibitory effects of LYP on the ES-2 xenografts were stronger than those of bestatin. These results suggest that LYP has a powerful inhibitory effect on the growth of OVCA cells and that the mechanism may be via a decrease in the expression of APN/CD13.

LYP, a bestatin dimethylaminoethyl ester, inhibited cancer angiogenesis both in vitro and in vivo.

Our previous study revealed that LYP, a bestatin dimethylaminoethyl ester, inhibited the growth of human ovarian carcinoma ES-2 xenografts in mice and suppressed aminopeptidase N (APN/CD13) activity more potently than bestatin. In this study, we examined the inhibitory effect of LYP on migration and formation of capillary tube of human umbilical vascular endothelial cells (HUVECs) in vitro and anti-angiogenesis in ES-2 xenografts in mice. LYP did not possess cytotoxicity to HUVEC proliferation according to the MTT assay and trypan blue exclusion assay. However, APN/CD13 activity on cell surface of HUVECs was suppressed in the presence of LYP as measured by quantifying the enzymatic cleavage of the substrate l-leucine-p-nitroanilide. The assays of scratch and transwell chamber showed that LYP significantly inhibited HUVEC migration and invasion through Matrigel coated polycarbonate filters. Capillary tube formation assay revealed that the number of branch points formed by HUVECs on 3-D Matrigel was reduced after incubation with LYP. The anti-angiogenesis of LYP was verified in ES-2 xenografts in mice. The mean vascular density (MVD) and mean vascular luminal diameter (MVLD) were markedly reduced by LYP after two weeks of intravenous injection as evaluated by CD34 immunohistochemical staining. LYP suppression of cancer angiogenesis was greater than that of bestatin. The inhibition of angiogenic molecules may involve in anti-angiogenesis of LYP. The levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and transforming growth factor-alpha (TGF-α) were decreased in HUVECs and ES-2 xenografts after treatment with LYP as determined by Western blot analysis. These results indicated that the high efficacy of LYP may partially relate to the inhibition of angiogenesis.

Ligustrazine derivatives. Part 3: Design, synthesis and evaluation of novel acylpiperazinyl derivatives as potential cerebrocardiac vascular agents.

A series of novel acylpiperazinyl Ligustrazine derivatives was designed, synthesized, and their protective effects on damaged ECV-304 cells and antiplatelet aggregation activities were evaluated. The results showed that compound E33 displayed most potential protective effects on the ECV-304 cells damaged by hydrogen peroxide, and compound E1 was found to be the most active antiplatelet aggregation agent. Structure-activity relationships were briefly discussed.

Pharmacophore model of influenza neuraminidase inhibitors--a systematic review.

Recently, the worldwide spread of A/H5N1 avian influenza with high virulence has highlighted the potential threat of a human influenza pandemic. The viral surface glycoprotein, neuraminidase (NA), has been found to be a potential target to control influenza virus. With an understanding of the enzyme mechanism, the X-ray crystallographic structures of NA and its substrate or inhibitors, and progress in computational chemistry, the information about NA binding sites and pharmacophore models is derived from existing inhibitors and will serve as design guidelines of more potent agents against NA. This article gives a systematic review of the recent advances in this area.

5-(Methoxy-carbon-yl)thio-phene-2-carboxylic acid.

In the title compound, C(7)H(6)O(4)S, a monoester derivative of 2,5-thio-phene-dicarboxylic acid, the carboxylic acid and the carboxylic acid ester groups are approximately coplanar with thio-phene ring, making a dihedral angle of 3.1 (4) and 3.6 (4)°, respectively. In the crystal structure, mol-ecules are connected by classical inter-molecular O-H⋯O hydrogen bonds, forming centrosymmetric dimers.

Role of sulfonamide group in matrix metalloproteinase inhibitors.

Sulfonamide hydroxamates were designed and synthesized as efficient matrix metalloproteinase (MMP) inhibitors since the discovery of CGS 27023A in 1994. The sulfonamide group was incorporated in the inhibitor to improve the enzyme-inhibitor binding, not only by forming hydrogen bonds to the enzyme but also by properly directing the hydrophobic substituent to the S1' pocket and enabling it to plunge in deeply. Some researchers even presumed that the sulfonamide group, together with the zinc binding group (ZBG), coordinated the zinc ion within the MMP active site. This review will illustrate the role of the sulfonamide group in MMP inhibitors.

Advances in matrix metalloproteinase inhibitors based on pyrrolidine scaffold.

Matrix metalloproteinases (MMPs) play an important role in many physiological and pathological processes. MMP inhibitors have been considered as potential therapeutics for neoplasitc, rheumatic and cardiovascular diseases. Our group and others have been developing pyrrolidine scaffold-based MMP inhibitors for a number of years, and numerous compounds have been reported in the literature. These compounds can be classified as sulfonamide pyrrolidine derivatives, proline-containing peptidomimetics and acyl pyrrolidine derivatives. These synthetic MMP inhibitors show low nanomolar activity for some MMP subclasses, thus confirming pyrrolidine ring an excellent scaffold from which to design MMP inhibitors. This review will focus primarily on the structure, activity and selectivity profiles of pyrrolidine scaffold-based MMP inhibitors.

Synthesis of new sulfonyl pyrrolidine derivatives as matrix metalloproteinase inhibitors.

A series of new sulfonyl pyrrolidine derivatives was designed, synthesized, and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and aminopeptidase N (AP-N). The results showed that these pyrrolidine derivatives exhibited highly selective inhibition against MMP-2 as compared with AP-N. The compounds 4c, 4j, 5a, and 5b were equally or more potent MMP-2 inhibitors than the positive control LY52. The FlexX docking was done to explain the reason for the different potency between MMP-2 and AP-N. Structure-activity relationships were also briefly discussed.

Design, synthesis and evaluation of novel sulfonyl pyrrolidine derivatives as matrix metalloproteinase inhibitors.

A series of novel sulfonyl pyrrolidine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and aminopeptidase N (AP-N). The results showed that these pyrrolidine derivatives exhibited highly selective inhibition against MMP-2 as compared with AP-N. Compounds 6a-d were more potent MMP-2 inhibitors than the positive control LY52. The structure-activity relationships were also briefly discussed.

Design, synthesis, and preliminary evaluation of 4-(6-(3-nitroguanidino)hexanamido)pyrrolidine derivatives as potential iNOS inhibitors.

A series of 4-(6-(3-nitroguanidino)hexanamido)pyrrolidine derivatives were synthesized and evaluated for their abilities to inhibit inducible nitric oxide synthase (iNOS) isoform. All target compounds were prepared in 11 steps from commercially trans-4-hydroxy-L-proline. The preliminary pharmacological test showed that three compounds, 17, 21, and 30, have the good potency (IC(50)=2.36, 2.68, 2.5 microM, respectively) which are compared to the NOS inhibitor N(G)-nitroarginine(L-NNA) (IC(50)=14.74 microM), and could be used as lead compounds for exploring new iNOS inhibitors in the future.

Novel aminopeptidase N inhibitors derived from 1,3,4-thiadiazole scaffold.

The aminopeptidase N (APN/CD13), overexpressed in tumor cells, plays a critical role in angiogenesis. In this study, we report the synthesis and in vitro enzyme inhibition assay of 1,3,4-thiadiazole scaffold compounds. These new compounds have potent inhibitory activities toward APN with IC(50) values in the micromol rang.

Design, synthesis and preliminary evaluation of novel pyrrolidine derivatives as matrix metalloproteinase inhibitors.

A series of novel pyrrolidine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and aminopeptidase N (AP-N). The results showed that these pyrrolidine derivatives exhibited highly selective inhibition against MMP-2 as compared with AP-N. The hydroxamates 8a-c were equally or more potent MMP-2 inhibitors than the positive control LY52. The binding mode of the most potent compound 8a with MMP-2 was proposed. Structure-activity relationships were also briefly discussed.

(S)-2-[(2R,3S)-2-Ammonio-3-hydr-oxy-3-(4-nitro-phen-yl)propanamido]-4-methyl-penta-noate monohydrate.

The structure of the title compound, C(15)H(21)N(3)O(6)·H(2)O, is of inter-est with respect to assumed anti-cancer activity. The title mol-ecules are linked through inter-molecular O-H⋯O hydrogen-bonded chains along the a axis. These chains are connected by inter-molecular N-H⋯O hydrogen bonds through the crystallographic screw axis along [010], forming layers, which are stabilized by other N-H⋯O bonds with water O atoms as acceptors and O-H⋯O bonds with water H atoms as donors. The H atoms of the protonated amino cation are also involved in inter-molecular N-H⋯O bonding inter-actions.

Inhibition of human gastric carcinoma cell growth by treatment of N(3)-o-toluyl-fluorouracil as a precursor of 5-fluorouracil.

N(3)-o-toluyl-fluorouracil (TFU), the pro-drug of 5-fluorouracil (5-FU), is the metabolite of N(1)-acetyl-N(3)-o-toluyl-fluorouracil (atofluding). We aimed to evaluate the efficacy of TFU as a precursor of 5-FU on the growth inhibition of human gastric carcinoma cell lines SGC-7901 and MKN-45. Growth of SGC-7901 and MKN-45 cells was remarkably suppressed by treatment with TFU in the presence of liver microsomal enzymes in vitro, suggesting that TFU may be converted to 5-FU by the enzymes. Similar treatment of TFU induced apoptosis of the cells, which was deduced from typical apoptotic features such as morphology, the formation of characteristic ladder pattern of DNA migration and the accumulation of sub-G1 phase. Cancer cells xenografts in nude mice were employed to evaluate the efficacy of TFU in vivo. Growth of human gastric carcinoma cells was significantly delayed by oral administration of TFU with low side effects. Apoptosis in xenografts was also observed by means of TUNEL staining method. These results suggest that the treatment of TFU in the presence of liver microsomal enzymes and the oral administration of TFU in mice induced anti-proliferation and apoptosis in gastric carcinoma cells. This suggests that TFU may be a promising pro-drug of 5-FU for cancer treatments.

Induction of apoptosis in human hepatocellular carcinoma cells by synthetic antineoplaston A10.

Antineoplaston A10 (3-phenylacetylamino-2,6-piperidinedion) is a naturally occurring substance and was the first antineoplaston in the human body to be chemically identified. The effect of antineoplaston A10 on human hepatocellular carcinoma cell lines HepG2 and HLE has been examined. Antineoplaston A10 displayed anti-proliferative action inhibiting cell growth in a dose- and time-dependent manner in vitro as measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and clonogenic assays. Incubation with antineoplaston A10 for 48 h induced apoptotic events such as a typical apoptotic morphology, formation of a characteristic ladder pattern of DNA migration and accumulation of sub-G1 phase cells. Next, hepatoma xenografts in nude mice were employed to study the antitumor effects of antineoplaston A10 in vivo. Oral administration of antineoplaston A10 delayed the growth of HepG2 and HLE cells in the mice without a reduction in body weight. A higher proportion of apoptotic cells in xenografts was observed by means of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. In addition, the level of expression of apoptotic marker p53 increased while that of anti-apoptotic protein bcl-2 decreased, as evaluated with immunohistochemical staining in the xenografts. These results suggested that antineoplaston A10 may inhibit the growth of human hepatoma cells through the induction of apoptosis.

Using caffeoyl pyrrolidine derivative LY52, a potential inhibitor of matrix metalloproteinase-2, to suppress tumor invasion and metastasis.

LY52 is a caffeoyl pyrrolidine derivative designed to fit the S'1 active pocket of gelatinases that act in tumor invasion and metastasis. Herein, we examined the effects of LY52 on expression of matrix metalloproteinase (MMP)-2 expression in human breast cancer MDA-MB-231 cells and on in vitro invasion and in vivo metastasis. LY52 significantly blocked MMP-2 activity as evidenced by a decrease in the degradation of succinylated gelatin. Gelatin zymography analysis showed that LY52 (0.1-200 microg/ml) inhibited expression of active MMP-2 in concanavalin A-stimulated MDA-MB-231 cells. Inhibition of MMP-2 expression was also observed in tissue of tumor xenografts in mice that were orally administered LY52 (25 or 100 mg/kg). Furthermore, LY52 displayed an inhibitory effect on in vitro invasion of MDA-MB-231 cells and pulmonary metastasis of B16F10 murine melanoma cells in mice without significant toxic effects. These results suggest that LY52 is a potential MMP-2 inhibitor that may effectively suppress tumor invasion and metastasis.

Inhibition of human gastric carcinoma cell growth by atofluding derivative N3-o-toluyl-fluorouracil.

AIM: To evaluate the growth inhibition efficacy of atofluding derivative N3-o-toluyl-fluorouracil (TFU) on human gastric carcinoma cell lines SGC-7901 and MKN-45. METHODS: Cell growth inhibition by TFU was measured by MTT and clonogenic assays without or with liver microsomal enzymes. Xenografts of cancer cells in nude mice were employed to study the anti-proliferative effects of TFU in vivo. RESULTS: TFU inhibited the growth of SGC-7901 and MKN-45 cells. However, the inhibitory effects of TFU on cell growth were not significant. The inhibition rates were enhanced in the presence of liver microsomal enzymes, ranging 4.73%-48.57% in SGC-7901 cells and 9.0%-62.02% in MKN-45 cells. In vivo, TFU delayed the growth of SGC-7901 and MKN-45 cells in nude mice. The inhibition rates were 40.49%, 63.24%, and 75.98% in SGC-7901 cells and 40.76%, 61.41%, and 82.07% in MKN-45 cells when the oral doses were 25, 50, and 100 mg/kg, respectively. TFU treatment was generally well tolerated by mice with less than 20% reduction in body weight. CONCLUSION: TFU inhibits the growth of human gastric carcinoma cells. The inhibition rates are increased in the presence of liver microsomal enzymes. The efficacy of TFU may be associated with the sustaining release of 5-fluorouracil (5-FU) mediated by the enzymes.