Humans have approximately 400 intact odorant receptors, but each
individual has a unique set of genetic variations that lead to variation in
olfactory perception. We used a heterologous assay to determine how often
genetic polymorphisms in odorant receptors alter receptor function. We
identified agonists for 18 odorant receptors and found that 63% of the
odorant receptors we examined had polymorphisms that altered in
vitro function. On average, two individuals differ functionally at
over 30% of their odorant receptor alleles. To show that these
in vitro results are relevant to olfactory perception, we
verified that variations in OR10G4 genotype explain over
15% of the observed variation in perceived intensity and over
10% of the observed variation in perceived valence for the high affinity
in vitro agonist guaiacol, but do not explain phenotypic
variation for the lower affinity agonists vanillin and ethyl vanillin.
The aim of the present study was to investigate the inhibitory effect of sodium houttuyfonate (SH) on synovial cell proliferation in vitro. Primary cells were obtained from the synovial tissue of a patient with rheumatoid arthritis (RA). The cells were divided into five treatment groups as follows: the control group (group 1), 25 μg/ml SH-treated group (group 2), 50 μg/ml SH-treated group (group 3), 100 μg/ml SH-treated group (group 4) and the 200 μg/ml SH-treated group (group 5). Following seven days of treatment, the proliferation rate of the synovial cells was then detected using an MTT assay. The expression level of proliferative synovial cells markedly decreased in the SH-treated groups in a dose-dependent manner compared with the control group. In conclusion, the present study demonstrated that SH was able to inhibit the proliferation of synovial cells obtained from a patient with RA. These results provide a potential theoretical basis for the development of a safe and effective treatment against RA in the future.
rheumatoid arthritis; sodium houttuyfonate; synovial proliferation; MTT assay
A 33 amino acid fragment sequence of 136 residue Hpa1 harpin expressed in transgenic wheat induces the phloem defence that efectively represses infestations of English grain aphid on the crop.
The harpin protein Hpa1 has multiple beneficial effects in plants, promoting plant growth and development, increasing crop yield, and inducing resistance to pathogens and insect pests. For these effects, the 10–40 residue fragment (Hpa110–42) isolated from the Hpa1 sequence is 1.3- to 7.5-fold more effective than the full-length protein. Here it is reported that the expression of Hpa110–42 under the direction of an insect-induced promoter induces the phloem-based defence to English grain aphid, a dominant species of wheat aphids. The expression of Hpa110–42 was found to compromise the colonization preference of aphids on the plant and further inhibit aphid reproduction in leaf colonies. In Hpa110–42-expressing wheat lines, moreover, aphid feeding from the phloem was repressed in correlation with the phloem-based defence. This defensive mechanism was shown as enhanced expression of wheat genes encoding phloem lectin proteins (PP2-A1 and PP2-A2) and β-1,3-glucan synthase-like enzymes (GSL2, GSL10, and GSL12). Both PP2-A and β-1,3-glucan formed high molecular mass polymers to block phloem sieve plate pores and therefore impede aphid feeding from the phloem. However, the phloem-based defence was impaired by treating plants with ethylene signalling inhibitors, suggesting the requirement for the ethylene signalling pathway. In addition, if Hpa110–42-expressing plants were subjected to attack by a small number of aphids, they newly acquired agriculturally beneficial characters, such as enhanced vegetative growth and increased tiller numbers and grain output values. These results suggest that the defensive and developmental roles of Hpa110–42 can be integrated into the germplasm of this agriculturally significant crop.
Agronomic traits; English grain aphid; ethylene signalling; Hpa110–42 expression; insect defence; phloem-based defence; transgenic wheat.
Han population is six times as likely as Kazak population to present with type 2 diabetes mellitus (T2DM) in China. We hypothesize that differential expression and CpG methylation of miR-375 may be an ethnic-related factor that influences the incidence of T2DM. The expression level of miR-375 was examined using real-time PCR on Kazak and Han T2DM plasma samples. Furthermore, the methylation levels of CpG sites of miR-375 promoter were determined by MassARRAY Spectrometry in these samples. The relative expression levels of plasma miR-375 in Kazak T2DM samples are 1, and the relative expression levels of plasma miR-375 in Han T2DM samples are 3. The mean level of miR-375 methylation, calculated from the methylation levels of the CpG sites, was 8.47% for the Kazak T2DM group and 10.38% for the Han T2DM group. Further, five CpG units showed a statistically significant difference between Kazak and Han T2DM samples, and, among them, four were hypomethylated and only one CpG unit showed hypermethylation in Kazak T2DM samples. These findings indicate that the expression levels of plasma miR-375 and its CpG methylation in the promoter region are ethnically different, which may contribute to the different incidence of diabetes observed in Kazak and Han populations.
Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including erlotinib, gefitinib, afatinib and icotinib are currently available as treatment for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, no head to head trials between these TKIs in mutated populations have been reported, which provides room for indirect and integrated comparisons.
We searched electronic databases for eligible literatures. Pooled data on objective response rate (ORR), progression free survival (PFS), overall survival (OS) were calculated. Appropriate networks for different outcomes were established to incorporate all evidences. Multiple-treatments comparisons (MTCs) based on Bayesian network integrated the efficacy and specific toxicities of all included treatments.
Twelve phase III RCTs that investigated EGFR-TKIs involving 1821 participants with EGFR mutation were included. For mutant patients, the weighted pooled ORR and 1-year PFS of EGFR-TKIs were significant superior to that of standard chemotherapy (ORR: 66.6% vs. 30.9%, OR 5.46, 95%CI 3.59 to 8.30, P<0.00001; 1-year PFS: 42.9% vs. 9.7%, OR 7.83, 95%CI 4.50 to 13.61; P<0.00001) through direct meta-analysis. In the network meta-analyses, no statistically significant differences in efficacy were found between these four TKIs with respect to all outcome measures. Trend analyses of rank probabilities revealed that the cumulative probabilities of being the most efficacious treatments were (ORR, 1-year PFS, 1-year OS, 2-year OS): erlotinib (51%, 38%, 14%, 19%), gefitinib (1%, 6%, 5%, 16%), afatinib (29%, 27%, 30%, 27%) and icotinib (19%, 29%, NA, NA), respectively. However, afatinib and erlotinib showed significant severer rash and diarrhea compared with gefitinib and icotinib.
The current study indicated that erlotinib, gefitinib, afatinib and icotinib shared equivalent efficacy but presented different efficacy-toxicity pattern for EGFR-mutated patients. Erlotinib and afatinib revealed potentially better efficacy but significant higher toxicities compared with gefitinib and icotinib.
Many diabetic patients complicated with wild to severe depression. It is unclear in diabetic medication whether depression perturbs the drug metabolic process of the hypoglycemic agents or not. The present study was designed to investigate the impact of chronic unpredicted mild stress (CUMS) –induced depression on mitiglinide (MGN) pharmacokinetics in rats. Adult female Sprague-Dawley rats in CUMS group were subjected to different types of stressors and the stress procedures lasted for 8 weeks. Control group without receiving stress had free access to food and water. Open-field test and 5-HT levels were assayed to evaluate the depression. After CUMS all rats were given 2.5 mg/kg of mitiglinide per os. The blood samples were collected at different time and mitiglinide plasma concentration was measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Non-compartmental statistical moment analysis was processed with DAS software. In CMUS-induced depression group, peak concentration (Cmax), peak time (Tmax), area under curve (AUC0 → ∞), mean residence time (MRT0 → ∞), and half-life (T1/2z) were reduced while total plasma clearance (CLz/F) was increased compared to control group. These preliminary results indicated that CUMS-induced depression alter the drug metabolic process of mitiglinide in rats. This finding will be significant in clinic.
Human serum albumin (HSA) is an ideal natural colloid that has been widely used in clinical practice for supplemental albumin or as a plasma substitute during therapeutic plasma exchanges to redress hypoproteinemia. However, a paucity of well-designed clinical trials, a lack of a clear cut survival benefit, and frequent case reports of adverse drug reaction (ADR) make the use of HSA controversial. This study aims to review and to comment on the reported ADRs of HSA in the People’s Republic of China, so as to provide the basis for rational HSA use in clinical settings. Data on the ADR case reports from HSA administration between January 1990 and December 2012 available from the China National Knowledge Infrastructure (CNKI) database, Wanfang data (WF), and Chinese Biomedical Literature (CBM) were reviewed. The reasons for using HSA, the types of ADRs, the causality of ADRs and the rationality for HSA administration were extracted and analyzed. In total, 61 cases of ADR reports were identified of which the primary disease of patients using HSA was malignant tumor (34.42%). The primary ADR was anaphylaxis (59.02%). Of the 61 cases, 30 were caused by irrational use of HSA. The most common irrational use was off-label use (56.67%), followed by inappropriate infusion rate. Therefore, we conclude that to avoid the occurrence of ADRs, guidelines for using HSA are needed to guarantee its rational use and HSA should be used strictly according to these guidelines. In addition, medical staff, including clinical pharmacists and nurses, should pay more attention to the patients who inject HSA to ensure its safe use in the clinic.
HSA; off-label use; ADR; plasma substitute; albumin; hypoproteinemia
Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are widely used for EGFR mutated non-small-cell lung cancer (NSCLC) patients, tumor sample availability and heterogeneity of the tumor remain challenging for physicians’ selection of these patients. Here, we developed a serum proteomic classifier based on matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) to predict the clinical outcome of patients treated with EGFR-TKIs.
A total of 68 patients were included in this study. All patients received EGFR-TKIs as second or third line treatment and blood samples were collected before treatment. Using magnetic bead assisted serum peptide capture coupled to MALDI-TOF-MS, pretreatment serum from 24 NSCLC patients was analyzed to develop a proteomic classifier (training set). In a blinded test set with 44 patients, each sample was classified into “good” or “poor” groups using this classifier. Survival analysis of each group was done based on this classification.
A 3-peptide proteomic classifier was developed from the training set. In the testing set, the classifier was able to distinguish patients of “good” or “poor” outcomes with 93% accuracy, sensitivity, and specificity. The overall survival and progression free survival of the predicted good group were found to be significantly longer than the poor group, not only in the whole population but also in certain subgroups, such as pathological adenocarcinoma and nonsmokers. With respect to the tumor samples available for EGFR mutation detection, all eight EGFR mutant tumors and three of the 12 wild type EGFR tumors were classified as good while nine of the 12 wild type EGFR tumors were classified as poor.
The current study has shown that a proteomic classifier can predict the outcome of patients treated with EGFR-TKIs and may aid in patient selection in the absence of available tumor tissue. Further studies are necessary to confirm these findings.
non-small-cell lung cancer; matrix assisted laser desorption ionization time of flight mass spectrometry; proteomic classifier; survival
Deoxynivalenol (DON) is a mycotoxin that reduces feed intake and animal performance, especially in swine. Arginine and glutamine play important roles in swine nutrition. The objective of this study was to determine the effects of dietary supplementation with arginine and glutamine on both the impairment induced by DON stress and immune relevant cytokines in growing pigs. A total of forty 60-d-old healthy growing pigs with a mean body weight of 16.28±1.54 kg were randomly divided into 5 groups, and assigned to 3 amino acid treatments fed 1.0% arginine (Arg), 1.0% glutamine (Gln) and 0.5% Arg+0.5% Gln, respectively, plus a toxin control and a non-toxin control. Pigs in the 3 amino acid treatments were fed the corresponding amino acids, and those in non-toxin control and toxin control were fed commercial diet with 1.64% Alanine as isonitrogenous control for 7 days. The toxin control and amino acid treatments were then challenged by feeding DON-contaminated diet with a final DON concentration of 6 mg/kg of diet for 21 days. No significant differences were observed between toxin control and the amino acid groups with regard to the average daily gain (ADG), although the values for average daily feed intake (ADFI) in the amino acid groups were significantly higher than that in toxin control (P<0.01). The relative liver weight in toxin control was significantly greater than those in non-toxin control, arginine and Arg+Glu groups (P<0.01), but there were no significant differences in other organs. With regard to serum biochemistry, the values of BUN, ALP, ALT and AST in the amino acid groups were lower than those in toxin control. IGF1, GH and SOD in the amino acid groups were significantly higher than those in toxin control (P<0.01). The IL-2 and TNFα values in the amino acid groups were similar to those in non-toxin control, and significantly lower than those in toxin control (P<0.01). These results showed the effects of dietary supplementation with arginine and glutamine on alleviating the impairment induced by DON stress and immune relevant cytokines in growing pigs.
Cofilin is a member of the actin depolymerizing factor (ADF)/cofilin family, which regulates actin dynamics. Increasing evidence suggests that mitochondrial translocation of cofilin appears necessary for the regulation of apoptosis.
We report that allyl isothiocyanate (AITC) potently induces mitochondria injury and apoptosis. These events were accompanied by a loss of polymerized filamentous actin (F-actin) and increase in unpolymerized globular actin (G-actin). AITC also induces dephosphorylation of cofilin through activation of PP1 and PP2A. Only dephosphorylated cofilin binds to G-actin and translocates to mitochondria during AITC-mediated apoptosis. Mechanistic study revealed that interruption of ROCK1/PTEN/PI3K signaling pathway plays a critical role in AITC-mediated dephosphorylation and mitochondrial translocation of cofilin and apoptosis. Our in vivo study also showed that AITC-mediated inhibition of tumor growth of mouse leukemia xenograft model is in association with dephosphorylation of cofilin.
These findings support a model in which induction of apoptosis by AITC stems primarily from activation of ROCK1 and PTEN, and inactivation of PI3K, leading in turn to activation of PP1 and PP2A, resulting in dephosphorylation of cofilin, which binds to G-actin and translocates to mitochondria, culminating in the dysfunction of mitochondria, release of cytochrome c and apoptosis.
Allyl isothiocyanate; Apoptosis; Cofilin; ROCK1; PI3K; Leukemia
In this study, 19 dicamphanoyl-dihydropyranochromone (DCP) and dicamphanoyl-dihydropyranoxanthone (DCX) derivatives, previously discovered as novel anti-HIV agents, were evaluated for their potential to reverse multi-drug resistance (MDR) in a cancer cell line over-expressing P-glycoprotein (P-gp). Seven compounds fully reversed resistance to vincristine (VCR) at 4 μM, a 20-fold enhancement compared to the first generation chemosensitizer, verapamil (4 μM). The mechanism of action of DCPs and DCXs was also resolved, since the most active compounds (3, 4, and 7) significantly increased intracellular drug accumulation due, in part, to inhibiting the P-gp mediated drug efflux from cells. We conclude that DCPs (3 and 4) and DCXs (7, 11, and 17) can exhibit polypharmacologic behavior by acting as dual inhibitors of HIV replication and chemoresistance mediated by P-gp. As such, they may be useful in combination therapy to overcome P-gp-associated drug resistance for AIDS treatment.
pyranochromone derivatives; chemoresistance; P-glycoprotein (P-gp) inhibitors; anti-HIV agents; dual function inhibitors
Myelodysplastic syndrome (MDS) is a complex family of pre-leukemic diseases in which hematopoietic stem cell defects lead to abnormal differentiation in one or more blood lineages. Disease progression is associated with increasing genomic instability and a large proportion of patients go on to develop acute myeloid leukemia. Primarily a disease of the elderly, it can also develop following chemotherapy. We have previously reported that CREB binding protein (Crebbp) heterozygous mice have an increased incidence of hematological malignancies, and others have shown that CREBBP is one of the genes altered by chromosomal translocations found in patients suffering from therapy-related MDS. This led us to investigate whether hematopoietic tumor development in Crebbp+/- mice is preceded by a myelodysplastic phase and whether we could uncover molecular mechanisms that might contribute to its development. We report here that Crebbp+/- mice invariably develop myelodysplastic/myeloproliferative neoplasm within 9-12 months of age. They are also hypersensitive to ionizing radiation and show a marked decrease in PARP1 activity after irradiation. In addition, protein levels of XRCC1 and APEX1, key components of base excision repair machinery, are reduced in unirradiated Crebbp+/- cells or upon targeted knock down of CREBBP levels. Our results thus provide validation of a novel myelodysplastic/myeloproliferative neoplasm mouse model and, more importantly, point to defective repair of DNA damage as a contributing factor to the pathogenesis of this currently incurable disease.
CREBBP; MDS/MPN; DNA repair; radiation hypersensitivity; PARP1
In this study, 1R,2R-dicamphanoyl-3,3-dimethydihydropyrano[2,3-c]xanthen-7(1H)-one (DCX) derivatives were designed and synthesized as novel anti-HIV agents against both wild-type and nonnucleoside reverse transcriptase (RT) inhibitor-resistant HIV-1 (RTMDR-1) strains. Twenty-four DCX analogs (6-29) were synthesized and evaluated against the non-drug-resistant HIV-1 NL4-3 strain, and selected analogs were also screened for their ability to inhibit the RTMDR-1 strain. Compared with the control 2-ethyl-3′,4′-di-O-(-)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (2-EDCP, 2), one of the best anti-HIV coumarin derivatives in our prior study, three DCX compounds (7, 12, and 22) showed better activity against both HIV strains with an EC50 range of 0.062 – 0.081 μM, and five additional compounds (8, 11, 16, 18, and 21) exhibited comparable anti-HIV potency. Six DCX analogs (7, 11-12, 18, and 21-22) also showed enhanced selectivity index (SI) values in comparison to the control. Structure-activity relationship (SAR) information suggested that the extended conjugated system of the pyranoxanthone skeleton facilitates the interaction of the small DCX molecule within the viral binding pocket, consequently leading to enhanced anti-HIV activity and selectivity. Compared to DCP compounds, DCX analogs are a more promising new class of anti-HIV agents.
1R,2R-dicamphanoyl-3,3-dimethydihydropyrano[2,3-c]xanthen-7(1H)-one (DCX); Anti-HIV activity; Structure-activity relationship (SAR)
Epstein-Barr virus (EBV) infection of primary human B cells drives their indefinite proliferation into lymphoblastoid cell lines (LCLs). B cell immortalization depends on expression of viral latency genes, as well as the regulation of host genes. Given the important role of microRNAs (miRNAs) in regulating fundamental cellular processes, in this study, we assayed changes in host miRNA expression during primary B cell infection by EBV. We observed and validated dynamic changes in several miRNAs from early proliferation through immortalization; oncogenic miRNAs were induced, and tumor suppressor miRNAs were largely repressed. However, one miRNA described as a p53-targeted tumor suppressor, miR-34a, was strongly induced by EBV infection and expressed in many EBV and Kaposi's sarcoma-associated herpesvirus (KSHV)-infected lymphoma cell lines. EBV latent membrane protein 1 (LMP1) was sufficient to induce miR-34a requiring downstream NF-κB activation but independent of functional p53. Furthermore, overexpression of miR-34a was not toxic in several B lymphoma cell lines, and inhibition of miR-34a impaired the growth of EBV-transformed cells. This study identifies a progrowth role for a tumor-suppressive miRNA in oncogenic-virus-mediated transformation, highlighting the importance of studying miRNA function in different cellular contexts.
By use of purer indices of PM and RM components than previous studies and adoption of three PM task types, the present study aimed to investigate the deficits of these two components underlying global impairment at a PM task in individuals with amnestic mild cognitive impairment (aMCI).
Nineteen aMCI patients and 22 normal controls were examined on event-, time- and activity-based PM tasks. Separate scores were obtained for initiation of intentions (i.e. PM component) and for the content of the intentions (i.e. RM component).
Individuals with aMCI achieved lower PM component (but not RM component) scores than NCs across all three PM tasks. Furthermore, there was a trend for greater impairment on activity-based than time-based and event-based PM tasks, but which did not reach significance. In addition, a significant association between PM component and an executive function test was observed in aMCI group. PM task performance, especially activity-based PM task performance and PM component performance, successfully discriminated between aMCI and NC and was able to do so above and beyond the executive function tests.
Our finding suggested that the deficits in PM component, related to a disrupted executive control processes, were responsible for the impaired ability of individuals with aMCI to realize delayed intentions.
Mild cognitive impairment; Time-based prospective memory; Event-based prospective memory; Activity-based prospective memory; Retrospective memory
This article will review selected herbal products used in traditional Chinese medicine, including medicinal mushrooms (巴西蘑菇 bā xī mó gū; Agaricus blazei, 雲芝 yún zhī; Coriolus versicolor, 靈芝 líng zhī; Ganoderma lucidum, 香蕈 xiāng xùn; shiitake, Lentinus edodes, 牛樟芝 niú zhāng zhī; Taiwanofungus camphoratus), Cordyceps (冬蟲夏草 dōng chóng xià cǎo), pomegranate (石榴 shí liú; Granati Fructus), green tea (綠茶 lǜ chá; Theae Folium Non Fermentatum), garlic (大蒜 dà suàn; Allii Sativi Bulbus), turmeric (薑黃 jiāng huáng; Curcumae Longae Rhizoma), and Artemisiae Annuae Herba (青蒿 qīng hāo; sweet wormwood). Many of the discussed herbal products have gained popularity in their uses as dietary supplements for health benefits. The review will focus on the active constituents of the herbs and their bioactivities, with emphasis on the most recent progress in research for the period of 2003 to 2011.
Herbal Products; Medicinal Mushrooms; Dietary Supplements; Traditional Chinese Medicine (TCM)
The era of targeted cancer therapies has arrived. However, due to the complexity of biological systems, the current progress is far from enough. From biological network modeling to structural/dynamic network analysis, network systems biology provides unique insight into the potential mechanisms underlying the growth and progression of cancer cells. It has also introduced great changes into the research paradigm of cancer-associated drug discovery and drug resistance.
Targeted cancer therapy; network systems biology; network modeling; network analysis; drug discovery; drug resistance
Aberrant protein glycosylation plays major roles in neurodegenerative diseases, including Parkinson's disease (PD). Glycoproteomics showed that the glycosylation of sodium channel β4 was significantly increased in human brain tissue. β4-specific antibodies reacted in immunoblot assays with the 35- and 38-kDa bands from the membrane fractions isolated from neonatal PD transgenic mice but only with the 35-kDa band of the neonatal wild-type mice. The size of the 38-kDa immunoreactive protein is in close agreement with previously reported, suggesting heavy glycosylation of this protein in adult wild-type and neonatal PD transgenic brain tissues. However, the neonatal wild-type mice membrane fractions only contained the 35-kDa immunoreactive protein, and the additional 38-kDa band was not shown until postnatal day 7. Enzymatic deglycosylation of the membrane preparations only converted the 38-kDa band into a faster migrating protein, which was consistent with heavy glycosylation of this protein. The glycosylated state of β4 was developmentally regulated and was altered in disease state. Neurite outgrowth assay demonstrated that overexpression of deglycosylated mutant β4-MUT accelerated neurite extension and increased the number of filopodia-like protrusions, when compared with β4-WT and the vector. These results suggest that extensive glycosylation of β4 subunit play roles in morphological changes, and the altered glycosylation may be involved in the pathogenesis of PD.
Voltage-gated sodium channel β4 subunit; Glycosylation; Filopodia-like protrusion; Neurite outgrowth; Parkinson's disease.
This article will review selected herbal products from Chinese Materia Medica that are used in Traditional Chinese Medicine. The herbs come from the upper, middle, and lower class medicines as listed in The Divine Husbandman's Herbal Foundation Canon (神農本草經 Shén Nóng Běn Cǎo Jīng). The review will focus on the active constituents of the herbs and their bioactivities, with emphasis on the most recent progress in research for the period of 2003 to 2011.
Herbal products; Chinese Materia Medica (CMM) (中藥 zhōng yào); Traditional Chinese Medicine (TCM); Shén Nóng Běn Cǎo Jīng (神農本草經 The Divine Husbandman's Herbal Foundation Canon by Shen Nong)
In this study, various 3′R,4′R-disubstituted-2′,2′-dimethydihydropyrano[2,3-f]chromone (DSP) derivatives were discovered as potent chemosensitizers in the treatment of multidrug resistant cancer cells. Twenty-four DSP analogs (5–28) were synthesized and evaluated against a multi-drug resistant (MDR) cell line (KB-Vin) with and without vincristine (VCR). All DSP analogs exhibited low intrinsic cytotoxicity. However, in combination treatment, most DSPs reversed resistance to VCR and lowered the GI50 value of VCR by 12–349-fold. At a concentration of 1μg/mL, three compounds, 11, 14 and 21, fully reversed resistance to VCR in KB-Vin cancer cells, a twofold increase compared to verapamil, a first generation chemosensitizer. Detailed structure-activity relationship (SAR) conclusions were established based on 3′ and 4′ substitutions. Moreover, a preliminary mechanism study indicated that the chemosensitizing activity of DSP analogs results from inhibition of P-glycoprotein (P-gp) over-expressed in MDR cancer cells.1
In a continued study, 23 3′R,4′R-di-O-(−)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5–27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 μM to 0.14 μM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 μM; TI 310 and 200, respectively), and were two-fold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 μM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5–10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates.
3′R,4′R-Di-O-(−)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives; HIV-1; Reverse transcriptase (RT); Structure-activity relationship (SAR)
A novel and efficient microwave-assisted one-pot reaction was developed to synthesize angular 2,2-dimethyl-2H-chromone containing compounds, which is the first and key step in the synthesis of potent DCK and DCP anti-HIV agents. The newly developed microwave synthesis conditions dramatically shortened the reaction time from 2 days to 4 hours with improved yields.
Microwave reaction; Angular 2; 2-dimethyl-2H-chromone; One-pot reaction; Anti-HIV