Displaying publications 21 - 40 of 81 in total

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  1. Fulltext A balanced randomised placebo controlled blinded phase IIa multi-centre study to investigate the efficacy and safety of AUT00063 versus placebo in subjective tinnitus: The QUIET-1 trial
    Hall DA, Ray J, Watson J, Sharman A, Hutchison J, Harris P, et al.
    Hear Res, 2019 06;377:153-166.
    PMID: 30939361 DOI: 10.1016/j.heares.2019.03.018
    AUT00063 is an experimental new medicine that has been demonstrated to suppress spontaneous hyperactivity by modulating the action of voltage-gated potassium-channels in central auditory cortical neurons of a rodent model. This neurobiological property makes it a good candidate for treating the central component of subjective tinnitus but this has not yet been tested in humans. The main purpose of the QUIET-1 (QUest In Eliminating Tinnitus) trial was to examine the effect of AUT00063 on the severity of tinnitus symptoms in people with subjective tinnitus. The trial was a randomised, placebo-controlled, observer, physician and participant blinded multi-centre superiority trial with two parallel groups and a primary endpoint of functional impact on tinnitus 28 days after the first drug dosing day. The trial design overcame the scale and logistical challenges of delivering a scientifically robust, statistically powered multi-centre study for subjective tinnitus within the National Health Service in England. The trial was terminated early for futility. Overall, 212 participants consented across 18 sites with 91 participants randomised to groups using age, gender, tinnitus symptom severity and hearing status as minimisation factors. While the pharmacokinetic markers confirm the uptake of AUT00063 in the body, within the expected therapeutic range, with respect to clinical benefit findings indicated that AUT00063 was not effective in alleviating tinnitus symptoms (1.56 point change in Tinnitus Functional Index). In terms of clinical harms, results indicated that a daily dose of 800 mg capsules of AUT00063 taken for 28 days was safe and well tolerated. These findings provide significant advances in the drug development field for hearing sciences, but raise questions about the predictive validity of certain rodent models of noise-induced hearing loss and tinnitus, as least for the mechanism evaluated in the present study. Trial Registration: (EudraCT) 2014-002179-27; NCT02315508.
    Matched MeSH terms: Pyrimidines/adverse effects; Pyrimidines/pharmacokinetics; Pyrimidines/therapeutic use*
  2. Fulltext Primary imatinib resistance in chronic myeloid leukemia patients in a developing country: BCR-ABL kinase domain mutations or BCR-ABL independent mechanisms?
    Yap E, Tumian NR, Azma RZ, Sharifah NA, Salwati S, Hamidah NH, et al.
    Malays J Pathol, 2017 Aug;39(2):107-113.
    PMID: 28866691 MyJurnal
    Clinical resistance to imatinib (IM) in chronic myeloid leukemia (CML) carries adverse consequences. We investigated 22 CML patients who developed IM-resistance for BCR-ABL kinase domain (KD) mutations. The median follow-up for this study was 101.9 months (range: 22.2 to 176.5 months) and the estimated mean overall survival was 150.87 months (95% CI: 130.0 to 171.0). Five out of 22 patients tested positive for BCR-ABL KD mutations: 2 had T315I, 2 had E255K and 1 had V289F mutations. Of the remaining 17 patients who did not harbor BCR-ABL KD mutations, 11 patients received nilotinib while the rest continued on IM. All 17 achieved haematological remission but only 5 patients achieved complete cytogenetic remission, 4 of whom did so after switching to nilotinib. Our study shows that most of our IM-resistant patients do not test positive for BCR-ABL KD mutations by available testing methods and the role of second generation tyrosine kinase inhibitors remains undetermined. A critical analysis of the BCR-ABL KD mutations and the underlying mechanisms/ pathways of BCR-ABL independent IM-resistance along with potential treatments in the horizon will be discussed.
    Matched MeSH terms: Pyrimidines
  3. Fulltext Differential responses of Vibrio sp. to young and mature leaves extracts of Terminalia catappa L
    Nadirah, M., Wee, T. L., Najiah, M.
    International Food Research Journal, 2013;20(2):961-966.
    MyJurnal
    Young and mature leaves of Terminalia catappa of alcoholic and aqueous extracts were evaluated for in vitro antibacterial activity against Vibrio sp. isolated from aquatic animals. Young leaves of T. catappa showed higher antibacterial activity when compared to mature leaves against Vibrio parahemolyticus, with methanolic and aqueous extracts exhibited the largest inhibition zones, 23 and 24 mm, respectively as determined by disc diffusion technique. Ethanolic extract of young leaves showed the lowest MIC and MBC at 3.13 mg/ml and 6.25 mg/ml, respectively. Both alcoholic and aqueous extracts of young and matures leaves exhibit variations in protein, RNA as well as pyrine and pyrimidines leakage of Vibrio sp. Cell membrane disruption is proposed as the mechanism of action of T. catappa leaves extract against Vibrio sp.
    Matched MeSH terms: Pyrimidines
  4. Method development and validation for the simultaneous determination of imatinib mesylate and N-desmethyl imatinib using rapid resolution high performance liquid chromatography coupled with UV-detection
    Tan KL, Ankathil R, Gan SH
    J Chromatogr B Analyt Technol Biomed Life Sci, 2011 Nov 15;879(30):3583-91.
    PMID: 22000961 DOI: 10.1016/j.jchromb.2011.09.048
    We developed a simple and sensitive method for the simultaneous detection of imatinib mesylate (IM) and its active metabolite, N-desmethyl imatinib (M1), in human serum samples. Separation was successfully achieved using an Agilent(®) ZORBAX Eclipse plus C(18) reversed phase column (50 mm × 2.1 mm, i.d.; 1.8 μm) under isocratic mobile phase conditions consisting of acetonitrile: 0.02 M potassium dihydrogen phosphate with 0.2% triethylamine at pH 3 (25:75, v/v) and ultra-violet detection was achieved at 235 nm. Extraction of the target compounds was completed using 100% cold acetonitrile. Good linearities (r(2)>0.99) for both IM and M1 were achieved for the concentration ranges of 50-1800 ng/mL and 50-360 ng/mL, respectively. The detection limits were 20 ng/mL and 10 ng/mL for M1 and IM, respectively. The intra- and inter-day precisions were less than 1% with percent recoveries of more than 90%. The method was successfully applied to calculate the pharmacokinetic parameters of chronic myeloid leukemia patients receiving imatinib. The method is suitable to be routinely applied for determination of IM and M1 in serum.
    Matched MeSH terms: Pyrimidines/blood*; Pyrimidines/metabolism; Pyrimidines/chemistry
  5. Criofolinine and vernavosine, new pentacyclic indole alkaloids incorporating pyrroloazepine and pyridopyrimidine moieties derived from a common yohimbine precursor
    Nge CE, Gan CY, Lim KH, Ting KN, Low YY, Kam TS
    Org. Lett., 2014 Dec 19;16(24):6330-3.
    PMID: 25454201 DOI: 10.1021/ol503072g
    Two new indole alkaloids characterized by previously unencountered natural product skeletons, viz., criofolinine (1), incorporating a pyrroloazepine motif within a pentacyclic ring system, and vernavosine (2, isolated as its ethyl ether derivative 3, which on hydrolysis regenerated the putative precursor alkaloid 2), incorporating a pyridopyrimidine moiety embedded within a pentacyclic carbon framework, were isolated from a Malayan Tabernaemontana species. The structures and absolute configuration of these alkaloids were determined on the basis of NMR and MS analysis and confirmed by X-ray diffraction analysis.
    Matched MeSH terms: Pyrimidines/chemistry*
  6. Development of solid dispersion systems of dapivirine to enhance its solubility
    Gorajana A, Ying CC, Shuang Y, Fong P, Tan Z, Gupta J, et al.
    Curr Drug Deliv, 2013 Jun;10(3):309-16.
    PMID: 23360246
    Dapivirine, formerly known as TMC 120, is a poorly-water soluble anti-HIV drug, currently being developed as a vaginal microbicide. The clinical use of this drug has been limited due to its poor solubility. The aim of this study was to design solid dispersion systems of Dapivirine to improve its solubility. Solid dispersions were prepared by solvent and fusion methods. Dapivirine release from the solid dispersion system was determined by conducting in-vitro dissolution studies. The physicochemical characteristics of the drug and its formulation were studied using Differential Scanning Calorimetry (DSC), powder X-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). A significant improvement in drug dissolution rate was observed with the solid dispersion systems. XRD, SEM and DSC results indicated the transformation of pure Dapivirine which exists in crystalline form into an amorphous form in selected solid dispersion formulations. FTIR and HPLC analysis confirmed the absence of drug-excipient interactions. Solid dispersion systems can be used to improve the dissolution rate of Dapivirine. This improvement could be attributed to the reduction or absence of drug crystallinity, existence of drug particles in an amorphous form and improved wettability of the drug.
    Matched MeSH terms: Pyrimidines/chemistry*
  7. Rapid determination of sildenafil and its analogues in dietary supplements using gas chromatography-triple quadrupole mass spectrometry
    Mokhtar SU, Chin ST, Kee CL, Low MY, Drummer OH, Marriott PJ
    J Pharm Biomed Anal, 2016 Mar 20;121:188-196.
    PMID: 26808068 DOI: 10.1016/j.jpba.2016.01.034
    Application of gas chromatography-triple quadrupole mass spectrometry for identification, confirmation and quantification of 6 phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, dimethylsildenafil, homosildenafil, thiosildenafil, thiodimethylsildenafil and thiohomosildenafil) in dietary supplements was investigated. The MS was operated in multiple reaction monitoring mode, for better sensitivity and selectivity. In this manner, the method is adequate to reduce background noise with less interference from co-eluting compounds in the samples. Two different ionisation techniques, electron ionisation (EI) and chemical ionisation (CI), were studied and compared. The chromatographic separation was performed on a short 10 m non-polar capillary column without any derivatisation step. This permitted fast analysis for all analogues with retention time less than 11 min, for both techniques. Use of backflushing can aid method retention time reduction and improves column maintenance. Evaluation of method validation included limit of detection (LOD), lower limit of quantitation (LLOQ), linearity, precision and recovery were performed for both EI and CI techniques. The LOD obtained varied from 0.03 to 1.50 μg/g and the LLOQ ranged from 0.10 to 5.00 μg/g. Good calibration linearity was obtained for all analogues for both techniques, with correlation coefficients (r(2)) higher than 0.99. Mean recoveries of all analogues using CI show higher values (83.4-108.8%) than that of EI (61.9-91.1%). The intra- and inter-assay precisions were evaluated for all analogues at spiked concentration of 10 μg/g and the relative standard deviation was less than 15% for both methods. These methods were then successfully applied to dietary supplement samples without prior derivatisation, confirming that the samples were adulterated with sildenafil and/or its analogues.
    Matched MeSH terms: Pyrimidines/chemistry
  8. Fulltext In vitro activity of fluconazole and voriconazole against clinical isolates of Candida spp. by E-test method
    Madhavan P, Jamal F, Chong PP, Ng KP
    Trop Biomed, 2010 Aug;27(2):200-7.
    PMID: 20962716 MyJurnal
    The in vitro susceptibility of clinical Candida isolates towards fluconazole and voriconazole was determined using the E-test method. A total of 41 clinical isolates recovered from patients since 2004 until 2009 from two local hospitals in Kuala Lumpur, Malaysia were used. These comprised Candida tropicalis, Candida albicans, Candida krusei, Candida parapsilosis, Candida rugosa, Candida dubliniensis and Candida glabrata. Strains from American Type Culture Collection were used as quality control. Lawn cultures of the isolates on RPMI-1640 agar medium supplemented with 2% glucose were incubated with the E-test strips at 35ºC for 48 h. Our results show that 71% were susceptible to fluconazole and 90% were susceptible to voriconazole. All strains of C. krusei were resistant to fluconazole and 50% were susceptible in a dose-dependent manner to voriconazole. There were 66% and 33% of C. glabrata that were resistant to fluconazole and voriconazole. Our study revealed that majority of the clinical Candida isolates was susceptible to fluconazole and voriconazole with a small percentage being resistant to both the drugs.
    Matched MeSH terms: Pyrimidines/pharmacology*
  9. Fulltext Synthesis of 2,4-Diaminopyrimidine Core-Based Derivatives and Biological Evaluation of Their Anti-Tubercular Activities
    Ouyang Y, Yang H, Zhang P, Wang Y, Kaur S, Zhu X, et al.
    Molecules, 2017 Sep 22;22(10).
    PMID: 28937657 DOI: 10.3390/molecules22101592
    Tuberculosis (TB) is a chronic, potentially fatal disease caused by Mycobacterium tuberculosis (Mtb). The dihyrofolate reductase in Mtb (mt-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (h-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, but the designed compounds contain a hydrophilic group, which may prevent the compounds from crossing the cell wall of Mtb to function at the whole cell level. In the current study, we designed and synthesized a series of mt-DHFR inhibitors that contain a 2,4-diaminopyrimidine core with side chains to occupy the glycerol binding site with proper hydrophilicity for cell entry, and tested their anti-tubercular activity against Mtb H37Ra. Among them, compound 16l showed a good anti-TB activity (MIC = 6.25 μg/mL) with a significant selectivity against vero cells. In the molecular simulations performed to understand the binding poses of the compounds, it was noticed that only side chains of a certain size can occupy the glycerol binding site. In summary, the novel synthesized compounds with appropriate side chains, hydrophobicity and selectivity could be important lead compounds for future optimization towards the development of future anti-TB drugs that can be used as monotherapy or in combination with other anti-TB drugs or antibiotics. These compounds can also provide much information for further studies on mt-DHFR. However, the enzyme target of the compounds still needs to be confirmed by pure mt-DHFR binding assays.
    Matched MeSH terms: Pyrimidines/chemistry*
  10. Fulltext Inequality in Drug Utilization among Chronic Myeloid Leukaemia Patients in Malaysia: A Cost-Utility Analysis
    Wan Puteh SE, Mohamad Selamat E, Aizuddin AN, Tumian NR, Sathar J
    Asian Pac J Cancer Prev, 2022 Dec 01;23(12):4253-4260.
    PMID: 36580008 DOI: 10.31557/APJCP.2022.23.12.4253
    BACKGROUND: The burden of chronic myeloid leukaemia (CML) is increasing due to longer patient survival, better life expectancy of the general population, and increasing drug prices. Funding is one of the main concerns in the choice of CML medication used worldwide; thus, patient assistance programmes were introduced to ensure accessibility to affordable treatment. In this study, we evaluated CML drug distribution inequality in Malaysia through patient assistance programmes, using pharmaco-economics methods to evaluate CML treatment from the care provider's perspective.

    METHODS: Patients with CML were recruited from outpatient haematological clinics at the national centre of intervention and referral for haematological conditions and a public teaching hospital. The health-related quality of life or utility scores were derived using the EuroQol EQ-5D-5L questionnaire. Costing data were obtained from the Ministry of Health Malaysia Casemix MalaysianDRG. Imatinib and nilotinib drug costs were obtained from the administration of the participating hospitals and pharmaceutical company.

    RESULTS: Of the 221 respondents in this study, 68.8% were imatinib users. The total care provider cost for CML treatment was USD23,014.40 for imatinib and USD43,442.69 for nilotinib. The governmental financial assistance programme reduced the total care provider cost to USD13,693.51 for imatinib and USD19,193.45 for nilotinib. The quality-adjusted life years (QALYs) were 17.87 and 20.91 per imatinib and nilotinib user, respectively. Nilotinib had a higher drug cost than imatinib, yet its users had better life expectancy, utility score, and QALYs. Imatinib yielded the lowest cost per QALYs at USD766.29.

    CONCLUSION: Overall, imatinib is more cost-effective than nilotinib for treating CML in Malaysia from the care provider's perspective. The findings demonstrate the importance of cancer drug funding assistance for ensuring that the appropriate treatments are accessible and affordable and that patients with cancer use and benefit from such patient assistance programmes. To establish effective health expenditure, drug distribution inequality should be addressed.

    Matched MeSH terms: Pyrimidines/adverse effects
  11. Metronidazole leads to enhanced uptake of imatinib in brain, liver and kidney without affecting its plasma pharmacokinetics in mice
    Tan SY, Kan E, Lim WY, Chay G, Law JH, Soo GW, et al.
    J Pharm Pharmacol, 2011 Jul;63(7):918-25.
    PMID: 21635257 DOI: 10.1111/j.2042-7158.2011.01296.x
    The pharmacokinetic interaction between metronidazole, an antibiotic-antiparasitic drug used to treat anaerobic bacterial and protozoal infections, and imatinib, a CYP3A4, P-glycoprotein substrate kinase inhibitor anticancer drug, was evaluated.
    Matched MeSH terms: Pyrimidines/adverse effects; Pyrimidines/blood; Pyrimidines/metabolism; Pyrimidines/pharmacokinetics*
  12. Recurrent Trichosporon asahii glossitis: a case report
    Shareef BT, Harun A, Roziawati Y, Bahari IS, Deris ZZ, Ravichandran M
    J Contemp Dent Pract, 2008;9(3):114-20.
    PMID: 18335127
    This case report aims at describing an infection of the tongue as a manifestation of a Trichosporon asahii infection, its association with bronchial asthma and steroid administration, and to present a review of the literature pertaining to its antifungal susceptibility profile.
    Matched MeSH terms: Pyrimidines/administration & dosage; Pyrimidines/therapeutic use
  13. Fulltext Imatinib mesylate in the treatment of chronic myeloid leukemia: a local experience
    Bee PC, Gan GG, Teh A, Haris AR
    Med J Malaysia, 2006 Dec;61(5):547-52.
    PMID: 17623954 MyJurnal
    This study was done to assess the overall response rate of imatinib mesylate in local patients with chronic myeloid leukaemia. A total of 69 patients were recruited with male/female ratio of 7:3. Of the 69 patients; 35% were in the chronic phase, 41% were in the accelerated phase, 17% were in blast crisis and the remaining 7% were after stem cell transplantation. Complete haematological response rates of patients in chronic phase, accelerated phase and blast crisis were 95.8%, 96.4% and 41.7% respectively. Thirty-eight percent of patients achieved complete cytogenetic response and 10% achieved partial cytogenetic response. The cytogenetic response rates were 80%, 41.7% and 18.2% in chronic, accelerated and blast crisis phase respectively (p < 0.005). Twenty-six percent of patients developed anaemia, 13% had neutropenia and 12% had thrombocytopenia after starting on treatment. In addition, 14% of patients developed peripheral oedema, 13% complained of musculoskeletal pain, 12% had gastrointestinal side effects which include nausea, vomiting and diarrhoea, 9% had grade 1 hepatotoxicity, 7% developed skin rashes and one patient had an abnormal renal function test. Patients taking 600mg or higher dosage of imatinib had more gastrointestinal side effects. Patients who weighed less than 60kg had a much higher risk of developing anaemia. Anaemia was a negative predictor of cytogenetic response. Presenting high white blood cell counts and absence of cytogenetic response were also negative predictors of survival. Overall survival was 87%. This was affected by the different phases of disease (chronic phase was better than accelerated and blast crisis) (p < 0.001). In conclusion, our local CML patients did well on treatment with imatinib.
    Matched MeSH terms: Pyrimidines/adverse effects; Pyrimidines/therapeutic use*
  14. Late-onset marrow aplasia due to imatinib in newly diagnosed chronic phase chronic myeloid leukaemia
    Chng WJ, Tan LH
    Leuk. Res., 2005 Jun;29(6):719-20.
    PMID: 15863215
    Matched MeSH terms: Pyrimidines/adverse effects*; Pyrimidines/therapeutic use*
  15. Fulltext Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd
    Hughes TP, Munhoz E, Aurelio Salvino M, Ong TC, Elhaddad A, Shortt J, et al.
    Br J Haematol, 2017 10;179(2):219-228.
    PMID: 28699641 DOI: 10.1111/bjh.14829
    The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2-75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).
    Matched MeSH terms: Pyrimidines/administration & dosage*; Pyrimidines/adverse effects
  16. Lack of hepato- and nephrotoxicity induced by antifungal drug voriconazole in laboratory rats
    Somchit N, Chung JH, Yaacob A, Ahmad Z, Zakaria ZA, Kadir AA
    Drug Chem Toxicol, 2012 Jul;35(3):304-9.
    PMID: 22288423 DOI: 10.3109/01480545.2011.614619
    Voriconazole is a new, potent broad-spectrum triazole systemic antifungal drug, a second-generation azole antifungal that is increasing in popularity, especially for the treatment of invasive aspergillosis and fluconazole-resistant invasive Candida infections. However, it is also known to induce hepatotoxicity clinically. The aim of this study was to investigate the hepatotoxicity and nephrotoxicity potential of voriconazole in vivo in rats. Forty rats were treated intraperitoneally with voriconazole as single (0, 10, l00, and 200 mg/kg) or repeated (0, 10, 50, and l00 mg/kg per day for 14 days) doses. Venous blood was collected for the repeated-dose group on days 1 and 14. Rats were sacrificed 24 hours after the last dose. Body weight, liver weight, and kidney weight of rats were recorded. Livers and kidneys samples were taken for histological and transmission electron microscopy (TEM) analysis. Results revealed that voriconazole had no effects on serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphotase, gamma glutamyl transpeptidase, blood urea nitrogen, and creatinine for both the single- and repeated-dose groups. However, histologically, in the repeated 50- and 100-mg/kg voriconazole-treated rats, mild focal inflammation was observed. Under TEM, only small changes in the 100 mg/kg/day group were revealed. These results collectively demonstrated that voriconazole did not induce significant hepatotoxicity and nephrotoxicity, even at very high doses.
    Matched MeSH terms: Pyrimidines/administration & dosage; Pyrimidines/adverse effects*; Pyrimidines/chemistry
  17. Dual treatments targeting IGF-1R, PI3K, mTORC or MEK synergize to inhibit cell growth, induce apoptosis, and arrest cell cycle at G1 phase in MDA-MB-231 cell line
    Ayub A, Yip WK, Seow HF
    Biomed Pharmacother, 2015 Oct;75:40-50.
    PMID: 26463630 DOI: 10.1016/j.biopha.2015.08.031
    Triple-negative breast cancers (TNBCs) are aggressive cancers that do not benefit from hormonal therapy or therapies that target HER2 receptors. Insulin-like growth factor 1 receptor (IGF-1R), which has been shown to be overexpressed in breast cancer, activates numerous downstream kinases that associate with cell proliferation and survival. This study compared the effects caused by dual treatments targeting IGF-1R, PI3K, mTORC, or MEK with those by single treatments in a TNBC cell line, MDA-MB-231. We used small-molecule kinase inhibitors, namely, NVP-AEW541, NVP-BKM120, KU0063794, and PD0325901 to target IGF-1R, PI3K, mTORC, and MEK, respectively. Combination treatments of PD0325901 with NVP-AEW541, NVP-BKM120 or KU0063794 and NVP-AEW541 with KU0063794 demonstrated a significant synergistic growth inhibition. These dual treatments increased apoptosis and/or cell cycle arrest at G0/G1 phase and enhanced the inhibition of phosphorylation of Akt or downstream molecules of mTORC1, as compared to the single treatments. Our study suggests that targeting multiple kinases in IGF-1R signaling may be a promising therapeutic approach.
    Matched MeSH terms: Pyrimidines
  18. Histone mRNA is subject to 3´ uridylation and re-adenylation in Aspergillus nidulans
    Mossanen-Parsi A, Parisi D, Browne-Marke N, Bharudin I, Connell SR, Mayans O, et al.
    Mol Microbiol, 2020 Oct 12.
    PMID: 33047379 DOI: 10.1111/mmi.14613
    The role of post-transcriptional RNA modification is of growing interest. One example is the addition of non-templated uridine residues to the 3´ end of transcripts. In mammalian systems uridylation is integral to cell cycle control of histone mRNA levels. This regulatory mechanism is dependent on the nonsense mediated decay (NMD) component, Upf1, which promotes histone mRNA uridylation and degradation in response to the arrest of DNA synthesis. We have identified a similar system in Aspergillus nidulans, where Upf1 is required for the regulation of histone mRNA levels. However, other NMD components are also implicated, distinguishing it from the mammalian system. As in human cells, 3´ uridylation of histone mRNA is induced upon replication arrest. Disruption of this 3´ tagging has a significant but limited effect on histone transcript regulation, consistent with multiple mechanisms acting to regulate mRNA levels. Interestingly, 3´ end degraded transcripts are also subject to re-adenylation. Both mRNA pyrimidine tagging and re-adenylation are dependent on the same terminal-nucleotidyltransferases, CutA and CutB, and we show this is consistent with the in vitro activities of both enzymes. Based on these data we argue that mRNA 3´ tagging has diverse and distinct roles associated with transcript degradation, functionality and regulation.
    Matched MeSH terms: Pyrimidines
  19. Design, Synthesis and Therapeutic Potential of Some 6, 6'-(1,4- phenylene)bis(4-(4-bromophenyl)pyrimidin-2-amine)analogues
    Kumar S, Narasimhan B, Lim SM, Ramasamy K, Mani V, Shah SAA
    Mini Rev Med Chem, 2019;19(7):609-621.
    PMID: 30526456 DOI: 10.2174/1389557519666181210162413
    BACKGROUND: A series of 6, 6'-(1,4-phenylene)bis(4-(4-bromophenyl)pyrimidin-2-amine) derivatives has been synthesized by Claisen-Schmidt condensation and its chemical structures was confirmed by FT-IR, 1H/13C-NMR spectral and elemental analyses. The molecular docking study was carried out to find the interaction between active bis-pyrimidine compounds with CDK-8 protein. The in vitro antimicrobial potential of the synthesized compounds was determined against Gram-positive and Gram-negative bacterial species as well fungal species by tube dilution technique. Antimicrobial results indicated that compound 11y was found to be most potent one against E. coli (MICec = 0.67 µmol/mL) and C. albicans (MICca = 0.17 µmol/mL) and its activity was comparable to norfloxacin (MIC = 0.47 µmol/mL) and fluconazole (MIC = 0.50 µmol/mL), respectively.

    CONCLUSION: Anticancer screening of the synthesized compounds using Sulforhodamine B (SRB) assay demonstrated that compounds 2y (IC50 = 0.01 µmol/mL) and 4y (IC50= 0.02 µmol/mL) have high antiproliferative potential against human colorectal carcinoma cancer cell line than the reference drug (5- fluorouracil) and these compounds also showed best dock score with better potency within the ATP binding pocket and may also be used lead for rational drug designing.

    Matched MeSH terms: Pyrimidines/chemical synthesis; Pyrimidines/pharmacology*; Pyrimidines/chemistry*
  20. Fulltext Molecular docking, synthesis and biological significance of pyrimidine analogues as prospective antimicrobial and antiproliferative agents
    Kumar S, Kaushik A, Narasimhan B, Shah SAA, Lim SM, Ramasamy K, et al.
    BMC Chem, 2019 Dec;13(1):85.
    PMID: 31384832 DOI: 10.1186/s13065-019-0601-z
    Pyrimidine nucleus is a significant pharmacophore that exhibited excellent pharmacological activities. A series of pyrimidine scaffolds was synthesized and its chemical structures were confirmed by physicochemical and spectral analysis. The synthesized compounds were evaluated for their antimicrobial potential towards Gram positive and negative bacteria as well as fungal species. They were also assessed for their anticancer activity toward a human colorectal carcinoma cell line (HCT116). Whilst results of antimicrobial potential revealed that compounds Ax2, Ax3, Ax8 and Ax14 exhibited better activity against tested microorganisms, the results of antiproliferative activity indicated that compounds Ax7 and Ax10 showed excellent activity against HCT116. Further, the molecular docking of pyrimidine derivatives Ax1, Ax9 and Ax10 with CDK8 (PDB id: 5FGK) protein indicated that moderate to better docking results within the binding pocket. Compounds Ax8 and Ax10 having significant antimicrobial and anticancer activities may be selected as lead compounds for the development of novel antimicrobial and anticancer agent, respectively.
    Matched MeSH terms: Pyrimidines
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