School Of Basic And Applied Sciences
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Item Photophysical properties of push-pull 8-aryl-deoxyguanosine probes within duplex and G-quadruplex structures(Royal Society of Chemistry, 2016) Blanchard, D.J.M.; Fadock, K.L.; Sproviero, M.; Deore, P.S.; Cservenyi, T.Z.; Manderville, R.A.; Sharma, P.; Wetmore, S.D.In this study, we outline the structural and photophysical properties of donor-acceptor (D-A) 8-aryl-2?-deoxyguanosine (8aryldG) probes within duplex and G-quadruplex (GQ) structures produced by the thrombin binding aptamer (TBA, 5?-GGTTG5G6TG8TGGTTGG). The probes vary in 8-aryl ring size, degree of twist angle between the aryl ring and nucleobase component, degree of acceptor character, and nature of visibly emissive charge transfer (CT) states. Probes with the aryl ring directly attached to the nucleobase favor the syn-conformation and strongly destabilize the duplex structure, as measured by UV thermal melting experiments. However, these probes can stabilize the antiparallel GQ produced by TBA when inserted into the G-tetrad at the syn-G5 position, and strongly decrease GQ stability when inserted at the anti-G6 position. Nucleoside probes with the aryl ring separated from the nucleobase by a vinyl linker favor the anti-conformation. Furthermore, the nature of the aryl group dictates an ability of these probes to be accomodated within the GQ at the anti-G6 position. 8AryldG probes that favor planar CT states (CTP) exhibit bright emission in both duplex and GQ structures, but lack fluorescence sensitivity to changes in the microenvironment. In contrast, probes that afford twisted CT states (CTT) exhibit weak fluorescence in duplex and GQ structures in water, but display fluorescence signalling capability for monitoring GQ formation in a crowded environment. ? The Royal Society of Chemistry 2016.Item Enhancing Bulge Stabilization through Linear Extension of C8-Aryl-Guanine Adducts to Promote Polymerase Blockage or Strand Realignment to Produce a C:C Mismatch(American Chemical Society, 2015) Sproviero, M.; Verwey, A.M.R.; Witham, A.A.; Manderville, R.A.; Sharma, P.; Wetmore, S.D.Aryl radicals can react at the C8-site of 2?-deoxyguanosine (dG) to produce DNA adducts with a C8-C linkage (denoted C-linked). Such adducts are structurally distinct from those possessing a flexible amine (N-linked) or ether (O-linked) linkage, which separates the C8-aryl moiety from the guanine nucleobase. In the current study, two model C-linked C8-dG adducts, namely, C8-benzo[b]thienyl-dG ([BTh]G) and C8-(pyren-1-yl)-dG ([Py]G), were incorporated into the NarI (12mer, NarI(12) and 22mer, NarI(22)) hotspot sequence for frameshift mutations in bacteria. For the first time, C-linked C8-dG adducts are shown to stabilize the -2 deletion duplex within the NarI sequence. Primer-elongation assays employing Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) demonstrates the influence of C8-aryl ring size and shape in promoting Dpo4 blockage or strand realignment to produce a C:C mismatch downstream of the adduct site. Molecular dynamics simulations of the -2 deletion duplex suggest that both anti and syn adduct structures are energetically accessible. These findings provide a rationale for describing the biochemical outcome induced by C-linked C8-dG adducts when processed by Dpo4. (Figure Presented) ? 2015 American Chemical Society.Item Effect of base sequence context on the conformational heterogeneity of aristolactam-I adducted DNA: Structural and energetic insights into sequence-dependent repair and mutagenicity(Royal Society of Chemistry, 2015) Kathuria, P.; Sharma, P.; Wetmore, S.D.Aristolochic acids (AAs) are nephrotoxic and potentially carcinogenic plant mutagens that form bulky DNA adducts at the exocyclic amino groups of the purines. The present work utilizes classical molecular dynamics simulations and free energy calculations to investigate the role of lesion site sequence context in dictating the conformational outcomes of DNA containing ALI-N6-dA, the most persistent and mutagenic adduct arising from the AAs. Our calculations reveal that the anti base-displaced intercalated conformer is the lowest energy conformer of damaged DNA in all sequence contexts considered (CXC, CXG, GXC and GXG). However, the experimentally-observed greater mutagenicity of the adduct in the CXG sequence context does not correlate with the relative thermodynamic stability of the adduct in different sequences. Instead, AL-N6-dA adducted DNA is least distorted in the CXG sequence context, which points toward a possible differential repair propensity of the lesion in different sequences. Nevertheless, the structural deviations between adducted DNA with different lesion site sequences are small, and therefore other factors (such as interactions between the adducted DNA and lesion-bypass polymerases during replication) are likely more important for dictating the observed sequence-dependent mutagenicity of ALI-N6-dA. ? The Royal Society of Chemistry 2016.Item Chemical composition and antiproliferative, antioxidant, and proapoptotic effects of fruiting body extracts of the lingzhi or reishi medicinal mushroom, ganoderma lucidum (Agaricomycetes), from India(Begell House Inc., 2016) Gill, B.S.; Sharma, P.; Navgeet, Kumar, S.Ganoderma lucidum is a renowned medicinal mushroom exploited as a panacea because of the broad spectrum of its bioactivities, which give it invaluable nutritional and clinical implications. This research was implemented with an incentive to explore and quantify various macromolecules encompassed in the oriental fungus; these vary in concentration with respect to the development/growth phase, host plants, and geographic location of collection. Chemical profiling of G. lucidum confirmed the presence of myco-constituents, their amounts varying in response to extreme climatic conditions. G. lucidum extract exhibited elevated levels of all myco-constituents but flavonoids, which were more pronounced when in a parasitic relationship with their host plants. Proapoptotic efficiency portrayed by the extracts against a prostate cancer cell line (PC-3) was also found to be similar. The samples collected from the Bathinda region, with Azadirachta and Acacia trees as the host plants, showed several-fold augmentation in levels of G. lucidum gredients compared with other variants. Elevated levels of myco-constituents highlight their significance in inhibiting prostate cancer cell proliferation, reducing reactive oxygen species, suppressing invasive potential, and inducing apoptosis. It was thus concluded that G. lucidum grown on Azadirachta plants was more efficient in exhibiting potent biological activities than G. lucidum grown on other host plants. ? 2016 Begell House, Inc.