Generation of the First Structure-Based Pharmacophore Model Containing a Selective “Zinc Binding Group” Feature to Identify Potential Glyoxalase-1 Inhibitors

Within this study, a unique 3D structure-based pharmacophore model of the enzyme glyoxalase-1 (Glo-1) has been revealed. Glo-1 is considered a zinc metalloenzyme in which the inhibitor binding with zinc atom at the active site is crucial. To our knowledge, this is the first pharmacophore model that has a selective feature for a “zinc binding group” which has been customized within the structure-based pharmacophore model of Glo-1 to extract ligands that possess functional groups able to bind zinc atom solely from database screening. In addition, an extensive 2D similarity search using three diverse similarity techniques (Tanimoto, Dice, Cosine) has been performed over the commercially available “Zinc Clean Drug-Like Database” that contains around 10 million compounds to help find suitable inhibitors for this enzyme based on known inhibitors from the literature. The resultant hits were mapped over the structure based pharmacophore and the successful hits were further docked using three docking programs with different pose fitting and scoring techniques (GOLD, LibDock, CDOCKER). Nine candidates were suggested to be novel Glo-1 inhibitors containing the “zinc binding group” with the highest consensus scoring from docking

Synthesis of C3′ Modified Nucleosides for Selective Generation of the C3′-Deoxy-3′-thymidinyl Radical: A Proposed Intermediate in LEE Induced DNA Damage

DNA damage pathways induced by low-energy electrons (LEEs) are believed to involve the formation of 2-deoxyribose radicals. These radicals, formed at the C3′ and C5′ positions of nucleotides, are the result of cleavage of the C–O phosphodiester bond through transfer of LEEs to the phosphate group of DNA oligomers from the nucleobases. A considerable amount of information has been obtained to illuminate the identity of the unmodified oligonucleotide products formed through this process. There exists, however, a paucity of information as to the nature of the modified lesions formed from degradation of these sugar radicals. To determine the identity of the damage products formed via the 2′,3′-dideoxy-C3′-thymidinyl radical (C3′_dephos sugar radical), phenyl selenide and acyl modified sugar and nucleoside derivatives have been synthesized, and their suitability as photochemical precursors of the radical of interest has been evaluated. Upon photochemical activation of C3′-derivatized nucleosides in the presence of the hydrogen atom donor tributyltin hydride, 2′,3′-dideoxythymidine is formed indicating the selective generation of the C3′_dephos sugar radical. These precursors will make the identification and quantification of products of DNA damage derived from radicals generated by LEEs possible

Novel Chrysin-De-Allyl PAC-1 Hybrid Analogues as Anticancer Compounds: Design, Synthesis, and Biological Evaluation

New chrysin-De-allyl-Pac-1 hybrid analogues, tethered with variable heterocyclic systems (4a–4o), were rationally designed and synthesized. The target compounds were screened for in vitro antiproliferative efficacy in the triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and normal human mammary epithelial cells (HMECs). Two compounds, 4g and 4i, had the highest efficacy and selectivity towards MDA-MB-231 cells, and thus, were further evaluated by mechanistic experiments. The results indicated that both compounds 4g and 4i induced apoptosis by (1) inducing cell cycle arrest at the G2 phase in MDA-MB-231 cells, and (2) activating the intrinsic apoptotic pathways in a concentration-dependent manner. Physicochemical characterizations of these compounds suggested that they can be further optimized as potential anticancer compounds for TNBC cells. Overall, our results suggest that 4g and 4i could be suitable leads for developing novel compounds to treat TNBC