Silica Materials for Medical Applications

The two main applications of silica-based materials in medicine and biotechnology, i.e. for bone-repairing devices and for drug delivery systems, are presented and discussed. The influence of the structure and chemical composition in the final characteristics and properties of every silica-based material is also shown as a function of the both applications presented. The adequate combination of the synthesis techniques, template systems and additives leads to the development of materials that merge the bioactive behavior with the drug carrier ability. These systems could be excellent candidates as materials for the development of devices for tissue engineering

Potassium-3-beta-hydroxy-20-oxopregn-5-en-17-alpha-yl sulfate: a novel inhibitor of 78 kDa glucose-regulated protein

Nizar M Mhaidat,1,2 Qosay A Al-Balas,1 Karem H Alzoubi,1 Rowan F AlEjielat2 1Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 2Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hashemite University, Zarqa, Jordan Background: Previous studies have shown the central role of 78 kDa glucose-regulated protein (GRP78) in colorectal cancer (CRC) survival and chemoresistance. In the present study, we aimed to design a GRP78 inhibitor and test its potential to inhibit CRC cells growth. Materials and methods: Computer-aided drug design was used to establish novel compounds as potential inhibitors of GRP78. Discovery Studio 3.5 software was used to evaluate a series of designed compounds and assess their mode of binding to the active site of the protein. The cytotoxicity of the designed compounds was evaluated using the MTT assay and the propidium iodide method. The effect of the inhibitor on the expression of GRP78 was evaluated by immunoblotting. Results: Among the designed compounds, only potassium-3-beta-hydroxy-20-oxopregn-5-en-17-alpha-yl sulfate (PHOS) has a potential to inhibit the growth of CRC cells. Inhibition of cellular growth was largely attributed to downregulation of GRP78 and induction of apoptotic cell death. Conclusion: These results introduce PHOS as a promising GRP78 inhibitor that could be used in future studies as a combination with chemotherapy in the treatment of CRC patients. Our ongoing studies aim to characterize PHOS safety profile as well as its mechanism of action. Keywords: UPR, apoptosis, GRP78, CRC, chemotherapy, computer-aided drug design (CADD

Novel glyoxalase-I inhibitors possessing a “zinc-binding feature” as potential anticancer agents

Qosay A Al-Balas,1 Mohammad A Hassan,1 Nizar A Al-Shar’i,1 Nizar M Mhaidat,2 Ammar M Almaaytah,3 Fatima M Al-Mahasneh,1 Israa H Isawi1 1Department of Medicinal Chemistry and Pharmacognosy, 2Department of Clinical Pharmacy, 3Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan Background: The glyoxalase system including two thiol-dependent enzymes, glyoxalase I (Glo-I) and glyoxalase II, plays an important role in a ubiquitous metabolic pathway involved in cellular detoxification of cytotoxic 2-oxoaldehydes. Tumor cells have high glycolytic activity, leading to increased cellular levels of these toxic metabolites. The increased activity of the detoxification system in cancerous cells makes this pathway a viable target for developing novel anticancer agents. In this study, we examined the potential utility of non-glutathione-based inhibitors of the Glo-I enzyme as novel anticancer drugs.Methods: Computer-aided drug design techniques, such as customized pharmacophoric features, virtual screening, and flexible docking, were used to achieve the project goals. Retrieved hits were extensively filtered and subsequently docked into the active site of the enzyme. The biological activities of retrieved hits were assessed using an in vitro assay against Glo-I.Results: Since Glo-I is a zinc metalloenzyme, a customized Zn-binding pharmacophoric feature was used to search for selective inhibitors via virtual screening of a small-molecule database. Seven hits were selected, purchased, and biologically evaluated. Three of the seven hits inhibited Glo-I activity, the most effective of which exerted 76.4% inhibition at a concentration of 25 µM.Conclusion: We successfully identified a potential Glo-I inhibitor that can serve as a lead compound for further optimization. Moreover, our in silico and experimental results were highly correlated. Hence, the docking protocol adopted in this study may be efficiently employed in future optimization steps. Keywords: cancer, glyoxalase-I, zinc-binding feature, flexible docking, Discovery Studio 3.5, keto

Design, synthesis, and biologic evaluation of novel chrysin derivatives as cytotoxic agents and caspase-3/7 activators

Buthina Abdallah Al-Oudat,1 Mohammad Ali Alqudah,2 Suaad Abdallah Audat,3 Qosay Ali Al-Balas,1 Tamam El-Elimat,1 Mohammad Abdelhafeez Hassan,1 Islam Nawaf Frhat,1 Marwah Mohammad Azaizeh2 1Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan; 2Department of Clinical Pharmacy, College of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan; 3Department of Chemistry, College of Science and Arts, Jordan University of Science and Technology, Irbid 22110, Jordan Background: Chrysin (5,7-dihydroxyflavone) is a widely distributed natural flavonoid found in many plant extracts, honey and propolis. Several studies revealed that chrysin possesses multiple biological activities including anti-cancer effects. It has been established that activation of apoptosis is the key molecular mechanism responsible for the cytotoxic potential of chrysin. The objective of this study was to design and synthesize potent chrysin analogues as potential cytotoxic agents.Methods: A series of chrysin derivatives (3a-m) bearing N'-alkylidene/arylideneacetohydrazide moiety were designed, synthesized, and evaluated for their antiproliferative activity against two human breast cancer cell lines, MDA-MB-231 and MCF-7 by applying the MTT colorimetric assay. Selected compounds were tested for their ability to induce apoptosis through caspase 3/7 activation in MDA-MB-231 cells only since MCF-7 cells lack procaspase 3.Results: Compounds (3a-m) were obtained as geometrical isomers (E/Z isomers) in good yields upon treatment of hydrazide 5 with different aliphatic and aromatic aldehydes. Most of the synthesized compounds demonstrated moderate-to-good activity against both cell lines. The cytotoxicity results revealed the importance of lipophilic moieties at C-4 position of ring D in imparting the cytotoxic activities to the compounds. Compound 3e with 4-benzyloxy substituent was found to be the most active among the synthesized compounds with IC50 3.3 µM against MDA-MB-231 and 4.2 µM against MCF-7 cell lines. The cytotoxic potential of compound 3e is comparable to that of the well-known anti-cancer agent doxorubicin. In addition, compounds substituted with fluoro (3b), nitro (3h), and dimethylamino (3j) exhibited good cytotoxicity with IC50<6.5 μM against MDA-MB-231 and ,12 μM against MCF-7. Selected compounds were able to induce apoptosis in MDA-MB-231 cells as indicated by caspase-3 and/or -7 activation. Conclusion: Our results show that the newly designed chrysin derivatives exert anticancer activity in human breast cancer cell lines, MDA-MB-231 and MCF-7. Therefore, they can be considered as leads for further development of more potent and selective cytotoxic agents. Keywords: apoptosis, chrysin, design, synthesis, cytotoxicity, caspase-3/7, antiproliferative agent