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Publication Metadata only Antitumor efficacy of ceranib-2 with nano-formulation of PEG and rosin esters(Humana Press Inc, 2021) Ben Taleb, Ali; Karakus, Selcan; Tan, Ezgi; Ilgar, Merve; Kutlu, Ozlem; Kutlu, Hatice Mehtap; Kilislioglu, Ayben; N/A; Gözüaçık, Devrim; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 40248Ceranib-2 is a recently discovered, poorly water-soluble potent ceramidase inhibitor, with the ability to suppress cancer cell proliferation and delay tumor growth. However, its poor water solubility and weak cellular bioavailability hinder its use as a therapeutic agent for cancer. PEGylated rosin esters are an excellent platform as a natural polymer for drug delivery applications, especially for controlling drug release due to their degradability, biocompatibility, capability to improve solubility, and pharmacokinetics of potent drugs. In this study, stable aqueous amphiphilic submicron-sized PEG400-rosin ester-ceranib-2 (PREC-2) particles, ranging between 100 and 350 nm in a 1:1 mixture, were successfully synthesized by solvent evaporation mediated by sonication. Conclusion: Stable aqueous PEGylated rosin ester nanocarriers might present a significant solution to improve solubility, pharmacokinetic, and bioavailability of ceranib-2, and hold promises for use as an anticancer adjacent drug after further investigations.Publication Metadata only Development of 2-(5,6,7-Trifluoro-1 H-Indol-3-yl)-quinoline-5-carboxamide as a potent, selective, and orally available inhibitor of human androgen receptor targeting its binding function-3 for the treatment of castration-resistant prostate cancer(Amer Chemical Soc, 2021) Leblanc, Eric; Ban, Fuqiang; Lawn, Sam; Huang, Chia-Chi Flora; Mohan, Sankar; Chang, Matthew E. K.; Flory, Mark R.; Ghaidi, Fariba; Lingadahalli, Shreyas; Chen, Gang; Yu, Ivan Pak Lok; Morin, Helene; Lallous, Nada; Gleave, Martin E.; Mohammed, Hisham; Young, Robert N.; Rennie, Paul S.; Cherkasov, Artem; N/A; N/A; Cavga, Ayşe Derya; Lack, Nathan Alan; PhD Student; Faculty Member; Graduate School of Sciences and Engineering; School of Medicine; N/A; 120842Prostate cancer (PCa) patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer (CRPC). Targeting the androgen receptor (AR) Binding Function-3 (BF3) site offers a promising option to treat CRPC. However, BF3 inhibitors have been limited by poor potency or inadequate metabolic stability. Through extensive medicinal chemistry, molecular modeling, and biochemistry, we identified 2-(5,6,7-trifluoro-1H-Indol-3-yl)-quinoline-5-carboxamide (VPC-13789), a potent AR BF3 antagonist with markedly improved pharmacokinetic properties. We demonstrate that VPC-13789 suppresses AR-mediated transcription, chromatin binding, and recruitment of coregulatory proteins. This novel AR antagonist selectively reduces the growth of both androgen-dependent and enzalutamide-resistant PCa cell lines. Having demonstrated in vitro efficacy, we developed an orally bioavailable prodrug that reduced PSA production and tumor volume in animal models of CRPC with no observed toxicity. VPC-13789 is a potent, selective, and orally bioavailable antiandrogen with a distinct mode of action that has a potential as novel CRPC therapeutics.Publication Metadata only May iron(III) complexes containing phenanthroline derivatives as ligands be prospective anticancer agents?(Elsevier, 2019) Matos, Cristina P.; Adiguzel, Zelal; Yildizhan, Yasemin; Cevik, Ozge; Nunes, Patrique; Ferreira, Liliana P.; Carvalho, Maria Deus; Campos, Debora L.; Pavan, Fernando R.; Pesso, Joao Costa; Garcia, Maria Helena; Tomaz, Ana Isabel; Correia, Isabel; Animal Laboratory; N/A; N/A; Cevatemre, Buse; Önder, Tuğba Bağcı; Ayhan, Ceyda Açılan; Researcher; Faculty Member; Faculty Member; Animal Laboratory; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; School of Medicine; School of Medicine; N/A; 184359; 219658We report the design, synthesis and biological studies on a group of mixed ligand Fe(111) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L2-, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl) amine, and different aromatic bases NN = 2,21-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO3 (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FUR, UV-Vis, H-1 and C-13 NMR and fluorescence spectroscopies. [Fe(phen)Cl-3] and [Fe(amphen)Cl-3] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via M1T analysis all compounds 1-6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin VPAAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and gamma H2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTh activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies.Publication Metadata only Resorufin enters the photodynamic therapy arena: a monoamine oxidase activatable agent for selective cytotoxicity(Amer Chemical Soc, 2020) Atakan, Gizem; Gunbas, Gorkem; Department of Chemistry; N/A; N/A; Department of Chemistry; Almammadov, Toghrul; Leylek, Özen; Özcan, Gülnihal; Kölemen, Safacan; Researcher; PhD Student; Faculty Member; Faculty Member; Department of Chemistry; Koç University Surface Science and Technology Center (KUYTAM) / Koç Üniversitesi Yüzey Teknolojileri Araştırmaları Merkezi (KUYTAM); Koç University Boron and Advanced Materials Application and Research Center (KUBAM) / Koç Üniversitesi Bor ve İleri Malzemeler Uygulama ve Araştırma Merkezi (KUBAM); Koç University Tüpraş Energy Center (KUTEM) / Koç Üniversitesi Tüpraş Enerji Merkezi (KÜTEM); College of Sciences; Graduate School of Health Sciences; School of Medicine; College of Sciences; N/A; N/A; 185014; 272051A red-absorbing, water-soluble, and iodinated resorufin derivative (R1) that can be selectively activated with a monoamine oxidase (MAO) enzyme was synthesized, and its potential as a photodynamic therapy (PDT) agent was evaluated. R1 showed high O-1(2) generation yields in aqueous solutions upon addition of MAO isoforms, and it was further tested in cell culture studies. R1 induced photocytotoxicity after being triggered by endogenous MAO enzyme in cancer cells with a much higher efficiency in SH-SYSY neuroblastoma cells with high MAO-A expression. Additionally, R1 displayed differential cytotoxicity between cancer and normal cells, without any considerable dark toxicity. To the best of our knowledge, R1 marks the first example of a resorufin-based photosensitizer (PS) as well as the first anticancer drug that is activated by a MAO enzyme. Remarkably, the target PDT agent was obtained only in three steps as a result of versatile resorufin chemistry.Publication Metadata only Taming oncogenic signaling at protein interfaces: challenges and opportunities(Bentham Science Publ Ltd, 2015) N/A; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Cavga, Ayşe Derya; Karahan, Nilay; Keskin, Özlem; Gürsoy, Attila; PhD Student; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; N/A; 26605; 8745Many key cellular events determining the thin line between healthy and oncogenic behavior rely on the proper functioning of protein-protein interactions (PPIs). Alterations that affect the affinity of a protein-protein binding site may destabilize a desired healthy interaction, or stabilize an oncogenic interaction. The understanding that there are a few key hot-spot residues that are mainly responsible for the binding energy of an interaction greatly widened the prospects of targeting oncogenic protein-protein interfaces enabling the use of small ligands in addition to biological molecules such as peptides and antibodies. Taming oncogenic signaling requires a deep understanding of protein interactions and their networks. Traditional representation of PPIs in signaling pathways as nodes and edges falls short of expressing interaction specific modulation of signals. Structural networks, deciphering which sites on a protein structure are responsible for each of the many interactions it may carry out, help understanding specific oncogenic mutations on signaling. We describe the key features of PPIs and their targeting, together with the advantages of structural networks, and provide four case studies demonstrating different opportunities for the aim of modulating oncogenic interactions.Publication Metadata only Unfolded protein response is involved in trans-platinum (ii) complex-induced apoptosis in prostate cancer cells via ros accumulation(2019) Karakaş, Didem; Oral, Arzu Y.; Yılmaz, Veysel T.; Ulukaya, Engin; Animal Laboratory; Cevatemre, Buse; Researcher; Animal Laboratory; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/A; N/ABackground: Prostate cancer is one of the most common cancer types and it is the sixth leading cause of cancer-related death in men worldwide. Even though novel treatment modalities have been developed, it still a lifethreatening disease. Therefore novel compounds are needed to improve the overall survival. Methods: In our study, it was aimed to evaluate the anti-cancer activity of newly synthesized Platinum (II) [Pt(II)] complex on DU145, LNCaP and PC-3 prostate cancer cell lines. The cytotoxic activity of Pt(II) complex was tested by SRB and ATP cell viability assays. To detect the mode of cell death; fluorescent staining, flow cytometry and western blot analyses were performed. Results: The Pt(II) complex treatment resulted in a decrease in cell viability and increasing levels of apoptotic markers (pyknotic nuclei, annexin-V, caspase 3/7 activity) and a decrease in mitochondrial membrane potential in a dose dependent manner. Among cell types, tested PC-3 cells were found to be more sensitive to Pt(II) complex, demonstrating elevation of DNA damage in this cell line. In addition, Pt(II) complex induced Endoplasmic Reticulum (ER) stress by triggering ROS generation. More importantly, pre-treatment with NAC alleviated Pt(II) complex-mediated ER stress and cell death in PC-3. Conclusion: These findings suggest an upstream role of ROS production in Pt(II) complex-induced ER stressmediated apoptotic cell death. Considering the ROS-mediated apoptosis inducing the effect of Pt(II) complex, it warrants further evaluation as a novel metal-containing anticancer drug candidate.