Author: Gunesch, Antonia P ; Pietschmann, Thomas ; Milke, Vanessa ; Kühl, David ; Haid, Sibylle ; Schulz, Thomas F ; Lasswitz, Lisa ; Brown, Richard J P ; Köhler, Natalie M ; Sake, Svenja M ; Nguyen, Tu-Trinh ; Brönstrup, Mark ; Wiegmann, Bettina ; Vieyres, Gabrielle ; Gerold, Gisa ; Rückert, Jessica ; Bilitewski, Ursula ; Matthaei, Alina ; Winkler, Melina ; Brogden, Graham ; Göhl, Matthias ; Zapatero-Belinchón, Francisco J

ABSTRACT Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases. Gene knock-out of the drugs’ host targets including cathepsin B and L (CTSB/L; VBY-825), the aryl hydrocarbon receptor (AHR; Phortress), the farnesyl-diphosphate farnesyltransferase 1 (FDFT1; P-3622), and the kelch-like ECH-associated protein 1 (KEAP1; Omaveloxolone), significantly modulated HCoV-229E infection, providing evidence that these compounds inhibited the virus through acting on their respective host targets. Counter-screening of all 134 primary compound candidates with SARS-CoV-2 and validation in primary cells identified Phortress, an AHR activating ligand, P-3622-targeting FDFT1, and Omaveloxolone, which activates the NFE2-like bZIP transcription factor 2 (NFE2L2) by liberating it from its endogenous inhibitor KEAP1, as antiviral candidates for both an Alpha - and a Betacoronavirus . This study provides an overview of HCoV-229E repurposing candidates and reveals novel potentially druggable viral host dependency factors hijacked by diverse coronaviruses.

01 Jul 2022·Future Medicinal Chemistry

Design, Synthesis and In Vitro Antiproliferation Activity of Some 2-aryl and -heteroaryl Benzoxazole Derivatives

Article

Author: Kuzu, Burak ; Burmaoglu, Serdar ; Turkmenoglu, Burcin ; Hepokur, Ceylan ; Algul, Oztekin

Background: Phortress produces reactive electrophilic metabolites that form DNA adducts only in sensitive tumor cells. The authors converted the 2-phenylbenzothiazole nucleus in phortress to 2-aryl and -heteroaryl benzoxazole derivatives (11 new and 14 resynthesized). All synthesized compounds were studied for antitumor activity in various cancer cells. Materials & methods: Cytotoxicity, cell morphology, flow cytometry and cell-cycle analyses of compounds were performed and more active derivatives were tested in the MCF-7 cell line. Conclusion: Methyl 2-(thiophen-2-yl)benzo[d]oxazole-6-carboxylate (BK89) has a higher effect than fluorouracil to induce apoptotic cell death (apoptosis value of 49.44%). Cell-cycle analysis shows that the compounds BK89 and methyl 2-(furan-2-yl)benzo[d]oxazole-6-carboxylate (BK82) can be used as potential cell-cycle blockers by arresting MCF-7 cells in G0/G1 phase at rates of 63% and 85%, respectively.

01 Jan 2021·European Journal of Medicinal ChemistryQ1 · MEDICINE

Synthesis of some new benzoxazole derivatives and investigation of their anticancer activities

Q1 · MEDICINE

Article

Author: Sağlık, Begüm Nurpelin ; Acar Çevik, Ulviye ; Kaplancıklı, Zafer Asım ; Kaya Çavuşoğlu, Betül ; Ilgın, Sinem ; Korkut Çelikateş, Büşra ; Osmaniye, Derya ; Levent, Serkan ; Özkay, Yusuf

Phortress is an anticancer prodrug, which has active metabolite (5F-203) being potent agonist of the aryl hydrocarbon receptor (AhR). The 5F-203 switches on cytochrome P450 CYP1A1 gene expression and thus exhibits anticancer activity. In this study, it is aimed to obtain new phortress analogues by bioisosteric replacement of benzothiazole core in the structure to benzoxazole ring system. Synthesis of compounds (3a-3p) were performed according to literature methods. Their structures were elucidated by IR, ¹H NMR, ¹³C NMR, 2D-NMR and HRMS spectroscopic methods. Cytotoxicity (MTT), inhibition of DNA synthesis and flow cytometric analysis assays were applied to determine anticancer activity of the compounds on colon (HT-29), breast (MCF7), lung (A549), liver (HepG2) and brain (C6) carcinoma cell types. When compared reference agent doxorubicin, compounds 3m and 3n displayed very attractive anticancer effect against carcinogenic cell lines. Due to structural similarity to phortress, biotransformation studies for 3m and 3n were examined by LCMS-IT-TOF system and probable metabolites of these compounds were determined. Induction potential of these compounds on CYP1A1/2 enzymes was also investigated to clarify possible mechanism of action. Interaction modes between CYP1A1 enzyme and compound 3n or its some metabolites were investigated by docking studies. In conclusion, findings of these study indicate that compounds 3m and 3n possess significant anticancer activity, probably with the same mechanism of action to Phortress.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	-	Cancer Research UK	-
Neoplasms	Phase 1	-	The University of Nottingham Students' Union	-
Neoplasms	Discovery	GB	Pharminox Ltd	-

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