0000000001307780
AUTHOR
Friedrich Hahn
Access to new highly potent antileukemia, antiviral and antimalarial agents via hybridization of natural products (homo)egonol, thymoquinone and artemisinin
Hybridization of natural products has high potential to further improve their activities and may produce synergistic effects between linked pharmacophores. Here we report synthesis of nine new hybrids of natural products egonol, homoegonol, thymoquinone and artemisinin and evaluation of their activities against P. falciparum 3D7 parasites, human cytomegalovirus, sensitive and multidrug-resistant human leukemia cells. Most of the new hybrids exceed their parent compounds in antimalarial, antiviral and antileukemia activities and in some cases show higher in vitro efficacy than clinically used reference drugs chloroquine, ganciclovir and doxorubicin. Combined, our findings stress the high pot…
The Complex Regulatory Role of Cytomegalovirus Nuclear Egress Protein pUL50 in the Production of Infectious Virus
The regulation of the nucleocytoplasmic release of herpesviral capsids is defined by the process of nuclear egress. Due to their large size, nuclear capsids are unable to traverse via nuclear pores, so that herpesviruses evolved to develop a vesicular transport pathway mediating their transition through both leaflets of the nuclear membrane. This process involves regulatory proteins, which support the local distortion of the nuclear envelope. For human cytomegalovirus (HCMV), the nuclear egress complex (NEC) is determined by the pUL50-pUL53 core that initiates multicomponent assembly with NEC-associated proteins and capsids. Hereby, pUL50 serves as a multi-interacting determinant that recru…
Cyclins B1, T1, and H differ in their molecular mode of interaction with cytomegalovirus protein kinase pUL97
Human cytomegalovirus (HCMV) is a common β-herpesvirus causing life-long latent infections. HCMV replication interferes with cell cycle regulation in host cells because the HCMV-encoded cyclin-dependent kinase (CDK) ortholog pUL97 extensively phosphorylates the checkpoint regulator retinoblastoma protein. pUL97 also interacts with cyclins B1, T1, and H, and recent findings have strongly suggested that these interactions influence pUL97 substrate recognition. Interestingly, here we detected profound mechanistic differences among these pUL97-cyclin interactions. Our study revealed the following. (i) pUL97 interacts with cyclins B1 and H in a manner dependent on pUL97 activity and HCMV-specifi…
Synthesis of Thymoquinone–Artemisinin Hybrids: New Potent Antileukemia, Antiviral, and Antimalarial Agents
[Image: see text] A series of hybrid compounds based on the natural products artemisinin and thymoquinone was synthesized and investigated for their biological activity against the malaria parasite Plasmodium falciparum 3D7 strain, human cytomegalovirus (HCMV), and two leukemia cell lines (drug-sensitive CCRF-CEM and multidrug-resistant subline CEM/ADR5000). An unprecedented one-pot method of selective formation of C-10α-acetate 14 starting from a 1:1 mixture of C-10α- to C-10β-dihydroartemisinin was developed. The key step of this facile method is a mild decarboxylative activation of malonic acid mediated by DCC/DMAP. Ether-linked thymoquinone–artemisinin hybrids 6a/b stood out as the most…
CCDC 1816140: Experimental Crystal Structure Determination
Related Article: Aysun Çapcı Karagöz, Christoph Reiter, Ean-Jeong Seo, Lisa Gruber, Friedrich Hahn, Maria Leidenberger, Volker Klein, Frank Hampel, Oliver Friedrich, Manfred Marschall, Barbara Kappes, Thomas Efferth, Svetlana B. Tsogoeva|2018|Bioorg.Med.Chem.|26|3610|doi:10.1016/j.bmc.2018.05.041
CCDC 1816139: Experimental Crystal Structure Determination
Related Article: Aysun Çapcı Karagöz, Christoph Reiter, Ean-Jeong Seo, Lisa Gruber, Friedrich Hahn, Maria Leidenberger, Volker Klein, Frank Hampel, Oliver Friedrich, Manfred Marschall, Barbara Kappes, Thomas Efferth, Svetlana B. Tsogoeva|2018|Bioorg.Med.Chem.|26|3610|doi:10.1016/j.bmc.2018.05.041