| Autor: |
O'Flaherty S; Department of Chemistry, RCSI University of Medicine and Health Sciences, 123, St. Stephen's Green, D02 YN77 Dublin, Ireland.; SSPC (Synthesis and Solid State Pharmaceutical Centre) Research Centre, V94 T9PX Limerick, Ireland., Luzina OA; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 Acad. Lavrentjev Ave., 630090 Novosibirsk, Russia., Dyrkheeva NS; Institute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrentjev Ave., 630090 Novosibirsk, Russia., Krier Y; Laboratoire Lorraine de Chimie Moléculaire, Université de Lorraine, CNRS, L2CM, 54000 Nancy, France., Leprince J; Inserm, Rouen Normandie Université, NorDiC UMR 1239, 76000 Rouen, France.; Rouen Normandie Université, HeRacLes UMS 51, PRIMACEN, 76000 Rouen, France., Zakharenko AL; Institute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrentjev Ave., 630090 Novosibirsk, Russia., Pokrovsky MA; V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 2 Pirogova str., 630090 Novosibirsk, Russia., Pokrovsky AG; V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 2 Pirogova str., 630090 Novosibirsk, Russia., Lavrik OI; Institute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrentjev Ave., 630090 Novosibirsk, Russia., Salakhutdinov NF; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 Acad. Lavrentjev Ave., 630090 Novosibirsk, Russia., Varbanov M; Laboratoire Lorraine de Chimie Moléculaire, Université de Lorraine, CNRS, L2CM, 54000 Nancy, France., Devocelle M; Department of Chemistry, RCSI University of Medicine and Health Sciences, 123, St. Stephen's Green, D02 YN77 Dublin, Ireland.; SSPC (Synthesis and Solid State Pharmaceutical Centre) Research Centre, V94 T9PX Limerick, Ireland., Volcho KP; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 Acad. Lavrentjev Ave., 630090 Novosibirsk, Russia.; V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 2 Pirogova str., 630090 Novosibirsk, Russia. |
| Abstrakt: |
Cationic antimicrobial peptides (AMPs), also called host defence peptides, have established antimicrobial and anticancer activities. Conjugation of an AMP to a bioactive molecule with complementary activity can address some of the clinical limitations of the peptide candidate. This approach has been particularly applied in antimicrobial applications of AMPs, but it remains relatively less explored in the generation of anticancer candidates. In this study, two usnic acid derivatives, based on hydrazinothiazole and benzylidenefuranone pharmacophore moieties, respectively, were conjugated to L-K6, a lysine/leucine-rich AMP, through a new pyrazole ligation intrinsically driven by the cargo molecule. Both components, the usnic acid derivative and the peptide, are selectively active against cancer cells, by targeting the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) and through DNA damage, respectively. The two conjugates, based on a hydrazone linkage, exhibited pleiotropic effects, ranging from reduction in the activity of the parent drugs to their conservation or even enhancement. Notably, the conjugates retained some anti-TDP1 activity and displayed intermediate, or even higher, cytotoxicities against glioblastoma cells, compared to their individual components. |
