2. Academic Validation
  3. Synthesis and structure-activity relationship of new nicotinamide phosphoribosyltransferase inhibitors with antitumor activity on solid and haematological cancer

Synthesis and structure-activity relationship of new nicotinamide phosphoribosyltransferase inhibitors with antitumor activity on solid and haematological cancer

  • Eur J Med Chem. 2023 Mar 15:250:115170. doi: 10.1016/j.ejmech.2023.115170.
Simone Fratta 1,  Paulina Biniecka 2,  Antonio J Moreno-Vargas 1,  Ana T Carmona 3,  Aimable Nahimana 2,  Michel A Duchosal 4,  Francesco Piacente 5,  Santina Bruzzone 5,  Irene Caffa 6,  Alessio Nencioni 6,  Inmaculada Robina 7
Affiliations

Affiliations

  • 1 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla, 41012, Spain.
  • 2 Central Laboratory of Hematology, Medical Laboratory and Pathology Department, Lausanne University Hospital, 1011, Lausanne, Switzerland.
  • 3 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla, 41012, Spain. Electronic address: [email protected].
  • 4 Central Laboratory of Hematology, Medical Laboratory and Pathology Department, Lausanne University Hospital, 1011, Lausanne, Switzerland; Service of Hematology, Oncology Department, Lausanne University Hospital, 1011, Lausanne, Switzerland.
  • 5 Department of Experimental Medicine, Section of Biochemistry, University of Genoa, 16132, Genoa, Italy.
  • 6 Department of Internal Medicine and Medical Specialties, University of Genoa, 16132, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy.
  • 7 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla, 41012, Spain. Electronic address: [email protected].
PMID: 36787658 DOI: 10.1016/j.ejmech.2023.115170
Abstract

Cancer cells are highly dependent on Nicotinamide phosphoribosyltransferase (NAMPT) activity for proliferation, therefore NAMPT represents an interesting target for the development of anti-cancer drugs. Several compounds, such as FK866 and CHS828, were identified as potent NAMPT inhibitors with strong anti-cancer activity, although none of them reached the late stages of clinical trials. We present herein the preparation of three libraries of new inhibitors containing (pyridin-3-yl)triazole, (pyridin-3-yl)thiourea and (pyridin-3/4-yl)cyanoguanidine as cap/connecting unit and a furyl group at the tail position of the compound. Antiproliferative activity in vitro was evaluated on a panel of solid and haematological Cancer cell lines and most of the synthesized compounds showed nanomolar or sub-nanomolar cytotoxic activity in MiaPaCa-2 (pancreatic Cancer), ML2 (acute myeloid leukemia), JRKT (acute lymphobalistic leukemia), NMLW (Burkitt lymphoma), RPMI8226 (multiple myeloma) and NB4 (acute myeloid leukemia), with lower IC50 values than those reported for FK866. Notably, compounds 35a, 39a and 47 showed cytotoxic activity against ML2 with IC50 = 18, 46 and 49 pM, and IC50 towards MiaPaCa-2 of 0.005, 0.455 and 2.81 nM, respectively. Moreover, their role on the NAD+ synthetic pathway was demonstrated by the NAMPT inhibition assay. Finally, the intracellular NAD+ depletion was confirmed in vitro to induced ROS accumulation that cause a time-dependent mitochondrial membrane depolarization, leading to ATP loss and cell death.

Keywords

Cancer; Cyanoguanidines; Cytotoxic agents; Furan; NAD(+); NAMPT inhibitors.

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