2. Academic Validation
  3. 1,2,3-Triazole-totarol conjugates as potent PIP5K1α lipid kinase inhibitors

1,2,3-Triazole-totarol conjugates as potent PIP5K1α lipid kinase inhibitors

  • Bioorg Med Chem. 2024 May 1:105:117727. doi: 10.1016/j.bmc.2024.117727.
Samer Haidar 1,  Ángel Amesty 2,  Sandra Oramas-Royo 2,  Claudia Götz 3,  Ehab El-Awaad 4,  Jana Kaiser 5,  Sarah Bödecker 5,  Amelie Arnold 5,  Dagmar Aichele 5,  Juan M Amaro-Luis 6,  Ana Estévez-Braun 7,  Joachim Jose 8
Affiliations

Affiliations

  • 1 Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, PharmaCampus, Corrensstr. 48, 48149 Münster, Germany; Faculty of Pharmacy, 17 April Street, Damascus University, Damascus 9411, Syria.
  • 2 Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez N° 2, 38206, La Laguna, Tenerife, Spain.
  • 3 Universität des Saarlandes - Campus Homburg, Medizinische Biochemie und Molekularbiologie, Kirrberger Str., Geb. 44, D-66421 Homburg, Germany.
  • 4 Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, PharmaCampus, Corrensstr. 48, 48149 Münster, Germany; Department of Pharmacology, Faculty of Medicine, Assiut University, 71515 Egypt.
  • 5 Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, PharmaCampus, Corrensstr. 48, 48149 Münster, Germany.
  • 6 Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez N° 2, 38206, La Laguna, Tenerife, Spain; Departamento de Química, Universidad de los Andes (Mérida), 5101, Venezuela.
  • 7 Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez N° 2, 38206, La Laguna, Tenerife, Spain. Electronic address: [email protected].
  • 8 Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, PharmaCampus, Corrensstr. 48, 48149 Münster, Germany. Electronic address: [email protected].
PMID: 38669736 DOI: 10.1016/j.bmc.2024.117727
Abstract

The human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) plays a key role in the development of prostate Cancer. In this work, seventeen derivatives of the natural diterpene totarol were prepared by copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of the correspondingO-propargylated totarol with aryl or alkyl azides and screened for their inhibitory activities toward hPIP5K1α. Five compounds, 3a, 3e, 3f, 3i, and 3r, strongly inhibited the Enzyme activity with IC50 values of 1.44, 0.46, 1.02, 0.79, and 3.65 µM, respectively, with the most potent inhibitor 3e 13-[(1-(3-nitrophenyl)triazol-4yl)methoxy]-totara-8,11,13-triene). These compounds were evaluated on their antiproliferative effects in a panel of prostate Cancer cell lines. Compound 3r inhibited the proliferation of LNCaP, PC3 and DU145 cells at 20 µM, strongly, but also has strong cytotoxic effects on all tested cells.

Keywords

Cancer; Inhibitors; PIP5K1α lipid kinase; Totarol.

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