Fuente: Biomolecules - Revista científica (MDPI) Biomolecules, Vol. 16, Pages 145: Novel Dorsomorphin Derivatives: Molecular Modeling, Synthesis, and Bioactivity Evaluation
Biomolecules doi: 10.3390/biom16010145
Authors:
Evangelia N. Tzanetou
Sandra Liekens
Konstantinos M. Kasiotis
Nikolas Fokialakis
Nikolaos Tsafantakis
Raul SanMartin
Haralampos Tzoupis
Konstantinos D. Papavasileiou
Antreas Afantitis
Serkos A. Haroutounian

Dorsomorphin, a pyrazolo[1,5-a]pyrimidine derivative, inhibits the bone morphogenetic protein (BMP) pathway by targeting the type I BMP receptors active in receptor-like kinases. However, the investigation of its—and its derivatives’—antiproliferative activity towards endothelial and cancer cell lines still requires reinforcement with additional studies. In the presented work, several dorsomorphin derivatives have been efficiently synthesized, based on a previously reported synthetic protocol with minor modifications. The endeavor was reinforced by a molecular docking study on the interactions of the designed derivatives with various protein targets, while the inhibitory effects of the synthesized novel molecules on the proliferation of murine leukemia cells (L1210), human T-lymphocyte cells (CEM), human cervix carcinoma cells (HeLa), and endothelial cells (human dermal microvascular, HMEC-1, and bovine aortic endothelial cells, BAECs) were investigated. Among the compounds tested, diphenol 22, emerged as the most promising bioactive lead since it demonstrated half-maximal inhibitory concentration (IC50) values below 9 μM in all tested lines except HeLa cells. In the same context, the carbamate derivative 6 was determined as a potent inhibitor of endothelial cell proliferation in BAECs at a low micromolar range. In conclusion, the presented work not only reveals promising antiproliferative dorsomorphin derivatives but also sets the basis for further exploitation of dorsomorphin’s bioactive portfolio, based on bioactivity results and molecular modeling calculations.