Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors
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Schiaffino Ortega, Santiago; Luque Navarro, Pilar María; Kimatrai Salvador, María; Ríos Marco, Pablo; Marco De La Calle, Carmen; Carrasco Jiménez, María Paz; López Cara, Luisa CarlotaEditorial
MDPI
Materia
Antitumoral drug Choline kinase inhibition Choline uptake
Date
2021-08-29Referencia bibliográfica
Schiaffino-Ortega, S... [et al.]. Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors. Pharmaceutics 2021, 13, 1360. [https://doi.org/10.3390/pharmaceutics13091360]
Sponsorship
Convocatoria 2019 Proyectos de I + D + i - RTI Tipo B "Ministerio de Innovacion y Ciencia" PID2019-109294RB-I00; University of Granada, Cei-BioticProject CEI2013-MP-1Abstract
Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the
treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic
cells. Here, we present the most in-depth structure-activity relationship studies of an interesting
series of non-symmetric choline kinase inhibitors previously reported by our group: 3a–h and
4a–h. They are characterized by cationic heads of 3-aminophenol bound to 4-(dimethylamino)- or
4-(pyrrolidin-1-yl)pyridinium through several linkers. These derivatives were evaluated both for
their inhibitory activity on the enzyme and their antiproliferative activity in a panel of six human
tumor cell lines. The compounds with the N-atom connected to the linker (4a–h) show the best
inhibitory results, in the manner of results supported by docking studies. On the contrary, the best
antiproliferative compounds were those with the O-atom bounded to the linker (3a–h). On the other
hand, as was predictable in both families, the inhibitory effect on the enzyme is better the shorter
the length of the linker. However, in tumor cells, lipophilicity and choline uptake inhibition could
play a decisive role. Interestingly, compounds 3c and 4f, selected for both their ability to inhibit
the enzyme and good antiproliferative activity, are endowed with low toxicity in non-tumoral cells
(e.g., human peripheral lymphocytes) concerning cancer cells. These compounds were also able to
induce apoptosis in Jurkat leukemic cells without causing significant variations of the cell cycle. It is
worth mentioning that these derivatives, besides their inhibitory effect on choline kinase, displayed a
modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to
the observed cytotoxicity.