Synthesis, biological evaluation, in silico modeling and crystallization of novel small monocationic molecules with potent antiproliferative activity by dual mechanism

Aguilera, Lucía Serrán; Mariotto, Elena; Rubbini, Gianluca; Navas, Francisco; Marco, Carmen; Carrasco-Jiménez, María P.; Ballarotto, Marco; Macchiarulo, Antonio; Hurtado‐Guerrero, R.; Viola, Giampietro; Cara, Carlota Lopez

doi:10.1016/j.ejmech.2020.112797

Cited by 5 publications

(17 citation statements)

References 35 publications

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“…Since recently, we have demonstrated that some ChoKα1 inhibitors, in addition to their effects on h ChoKα1 activity, are able to reduce choline uptake into the cell [ 13 ], we decided to investigate whether these compounds were also capable of inhibiting choline uptake in HepG2 cells. The two compounds chosen were 3d ( Table 1 and Table 3 ), which show moderate enzyme inhibition but very good antiproliferative values.…”

Section: Resultsmentioning

confidence: 99%

“…Choline uptake was determined as previously reported [ 13 ]. Briefly, HepG2 cells (200,000 cells/well) were incubated for 10 min at 37 °C either in a medium containing different concentrations of ChoKα1 inhibitors or only with the medium as controls.…”

Section: Methodsmentioning

confidence: 99%

“…[ 10 , 11 , 12 ] ChoKα appears overexpressed in 40–60% of breast, prostate, lung, colon, ovarian, and bladder cancers, which represent 70% of all cancers in developed countries. For this reason, ChoK has been proposed as a prognostic marker of progression [ 7 ] as well as a molecular target in oncology [ 13 , 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Due to its vital and widely studied role in cell division and tumor formation, ChoK emerged as a potential target for various cancers [ 11 , 12 , 13 ], particularly, Ras-induced carcinogenesis. The Ras effectors serine/threonine kinase (Raf-1), the Ral-GDP dissociation stimulator (Ral-GDS) and the phosphatidylinositol 3-kinase (PI3K) are all involved in ChoK activation during tumorigenesis [ 7 , 9 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…The size of symmetrical biscationic inhibitors was appropriate to bind simultaneously in both the ATP and Cho putative binding sites of the protein model [ 19 , 20 , 21 , 22 , 23 , 24 ]. On the other hand, we have recently reported a new series of small monocationic molecules where the inhibition of choline uptake has emerged as a major contributor to the antiproliferative outcome of this class of compounds [ 13 ]. The results provided in the present study can complement the earlier outcomes reported since docking studies have been done in more appropriate crystal structures.…”

Section: Introductionmentioning

confidence: 99%

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Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

et al. 2021

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

et al. 2021

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Anticancer Activity and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

Schiaffino-Ortega¹,

Mariotto²,

Luque-Navarro³

et al. 2021

Preprint

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Choline kinase inhibitors are an important 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 characterization and the structure activity relationship of a series of non-symmetrical choline kinase inhibitors characterized by a 3-aminophenol moiety, bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium cationic heads through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and for their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the best inhibitory results were those connected to the linker by the N-atom (4a-h) and these results are supported by docking studies. The compounds with the best antiproliferative results were those connected to the linker by the O-atom (3a-h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is greater the shorter the length of the linker, while 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 a low toxicity in non-tumoral cells (e.g human peripheral lymphocytes) respect to cancer cells. These compounds were also able to induce to induce apoptosis in Jurkat leukemic cells without causing significative variations of cell cycle. It is worth to mention that these derivatives, beside 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.

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New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity

et al. 2021

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In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting Plasmodium falciparum Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory activity, whereas an effect of the type of cationic heads used could be observed. SARs determined that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good inhibitory values have been related to the proposed mechanism of action, some of them still show discrepancies and further studies are needed to determine their specific molecular target.

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Synthesis, biological evaluation, in silico modeling and crystallization of novel small monocationic molecules with potent antiproliferative activity by dual mechanism

Cited by 5 publications

References 35 publications

Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

Anticancer Activity and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity

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