Symmetrical Bis-Quinolinium Compounds:  New Human Choline Kinase Inhibitors with Antiproliferative Activity against the HT-29 Cell Line

Sánchez‐Martín, Rosario M.; Campos, Joaquı́n M.; Conejo‐García, Ana; Cruz‐López, Olga; Báñez-Coronel, Mónica; Rodrı́guez-González, Agustı́n; Gallo, Miguel Á.; Lacal, Juan Carlos; Espinosa, Antonio

doi:10.1021/jm049061o

Cited by 52 publications

(40 citation statements)

References 42 publications

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“…Compounds were synthesized as previously described (15)(16)(17)(18)(19)(20)35). The structure of all the compounds are shown as derivatives of the general structure depicted in Supplementary Fig.…”

Section: Synthesis Of Compoundsmentioning

confidence: 99%

“…A successful series of symmetrical bis-quinolinium compounds based on the hemicolinium-3 (HC-3) molecule have been synthesized as inhibitors of ChoKa with promising activity as antiproliferative compounds against tumor-derived cells and as antitumoral drugs in xenografts models (13)(14)(15)(16)(17)(18)(19)(20). MN58b, a first-generation ChoKa inhibitor, shows a potent in vitro antiproliferative activity and in vivo antitumoral activity (1,13,14).…”

Section: Introductionmentioning

confidence: 99%

“…Once the proof-of-principle that ChoKa is a validated target in oncology has been set up, a very intensive activity has been developed for the identification of novel ChoKa inhibitors with potential use as antitumoral drugs (15)(16)(17)(18)(19)(20)(28)(29)(30)(31) and also as antiparasitic compounds (32,33).…”

Section: Introductionmentioning

confidence: 99%

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Preclinical Characterization of RSM-932A, a Novel Anticancer Drug Targeting the Human Choline Kinase Alpha, an Enzyme Involved in Increased Lipid Metabolism of Cancer Cells

Lacal

Campos

2015

Molecular Cancer Therapeutics

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Choline kinase a (CHKA; here designated as ChoKa) is the first enzyme in the CDP-choline pathway, implicated in phospholipids metabolism. It is overexpressed in several human tumors such as breast, lung, bladder, colorectal, prostate, ovary, and liver. The overexpression of ChoKa has oncogenic potential and synergizes with other known oncogenes. It has been proposed as a novel cancer drug target with a distinct mechanism of action. We have generated a set of ChoKa inhibitors with potent in vitro antiproliferative and in vivo antitumoral activity against human xenografts in mice, showing high efficacy with low toxicity profiles. Among these inhibitors, RSM-932A has been chosen for further clinical development due to its potent antiproliferative activity in vitro against a large variety of tumorderived cell lines, a potent in vivo anticancer activity, and lack of toxicity at the effective doses. Here, we provide the preclinical evidence to support the use of RSM-932A as a good candidate to be tested in clinical trials as the "first in humans" drug targeting ChoKa.

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Section: Synthesis Of Compoundsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Preclinical Characterization of RSM-932A, a Novel Anticancer Drug Targeting the Human Choline Kinase Alpha, an Enzyme Involved in Increased Lipid Metabolism of Cancer Cells

Lacal

Campos

2015

Molecular Cancer Therapeutics

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“…Finally, 4,7-diaminoquinoline was prepared from 4-amino-7-nitroquinoline by reduction with excess stannous chloride (SnCl 2 ) over 2 h in HCl and glacial acetic acid at 60 C (supplementary Scheme S5). 41 The product was obtained after base extraction into CHCl 3 with NaOH after stirring, filtering and washing with acetone.…”

Section: Synthesismentioning

confidence: 99%

Structure–activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods

Nsumiwa

Kuter

Wittlin

et al. 2013

Bioorganic & Medicinal Chemistry

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In order to probe structure-activity relationships of association with ferriprotoporphyrin IX (log K) and inhibition of -hematin formation, a series of 4-aminoquinolines with varying substituents at the 7-position (X) have been synthesized. These have been further elaborated by introduction of two different R groups on the 4-amino nitrogen atom in the form of methyl (R = Me) and ethylamine (R = EtNH 2 ) side chains. Data for a previously investigated series containing an N,N-diethyl-ethylamine side chain were also compared with the findings of this study. Experimentally, log K values for the simple 4-aminoquinoline series (R = H) were found to correlate with the hydrophobicity constant () of the group X. The log K values for the series with R = Me and EtNH 2 were found to correlate with those of the series with R = H. The log of the 50% -hematin inhibitory activity (log BHIA 50 ) was found to correlate with log K and either meta ( m ) or para ( p ) Hammett constants for the series with R = Me and EtNH 2 , but not the simple series with R = H. To further improve predictability, correlations with ab initio electrostatic parameters, namely Mulliken and CHelpG charges were investigated. The best correlations were found with CHelpG charges which indicated that log K values can be predicted from the charges on atom H-8 and the group X in the quinolinium species computed in vacuum, while log BHIA 50 values can be predicted from the CHelpG charges on C-7, C-8 and N-1 for the neutral species in vacuum. These correlations indicate that association and inhibition of -hematin formation are separately determined. They also suggest that electron withdrawing groups at the 7-position, but not necessarily hydrophobic groups are required for hemozoin inhibition. The upshot is that the correlations imply that considerably more hydrophilic hemozoin inhibitors are feasible.Keywords: hemozoin; DFT; antimalarials; quinolines; structure-activity relationships; ferriprotoporphyrin IX 3 IntroductionQuinoline antimalarials such as quinine and chloroquine have had a long and successful history. 1 Subsequent emergence of chloroquine resistance has led to the use of other quinoline derivative antimalarials such as mefloquine and amodiaquine. Indeed, the development and clinical deployment of new quinoline antimalarials continues to this day.For example, piperaquine, a bis-4-aminoquinoline effective against chloroquine-resistant strains that consists of two 4-aminoquinoline moieties attached by a linker has only recently been introduced into clinical use. 2 Ferroquine, a 4-amino-7-chloroquinoline with a ferrocenyl side-chain is currently in phase IIB clinical trials. 3 In addition, research on new quinoline antimalarials retains considerable interest, such as that on so-called "reversed chloroquines"and related compounds that are both antimalarially active and inhibit the chloroquine resistance mechanism of the parasite. 4-10The class of 4-aminoquinoline antimalarials are believed to act by inhibiting the incorporation of ferrih...

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“…In other cases, a variety of heterocyclic cores are connected through linkers of different structural features. For example, bis-azepines [7], bis-isooxazoloazepanes [8], bisindenoquinolines [9] and bis-quinolinium compounds [10] have been described and evaluated.…”

Section: Introductionmentioning

confidence: 99%

New Green Synthesis and Antineoplastic Activity of Bis (3-Arylimidazolidinyl-1) Methanes

Perillo¹,

Villalonga²,

Amiano³

et al. 2013

OJMC

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A new green synthesis and anti-tumor activity of the series of bis (3-arylimidazolidinyl-1) methanes 1 -6 are described. The compounds were synthesized from the corresponding N-arylethylenediamine and trioxane as sources of formaldehyde and the reactions were performed in heterogeneous phase catalyzed by an acidic ion-exchange resin (Amberlyst 15). The compounds were tested with the Sulforhodamine B assay according to the protocol of the National Cancer Institute for several cell lines. The results were expressed as percentage inhibition of growth cell in comparison with the full growth of the cells without treatment. Cytotoxicity on normal cells using the Annexing-PI staining and flow cytometry has been evaluated. The parent compound, bis(3-phenylimidazolidinyl-1)methane 1 and the monohalogenated derivatives 4-chlorophenyl 3 and 3-bromophenyl 5 showed antineoplastic activity, 60%, 82% and 89% inhibition growth cell respectively on the human colon cell line (HCT116). The 4-tolyl derivative 6 presented inhibitory activity (73% inhibition of growth cell) on human lung adenocarcinoma cell line (A549) and 62% on human mammary cell line MCF-7.

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Symmetrical Bis-Quinolinium Compounds: New Human Choline Kinase Inhibitors with Antiproliferative Activity against the HT-29 Cell Line

Cited by 52 publications

References 42 publications

Preclinical Characterization of RSM-932A, a Novel Anticancer Drug Targeting the Human Choline Kinase Alpha, an Enzyme Involved in Increased Lipid Metabolism of Cancer Cells

Preclinical Characterization of RSM-932A, a Novel Anticancer Drug Targeting the Human Choline Kinase Alpha, an Enzyme Involved in Increased Lipid Metabolism of Cancer Cells

Structure–activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods

New Green Synthesis and Antineoplastic Activity of Bis (3-Arylimidazolidinyl-1) Methanes

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