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

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: - and -. They are characterized by cationic heads of 3-aminophenol bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium through several linkers.

Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2- d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors.

The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3',4',5'-trimethoxyanilino)thieno[3,2- d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3',4',5'-trimethoxyanilino)-6-( p-tolyl)thieno[3,2- d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC) values in the single- or double-digit nanomolar range.

2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition.

Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity.

Design, synthesis, crystallization and biological evaluation of new symmetrical biscationic compounds as selective inhibitors of human Choline Kinase α1 (ChoKα1).

A novel family of compounds derivative of 1,1'-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bispyridinium or -bisquinolinium bromide (10a-l) containing a pair of oxygen atoms in the spacer of the linker between the biscationic moieties, were synthesized and evaluated as inhibitors of choline kinase against a panel of cancer-cell lines. The most promising compounds in this series were 1,1'-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))bis(4-(dimethylamino)pyridinium) bromide (10a) and 1,1'-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bis(7-chloro-4-(pyrrolidin-1-yl)quinolinium) bromide (10l), which inhibit human choline kinase (ChoKα1) with IC50 of 1.0 and 0.

Design, synthesis, in vitro, and in vivo anticancer and antiangiogenic activity of novel 3-arylaminobenzofuran derivatives targeting the colchicine site on tubulin.

A new series of compounds characterized by the presence of a 2-methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at each of the four possible positions of the benzene portion of the 3-(3',4',5'-trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against cancer cells in culture and, for selected, highly active compounds, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. The greatest antiproliferative activity occurred with a methoxy group introduced at the C-6 position, the least with this substituent at C-4. Thus far, the most promising compound in this series was 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-6-methoxybenzo[b]furan (3g), which inhibited cancer cell growth at nanomolar concentrations (IC50 values of 0.

SWI/SNF proteins as targets in cancer therapy.

Recent identification of synthetic lethal interactions involving several proteins of the SWI/SNF complex discussed in this Research Highlight has opened the possibility of new cancer therapeutic approaches.

1H, 13C NMR studies of new 3-aminophenol isomers linked to pyridinium salts.

(1)H and (13)C NMR spectroscopic data of 20 new non-symmetrical compounds were assigned by a combination of 1D and 2D NMR experiments (DEPT, HSQC, and HMBC). These compounds contain a 4-(N,N-dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium moiety and a 3-nitro-, 3-amino-, or 3-hydroxyphenyl ring, linked by p-xylene, 4,4'-dimethylbiphenyl, 1,2-bis(p-tolyl)ethane, or 1,4-bis(p-tolyl)butane.

New non-symmetrical choline kinase inhibitors.

Identification of novel and selective anticancer agents remains an important and challenging goal in pharmacological research. Choline kinase (ChoK) is the first enzyme in the CDP-choline pathway that synthesizes phosphatidylcholine (PC), the major phospholipid in eukaryotic cell membranes. In the present paper, a new family of non-symmetrical monocationic compounds is developed including a 3-aminophenol moiety, bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium cationic heads through several linkers.

In silico pharmacology for a multidisciplinary drug discovery process.

The process of bringing new and innovative drugs, from conception and synthesis through to approval on the market can take the pharmaceutical industry 8-15 years and cost approximately $1.8 billion. Two key technologies are improving the hit-to-drug timeline: high-throughput screening (HTS) and rational drug design.