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

Seeking for new anticancer drugs with strong antiproliferative activity and simple molecular structure, we designed a novel series of compounds based on our previous reported pharmacophore model composed of five moieties. Antiproliferative assays on four tumoral cell lines and evaluation of Human Choline Kinase CKα1 enzymatic activity was performed for these compounds. Among tested molecules, those ones with biphenyl spacer showed betters enzymatic and antiproliferative activities (n-v). Docking and crystallization studies validate the hypothesis and confirm the results. The most active compound (t) induces a significant arrest of the cell cycle in G0/G1 phase that ultimately lead to apoptosis, following the mitochondrial pathway, as demonstrated for other choline kinase inhibitors. However additional assays reveal that the inhibition of choline uptake could also be involved in the antiproliferative outcome of this class of compounds.

C24-hydroxylated stigmastane derivatives as Liver X Receptor agonists.

Phytosterols are stucturally correlated to the endogenous ligands of Liver X Receptor (LXR), a ligand-activated nuclear receptor that has emerged as an attractive drug target due to its ability to integrate metabolic and inflammatory signaling. Natural and semi-synthetic phytosterol derivatives characterized by the presence of side-chain oxygenated functions have shown to be able to modulate LXR activity. Here, we describe the efficient synthesis of four stigmastane derivatives, endowed with a hydroxyl group at C24 position, namely (24R)- and (24S)-stigmasta-5,28-diene-3ß,24-ols (also referred to as saringosterols, 10a and 10b) and (24R)- and (24S)-stigmasta-5-ene-3ß,24-ols (11a and 11b), starting from the readily available stigmasterol. Thanks to X-ray crystallography the absolute configuration of the newly created chiral centers was definitively assigned for all the four compounds. The subsequent luciferase assays with GAL-4 chimeric receptors evidenced the ability of the two 24(S)-epimers, 10b and 11b, to interact with LXRs, showing the same degree of affinity as (22R)-hydroxycholesterol (1). With regard to the isoform selectivity both the derivatives 10b and 11b showed a preference for LXRß, up to 4-fold in terms of efficacy for 11b. The gene expression profiling of (24S)-stigmasta-5,28-diene-3ß,24-ol (10a) and (24S)-stigmasta-5-ene-3ß,24-ol (11a) demonstrated the capability of both the compounds to induce the expression of four well-known LXR target genes, such as ABCA1, SREBP1c, FASN, and SCD1 in U937 monocytic cell line, thus supporting the hypothesis they were LXR positive modulators.

Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists.

A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXRα agonists, whereas 20, 22, and 25 showed good selectivity for the LXRß isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXRß, while it was virtually inactive at LXRα (EC50 = 14.51 µM). Interestingly, 13, 19, 20, and 25 showed to be LXR target gene-selective modulators, by strongly inducing the expression of ABCA1, while poorly or not activating the lipogenic genes SREBP1 and SCD1 or FASN, respectively.

New more polar symmetrical bipyridinic compounds: new strategy for the inhibition of choline kinase α1.

AIM: Research of the antitumor properties of biscationic compounds has received significant attention over the last few years. RESULTS: A novel family of 1,1'-([2,2'-bipyridine]-5,5'-diylbis(methylene))bis-substituted bromide (9a-k), containing two nitrogen atoms in the linker, considered as hypothetical hydrogen bond acceptors, were synthesized and evaluated as ChoK inhibitors and their antiproliferative activity against six cancer cell lines. CONCLUSION: The most promising compounds in this series are 1,1'-([2,2'-bipyridine]-5,5'-diylbis(methylene))bis(4-(methyl(phenyl)amino)-quinolinium bromide derivatives 9g-i (analogs to RSM932A), that significantly inhibit cancer cell growth at even submicromolar concentrations, especially against leukemia cells. Compounds 9g-i also inhibit the ChoKα1 with good or moderate values, as predicted by initial docking studies. In addition, the most active compound 9h remarkably induces apoptosis in two cell lines following the mitochondrial pathway.