In search of constrained FTY720 and phytosphingosine analogs as dual acting anticancer agents targeting metabolic and epigenetic pathways

Abstract

A series of compounds containing pyrrolidine and pyrrolizidine cores with appended hydrophobic substituents were prepared as constrained analogs of FTY720 and phytosphingosine. The effect of these compounds on the viability of cancer cells, on downregulation of the nutrient transport systems, and on their ability to cause vacuolation was studied. An attempt to inhibit HDACs with some phosphate esters of our analogs was thwarted by our failure to reproduce the reported inhibitory action of FTY720-phosphate.

2-Oxa-5-azabicyclo[2.2.1]heptane as a Platform for Functional Diversity: Synthesis of Backbone-Constrained γ-Amino Acid Analogues

“…We used the readily available Weinreb amide 1 to obtain a series of ketones 2a – k , which were reacted with the Li enolate prepared from ethyl acetate to afford the corresponding tertiary alcohols (Table ). Treatment with tosic anhydride in pyridine resulted in the selective tosylation of the secondary alcohol.…”

“…In general, good yields were obtained when the Weinreb amide 1 was subjected to a series of organomagnesium nucleophiles (Table , 2a – k ) except for the addition of iso -butyl MgBr to give 2i , which was attributed to steric hindrance (Table , entry 9). Interestingly, an excess of the R 1 MgX reagent was needed to reach full conversion in all cases, which is consistent with previous observations of 1 . Excellent stereochemical control was conserved in the additions of the enolate anion to benzylic ketones 2a – d (Table , entries 1–4).…”

Identification of Compounds with Potential Therapeutic Uses from Sweet Pepper (Capsicum annuum L.) Fruits and Their Modulation by Nitric Oxide (NO)

“…Phytosphingosine suppresses the ERK1/2 pathway and activates the p38 MAPK pathway with concomitant induction of the translocation of Bax from the cytosol to mitochondria, all of them leading to an intracellular signaling cascade that ends with caspase-dependent cellular apoptosis [ 99 ]. In this regard, phytosphingosine was investigated to function as an anticancer agent whose targets include nutrient transport systems and cell vacuolation [ 100 ]. Additionally, phytosphingosine stimulates the human keratinocyte differentiation and, in hairless mouse skin, it inhibits the inflammatory epidermal hyperplasia induced by 12-O-tetradeconoylphorbol-13-acetate (TPA) [ 101 ].…”

Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A

“…It was evident that appending tricyclic heterocycles such as phenoxazine and phenothiazine as hybrid structures was not beneficial to the intrinsic activity of the lead compound 3. In a previous study involving modifications of the octyl aryl appendage, 25 we realized the importance of maintaining its hydrophobic character, since the introduction of polar groups resulted in substantial loss to cytotoxicity. However, it now appears that appending etherlinked heterocyclic units at the 2-hydroxymethyl group as in compounds 6-7 in the current series, resulted in only a 2-4 fold loss of cytoxicity and modest down-regulation at 10 μM compared to the lead compound 3.…”