Design, Synthesis, and Antileukemic Activity of Stereochemically Defined Constrained Analogues of FTY720 (Gilenya)

Abstract

FTY720 functions as an immunosuppressant due to its effect on sphingosine-1-phosphate receptors. At doses well above those needed for immunosuppression, FTY720 also has anti-neoplastic actions. Our published work suggests that at least some of FTY720’s anti-cancer activity is independent of its effects on S1P receptors and due instead to its ability to induce nutrient transporter down-regulation. Compounds that trigger nutrient transporter loss but lack FTY720’s S1P receptor-related, dose-limiting toxicity have the potential to be effective and selective anti-tumor agents. In this study, a series of enantiomerically pure and stereochemically diverse O-substituted benzyl ethers of pyrrolidines was generated and tested for the ability to kill human leukemia cells. The stereochemistry of the hydroxymethyl was found to be a key determinant of compound activity. Moreover, phosphorylation of this group was not required for anti-leukemic activity.

Azacyclic FTY720 Analogues That Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in Vivo

“…This caused a dramatic loss of activity, suggesting that electrostatic interactions with the target may be critical for compound activity as lactams should be equally stable (Figure 3 and Table 1). These findings also suggest that, in contrast to our earlier report of the O -arylmethyl pyrrolidine analogues 23 of FTY720, stereochemistry in this series of C -aryl analogues is not important for interaction with the anticancer target. We therefore did not prepare the remaining diastereoisomers and enantiomers in this series.…”

“…23 We also demonstrated a stereochemical dependence, since the enantiomeric (2 S ,4 R )-enantiomer was six times less active. However, this series of constrained FTY720 analogues exhibited much lower potency against other types of tumor cell lines (vide infra).…”

“…Compounds that were active in prostate cancer cell lines also killed BCR-Abl-positive leukemia cells with similar potency to FTY720 (Table 2). However, compound 21 23 (Figure 5), which is a more potent analogue than an FTY720 in SupB15 cells, is also more potent than compounds in the C -aryl series in this cell line. It is of interest that compound 5 was more active than compound 21 or 22 in prostate cancer cell lines (Table 1) suggesting that the C -aryl series is better suited to use against solid tumors while the O -benzyl 21 is the most potent against leukemia.…”

“…We therefore returned to the original C -aryl constrained pyrrolidine analogue series 18 since it displayed S1P isoform selectivity. We prepared compounds 1–4 which represent four out of the eight possible diastereomers and enantiomers 24 as initial probes to evaluate their anticancer activity and to assess possible stereo-chemical preferences as in the O -arylmethyl pyrrolidine series 23 relative to FTY720 in PC3 and DU145 cancer cell lines. Although not as potent as FTY720, compounds 1 and 2 limited cell proliferation in a Cell Titer Glo assay that measures ATP content per well as an indicator of live cell mass (Table 1).…”

An Easy Access to the Synthesis of Sugar‐Based N‐Methyl‐Pyrrolidine via [3 + 2] Cycloaddition Methodology

“…A wide variety of dipoles and dipolarophiles are used to obtain various heterocyclic skeleton. Among the various dipoles used, azomethine ylide is extensively used for the construction of various biologically active compounds . Infact, Rizzi has observed the formation of azomethine ylide by the thermal decarboxylation of α‐amino acids whose rate was accelerated in the presence of the carbonyl compounds .…”