Highly Substituted Cyclopentane–CMP Conjugates as Potent Sialyltransferase Inhibitors

Sialylconjugates on cell surfaces
are involved in many biological
events such as cellular recognition, signal transduction, and immune
response. It has been reported that aberrant sialylation at the nonreducing
end of glycoconjugates and overexpression of sialyltransferases (STs)
in cells are correlated with the malignance, invasion, and metastasis
of tumors. Therefore, inhibitors of STs would provide valuable leads
for the discovery of antitumor drugs. On the basis of the transition
state of the enzyme-catalyzed sialylation reaction, we proposed that
the cyclopentane skeleton in its two puckered conformations might
mimic the planar structure of the donor (CMP-Neu5Ac) in the transition
state. A series of cyclopentane-containing compounds were designed
and synthesized by coupling different cyclopentane α-hydroxyphosphonates
with cytidine phosphoramidite. Their inhibitory activities against
recombinant human ST6Gal-I were assayed, and a potent inhibitor 48l with a Ki of 0.028 ± 0.006 μM was identified. The results
show that the cyclopentanoid-type compounds could become a new type
of sialyltransferase inhibitors as biological probes or drug leads.