Sunday, October 11, 2015

New Cyclopentane-Based Sialyltranferase Inhibitors as Lead Compounds for the Chemotherapeutic Treatment of Cancer

            Sialic acid-containing glycoconjugate antigens play a critical role in a number of physiological and pathological biochemical processes, including cell-cell adhesion, immune defense and, importantly, tumor cell metastasis. Sialyltransferase enzymes catalyze the transfer of sialic acids to terminal non-reducing positions on growing oligosaccharide chains of glycoconjugates. Sialyltransferases of all origins and subtypes share the same donor substrate, cytidine monophosphate N-acetylneuraminic acid (CMP-Neu5Ac). The enzyme-catalyzed transfer reaction is thought to proceed via an SN1-like mechanism (outlined below) wherein partial dissociation of the cytosine monophosphate leads to formation of a trigonal planar oxocarbenium species in the transition state. Overexpression these enzymes and the consequent overpresentation of sialylated antigens on cell surfaces are correlated with poor prognosis in several different types of carcinomas. As such, the discovery of cell-permeable inhibitors of sialyltransferase is considered a promising strategy for antitumor drug development.
            Soyasaponin I is a glycosylated pentacyclic triterpenoid natural product derived from soybean that displays significant inhibition (Ki = 210 nM) of a particular sialyltransferase subtype. Related derivatives of the bile acid steroid lithocholic acid were later developed as potent inhibitors of a sialyltransferase and one of those (Lith-O-Asp, structure shown below) could effectively attenuate the total sialylation on cancer cell surfaces and suppress tumor cell metastasis in in vivo animal models of cancer.
            However, the most potent sialyltransferase inhibitors developed to date are structures that mimic the aforementioned three-dimensional structure of the transition state of the enzymatic process (for a classic example of transition state analogue design, see here). A potent transition-state analogue related to the CMP-Neu5Ac glycosyl donor was first described by Richard Schmidt’s group in 2002. More recently, Xin-Shan Ye’s laboratory in Beijing, China has reported a series of highly substituted cyclopentane-containing compounds (highlighted example shown below) that were designed based on similar principles of enzyme-binding. I’ve advocated elsewhere that the cyclopentane ring is an excellent scaffold for drug discovery. Ye’s new cyclopentanoid phosponates, whose overall conformation (likely an interconverting half-chair and envelope) effectively mimics the somewhat planar character of the CMP-Neu5Ac-derived oxocarbenium ion in the enzyme transition state, provide additional support for this arguably underutilized MedChem concept. The most potent cyclopentane derivative was synthesized by a 20-step sequence of reactions and displays outstanding inhibitory activity against recombinant human ST6Gal-I. Detailed structure-activity relationships across the series are also reported. This study further illustrates the utility of the cyclopentane motif as a modular scaffold for medicinal chemistry development programs.


  1. In the first scheme you depicted a diastereomer of the furan ring, when going from the first structure to the second. Is this supposed to happen?

  2. Thank you for pointing that out! That is NOT supposed to be furan diastereomer. I think that when I did the 'object: flip horizontal' function in ChemDraw, the software did not flip the relative stereochemistry. I will get it fixed up soon. Thanks again!

  3. Edit: Several relative stereochemistry mistakes in the cytidine monophosphate-containing structures have been corrected. Thanks to a reader for pointing these out.