A semisynthetic strategy to obtain monophosphoryl lipid A derivatives equipped with clickable (azide, alkyne, double bond, or thiol precursor) moieties, starting from the native lipid A isolated from Escherichia coli, is presented. These lipid A derivatives can be conjugated with other interesting biomolecules, such as tumor-associated carbohydrate antigens (TACAs). In this way, the immunostimulant activity of monophosphoryl lipid A can significantly improve the immunogenicity of TACAs, thus opening access to potential self-adjuvant anticancer vaccine candidates. A monophosphoryl lipid A−Thomson-Friedenreich (TF) antigen conjugate was obtained to demonstrate the feasibility of this methodology, which stands as a valuable, rapid, and scalable alternative to the highly complex approaches of total synthesis recently reported to the same aim. A preliminary evaluation of the immunological activity of this conjugate as well as of other semisynthetic lipid A derivatives was also reported.
Development of Clickable Monophosphoryl Lipid A Derivatives toward Semisynthetic Conjugates with Tumor-Associated Carbohydrate Antigens / Ziaco, Marcello; Górska, Sabina; Traboni, Serena; Razim, Agnieszka; Casillo, Angela; Iadonisi, Alfonso; Gamian, Andrzej; Corsaro, MARIA MICHELA; Bedini, Emiliano. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 60:(2017), pp. 9757-9768. [10.1021/acs.jmedchem.7b01234]