Synthesis and Antiproliferative Activity of Nitric Oxide-Donor Largazole Prodrugs

Matteo Borgini; Claudio Zamperini; Federica Poggialini; Luca Ferrante; Vincenzo Summa; Maurizio Botta; Romano Di Fabio

doi:10.1021/acsmedchemlett.9b00643

Synthesis and Antiproliferative Activity of Nitric Oxide-Donor Largazole Prodrugs

ACS Med Chem Lett. 2020 Feb 7;11(5):846-851. doi: 10.1021/acsmedchemlett.9b00643. eCollection 2020 May 14.

Authors

Matteo Borgini¹, Claudio Zamperini^{1

2}, Federica Poggialini¹, Luca Ferrante³, Vincenzo Summa⁴, Maurizio Botta^{1

2

5}, Romano Di Fabio^{3

4}

Affiliations

¹ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
² Lead Discovery Siena S.r.l., Castelnuovo Berardenga, 53019 Siena, Italy.
³ Promidis, Via Olgettina 60, 20132 Milano, Italy.
⁴ IRBM Science Park, Via Pontina Km 30.600, 00070 Pomezia, Italy.
⁵ Biotechnology College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, Pennsylvania 19122, United States.

Abstract

The marine natural product Largazole is the most potent Class I HDAC inhibitor identified to date. Since its discovery, many research groups have been attracted by the structural complexity and the peculiar anticancer activity, due to its capability to discriminate between tumor cells and normal cells. Herein, we discuss the synthesis and the in vitro biological profile of hybrid analogues of Largazole, as dual HDAC inhibitor and nitric oxide (NO) donors, potentially useful as anticancer agents. In particular, the metabolic stability of the modified thioester moiety of Largazole, bearing the NO-donor function/s, the in vitro release of NO, and the antiproliferative activity in tumor cell lines are presented.