title: Synthesis and biological evaluation of non-glucose glycoconjugatedN-hydroyxindole class LDH inhibitors as anticancer agents.
abstract: Inhibitors of human lactate dehydrogenase A (LDH-A) are promising therapeutic agents against cancer. The development of LDH-A inhibitors that possess cellular activities has so far proved to be particularly challenging, since the enzyme's active site is narrow and highly polar. In the recent past, we were able to develop a glucose-conjugatedN-hydroxyindole-based LDH-A inhibitor designed to exploit the sugar avidity expressed by cancer cells (the Warburg effect). Herein we describe a structural modulation of the sugar moiety of this class of inhibitors, with the insertion of α-D-mannose, β-D-gulose, or β-N-acetyl-D-glucosamine portions in their structures. Their stereospecific chemical synthesis, which involves a substrate-dependent stereospecific glycosylation step, and their biological activity in reducing lactate production and proliferation in cancer cells are reported. Interestingly, the α-D-mannose conjugate displayed the best properties in the cellular assays, demonstrating an efficient antiglycolytic and antiproliferative activity in cancer cells.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Di Bussolo
authors.affiliation: Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: Emilia C
authors.initials: EC
authors.lastname: Calvaresi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Granchi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Del Bino
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Ileana
authors.initials: I
authors.lastname: Frau
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Maria Chiara Dasso
authors.initials: MC
authors.lastname: Lang
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.affiliation: Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo