Total Synthesis and Molecular Target of Largazole, a Histone Deacetylase Inhibitor

Abstract

Full details of the concise and convergent synthesis (eight steps, 19% overall yield), its extension to the preparation of a series of key analogues, and the molecular target and pharmacophore of largazole are described. Central to the synthesis of largazole is a macrocyclization reaction for formation of the strained 16-membered depsipeptide core followed by an olefin cross-metathesis reaction for installation of the thioester. The biological evaluation of largazole and its key analogues, including an acetyl analogue, a thiol analogue, and a hydroxyl analogue, suggested that histone deacetylases (HDACs) are molecular targets of largazole and largazole is a class I HDAC inhibitor. In addition, structure-activity relationship (SAR) studies revealed that the thiol group is the pharmacophore of the natural product. Largazole's HDAC inhibitory activity correlates with its antiproliferative activity.

Anticolon Cancer Activity of Largazole, a Marine-Derived Tunable Histone Deacetylase Inhibitor

“…We devised an efficient total synthesis that can provide gram-scale quantities of largazole for rigorous biological evaluation (Ying et al, 2008b). We already established the mode of action of largazole.…”

“…Largazole is a prodrug and liberates largazole thiol that can chelate Zn 2ϩ in the active site of class I HDACs ( Fig. 1) (Ying et al, 2008b). Subsequently, we have initiated structure-activity relationship (SAR) studies (Ying et al, 2008a).…”

Apratoxin A Reversibly Inhibits the Secretory Pathway by Preventing Cotranslational Translocation

“…Among those, marine cyanobacteria have emerged as major producers of bioactive secondary metabolites (Gerwick et al, 2001). For example, we recently described some of the most potent natural elastase inhibitors (Taori et al, 2007) and one of the most potent class I histone deacetylase inhibitors Ying et al, 2008) known, isolated from Floridian marine cyanobacteria. Whereas structure-based approaches led to their target identification, for other natural products the target is less obvious, necessitating extensive mechanistic studies on the cellular and molecular level to rationalize the biological activity.…”

Synthesis of Macrocyclic Lactams and Lactones Containing Sulfur and Nitrogen

“…и проявил свойства ингибитора деацетилазы гистонов (HDAC). [49] В литературе приведены многочисленные методики синтезы ларгазола 92, [50][51][52][53][54][55][56][57][58] отличающиеся методами создания тиазол-тиазолинового фрагмента, стадиями макроциклизации и введения боковой цепи. Один из них [58] базировался на макролактамизации ациклического предшественника 93, который, в свою очередь, был получен из двух синтонов 94 и 95 (Схема 26).…”