Structure and Activity of Largazole, a Potent Antiproliferative Agent from the Floridian Marine Cyanobacterium Symploca sp.

Abstract

The identification of new pharmacophores is of paramount biomedical importance and natural products have recently been regaining attention for this endeavor. 1 This renaissance is closely tied to the successful exploitation of the marine environment which harbors unmatched biodiversity that is presumably concomitant with chemical diversity. 2 In particular, marine cyanobacteria are prolific producers of bioactive secondary metabolites, 3 many of which are modified peptides or peptide-polyketide hybrids with promising antitumor activities, such as dolastatin 10, 4 curacin A, 5 and apratoxin A. 6 As a result of our ongoing investigations to identify new drug leads from cyanobacteria in Florida, we report here the structure determination and preliminary biological characterization of a marine cyanobacterial metabolite with novel chemical scaffold and nanomolar antiproliferative activity from a cyanobacterium of the genus Symploca. Symploca species have scarcely been investigated compared to the more prevalent Lyngbya spp., yet a Palauan Symploca sp. previously yielded the clinical trial compound dolastatin 10, 4 prompting us to target this genus.A sample of Symploca sp. was collected from Key Largo, Florida Keys, and extracted with organic solvents. The resulting cytotoxic crude extract was subjected to bioassay-guided fractionation by solvent partition, silica gel chromatography, and reversed-phase HPLC to yield largazole (1) as a colorless, amorphous solid {[R] 20 D +22 (c 0.1, MeOH)}.

Thiazoles in Peptides and Peptidomimetics

“…[ [82][83][84][85][86] Largazole features a macrocycle containing a thiazole fused to a 4-methylthiazoline. An octanoyl moiety is attached to the macrocycle by way of a thioester to the 3-hydroxy-7-mercaptohept-4-enoic acid subunit and serves to produce a pro-drug, which on thioester hydrolysis releases the thiolate that inhibits potently histone deacetylase enzymes.…”

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).…”

The Hendrickson ‘POP’ reagent and analogues thereof: synthesis, structure, and application in organic synthesis

“…collected in the Florida Keys (Scheme 16). 64 The structure features an α-methylcysteine-derived thiazoline connected to a thiazole and the presence of a caprylic acid-derived thioester. Largazole has shown potent antiproliferative activity against a number of cancer cell-lines including MDA-MB-231 mammary cells (GI 50 7.7 nM), and IMR-32 neuroblastoma cells (GI 50 16 nM).…”