Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability

Benelkebir, Hanae; Marie, Sabrina; Hayden, Annette; Lyle, Jason; Loadman, Paul M.; Crabb, Simon J.; Packham, Graham; Ganesan, A.

doi:10.1016/j.bmc.2011.02.024

Cited by 53 publications

(79 citation statements)

References 51 publications

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“…5 Additionally, largazole ( 1 ) has shown a variety of other biological activities, such as the in vitro and in vivo induction of osteoblast differentiation biomarkers, 6 the sensitization of EBV+ tumor cells to the anti-herpes drug ganciclovir (GCV), 7 the inhibition of ubiquitin activating enzyme, E1, 8 and the in vitro and in vivo induction of apoptosis in hepatic stellate cells (HSC) in liver fibrosis models. 9 These promising biological activities led to 11 total syntheses 2,3,10–18 and a wide variety of analogues of largazole ( 1 ). 2–4,10,12,13,16,18–27 …”

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confidence: 99%

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Evaluation of class I HDAC isoform selectivity of largazole analogues

Kim

Park

Salvador

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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Largazole is a potent class I selective histone deacetylase (HDAC) inhibitor. The majority of largazole analogues to date have modified the thiazole-thiazoline and the warhead moiety. In order to elucidate class I-specific structure–activity relationships, a series of analogues with modifications in the valine or the linker region were prepared and evaluated for their class I isoform selectivity. The inhibition profile showed that the C2 position of largazole has an optimal steric requirement for efficient HDAC inhibition and that substitution of the trans-alkene in the linker with an aromatic group results in complete loss of activity. This data will aid the design of class I isoform selective HDAC inhibitors.

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confidence: 99%

“…9 These promising biological activities led to 11 total syntheses 2,3,10–18 and a wide variety of analogues of largazole ( 1 ). 2–4,10,12,13,16,18–27 …”

mentioning

confidence: 99%

Evaluation of class I HDAC isoform selectivity of largazole analogues

Kim

Park

Salvador

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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“…Cleavage of the octanoyl ester in largazole by liver microsomes was found to be very rapid (t 1/2 o5 minutes), suggesting that other esters should be preferred for in vivo applications. 80 Among the depsipeptide analogues that illustrate the above SAR trends are compounds 49-51. In compound 49, reported by Ganesan, the FK228 scaffold has been simplified without loss of activity (HeLa HDACs IC 50 5 nM) by (i) replacing the dehydrobutyrine residue with a chemically inert valine and (ii) replacing a second valine residue by glycine.…”

Section: The Depsipeptide Natural Products With a Thiol Warheadmentioning

confidence: 98%

“…78 Meanwhile, Ganesan's analogue 51 shows that replacement of the thiazoline ring in largazole by a simpler achiral a-aminoisobutyric acid residue is tolerated (HeLa HDACs IC 50 1 nM). 80 A different approach was taken by Ahn, who redesigned the spacer present in the depsipeptide natural products by employing an isosteric thiol. Instead of the b-hydroxy acid unit that needs to be obtained by total synthesis (Scheme 4.4), Ahn linked differentially protected aspartic acid to cysteamine …”

Section: The Depsipeptide Natural Products With a Thiol Warheadmentioning

confidence: 99%

Macrocyclic Inhibitors of Zinc-dependent Histone Deacetylases (HDACs)

Ganesan

2014

Macrocycles in Drug Discovery

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The modulation of epigenetic targets has recently become an attractive strategy for drug discovery. Among these, it is the inhibition of histone deacetylases (HDACs) that has received the most attention. Numerous HDAC inhibitors have advanced to clinical trials and two have received FDA approval as anticancer agents. This chapter reviews natural and synthetic inhibitors of zinc-dependent HDACs that contain a macrocyclic scaffold including the trapoxin and apicidin cyclic tetrapeptides, the FK228 depsipeptide family, the azumamides and fully synthetic macrocycles.

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“…Largazole (Fig. 4) is a depsipeptide, initially isolated by the Floridian Symploca spp [49] and now produced by synthesis [50,51] and is a potent antiproliferative agent with selectivity for cancer cells over non transformed cells [49] acting on HDAC [49]. Largazole is a pro-drug that after metabolic activation (thioester hydrolysis or disulfide reduction, respectively) as Largazole thiol chelates Zn 2+ in the active site of class I HDAC [51].…”

Section: Symploca Derivativesmentioning

confidence: 99%