- Largazole arrests cell cycle at g1 phase and triggers proteasomal degradation of E2F1 in lung cancer cells
-
Aberration in cell cycle has been shown to be a common occurrence in lung cancer, and cell cycle inhibitor represents an effective therapeutic strategy. In this study, we test the effects of a natural macrocyclic depsipeptide largazole on lung cancer cells and report that this compound potently inhibits the proliferation and clonogenic activity of lung cancer cells but not normal bronchial epithelial cells. Largazole arrests cell cycle at G1 phase with up-regulation of the expression of cyclin-dependent kinase inhibitor p21. Interestingly, largazole enhances the E2F1-HDAC1 binding affinity and induces a proteasomal degradation of E2F1, leading to suppression of E2F1 function in lung cancer but not normal bronchial epithelial cells. Because E2F1 is overexpressed in lung cancer tumor samples, these data indicate that largazole is an E2F1-targeting cell cycle inhibitor, which bears therapeutic potentials for this malignant neoplasm.
- Wu, Li-Chuan,Wen, Zhe-Sheng,Qiu, Ya-Tao,Chen, Xiao-Qin,Chen, Hao-Bin,Wei, Ming-Ming,Liu, Zi,Jiang, Sheng,Zhou, Guang-Biao
-
-
Read Online
- Total synthesis of largazole
-
The stereocontrolled total synthesis of largazole was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction, thiazoline-thiazole formation, and macrolactamization by use of the Mukaiyama reagent. Georg Thieme Verlag Stuttgart.
- Ren, Qi,Dai, Lu,Zhang, Hui,Tan, Wenfei,Xu, Zhengshuang,Ye, Tao
-
-
Read Online
- Concise total synthesis of largazole
-
The concise total synthesis of largazole was accomplished. The key step included the use of the Nagao thiazolidinethione auxiliary for the diastereoselective acetate aldol reaction and it acts as an acylating agent for the peptide formation.
- Xiao, Qiong,Wang, Li-Ping,Jiao, Xiao-Zhen,Liu, Xiao-Yu,Wu, Qian,Xie, Ping
-
-
Read Online
- A concise total synthesis of largazole, solution structure, and some preliminary structure activity relationships
-
(Chemical Equation Presented) A total synthesis of largazole that proceeds in 8 steps from commercial materials is reported, along with some structure-activity relationships. A combination of NMR studies and molecular modeling have also provided a preliminary picture of the conformation of largazole.
- Nasveschuk, Christopher G.,Ungermannova, Dana,Liu, Xuedong,Phillips, Andrew J.
-
-
Read Online
- Synthesis and biological activity of largazole and derivatives
-
A modular synthesis of the marine natural product largazole and related synthetic analogues is described. Largazole was prepared in 19% overall yield through a synthetic route with a longest linear sequence of nine steps. Activity tests showed the necessity of the thiobutenyl moiety for antiproliferative activity. (Chemical Equation Presented).
- Seiser, Tobias,Kamena, Faustin,Cramer, Nicolai
-
-
Read Online
- Total synthesis and molecular target of largazole, a histone deacetylase inhibitor
-
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.
- Ying, Yongcheng,Taori, Kanchan,Kim, Hyoungsu,Hong, Jiyong,Luesch, Hendrik
-
-
Read Online
- Total syntheses of the histone deacetylase inhibitors largazole and 2-epi-largazole: Application of N-Heterocyclic carbene mediated acylations in complex molecule synthesis
-
Details of the evolution of strategies toward convergent assembly of the histone deacetylase inhibiting natural product largazole exploiting γ,δ-unsaturated-α,β-epoxy-aldehydes and a thiazole-thiazoline containing ω-amino-acid are described. The initial N-heterocyclic carbene mediated redox amidation exploying these two types of building blocks representing largazole's structural domains of distinct biosynthetic origin directly afforded the seco-acid of largazole. This was accomplished without any protecting groups resident upon either thioester bearing epoxy-aldehyde or the tetrapeptide. However, the ineffective production of largazole via the final macrolactonization led to an alternative intramolecular esterification/macrolactamization strategy employing the established two building blocks. This provided largazole along with its C2-epimer via an unexpected inversion of the α-stereocenter at the valine residue. The biological evaluation demonstrated that both largazole and 2-epi-largazole led to dose-dependent increases of acetylation of histone H3, indicating their potencies as class I histone deacetylase selective inhibitiors. Enhanced p21 expression was also induced by largazole and its C2 epimer. In addition, 2-epi-largazole displayed more potent activity than largazole in cell viability assays against PC-3 and LNCaP prostate cancer cell lines.
- Wang, Bo,Huang, Po-Hsien,Chen, Ching-Shih,Forsyth, Craig J.
-
-
Read Online
- METHOD FOR PREPARING LARGAZOLE ANALOGS AND USES THEREOF
-
Analogs of largazole are described herein. Methods of treating cancer and blood disorders using largazole and largazole analogs and pharmaceutical compositions comprising the same are additionally described herein. Methods for preparing largazole analogs are likewise described.
- -
-
-
- PROCESS FOR THE PREPARATION OF CYCLIC DEPSIPEPTIDES
-
Processes for preparing compounds of Formula (1) and Formula (2) are described, wherein X, Y, Z, R1-R7, L and n are defined herein. Intermediates useful in the preparation of the compounds of Formula (1) and Formula (2) are also described.
- -
-
-
- Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability
-
The total synthesis of largazole and four analogues is reported. All analogues were nanomolar HDAC inhibitors. The antiproliferative activity is driven by lipophilicity and cell permeability. In murine liver homogenates, largazole is rapidly metabolized (half-life ≤5 min) to the thiol which has a half-life of 51 min.
- Benelkebir, Hanae,Marie, Sabrina,Hayden, Annette L.,Lyle, Jason,Loadman, Paul M.,Crabb, Simon J.,Packham, Graham,Ganesan
-
p. 3650 - 3658
(2011/08/03)
-
- Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: Synthesis and biological evaluation
-
The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn2+ were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin.
- Bhansali, Pravin,Hanigan, Christin L.,Casero, Robert A.,Tillekeratne, L. M. Viranga
-
p. 7453 - 7463
(2012/01/03)
-
- Total synthesis and biological evaluation of largazole and derivatives with promising selectivity for cancers cells
-
Chemical Equation Presented The efficient total synthesis of the natural substance largazole is described. Using this strategy, a small library of largazole analogs was developed. Structure-activity relationship studies suggested that the geometry of the alkene in the side chain is critical. While the largazole's analogues with frans-alkene are potent for the antiproliferative effect, those with cis-alkene are completely Inactive. Most Importantly, replacement of valine with tyrosine in largazole increased selectivity toward human cancer cells over human normal cells more than 100-fold.
- Zeng, Xin,Yin, Biaolin,Hu, Zheng,Liao, Chenzhong,Liu, Jinglei,Li, Shang,Li, Zheng,Nicklaus, Marc C.,Zhou, Guangbiao,Jiang, Sheng
-
supporting information; experimental part
p. 1368 - 1371
(2010/06/15)
-
- Method for preparing largazole analogs and uses thereof
-
Analogs of largazole are described herein. Methods of treating cancer and blood disorders using largazole and largazole analogs and pharmaceutical compositions comprising the same are additionally described herein. Methods for preparing largazole analogs are likewise described.
- -
-
Page/Page column 30
(2010/03/02)
-
- Synthesis and biological characterization of the histone deacetylase inhibitor largazole and C7- modified analogues
-
Largazole 4a and analogues with modifications at the C7 position, as well as 2,4′-bithiazole 5a, have been synthesized using an acyclic cross-metathesis of the corresponding depsipeptide structures assembled by N-C6(O) or C15(O)-N lactam formation. Similar to the parent system 4a, the series of largazole depsipeptides 4b-d, but not 2,4′-bithiazole 5a, showed a marked inhibition of recombinant HDAC1 and selectivity over HDAC4, as well as strong pro-apoptotic effects on the NB4 leukemia cell line, but they failed to induce differentiation to mature granulocytes. Functional assays of the analogues correlated with the in vitro activities, as shown by increased H3 and α-tubulin acetylation levels and p21WAF1/CIP1 up-regulation in NB4 cells. The activity of the natural product HDACi largazole 4a is not significantly altered by the presence of groups of different size (H, Et, Ph) at C7 on the dihydrothiazole ring.
- Souto, José A.,Vaz, Esther,Lepore, Ilaria,P?ppler, Ann-Christin,Franci, Gianluigi,álvarez, Rosana,Altucci, Lucia,De Lera, ángel R.
-
experimental part
p. 4654 - 4667
(2010/10/02)
-
- Total synthesis of largazole-devolution of a novel synthetic strategy
-
The cyanobacterial isolate largazole embodies a compelling combination of a relatively simple, yet unique cyclic depsipeptide structure with remarkable levels of selective cytotoxicity against cancer cell lines versus nontransformed cells. The unique stru
- Wang, Bo,Forsyth, Craig J.
-
experimental part
p. 2873 - 2880
(2010/02/28)
-
- METHODS OF PREPARATION OF MACROCYCLIC COMPOUNDS
-
The instant invention describes methods for producing macrocyclic compounds having antiproliferation activity, and useful in methods of treating disorders such as cancer, tumors and cell proliferation related disorders.
- -
-
-
- Enantioselective total synthesis of (+)-largazole, a potent inhibitor of histone deacetylase
-
(Chemical Equation Presented) An enantioselective total synthesis of the cytotoxic natural product (+)-largazole (1) is described. It is a potent histone deacetylase inhibitor. Our synthesis is convergent and involves the assembly of thiazole 3-derived carboxylic acid with amino ester 4 followed by cycloamidation of the corresponding amino acid. The synthesis features an efficient cross-metathesis, an enzymatic kinetic resolution of a β-hydroxy ester, a selective removal of a Boc-protecting group, a HATU/HOAt-promoted cycloamidation reaction, and synthetic manipulations to a sensitive thioester functional group.
- Ghosh, Arun K.,Kulkarni, Sarang
-
supporting information; experimental part
p. 3907 - 3909
(2009/07/01)
-
- Total synthesis and biological mode of action of largazole: A potent class I histone deacetylase inhibitor
-
The efficient total synthesis of the recently described natural substance largazole (1) and its active metabolite largazole thiol (2) is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-drug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite 2, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and 2 have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances.
- Bowers, Albert,West, Nathan,Taunton, Jack,Schreiber, Stuart L.,Bradner, James E.,Williams, Robert M.
-
supporting information; experimental part
p. 11219 - 11222
(2009/02/05)
-
