Largazole Transformed Mammary Epithelial Cells (MDAMB-231) GI 50 : 7.7nM LC 50 : 117nM Nontransformed Mammary Epithelial Cells (NMuMG) GI 50 : 122nM LC 50 : 272nM Fibroblastic osteosarcoma cells (U2OS) GI 50 : 55nM LC 50 : 94nM Nontransformed Fibroblast (NIH3T3) GI 50 : 480nM LC 50 : >8µM Colon Cancer Line (HT29) GI 50 : 12nM LC 50 : 22nM Neuroblastoma (IMR-32) GI 50 : 16nM LC 50 : 22nM Taori, K.; Paul, V. J.; Luesch, H. Journal of the American Chemical Society 2008, 130, 1806 S N H O O O S N S N NH O O
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Bowers, A.; West, N.; Taunton, J.; Schreiber, S. L.; Bradner, J. E.; Williams, R. M. Journal of the American Chemical Society 2008, 130, 11219.
• Antiproliferative effects of largazole (red) and largazole thiol (blue)
• human malignant melanoma cell lines• Largazole is more potent in antiproliferative effect
than largazole thiolBowers, A.; West, N.; Taunton, J.; Schreiber, S. L.; Bradner, J. E.; Williams, R. M. Journal of the American Chemical Society 2008, 130, 11219.
• Cytomegalovirus promoter• Induction of promoter by largazole analogues• Measured Phosphatase units to calculate ED50
values
Numajiri, Y.; Takahashi, T.; Takagi, M.; Shin-ya, K.; Doi, T. Synlett 2008, 2008, 2483
Isostere AnaloguesHDAC 1 HDAC 2 HDAC 3 HDAC 6
Largazole 40 42 96 >1000
Free Thiol 0.1 0.8 1 40
>3000 >3000 >3000 >3000
0.9 4 4 1500
S NH
O NH OSN
S
NNH
O
O
HS NH
NH OSN
S
NNH
O
O
-Purified Human HDAC’s IC50 values in nM-Probably due to changed conformational space on nitrogen vs. oxygen
Bowers, A. A.; Greshock, T. J.; West, N.; Estiu, G.; Schreiber, S. L.; Wiest, O.; Williams, R. M.; Bradner, J. E. Journal of the American Chemical Society 2009, 131, 2900
IC50 of Human HDACs of Other Analogues
HDAC1 (µM) HDAC2 (µM) HDAC3 (µM) HDAC6 (µM)
Largazole Thiol 0.0012 0.0035 0.0034 0.049
Enantiomer 1.2 3.1 1.9 2.2
C-2 Epimer 0.030 0.082 0.084 0.68
0.11 0.80 0.58 13
>30 >30 >30 >30C7H15 S N
H
O O OSN
S
NN
O
O
NH
O OSN
S
NNH
O
O
CO2H
Bowers, A. A.; West, N.; Newkirk, T. L.; Troutman-Youngman, A. E.; Schreiber, S. L.; Wiest, O.; Bradner, J. E.; Williams, R. M. Organic Letters 2009, 11, 1301
• Pyridine substitution of thiazole resulted in increased potency
• Methyl group in C-7 position is not important• Linker analogues did not result in increased
potency• Enantiomer potency decreased by 3 orders of
magnitude
• Also synthesized but not tested
NH
O OSN
S
NNH
O
O
HS
O
NH
O OSN
S
NNH
O
O
HS
O
Bowers, A. A.; West, N.; Newkirk, T. L.; Troutman-Youngman, A. E.; Schreiber, S. L.; Wiest, O.; Bradner, J. E.; Williams, R. M. Organic Letters 2009, 11, 1301
C-7 demethylationHDAC1 HDAC2 HDAC3 HDAC6 HCT-116
Largazole 0.0137 0.190 0.245 11.5 0.025±0.004
2.0 18.5 16.8 14.7 24.1±3.0
NA NA NA NA >100
Macrocycle dimer with one octanoyl linker
NA 51.8 22.6 NA 26.8±3.7
S NH
O O OSN
S
NNH
O
O
S NH
O O OSN
S
NNH
O
O
-Purified Human HDAC’s. IC50 Values in µM-C-7 demethylation decreases potency-C17 stereochemistry is crucial-Macrocycle dimer was surprisingly active in HDAC 2 and 3 but not 1
-Purified Recombinant HDAC’s-Size of substituent on C-7 position does not affect activity
Souto, J. A.; Vaz, E.; Lepore, I.; Poppler, A.-C.; Franci, G.; Alvarez, R.; Altucci, L.; de Lera, A. n. R. Journal of Medicinal Chemistry 2010, 53, 4654
HDAC inhibition (nM) MCF-7 inhibition (nM)
Largazole 572±29 5±1
Free Thiol 0.043±0.026 277±130
17.2±2.3 377±62
0.17±0.05 2458±1135
3.15±0.35 >10000
0.99±0.07 5902±1698
HS NH
O OSN
S
NNH
O
O
HS NH
O OSN
S
NNH
O
O
HS NH
O OSN
NH
O
O NH O
HS NH
O OSN
S
NNH
O
O
Ph
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.; M
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.; Ly
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• Valine, glycine, and thiazoline groups could be replaced with slight decrease in activity
• Cell growth inhibition does not correlate necessarily with HDAC inhibition
• Half life of compounds is a concern• No specification on what HDAC was used
Benelkebir, H.; Marie, S.; Hayden, A. L.; Lyle, J.; Loadman, P. M.; Crabb, S. J.; Packham, G.; Ganesan, A. Bioorganic & Medicinal Chemistry, In Press, Corrected Proof
Liu, Y.; Salvador, L. A.; Byeon, S.; Ying, Y.; Kwan, J. C.; Law, B. K.; Hong, J.; Luesch, H. Journal of Pharmacology and Experimental Therapeutics 2010, 335, 351.
S NH
O OSN
S
NNH
O
O
N
S NH
O OSN
S
NNH
O
O
S
S NH
O OSN
S
NNH
O
O
OH
27 28 29
Bhansali, P.; Hanigan, C. L.; Casero, R. A.; Tillekeratne, L. M. V. Journal of Medicinal Chemistry 2011, 54, 7453.