14 research outputs found
Largazole and Analogues with Modified Metal-Binding Motifs Targeting Histone Deacetylases: Synthesis and Biological Evaluation
The histone deacetylase inhibitor largazole <b>1</b> was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using <i>tert</i>-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 Zn<sup>2+</sup> were synthesized, and their biological activities were evaluated. They were less potent than largazole <b>1</b> in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole <b>1</b> and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin
Polymeric Prodrugs Targeting Polyamine Metabolism Inhibit Zika Virus Replication
The
Zika virus (ZIKV) is primarily transmitted via an infected
mosquito bite, during sexual intercourse, or in utero mother to child
transmission. When a fetus is infected, both neurological malformations
and deficits in brain development are frequently manifested. As such,
there is a need for vaccines or drugs that may be used to cure ZIKV
infections. Metabolic pathways play a crucial role in cell differentiation
and development. More importantly, polyamines play a key role in replication
and translation of several RNA viruses, including ZIKV, Dengue virus,
and Chikungunya virus. Here, we present polyamine analogues (BENSpm
and PG11047) and their corresponding polymer prodrug derivatives for
inhibiting ZIKV infection by intersecting with polyamine catabolism
pathways. We tested the compounds against ZIKV African (MR766) and
Asian (PRVABC59) strains in human kidney epithelial (Vero) and glioblastoma
derived (SNB-19) cell lines. Our results demonstrate potent inhibition
of ZIKV viral replication in both cell lines tested. This antiviral
effect was mediated by the upregulation of two polyamine catabolic
enzymes, spermine oxidase, and spermidine (SMOX)/spermine N1-acetyltransferase
(SAT1) as apparent reduction of the ZIKV infection following heterologous
expression of SMOX and SAT1. On the basis of these observations, we
infer potential use of these polyamine analogues to treat ZIKV infections
Low Molecular Weight Amidoximes that Act as Potent Inhibitors of Lysine-Specific Demethylase 1
The recently discovered enzyme lysine-specific demethylase
1 (LSD1)
plays an important role in the epigenetic control of gene expression,
and aberrant gene silencing secondary to LSD1 dysregulation is thought
to contribute to the development of cancer. We reported that (bis)guanidines,
(bis)biguanides, and their urea- and thiourea isosteres are potent
inhibitors of LSD1 and induce the re-expression of aberrantly silenced
tumor suppressor genes in tumor cells in vitro. We now report a series
of small molecule amidoximes that are moderate inhibitors of recombinant
LSD1 but that produce dramatic changes in methylation at the histone
3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6
lung carcinoma cells. In addition, these analogues increase cellular
levels of secreted frizzle-related protein (SFRP) 2, H-cadherin (HCAD),
and the transcription factor GATA4. These compounds represent leads
for an important new series of drug-like epigenetic modulators with
the potential for use as antitumor agents
Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue
A number
of analogues of the marine-derived histone deacetylase
inhibitor largazole incorporating major structural changes in the
depsipeptide ring were synthesized. Replacing the thiazole-thiazoline
fragment of largazole with a bipyridine group gave analogue <b>7</b> with potent cell growth inhibitory activity and an activity
profile similar to that of largazole, suggesting that conformational
change accompanying switching hybridization from sp<sup>3</sup> to
sp<sup>2</sup> at C-7 is well tolerated. Analogue <b>7</b> was
more class I selective compared to largazole, with at least 464-fold
selectivity for class I HDAC proteins over class II HDAC6 compared
to a 22-fold selectivity observed with largazole. To our knowledge <b>7</b> represents the first example of a potent and highly cytotoxic
largazole analogue not containing a thiazoline ring. The elimination
of a chiral center derived from the unnatural amino acid <i>R</i>-α-methylcysteine makes the molecule more amenable to chemical
synthesis, and coupled with its increased class I selectivity, <b>7</b> could serve as a new lead compound for developing selective
largazole analogues
Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue
A number
of analogues of the marine-derived histone deacetylase
inhibitor largazole incorporating major structural changes in the
depsipeptide ring were synthesized. Replacing the thiazole-thiazoline
fragment of largazole with a bipyridine group gave analogue <b>7</b> with potent cell growth inhibitory activity and an activity
profile similar to that of largazole, suggesting that conformational
change accompanying switching hybridization from sp<sup>3</sup> to
sp<sup>2</sup> at C-7 is well tolerated. Analogue <b>7</b> was
more class I selective compared to largazole, with at least 464-fold
selectivity for class I HDAC proteins over class II HDAC6 compared
to a 22-fold selectivity observed with largazole. To our knowledge <b>7</b> represents the first example of a potent and highly cytotoxic
largazole analogue not containing a thiazoline ring. The elimination
of a chiral center derived from the unnatural amino acid <i>R</i>-α-methylcysteine makes the molecule more amenable to chemical
synthesis, and coupled with its increased class I selectivity, <b>7</b> could serve as a new lead compound for developing selective
largazole analogues
Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout
We report the first well-characterized selective chemical
probe
for histone deacetylase 10 (HDAC10) with unprecedented selectivity
over other HDAC isozymes. HDAC10 deacetylates polyamines and has a
distinct substrate specificity, making it unique among the 11 zinc-dependent
HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates,
we systematically inserted an amino group (“aza-scan”)
into the hexyl linker moiety of the approved drug Vorinostat (SAHA).
This one-atom replacement (C→N) transformed SAHA from an unselective
pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization
of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ‑748, with
potency and selectivity demonstrated by cellular and biochemical target
engagement, as well as thermal shift assays. Cocrystal structures
of our aza-SAHA derivatives with HDAC10 provide a structural rationale
for potency, and chemoproteomic profiling confirmed exquisite cellular
HDAC10-selectivity of DKFZ‑748 across the target
landscape of HDAC drugs. Treatment of cells with DKFZ‑748, followed by quantification of selected polyamines, validated for
the first time the suspected cellular function of HDAC10 as a polyamine
deacetylase. Finally, in a polyamine-limiting in vitro tumor model, DKFZ‑748 showed dose-dependent growth inhibition of
HeLa cells. We expect DKFZ‑748 and related probes
to enable further studies on the enigmatic biology of HDAC10 and acetylated
polyamines in both physiological and pathological settings
Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout
We report the first well-characterized selective chemical
probe
for histone deacetylase 10 (HDAC10) with unprecedented selectivity
over other HDAC isozymes. HDAC10 deacetylates polyamines and has a
distinct substrate specificity, making it unique among the 11 zinc-dependent
HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates,
we systematically inserted an amino group (“aza-scan”)
into the hexyl linker moiety of the approved drug Vorinostat (SAHA).
This one-atom replacement (C→N) transformed SAHA from an unselective
pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization
of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ‑748, with
potency and selectivity demonstrated by cellular and biochemical target
engagement, as well as thermal shift assays. Cocrystal structures
of our aza-SAHA derivatives with HDAC10 provide a structural rationale
for potency, and chemoproteomic profiling confirmed exquisite cellular
HDAC10-selectivity of DKFZ‑748 across the target
landscape of HDAC drugs. Treatment of cells with DKFZ‑748, followed by quantification of selected polyamines, validated for
the first time the suspected cellular function of HDAC10 as a polyamine
deacetylase. Finally, in a polyamine-limiting in vitro tumor model, DKFZ‑748 showed dose-dependent growth inhibition of
HeLa cells. We expect DKFZ‑748 and related probes
to enable further studies on the enigmatic biology of HDAC10 and acetylated
polyamines in both physiological and pathological settings
Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout
We report the first well-characterized selective chemical
probe
for histone deacetylase 10 (HDAC10) with unprecedented selectivity
over other HDAC isozymes. HDAC10 deacetylates polyamines and has a
distinct substrate specificity, making it unique among the 11 zinc-dependent
HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates,
we systematically inserted an amino group (“aza-scan”)
into the hexyl linker moiety of the approved drug Vorinostat (SAHA).
This one-atom replacement (C→N) transformed SAHA from an unselective
pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization
of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ‑748, with
potency and selectivity demonstrated by cellular and biochemical target
engagement, as well as thermal shift assays. Cocrystal structures
of our aza-SAHA derivatives with HDAC10 provide a structural rationale
for potency, and chemoproteomic profiling confirmed exquisite cellular
HDAC10-selectivity of DKFZ‑748 across the target
landscape of HDAC drugs. Treatment of cells with DKFZ‑748, followed by quantification of selected polyamines, validated for
the first time the suspected cellular function of HDAC10 as a polyamine
deacetylase. Finally, in a polyamine-limiting in vitro tumor model, DKFZ‑748 showed dose-dependent growth inhibition of
HeLa cells. We expect DKFZ‑748 and related probes
to enable further studies on the enigmatic biology of HDAC10 and acetylated
polyamines in both physiological and pathological settings
Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout
We report the first well-characterized selective chemical
probe
for histone deacetylase 10 (HDAC10) with unprecedented selectivity
over other HDAC isozymes. HDAC10 deacetylates polyamines and has a
distinct substrate specificity, making it unique among the 11 zinc-dependent
HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates,
we systematically inserted an amino group (“aza-scan”)
into the hexyl linker moiety of the approved drug Vorinostat (SAHA).
This one-atom replacement (C→N) transformed SAHA from an unselective
pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization
of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ‑748, with
potency and selectivity demonstrated by cellular and biochemical target
engagement, as well as thermal shift assays. Cocrystal structures
of our aza-SAHA derivatives with HDAC10 provide a structural rationale
for potency, and chemoproteomic profiling confirmed exquisite cellular
HDAC10-selectivity of DKFZ‑748 across the target
landscape of HDAC drugs. Treatment of cells with DKFZ‑748, followed by quantification of selected polyamines, validated for
the first time the suspected cellular function of HDAC10 as a polyamine
deacetylase. Finally, in a polyamine-limiting in vitro tumor model, DKFZ‑748 showed dose-dependent growth inhibition of
HeLa cells. We expect DKFZ‑748 and related probes
to enable further studies on the enigmatic biology of HDAC10 and acetylated
polyamines in both physiological and pathological settings
Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout
We report the first well-characterized selective chemical
probe
for histone deacetylase 10 (HDAC10) with unprecedented selectivity
over other HDAC isozymes. HDAC10 deacetylates polyamines and has a
distinct substrate specificity, making it unique among the 11 zinc-dependent
HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates,
we systematically inserted an amino group (“aza-scan”)
into the hexyl linker moiety of the approved drug Vorinostat (SAHA).
This one-atom replacement (C→N) transformed SAHA from an unselective
pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization
of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ‑748, with
potency and selectivity demonstrated by cellular and biochemical target
engagement, as well as thermal shift assays. Cocrystal structures
of our aza-SAHA derivatives with HDAC10 provide a structural rationale
for potency, and chemoproteomic profiling confirmed exquisite cellular
HDAC10-selectivity of DKFZ‑748 across the target
landscape of HDAC drugs. Treatment of cells with DKFZ‑748, followed by quantification of selected polyamines, validated for
the first time the suspected cellular function of HDAC10 as a polyamine
deacetylase. Finally, in a polyamine-limiting in vitro tumor model, DKFZ‑748 showed dose-dependent growth inhibition of
HeLa cells. We expect DKFZ‑748 and related probes
to enable further studies on the enigmatic biology of HDAC10 and acetylated
polyamines in both physiological and pathological settings