Synthesis and Evaluation of Azalanstat Analogues as Heme Oxygenase Inhibitors.

Vlahakis, Jason Z.; Kinobe, Robert T.; Bowers, Raymond J.; Brien, James F.; Nakatsu, Kanji; Szarek, Walter A.

doi:10.1002/chin.200528132

Cited by 18 publications

(44 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A medicinal chemistry programme was initiated based on the lead compound, QC-1, and the topological analysis shown in figure 3. The resultant analogues were screened by an in vitro CO formation assay, using microsomal preparations from rat spleen and brain as physiological sources of HO-1 and HO-2, respectively [69]. The in vivo efficacies of some select compounds were also evaluated in mice and rats, as well as in cultured renal proximal tubule epithelial cells [70].…”

Section: Structural Conservation Of Heme Oxygenase Isozymesmentioning

confidence: 99%

“…The in vivo efficacies of some select compounds were also evaluated in mice and rats, as well as in cultured renal proximal tubule epithelial cells [70]. Initial studies identified a number of compounds that were selective for the inducible HO-1 isozyme [69]. Indeed, kinetic analyses of QC-1 and its analogues confirmed a non-competitive mode of inhibition, unlike the metalloporphyrins that compete for the heme-binding site, thus putatively minimizing the chances of cross-reactivity with other heme-binding proteins such as NOS and sGC, and increasing selectivity for the HO isozymes.…”

Section: Structural Conservation Of Heme Oxygenase Isozymesmentioning

confidence: 99%

“…Indeed, kinetic analyses of QC-1 and its analogues confirmed a non-competitive mode of inhibition, unlike the metalloporphyrins that compete for the heme-binding site, thus putatively minimizing the chances of cross-reactivity with other heme-binding proteins such as NOS and sGC, and increasing selectivity for the HO isozymes. The initial structure-activity relationship (SAR) study [69] investigated the ortho-, meta-and para-amino derivatives of each of the four diastereomeric analogues of QC-1. Although no pattern in potency/selectivity for HO-1 was observed with respect to the position of the amino functionality, it was found that the (2S,4S) and the (2R,4S) diastereomeric configurations produced analogues with greater potency and selectivity for HO-1.…”

Section: Structural Conservation Of Heme Oxygenase Isozymesmentioning

confidence: 99%

“…While initial work had concluded that the aminothiophenol moiety in the northeastern region of azalanstat is not essential for HO inhibition, it had been noticed that general HO potency was dependent upon the position of the nitrogen atom and that, more importantly, its removal altogether enhanced HO-1 selectivity [69,71,72]. Thus, further investigation of this region was postulated to be important in determining selectivity for HO-2 using thiophenol and substituted phenol derivatives as well as small functionalized derivatives at the 4-position of the dioxolane ring, i.e.…”

Section: A Novel Inducible Binding Modementioning

confidence: 99%

See 3 more Smart Citations

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Rahman

Vukomanovic

Vlahakis

et al. 2013

J. R. Soc. Interface.

Self Cite

View full text Add to dashboard Cite

The development of heme oxygenase (HO) inhibitors, especially those that are isozyme-selective, promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties and may play a role in several disease states, making it an enticing therapeutic target. Traditionally, the metalloporphyrins have been used as competitive HO inhibitors owing to their structural similarity with the substrate, heme. However, given heme's important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), non-selectivity is an unfortunate side-effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort to develop novel compounds as potent, selective inhibitors of HO. This resulted in the creation of non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated, which provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies.

show abstract

Section: Structural Conservation Of Heme Oxygenase Isozymesmentioning

confidence: 99%

Section: Structural Conservation Of Heme Oxygenase Isozymesmentioning

confidence: 99%

Section: Structural Conservation Of Heme Oxygenase Isozymesmentioning

confidence: 99%

Section: A Novel Inducible Binding Modementioning

confidence: 99%

See 2 more Smart Citations

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Rahman

Vukomanovic

Vlahakis

et al. 2013

J. R. Soc. Interface.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the course of designing a series of novel HO inhibitors (Vlahakis et al, 2005;Kinobe et al, 2006), we have synthesized a number of imidazole-dioxolane compounds that share structural features with the azole antifungal agents. This raised the possibility that KTZ might derive its anticancer activity through mimicry of the actions of zinc protoporphyrin, namely HO inhibition.…”

mentioning

confidence: 99%

Inhibition of the Enzymatic Activity of Heme Oxygenases by Azole-Based Antifungal Drugs

Kinobe¹,

Dercho²,

Vlahakis³

et al. 2006

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Ketoconazole (KTZ) and other azole antifungal agents are known to have a variety of actions beyond the inhibition of sterol synthesis in fungi. These drugs share structural features with a series of novel heme oxygenase (HO) inhibitors designed in our laboratory. Accordingly, we hypothesized that therapeutically used azole-based antifungal drugs are effective HO inhibitors. Using gas chromatography to quantify carbon monoxide formation in vitro and in vivo, we have shown that azole-containing antifungal drugs are potent HO inhibitors. Terconazole, sulconazole, and KTZ were the most potent drugs with IC 50 values of 0.41 Ϯ 0.01, 1.1 Ϯ 0.4, and 0.3 Ϯ 0.1 M for rat spleen microsomal HO activity, respectively. Kinetic characterization revealed that KTZ was a noncompetitive HO inhibitor. In the presence of KTZ (2.5 and 10 M), K m values for both rat spleen and brain microsomal HO were not altered; however, a significant decrease in the catalytic capacity (V max ) was observed (P Ͻ 0.005). KTZ was also found to weakly inhibit nitric-oxide synthase with an IC 50 of 177 Ϯ 2 M but had no effect on the enzymatic activity of NADPH cytochrome P450 reductase. Because these drugs were effective within the concentration range observed in humans, it is possible that inhibition of HO may play a role in some of the pharmacological actions of these antimycotic drugs.

show abstract

X-ray Crystallographic and Biochemical Characterization of the Inhibitory Action of an Imidazole−Dioxolane Compound on Heme Oxygenase^,

et al. 2007

View full text Add to dashboard Cite

Heme oxygenase (HO) catalyzes the regiospecific cleavage of the porphyrin ring of heme using reducing equivalents and O2 to produce biliverdin, iron, and CO. Because CO has a cytoprotective effect through the p38-MAPK pathway, HO is a potential therapeutic target in cancer. In fact, inhibition of the HO isoform HO-1 reduces Kaposi sarcoma tumor growth. Imidazole-dioxolane compounds have recently attracted attention because they have been reported to specifically inhibit HO-1, but not HO-2, unlike Cr-containing protoporphyrin IX, a classical inhibitor of HO, that inhibits not only both HO isoforms but also other hemoproteins. The inhibitory mechanism of imidazole-dioxolane compounds, however, has not yet been characterized. Here, we determine the crystal structure of the ternary complex of rat HO-1, heme, and an imidazole-dioxolane compound, 2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane. This compound bound on the distal side of the heme iron, where the imidazole and 4-chlorophenyl groups were bound to the heme iron and the hydrophobic cavity in HO, respectively. Binding of the bulky inhibitor in the narrow distal pocket shifted the distal helix to open the distal site and moved both the heme and the proximal helix. Furthermore, the biochemical characterization revealed that the catalytic reactions of both HO-1 and HO-2 were completely stopped after the formation of verdoheme in the presence of the imidazole-dioxolane compound. This result should be mainly due to the lower reactivity of the inhibitor-bound verdoheme with O2 compared to the reactivity of the inhibitor-bound heme with O2.

show abstract

Synthesis and Evaluation of Azalanstat Analogues as Heme Oxygenase Inhibitors.

Cited by 18 publications

References 1 publication

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Inhibition of the Enzymatic Activity of Heme Oxygenases by Azole-Based Antifungal Drugs

X-ray Crystallographic and Biochemical Characterization of the Inhibitory Action of an Imidazole−Dioxolane Compound on Heme Oxygenase^,

Contact Info

Product

Resources

About

Synthesis and Evaluation of Azalanstat Analogues as Heme Oxygenase Inhibitors.

Cited by 18 publications

References 1 publication

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Inhibition of the Enzymatic Activity of Heme Oxygenases by Azole-Based Antifungal Drugs

X-ray Crystallographic and Biochemical Characterization of the Inhibitory Action of an Imidazole−Dioxolane Compound on Heme Oxygenase,

Contact Info

Product

Resources

About

X-ray Crystallographic and Biochemical Characterization of the Inhibitory Action of an Imidazole−Dioxolane Compound on Heme Oxygenase^,