TABLE 1.
Inhibitor | Active Metabolite | Type of Inhibition | IC50 |
Other Features | References | ||
---|---|---|---|---|---|---|---|
hALDH1A1 | hALDH2 | hALDH3A1 | |||||
μM | μM | μM | |||||
Ampal | Thioampal | Irreversible | N.A. | N.A. | N.A. | In rat hepatoma cells (JM2), thioampal derivatives inhibited ALDH1 and ALDH3 isoenzymes significantly. Also noted were growth inhibition and anti-tumor activity by these derivatives. | Quemener et al., 1989; Canuto et al., 2001; Quash et al., 2008 |
Benomyl | MBT | Irreversible | N.A. | N.A. | N.A. | MBT showed IC50 of 0.23 μM with mouse ALDH2, with activation by microsomes. The activation is inhibited by P450 inhibitor. | Axness and Fleeker, 1979; Staub et al., 1998, 1999 |
Citrala | Neral and geranial | Reversible noncompetitive | N.A. | N.A. | N.A. | Geranial showed positive cooperativity with hALDH2; n ≈ 2–2.5; Citral Ki for Rat ALDH2 = 360 nM | Boyer and Petersen, 1991; Kikonyogo et al., 1999 |
Chloral hydratea | Chloral hydrate | Reversible competitive | 1–10 | N.A. | N.A. | Also inhibits esterase activity noncompetitively (Ki = 19 μM) with NAD+ | Blackwell et al., 1983 |
Chlorpropamide analogs NPI-1 API-1 | NPI-1 | Irreversible | N.A. | N.A. | 121 | All of the analogs tested were proven to be more active against human tumor isolated ALDH3A1 than against normal tissue ALDH3A1. | Lee et al., 1992; Nagasawa et al., 1995; Rekha et al., 1998 |
API-1 | N.A. | N.A. | 223 | ||||
Coprine | 1-Amino cyclopropanol | Irreversible | 50 | N.A. | N.A. | Inhibits the esterase activity. Displays mutagenicity and gonadotoxicity. | Marchner and Tottmar, 1983; Michelot, 1992 |
Cyanamide | HNO | Irreversible | N.A. | 10 | N.A. | Requires activation by catalase. Also inhibits catalase activity. Liver injury reported with simultaneous consumption of alcohol. | Shirota et al., 1987; Nagasawa et al., 1990 |
Daidzin | Daidzin | Reversible competitive | 28 | 0.29 | N.A. | Structure analogs are being developed as antidipsotropic agents. | Lowe et al., 2008; Arolfo, 2009 |
CVT-10216 | CVT-10216 | 1.3 | 0.029 | N.A. | |||
DEABa | DEAB | Reversible competitive | 0.55 | N.A. | N.A. | No activation required. Confers sensitivity to cyclophosphamide-resistant cells. | Croker and Allan, 2011 |
DPABa | DPAB | <1 | N.A. | N.A. | |||
Disulfiram | Disulfiram | Irreversible | 0.15 | 1.45 | N.A. | Inhibits dopamine β-hydroxylase; displays copper chelation activity; inhibits carboxylesterase and cholinesterase. | Lipsky et al., 2001; Lin et al., 2010; Schroeder et al., 2010; Wang et al., 2011 |
DDTC-SO | 0.27 | 2.2 | N.A. | ||||
DDTC-SO2 | 0.12 | 62 | N.A. | ||||
DETC-SO | N.A. | 1.2 | N.A. | ||||
DETC-SO2 | N.A. | 0.4 | N.A. | ||||
Gossypol | Gossypol | Reversible noncompetitive | 75 | 45 | 7.5 (competitive) | Inhibits several other dehydrogenase enzymes. Interacts with alcohol in system to form a toxic metabolite, sufficient for aversion from drinking. Known for antitumor, antiviral, and antiparasitic activities. | Burgos et al., 1986; Rekha and Sladek, 1997; Pang et al., 2011 |
Kynurenine Tryptophan metabolites | KA | N.A. | N.A. | N.A. | N.A. | Tryptophane metabolites in the kynurenine pathway seem to have the potential for ALDH2 specific inhibition. | Badawy and Morgan, 2007; Badawy et al., 2011 |
3-HK | N.A. | N.A. | N.A. | N.A. | |||
3-HAA | N.A. | N.A. | N.A. | N.A. | |||
Molinate | Molinate | Irreversible | N.A. | >50 | N.A. | Molinate sulfoxide was found to inhibit ALDH activity in mouse striatal synaptosomes only, suggesting other isozymes as possible targets. | Allen et al., 2010 |
Molinate sulfoxide | High | ||||||
Molinate sulfone | <50 | ||||||
Nitroglycerina | NO3− | Irreversible | N.A. | N.A. | N.A. | DTT but not GSH partially protected GTN-induced inhibition of dehydrogenase activity. ALDH2 inactivation has a role in impaired GTN reduction and nitrate tolerance | Chen, 2002; Beretta et al., 2008; Daiber et al., 2010; Wenzl et al., 2011 |
Pargylinea | Propiolaldehyde | Reversible competitive | 1.6 | 1.8 | N.A. | Activated by CYP2E1 in liver microsomes; irreversible inhibitor of monoaminoxidase | DeMaster et al., 1980, 1986; Moridani et al., 2001 |
N.A., inhibition data not available for hALDHs, although data exists for inhibition of mouse and other mammalian isozymes; API-1, 4-chloro-N-ethyl-N-[(propylamino)carbonyl]benzenesulfonamide; NPI-1, (benzoyloxy)[(4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethyl ester; KA, kynurenic acid; 3-HK, 3-hydroxykynurenine; 3-HAA, 3-hydroxyanthranilic acid.
These compounds are not strict inhibitors but competitive substrates capable of inactivation through Michael-adduct formation in the active site.