Aldolase-inhibiting aromatic compounds

Abstract: The invention relates to novel aldolase-inhibiting compounds that can be advantageously used as medicaments (in therapeutic doses), especially for treating certain cancers, due to the inhibition efficacy thereof. An inventive compound corresponds to general formula (I) wherein the aldehyde group (—CHO) and the phenol group (—OH) are linked to two carbon atoms adjacent to the same aromatic chain, i.e., the first aromatic chain, and R is a phosphate group or a phosphate group mimetic linked to a carbon atom of the second aromatic chain. (end of abstract)

Aldolase-inhibiting aromatic compounds description/claims

Brief Patent Description

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Patent Application Claims

The invention relates to novel glycolysis-inhibiting compounds whose action is in the form of aldolase inhibition. The invention also relates to their synthesis method and applications, particularly in the manufacture of medicaments for treating cancer.

Glycolysis is a complex mechanism involving a cascade of ten different enzymes for ensuring anaerobic conversion with release of energy stored in the form of adenosine-5-triphosphate (ATP).

Among the ten enzymes involved in glycolysis, the aldolases (fructose-1,6-bisphosphate aldolases) and homotetrameric enzymes take part in an important stage: cleavage of the fructose-1,6-bisphosphate (Fru(1,6)P₂) into two phosphate trioses, dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP). Splitting of the (Fru(1,6)P₂) by the aldolases is performed by a multi-stage mechanism whereby several clearly identified intermediate products are defined.

Aldolases are essential to the glycolysis path, and consequently valuable in pyruvate and ATP synthesis.

Aldolases fall into two classes (Ruther et al., 1964, Fred. Proc. Fed. Am. Soc. Exp. Biol., 23:1248-1257), with those of one class distinguished from those of the other in particular by their sources, though by their function mode as well. Class I aldolases, found in animal species, higher plants and certain parasites fix the (Fru(1,6)P₂) by forming a proton imine (or Schiff base) between a lysine residue (lys-229) in the active site and the substrate. Class II aldolases are specific to procaryote organisms. They need to have a bivalent metal ion at their catalytic site for fixing and stabilizing the substrate in the enol form prior to cleavage.

Among the currently known class I aldolase inhibiters, we can cite the competitive inhibitors, in particular those described in Blonski C. et al., 1997 (Biochem J., 323:71-77): phosphated derivatives of hydroquinone (HQN-P₂), resorcinol (RSN-P₂) and benzaldehyde-4-phosphate (HBA-P). When tested on rabbit muscle aldolase, these inhibitors demonstrate a dissociation constant (or inhibition constant) K_iof around 135, 50 and 500 μM. Also known are phosphorylated compounds of inhibition constant K_iin the order of 30-40 μM (Hartman, et al., 1965, Biochemistry, 4:1068-1075).

We can also cite 2-hydroxybenzaldehyde-4-phosphate (Blonski C. et al., 1997 Biochem J., 323:71-77), a reversible inhibitor that depends on the global inhibition constant time K_i* of 35±5 μM, capable of reducing 80% of aldolase activity at an inhibitor concentration of around 200 μM.

The same as these compounds, the other presently known aldolase inhibitors (Gefflaut T. et al., 1995, Prog. Biophys. Mol. Biol., 63(3):301-340), and glycolysis inhibitors in general, show weak inhibiting activity, unless used at extremely high concentrations, which considerably limits their field of application. Moreover, their application at weak concentrations, for example at concentrations compatible with therapeutic doses, can scarcely be envisaged.

A great many applications, and in particular in medicine, strive for significant glycolysis inhibition, at inhibitor concentrations weak enough to avoid any harmful effect on the patient. Accordingly, we are aware of one approach, known as the glycerol rescued hypoglycemia (GRH) approach, designed to treat certain cancers and solid tumors (McCarty M. F., 2001, Med. Hypotheses, 56:286-289), and which in particular is based on two findings.

First, it has been shown that solid tumors and lethal cancers that develop in tissues with a predominant weak oxygen concentration (hypoxia conditions) have a phenotype that causes glycolysis to act as a single path for energy production. It has also been shown that cells of this type are also characterized by the absence of glycerol kinase activity, a particular enzyme making it possible for healthy cells to use glycerol as a glucose replacement.

The GRH approach thus contemplates inhibiting the glycolysis path in all of the patient\'s cells, while providing a sufficient dose of glycerol by way of a single energy source. Cancer cells whose glycolysis represents the main ATP synthesis path are thus “starved” and unable to use glycose or glycerol as an alternative source of energy to glucose. As for healthy cells, owing to glycerol-kinase activity and other enzymes from the lower part of glycolysis (those of triose), they can use glycerol to synthesize pyruvate. Thus the cancer cells are starved while healthy tissues are ensured of getting enough energy.

Nevertheless, at the present no cancer treatment involving the GRH approach has yet to be undertaken owing to the absence of suitably efficient glycolysis inhibitors, and more specifically inhibitors of one of the enzymes from the top of glycolysis (those of hexoses).

By the same token, with glycolysis representing the only energy synthesis path for many parasites, glycolysis blocking could also be a very promising approach for treating many diseases of parasitic origin.

Accordingly there currently exists a real need to have at least one efficient glycolysis inhibitor available, especially with an eye toward conquering cancer as well as certain parasitic diseases, or in terms of eradicating any organism for which glycolysis is a principal, or essential, energy synthesis path.

The present invention contemplates filling in the aforementioned gaps by proposing new chemical compounds able to inhibit glycolysis, and in particular the activity of class I aldolases.

More specifically, the invention contemplates compounds that, owing to their aldolase inhibition efficacy can be used as medicaments, i.e., effectively when at therapeutic doses, in particular as part of cancer treatment.

The invention also relates to proposing applications of these compounds as glycolysis inhibitor agents, except for therapeutic applications. By extension, the invention relates to proposing new medicaments, in particular for treating cancer and/or parasitic diseases.

Lastly, the invention relates to a inventive process for synthesizing compounds, one that is simple to carry out, with sufficient quantities and inexpensive, in other words, a process compatible with the economic limitations of industrial-scale production.

The following terminology will be used throughout the document:

- aromatic chain: the conjugate cycle of an aromatic nucleus wherein free electrons can shift from one carbon atom to another without linking to either of them (delocalization of electrons due to the effect of resonance), and from one carbon atom in a chain to a carbon atom in another chain; naphthalene-type aromatic nuclei used in the present invention thus have alternating simple links (a links) and double links (π links), resulting in a highly delocalized system of π electrons between the two aromatic chains forming these nuclei,