Polyphosphates and pyrophosphates of pentopyranoses and pentofuranoses as allosteric effectors of human hemoglobin: synthesis, molecular recognition, and oxygen release.

Perphosphorylated pentopyranoses and pentofuranoses were synthesized from parent carbohydrates as potential allosteric effectors of hemoglobin (Hb). The construction of seven- and eight-membered cyclic pyrophosphates was also carried out successfully on most of the pentoses. All final compounds were tested for their efficiency on oxygen release from human Hb. Most proved to be efficient allosteric effectors, some of them with an affinity toward Hb and an effect on oxygen release from Hb approaching that of myo-inositol hexakisphosphate, which is one of the most active allosteric effectors of Hb. The efficacy was higher for free phosphates than for pyrophosphates.

Polyphosphates and pyrophosphates of hexopyranoses as allosteric effectors of human hemoglobin: synthesis, molecular recognition, and effect on oxygen release.

Polyphosphorylated and perphosphorylated hexopyranose monosaccharides and disaccharides were synthesized from parent or partially protected carbohydrates as potential allosteric effectors of hemoglobin. A study toward the construction of seven- and eight-membered cyclic pyrophosphates was also performed on the sugars which had the proper orientation, protection, and number of phosphates. All final compounds were tested for their efficiency on oxygen release from human hemoglobin. Several compounds presented higher potency than myo-inositol hexakisphosphate, which is the most efficient of the known allosteric effectors of hemoglobin. Structure-activity relationships were analyzed. The affinity and efficiency depend on the number of phosphates attached to the carbohydrate skeleton and are related primarily to the number of negative charges present. Other effects operate, but play a lesser role.

Tetrakisphosphates and bispyrophosphates of myo-inositol derivatives as allosteric effectors of human hemoglobin: Synthesis, molecular recognition, and oxygen release.

Various 2,5- and 1,4-substituted and unsubstituted myo-inositol tetrakisphosphates and bispyrophosphates were prepared following a general synthetic pathway. All final compounds were tested for their capability to induce oxygen release from human hemoglobin. Most of these proved to be efficient allosteric effectors, with similar affinities for hemoglobin to that of myo-inositol hexakisphosphate, which is one of the best known allosteric effectors of hemoglobin. The efficacy was found to be higher for free phosphates than pyrophosphates. As allosteric Hb effectors, these compounds enable enhanced oxygen release. These effects increase with the strength of Hb binding and correspond primarily to electrostatic interactions. Stereochemical and steric factors also play a significant but secondary role in molecular recognition. In view of the central role played by hypoxia in numerous types of diseases, the exploration of myo-inositol phosphate derivatives represents an important avenue in the search for substances which act on the oxygenation status of tissues and may have significant potential in the discovery and development of novel drug candidates.

myo-Inositol trispyrophosphate: a novel allosteric effector of hemoglobin with high permeation selectivity across the red blood cell plasma membrane.

myo-Inositol trispyrophosphate (ITPP), a novel membrane-permeant allosteric effector of hemoglobin (Hb), enhances the regulated oxygen release capacity of red blood cells, thus counteracting the effects of hypoxia in diseases such as cancer and cardiovascular ailments. ITPP-induced shifting of the oxygen-hemoglobin equilibrium curve in red blood cells (RBCs) was inhibited by DIDS and NAP-taurine, indicating that band 3 protein, an anion transporter mainly localized on the RBC membrane, allows ITPP entry into RBCs. The maximum intracellular concentration of ITPP, determined by ion chromatography, was 5.5×10(-3) M, whereas a drop in concentration to the limit of detection was observed in NAP-taurine-treated RBCs. The dissociation constant of ITPP binding to RBC ghosts was found to be 1.72×10(-5) M. All data obtained indicate that ITPP uptake is mediated by band 3 protein and is thus highly tissue-selective towards RBCs, a feature of major importance for its potential therapeutic use.

Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo-inositol trispyrophosphate.

A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles. myo-Inositol trispyrophosphate (ITPP) is a recently identified membrane-permeant molecule that causes allosteric regulation of Hb oxygen binding affinity. In normal mice, i.p. administration of ITPP (0.5-3 g/kg) caused a dose-related increase in the oxygen tension at which Hb is 50% saturated (p50), with a maximal increase of 31%. In parallel experiments, ITPP caused a dose-related increase in maximal exercise capacity, with a maximal increase of 57 +/- 13% (P = 0.002). In transgenic mice with severe heart failure caused by cardiac-specific overexpression of G alpha q, i.p. ITPP increased exercise capacity, with a maximal increase of 63 +/- 7% (P = 0.005). Oral administration of ITPP in drinking water increased Hb p50 and maximal exercise capacity (+34 +/- 10%; P < 0.002) in normal and failing mice. Consistent with increased tissue oxygen availability, ITPP decreased hypoxia inducible factor-1alpha mRNA expression in myocardium. It had no effect on myocardial contractility in isolated mouse cardiac myocytes and did not affect arterial blood pressure in vivo in mice. Thus, ITPP decreases the oxygen binding affinity of Hb, increases tissue oxygen delivery, and increases maximal exercise capacity in normal mice and mice with severe heart failure. ITPP is thus an attractive candidate for the therapy of patients with reduced exercise capacity caused by heart failure.

Novel 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazones: orally effective anti-inflammatory drug candidates.

We described herein the molecular design of novel in vivo anti-inflammatory 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives (1) planned by applying the molecular hybridization approach. This work also points out to the discovery of LASSBio-930 (1c) as a novel anti-inflammatory and anti-hyperalgesic prototype, which was able to reduce carrageenan-induced rat paw edema with an ED(50) of 97.8 micromol/kg, acting mainly as a non-selective COX inhibitor.

Privileged structures: a useful concept for the rational design of new lead drug candidates.

Privileged structures are defined as molecular frameworks which are able of providing useful ligands for more than one type of receptor or enzyme target by judicious structural modifications. In the present work, we describe some examples and applications of the usefulness of the privileged structure concept for the structural design of new drug candidates, by discussing the eligibility of such motifs, including the identification of the N-acylhydrazone template as privileged structures.

Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives: Discovery of LASSBio-881, a new ligand of cannabinoid receptors.

We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity.