Michel Mayer

Synthesis and cytotoxicity of gossypol related compounds.

Gossypol, gossypolone, reduced gossypol and new Schiffs bases of racemic gossypol and gossypolone were extracted or synthesized. Their cytotoxic activities on KB human cancer cells were determined. Gossypolone and the ethylamine derivative of gossypolone were the most active compounds (IC(50) in the micromolar range in both cases). The cytotoxicity of gossypol and gossypolone was increased when the tests were performed in the absence of serum and decreased when catalase as well as mannitol were added to the culture medium.

New thioderivatives of gossypol and gossypolone, as prodrugs of cytotoxic agents.

New dithiane or dithiolane derivatives of gossypol and gossypolone were synthesized with dithiolethane or dithiolpropane in the presence of BF(3)/Et(2)O. These thioderivatives exhibited low toxicity on KB cells (human epidermoid carcinoma cells of the mouth). They react easily with electrophiles in aprotic solvents to regenerate gossypolone or to form dehydrogossypoldithianes and dehydrogossypoldithiolanes, which display higher toxicity on KB cells. In addition, the low toxicity of gossypol thioderivatives was reversed by nitric oxide donors in physiological media. These experiments suggest that gossypol and gossypolone dithianes and dithiolanes can be used as prodrugs that target tumor cells surrounded by high concentrations of nitric oxide.

Use of BOP-Cl in the presence of Boc-amino monothioacids for the thioacylation of iminoacid residues

BOP-Cl was found to be an efficient coupling reagent for the introduction of thiopeptide bonds on imino acid residues (Pro, Sar). Boc-amino monothioacids were coupled at moderate temperature (0 degree C-RT) with fair yields and with retained optical purity. The mechanism of the coupling reaction is discussed.

N-acylated pentapeptides antagonists of substance P on guinea-pig ileum.

Summary Pentapeptides X-D,Trp-Phe-D.Trp-Leu-Y-NH2 (X = H, Boc, parachydroxyphenylacetyl, Y = Met,Leu,Nle,Phe) were tested as antagonists against Substance P and against a specific agonist of the muscular receptor of neurokinins on the guinea-pig ileum . Weak antagonist or agonist activities could be observed with the free or the Boc-protected pentapeptides whilst the acylated compounds could be compared favorably with the best antagonists already described.

Activity of the C-terminal part of substance P on guinea pig ileum and trachea preparations I. N-acylated pentapeptides SP(7–11)

Abstract Acylated pentapeptide XPhePheGlyLeuMetNH2 analogs of the substance P (7–11) sequence were synthesized by solution method and their spasmogenic activities were evaluated on guinea pig ileum (GPI) and trachea (GPT). Pentapeptide SP(7–11) had the lowest potency and its N-acylation increased its activity in both tests, with some derivatives being more active than SP itself. Results obtained on GPI suggest a close dependence of activity upon structural factors in the vicinity of the Phe7 N-terminus, whereas the activity on GPT seems more dependent upon the hydrophobicity of the analogs.

Design of potent dynorphin A-(1-9) analogues devoid of supraspinal motor effects in mice

Four analogues of dynorphin (Dyn) A-(1-9) incorporating D-Leu in position 8 alone or in combination with the nonhydrolysable psi [CS-NH] thiopeptide bond surrogate between positions 6 and 7 were tested in vitro for their ability to compete with the binding of selective kappa, mu, and delta opioid ligands, using membrane preparations of guinea pig cerebellum (kappa) and rat brain (mu and delta), for their ability to block the electrically induced contractions of the guinea pig ileum, and for their in vivo antinociceptive (writhing test) and motor (motor dysfunction assay) activities in mice. [D-Leu8]Dyn A-(1-9) displayed an affinity and a selectivity for the kappa opioid receptor that were comparable with those of Dyn A-(1-9). The potencies of [D-Leu8]Dyn A-(1-9) in the guinea pig ileum, writhing, and motor dysfunction assays were markedly enhanced (8-12 fold) compared with those of Dyn A-(1-9). [6 psi 7(CS-NH),D-Leu8]Dyn A-(1-9), [Lys6, 6 psi 7(CS-NH),D-Leu8] Dyn A-(1-9), and [Leu6, 6 psi 7(CS-NH), D-Leu8]Dyn A-(1-9) were somewhat less potent than [D-Leu8]Dyn A-(1-9) in all opioid assays. However, the thiopeptides were more potent analgesics than Dyn A-(1-9)(ED50 of 29.5, 23.9, and 15.5 nmol/mouse, respectively, compared with 90.7 nmol/mouse for Dyn A-(1-9)) and caused little or no motor impairment at analgesic doses.

Synthesis and biological activities of neurokinin pseudopeptide analogues containing a reduced peptide bond

A series of pseudopeptides, analogues of neurokinin selective agonists, in which a peptide bond was replaced by a (CH2NH) bond were synthesized. The biological activities of these compounds were determined on selective pharmacological preparations: the dog carotid artery for NK-1, the rabbit pulmonary artery devoid of endothelium for the NK-2 and the rat portal vein for the NK-3 receptors. The results reported in this study indicate that insertion of a pseudopeptide bond in various positions of these selective agonists resulted in a great decrease in potency compared to the parent compounds. Furthermore, the selectivity of agonists is maintained by the use of a methylene amino group in position 9–10 (Sar) for the NK-1 or in position 7–8 (MePhe) for the NK-3 selective compound. The selectivity is greatly diminished for the NK-2 analogues.

Contractile activity of the N-acylated C-terminal part of substance P7–11 in guinea pig trachea

SummarySubstance P, neurokinin A, neurokinin B, and N-acylated pentapeptide X-Phe-Phe-Gly-Leu-Met-NHin2 analogs of substance P7–11 were tested for their spasmogenic activities in intact or in epithelium-denuded tracheal strips from guinea pig. Epithelium removal enhanced the efficacies and potencies relative to substance P of all the peptides tested in guinea pig trachea. In epithelium-containing preparations, the presence of a cyclic substituent (o-hydroxyphenyl-acetyl, p-hydroxyphenyl-acetyl, pyroglutamyl) in Phe7 greatly enhanced the potency and efficacy compared to substance P. These substitutions were twice as active as neurokinin A itself. The presence of an aliphatic chain (non-protected and t-butyloxycarbonyl-protected aminopropyl and aminocaproyl) in Phe7 also improved the potency and the efficacy of the synthetic peptides. The aliphatic substituents could favour an increase in local concentration of the peptides in the vicinity of the receptor(s) allowing a more effective ligand-receptor interaction. Thus, lipophilicity could be determinant in the potency of the peptides in intact guinea pig trachea. In epithelium-denuded tracheal strips from guinea pig, all the synthetic peptides were more effective than substance P but less active than neurokinin A which probably reflects the presence of the NK2 receptor subtype, which may be predominant in this type of epithelium-denuded preparation. Our results suggest that hydrophobicity plays a strong role in the interaction of the peptides, namely substance P and its analogues with the membrane and possibly the receptors themselves.

N-acylated pentapeptides antagonists of substance P on guinea-pig ileum

Pentapeptides X-D.Trp-Phe-D.Trp-Leu-Y-NH2 (X = H, Boc, parahydroxyphenylacetyl, Y = Met,Leu,Nle,Phe) were tested as antagonists against Substance P and against a specific agonist of the muscular receptor of neurokinins on the guinea-pig ileum. Weak antagonist or agonist activities could be observed with the free or the Boc-protected pentapeptides whilst the acylated compounds could be compared favorably with the best antagonists already described.

Activity of the C-Terminal Part in Tachykinins on Guinea Pig Ileum and Trachea Preparations

Many structure-activity studies of C-terminal partial sequences of Substance P (SP) have established that the major potency of this peptide corresponds to the hepta or octa fragments [1,2]. Modifications of such hydrophobic peptides to enhance their activities were attempted through substitutions by sugar moieties or introduction of sulfonium or sulfoxyde groups into the methionine, but did not increase the affinity [3,4].