Carlos Sunkel

Synthesis and Structure of New Pyrido[2,3-d]pyrimidine Derivatives with Calcium Channel Antagonist Activity

We gratefully acknowledge to ALTER S. A. for studentship (to A. P and R. A.) and financial support

Synthesis and chromatographic separation of the stereoisomers of furnidipine

Abstract The four stereoisomers of methyl tetrahydrofuran-2-ylmethyl 2,6-dimethyl-4-(o-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxilate (furnidipine), have been synthesized and separated by chiral chromatography using D-phenylglycine as chiral stationary phase. Enantiomeric purity of stereoisomers is determined by HPLC-CSP technique and configurations deduced via X-ray crystallography.

1,5-Bis- (N-benzyl-N,N-diethylammoninm) diethylether, dichloride (BBDE C1). A novel bis-ammonium salt as phase transfer catalyst☆

Authors wish to thank the Centro para el Desarrollo Tecnologico e Industrial from Spanish Ministerio de Industria y Energia, for financial support.

Synthesis and biological evaluation of 2,6-di-tert-butylphenol hydrazones as 5-lipoxygenase inhibitors

Abstract The preparation of hydrazone derivatives of 3,5-di- tert -butyl-4-hydroxybenzaldehyde and the inhibition of 5-lipoxygenase (5-LO) by these compounds is discussed.

Intererence of the PAF receptor antagonist, PCA 4248, with the rat pleurisy evoked by inflammatory mediators or allergen

This study investigated the effect of the platelet-activating factor (PAF) receptor antagonist, PCA 4248, on the rat pleurisy caused by PAF, serotonin, bradykinin, histamine or allergen. The pleurisy was assessed by measuring liquid extravasation and leucocyte infiltration. Oral pretreatment with PCA 4248 (2.5-20 mg/kg) completely inhibited the pleural exudation caused by intrathoracic (i.t.) injection of PAF (1 microgram/cavity) (ED50 = 6.1 mg/kg), partially (42% reduction) the one induced by serotonin (100 micrograms/cavity), but was inactive against histamine (200 micrograms/cavity) or bradykinin (50 micrograms/cavity). PCA 4248 blocked the increase in the number of neutrophils, eosinophils and mononuclear cells observed 6 h after the i.t. injection of PAF, as well as the selective eosinophil accumulation noted 24 h later. In actively sensitized rats, PCA 4248 (20 mg/kg) failed to modify the increase in the total leucocyte counts noted 4 h after ovalbumin (12 micrograms/cavity), but dose dependently inhibited the pleural exudation observed within 1 h and the late eosinophil infiltration noted 24 h post-antigen. These observations led us to suggest that PCA 4248 is a potent PAF antagonist with anti-serotoninergic properties. Its interference with exudation and eosinophil infiltration caused by allergen is consistent with the interpretation that PCA 4248 may be useful in the management of allergic dysfunctions.

PCA 50941, a novel Ca2+ channel agonist

PCA 50941 is a novel 1,4-dihydropyridine derivative. Its vasoconstricting effects prompted a systematic comparison with the prototypic Ca2+ channel activator, Bay K 8644. The two compounds exhibit marked analogies and differences in their cardiovascular profiles. PCA 50941 exhibits a pronounced vascular over cardiac selectivity while Bay K 8644 has both potent vasoconstrictor effects and strong cardiac positive inotropic actions. PCA 50941 exhibits either poor positive inotropic effects (isolated guinea-pig atria) or clear negative inotropic effects (isolated perfused rat heart). Both compounds reduced by 10-40% the coronary flow in the perfused rat heart. However, PCA 50941 had slight vasoconstrictor effects in pig coronary arteries, causing their relaxation at nanomolar/micromolar concentrations; this contrasts with the almost pure, marked vasoconstrictor effects of Bay K 8644 in coronary arteries. In the rat aorta PCA 50941 exhibited a biphasic pattern of vasoconstriction and vasorelaxation, and in portal vein it markedly reduced the Ca(2+)-evoked contractions; Bay K 8644 behaved as a pure vasoconstrictor in these two preparations. It is concluded that the racemic compound, PCA 50941, exhibits different degrees of Ca2+ agonism and Ca2+ antagonism by acting upon 1,4-dihydropyridine receptors of different cardiovascular tissues. Its tissue selectivity and its prolonged duration of action give PCA 50941 a cardiovascular profile more favourable than that of other 1,4-dihydropyridine Ca2+ agonist existing to date.

Antiproliferative effects of PCA‐4230, a new antithrombotic drug, in vascular smooth muscle cells

In the present study we examined the effects of PCA‐4230, a novel antithrombotic agent, on the growth of cultured A10 vascular smooth muscle cells (rat aorta). The action of PCA‐4230 on cell proliferation and on serum‐induced DNA synthesis was determined by measuring the cell number and the incorporation of the thymidine analogue 5‐bromo‐2′‐deoxyuridine (BrdU), respectively. PCA‐4230 reversibly inhibited vascular smooth muscle cell proliferation. The increase in cell number was significantly reduced in the presence of 1 and 50 μm PCA‐4230. DNA synthesis was concentration‐dependently inhibited by PCA‐4230 (0.5 to 50 μm) in A10 cells that were synchronized by 48 h serum starvation and then re‐stimulated by serum repletion, with an IC50 value of 13 μm. However, serum‐induced DNA synthesis in bovine aortic endothelial cells was not significantly affected by PCA‐4230. In addition, PCA‐4230 (50 μm) caused a significant drop in PDGF‐BB‐mediated BrdU incorporation in A10 cells. The effect of PCA‐4230 on serum‐induced DNA synthesis was compared to that elicited by nifedipine, another dihydropyridine‐class inhibitor of vascular smooth muscle proliferation. PCA‐4230 (10 μm) elicited a degree of inhibition similar to that of nifedipine at equimolar concentration. To define the nature of the cell proliferation inhibition, an evaluation of cell cycle progression was undertaken. Flow cytometry studies of DNA content in synchronized cells revealed a block of the serum‐inducible cell cycle progression. This inhibitory effect was markedly reduced when PCA‐4230 was added 2 h after serum repletion. Accordingly, PCA‐4230 (50 μm) caused a 95 and 90% decrease in the elevation of c‐fos and c‐jun proto‐oncogenes expression as evaluated by Northern blot analysis of mRNA induced early after serum addition. The present results indicate that PCA‐4230 inhibits vascular smooth muscle cell proliferation, in culture, by altering the cell cycle progression. Flow cytometric studies of DNA content and the down regulation of c‐fos and c‐jun proto‐oncogenes, suggest that the drug is acting at the early G0/G1 transition phase. PCA‐4230 may hold promising potential for the prevention of structural abnormalities of blood vessels associated with atherosclerosis and vascular diseases.

A tricin derivative from Deschampsia antarctica Desv. inhibits colorectal carcinoma growth and liver metastasis through the induction of a specific immune response

In colorectal carcinoma patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic colorectal carcinoma have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina in colorectal carcinoma models. We used human and murine colorectal carcinoma cell lines for investigating proliferation, apoptosis, and cell-cycle effects of Antartina therapy in vitro. Avatar and immunocompetent colorectal carcinoma animal models were applied for evaluating the effects of Antartina in vivo. Immune response against colorectal carcinoma model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T-cell subpopulation, and by tumor rechallenge experiments. Antartina inhibits in vitro human colorectal carcinoma cell proliferation; however, in vivo experiments in Avatar colorectal carcinoma model Antartina display a limited antitumor effect. In an immunocompetent colorectal carcinoma mice model, Antartina potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in >30% of mice and increased animal survival. In addition, Antartina induced a potent specific cytotoxic T-cell response against colorectal carcinoma and a long-lasting antitumor immunity. Interestingly, Antartina increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina has the ability to induce antitumor immunity against colorectal carcinoma and can be used to develop new tools for the treatment of colorectal carcinoma. Mol Cancer Ther; 17(5); 966–76. ©2018 AACR.