Penélope Merino-Montiel

Synthesis and antioxidant activity of O-alkyl selenocarbamates, selenoureas and selenohydantoins.

The preparation of three different families of lipophilic organoselenium compounds (aryl- and sugar-derived selenoureas, O-alkyl selenocarbamates and selenohydantoins) has been carried out in order to evaluate their in vitro antioxidant profile, analyzing the influence of the selenium-containing functional group, and the substituents on the activity. Title compounds have therefore been studied for the first time as free radical, hydrogen peroxide, alkyl peroxides and nitric oxide scavengers using colorimetric methods; furthermore, their glutathione peroxidase-like activity has also been analyzed by NMR spectroscopy. Free radical scavenging activity has been evaluated using the DPPH method; the strongest free radical scavengers were found to be both, aryl- and sugar-derived selenoureas, with EC₅₀ values ranging 19-46 μM. Concerning anti-H₂O₂ activity, measured by the horseradish peroxidase-mediated oxidation of phenol red, the best results were achieved for aryl selenohydantoins, showing a 61-76% inhibition at 0.5 mM concentration. Organoselenium compounds were also found to be capable of inhibiting the chain reaction involving lipid peroxidation (ferric thiocyanate method); thus, when tested at 0.74 mM, sugar selenocarbamates exhibited 49-71% inhibition of alkyl peroxides-mediated degradation of linoleic acid. Nitric oxide scavenging was studied by transforming sodium nitroprusside into nitrite ion, which in turn was transformed into an easily UV-detectable azocompound; aryl selenocarbamates exhibited 64-80% inhibition at 0.71 mM concentration. It has also been demonstrated that selenoxo compounds can behave as excellent glutathione peroxidase mimics; thus a 0.05 molar equiv. of the title compounds catalyzed efficiently the H₂O₂-mediated oxidation of dithiothreitol into the corresponding cyclic disulfide, mimicking removal of H₂O₂ exerted by glutathione peroxidase; t(1/2) values were found to be quite low for aryl- and sugar-derived selenoureas (2.0-12.7 min).

Diosgenin-based thio(seleno)ureas and triazolyl glycoconjugates as hybrid drugs. Antioxidant and antiproliferative profile

The stereoselective preparation of diosgenin-derived thio(seleno)ureas and glycomimetics bearing a 1,2,3-triazolyl tether on C-3 has been accomplished. The key steps in the synthetic pathway are the incorporation of an amino moiety and its further transformation into thio- and selenoureas, and also a click chemistry reaction involving a propargyl residue and an azido moiety to afford carbohydrate-derived 1,2,3-triazoles; subsequent BF3-promoted acetolysis of the spiranic moiety afforded the corresponding 22-oxocholestanic structure. The N-phenyl selenourea, an hitherto unknown steroidal derivative, turned out to be a potent ROS scavenger, in particular against free radicals (EC50 = 29.47 ± 2.33 μM, DPPH method), and as a glutathione peroxidase mimic in the elimination of H2O2 (t1/2 = 4.8 min, 1% molar ratio). 22-Oxocholestane structures bearing a C-3 azido, propargyl, thioureido, and particularly selenoureido moiety behaved as strong antiproliferative agents against HeLa cells (IC50 1.87-11.80 μM). N-phenyl selenourea also exhibited IC50 values lower than 6.50 μM for MDA-MB-231, MCF-7 and HepG2 cancer cells; apoptosis was found to be involved in its mode of action. Such compound was also capable of efficiently eliminating ROS endogenously produced by HeLa cells. Antiproliferative properties of thioxo and selenoxo derivatives were stronger than diosgenin.

Synthesis of steroidal derivatives containing substituted, fused and spiro pyrazolines

An efficient and facile synthesis of fused, substituted and spiro pyrazoline steroid derivatives through a cycloaddition reaction of different α,β-unsaturated ketones with hydrazine acetate in acetic acid is reported. Depending on the starting material, the ring closure reaction provided a mixture of two steroidal pyrazoline epimers that were separated and studied by NMR techniques. In one case it was possible to isolate and characterize the hydrazone derivative as the reaction intermediate, which confirms the mechanism proposed in the literature [11,25,26].

Synthesis of monomeric and dimeric steroids containing [1,2,4]triazolo[1,5-a]pyrimidines

The synthesis of several monomeric and dimeric steroidal [1,2,4]triazolo[1,5-a]pyrimidines (TPs) derived from steroids are described. These derivatives were prepared from α,β-unsaturated carbonyl compounds through a Claisen Schmidt condensation and rearrangement of the spiro moiety followed by a cycloaddition with 3-amino-1,2,4-triazole. The antiproliferative activity of compounds 7, 13-15 was tested against human cancer cells; several IG50 values were below 10μM.

Glycosidase inhibitors: versatile tools in glycobiology

Imino sugars, despite being firstly studied as inhibitors more than forty years ago, are still a relevant target in Medicinal and Bioorganic Chemistry, because of their numerous and substantial biological activities. This review covers the most significant reports concerning the synthesis and evalua...

Novel synthesis of steroidal oximes and lactams and their biological evaluation as antiproliferative agents

HIGHLIGHTSTwo novel and short methods to introduce the hydroxyimino group at C‐6 on the steroidal skeleton are described.An efficient route to obtain B‐homolactams in just three steps from the natural steroids is presented.The antiproliferative activity of the new steroidal oximes and lactams was evaluated. ABSTRACT A novel three‐step methodology to obtain 6a‐aza‐B‐homo steroidal lactams has been developed starting from the easily available cholesterol and pregnenolone. In addition, a new procedure for the synthesis of a 6a‐aza‐B‐homo steroidal lactam analog of vespertilin, starting from diosgenin has been established. In both synthetic pathways, the key intermediate is a hydroxyimino derivative obtained in a one‐ or two‐step sequence from the starting materials. These methods avoid the use of hazardous oxidant agents in the process. The new steroidal oximes and lactams were examined for their antiproliferative activities against several tumor cell lines. The 6,23‐dihydroxyimino derivative exhibited the highest activity with GI50 values of 11–22 &mgr;M.

Unprecedented spiro-annelated sugar isoureas, guanidines and amidines as new families of glycosidase inhibitors

We report the synthesis and evaluation of the hitherto unknown spiranic isoureas, guanidines and amidines derived from carbohydrates as novel glycosidase inhibitors. The effect of the heterocyclic moiety and its substituents on the inhibition was studied, and as a result, a potent α-galactosidase inhibitor (Ki 35 μM) bearing an isoureido motif was achieved.

Epimerization of C-22 in (25R)- and (25S)-sapogenins.

Most of the naturally occurring steroidal sapogenins (C-23 non-substituted frameworks), possess an R configuration at the spiro C-22 center. Their C-22 epimers have become important targets in biological research. This paper describes a procedure to obtain 22S-spirostans from 22R-sapogenins and pseudosapogenin skeletons, without affecting the chirality at either C-25 or C-20. An optimal way to synthesize the pair of C-22 stereoisomers of 23-acetyldiosgenin is also reported. The latter was obtained from a 22,26-epoxycholestane or from 23-acetylfurostene compounds.

CHAPTER 3:Synthesis of Organoselenium Derivatives of Biological Relevance

Herein we report recent contributions to the synthesis of organoselenium derivatives featured with relevant biological properties. They are classified into structural families, and the most significant examples are considered (isoselenocyanates, selenoureas, selenocarbamates, selenosugars, and heterocyclic derivatives). This information can be of interest in biological areas ranging from biochemistry to medicinal chemistry.