Alfonso Lira-Rocha

Role of Allyl Group in the Hydroxyl and Peroxyl Radical Scavenging Activity of S-Allylcysteine

S-Allylcysteine (SAC) is the most abundant compound in aged garlic extracts, and its antioxidant properties have been demonstrated. It is known that SAC is able to scavenge different reactive species including hydroxyl radical (•OH), although its potential ability to scavenge peroxyl radical (ROO•) has not been explored. In this work the ability of SAC to scavenge ROO• was evaluated, as well as the role of the allyl group (-S-CH(2)-CH═CH(2)) in its free radical scavenging activity. Two derived compounds of SAC were prepared: S-benzylcysteine (SBC) and S-propylcysteine (SPC). Their abilities to scavenge •OH and ROO• were measured. A computational analysis was performed to elucidate the mechanism by which these compounds scavenge •OH and ROO•. SAC was able to scavenge •OH and ROO•, in a concentration-dependent way. Such activity was significantly ameliorated when the allyl group was replaced by benzyl or propyl groups. It was shown for the first time that SAC is able to scavenge ROO•.

Receptor-binding studies of 1-N-substituted melatonin analogues

In order to analyse the relevance of the indole electronic region in the binding of melatonin to its receptors, we prepared several analogues with p-H, p-NO(2), p-MeO, p-F and p-Me of benzyl, benzoyl and phenyl substituents at position 1 of the melatonin skeleton. The electronic properties of the analogues, as calculated with the semiempirical method AM1, were correlated with their affinity for the melatonin receptor from chicken brain membranes. Different trends were observed for each compound series. Compound 5c, with a p-NO(2)-benzoyl group, showed the best affinity indicating the importance of a polar bulky group in the receptor interaction.

Molecular modeling of tricyclic compounds with anilino substituents and their intercalation complexes with DNA sequences

Although 9-anilinoacridines are among the best studied antitumoral intercalators, there are few studies about the effect of isosteric substitution of a benzene moiety for a heterocycle ring in the acridine framework. According to these studies, this approach may lead to effective cytotoxic agents, but good cytotoxic activity depends on structural requirements in the aniline ring which differ from those in 9-anilinoacridines. The present paper deals with molecular modeling studies of some 9-anilino substituted tricyclic compounds and their intercalation complexes (in various DNA sequences) resulting from docking the compounds into various DNA sequences. As expected, the isosteric substitution in 9-anilinoacridines influences the LUMO energy values and orbital distribution, the dipole moment, electrostatic charges and the conformation of the anilino ring. Other important differences are observed during the docking studies, for example, changes in the spatial arrangement of the tricyclic nucleus and the anilino ring at the intercalation site. Semiempirical calculations of the intercalation complexes show that the isosteric replacement of a benzene ring in the acridine nucleus affects not only DNA affinity but also base pair selectivity. These findings explain, at least partially, the different structural requirements observed in several 9-anilino substituted tricyclic compounds for cytotoxic activity. Thus, the data presented here may guide the rational design of new agents with different DNA binding properties and/or a cytotoxic profile by isosteric substitution of known intercalators.

Anxiolytic-like effects of a new 1-N substituted analog of melatonin in pinealectomized rats

In spite of the wide variety of drugs available for treating anxiety, this disorder continues to represent a worldwide health problem that is classified within the first 10 causes of disability. Therefore, the search continues for new antianxiety agents, particularly those not related to benzodiazepines. Even though melatonin has been prescribed as an anxiolytic drug, its use is currently limited due to its short half-life and photo-sensitivity, among other disadvantages. The present study explores the antianxiety properties of a new 1-N substituted melatonin analog, M3C, in pinealectomized rats submitted to two behavioral tests (the cumulative burying behavior paradigm and the elevated plus-maze). Results from both tests show that M3C is effective as an anxiolytic-like agent, at doses lower than any other melatonin analog previously reported. The blocking of these actions by luzindole together with the available data suggests that the anxiolytic properties of M3C are mediated by MT1 and MT2 receptors.

Polyhydroxyagarofuran derivatives from Rzedowskia tolantonguensis

Abstract The structures of Rzedowskins A, B, C and D, new sesquiterpenes of the polyhydroxyagarofuran-type and constituents of Rzedowskia tolantonguensis, were established by chemical and spectroscopic methods.

Behavioural actions of two new 1-N substituted analogues of melatonin

Melatonin has been mainly used for alleviating some disorders related with insomnia and circadian rhythmicity. The use of this hormone has been limited, among others, due to its short half-life and instability. This study reports some behavioural actions of two new melatonin analogues that incorporate a phenyl or a benzoyl group at the nitrogen atom of the melatonin molecule. Although diazepam was about 10 times more potent than either of the melatonin analogues, results show that in general these last display better anxiolytic, anticonvulsant and sedative actions than the original molecule.

Proteomic Profiling Reveals the Induction of UPR in Addition to DNA Damage Response in HeLa Cells Treated With the Thiazolo[5,4-b]Quinoline Derivative D3ClP.

9‐[(3‐chloro)phenylamine]‐2‐[3‐(diethylamine)propylamine]thiazolo[5,4‐b]quinolone (D3ClP) is a bioisostere of N‐(4‐(acridin‐9‐ylamino)‐3‐methoxyphenyl)methanesulfonamide (m‐AMSA) a DNA topoisomerase II inhibitor with proven cytotoxic activity and known to induce DNA damage and apoptotic cell death in K562 cells. However, recent evidence is not consistent with DNA topoisomerase II (DNA TOP2) as the primary target of D3ClP, in contrast to m‐AMSA. We provide evidence of histone γH2AX phosphorylation at Ser135 in HeLa cells treated with D3ClP, a marker of DNA double strand repair through Mre11‐Rad50‐Nbs1 (MRN) pathway. Using two‐dimensional gel electrophoresis and mass spectrometry, the upregulation of the protein GRP78, the cleavage of Cytokeratin 18, and the downregulation of prothymosine, calumenin, and the α chain of the nascent polypeptide associated complex were observed in HeLa cells treated with D3ClP. An increase in GRP78 has been related with the onset and progression of the unfolded protein response (UPR), a process aimed to reduce endoplasmic reticulum (ER) stress and protein misfolding. The IRE1‐α dependent splicing of mRNA encoding X‐box binding protein 1 was detected. Microtubule‐associated Proteins 1A/1B, Light Chain 3‐II (LC3b‐II) accumulation was observed, and suggest some involvement of autophagy. The production of the pro‐apoptotic protein DNA‐damage‐inducible protein 153 (GADD‐153) was also detected. These results, are consistent with the induction of the UPR and the DNA‐Damage Response in D3ClP‐treated HeLa cells, and are also consistent with a concurrent apoptotic cell death. J. Cell. Biochem. 118: 1164–1173, 2017.

Synthesis, cytotoxic activity, DNA binding and molecular docking studies of novel 9-anilinothiazolo[5,4-b]quinoline derivatives

Novel thiazolo[5,4-b]quinoline derivatives were prepared with or without a (2-(azacycloalkyl)ethyl)amino substituent at the 2-position. The effect of the substituent at 2-position on cytotoxic activity, DNA-intercalation and cytotoxic properties were evaluated. Substituents at 2-position bearing an aliphatic amine favored cytotoxicity, while removal of these substituents resulted in low or negligible cytotoxic properties. Additionally, the in silico predicted binding mode of the novel compounds into DNA correlated with the experimental intercalation data. These results suggest a strong influence of the substituent at 2-position on the DNA intercalation properties.

A direct synthetic route to fused tricyclic quinolones from 2,3-diaminoquinolin-4(1H)one

Abstract Fused tricyclic heterocycles are useful compounds in many areas of chemistry. In this study, 2,3-diaminoquinolin-4(1H)one (5), a key intermediate for the preparation of tricyclic compounds, was prepared from isatoic anhydride in four steps with high yields under mild conditions and an easy workup, with most of the reactions carried out in aqueous medium. Compound 5 was transformed into a series of tricyclic fused products 8 and 9.