M. Teresa Ramos

Cerium(IV) ammonium nitrate is an excellent, general catalyst for the Friedländer and Friedländer-Borsche quinoline syntheses: very efficient access to the antitumor alkaloid luotonin A.

The use of cerium(IV) ammonium nitrate as a catalyst of the Friedländer reaction allows the synthesis of polysubstituted quinoline derivatives in excellent yields, avoiding the traditional harshly basic or acidic conditions. Unlike most other previously known reagents, CAN allows double condensations and is also an excellent catalyst for the Borsche variation of the Friedländer reaction, which has been applied to the very efficient synthesis of the antitumor alkaloid luotonin A.

An Overview of Analytical Techniques Employed to Evidence Drug-DNA Interactions. Applications to the Design of Genosensors

The demonstration of the existence of non-covalent bonding interactions between different biomolecules (DNA, enzymes, proteins) and drugs or potentially mutagenic agents requires sensitive analytical techniques. Technological advances in key techniques, together with the miniaturization in fluorescence or surface plasmons resonance techniques, have allowed obtaining information in real time concerning the nature, the localization and the strength of drug-DNA interactions. The present chapter describes these analytical techniques and their application to achieve two fundamental goals, namely a deeper knowledge of the nature of the interactions and their application to the design of different devices (aptamers, molecular beacons, DNA-arrays, genosensors) consisting of short single stranded oligonucleotides produced in vitro by well-established methods (polymerase chain reaction, PCR; systematic evolution of ligands by exponential enrichment, SELEX,...) that are capable to detect genetic peculiarities and diseases, biological entities (micro-organisms, genetically modified seeds...) and also genotoxic agents in the environment and in foodstuffs.

Efficient synthesis of 2-acylquinolines based on an aza-vinylogous Povarov reaction

The aza-vinylogous Povarov reaction between α-ketoimines and α,β-unsaturated dimethylhydrazones in the presence of indium trichloride affords 2-acyl-4-alkyl-4-dimethylhydrazonomethyl-1,2,3,4-tetrahydroquinolines with good cis/trans diastereoselectivities. These compounds were readily transformed into highly substituted 2-acylquinolines using a two-reaction sequence involving the oxidative generation of a C-4 nitrile group, followed by its elimination under thermal conditions. Alternatively, a one-pot protocol based on the reaction of hydrazones with magnesium monoperoxyphthalate hexahydrate in refluxing methanol afforded the target 2-acylquinolines in good to excellent yields. This methodology was also extended to the preparation of 2-arylquinolines.

B-ring-aryl substituted luotonin A analogues with a new binding mode to the topoisomerase 1-DNA complex show enhanced cytotoxic activity.

Topoisomerase 1 inhibition is an important strategy in targeted cancer chemotherapy. The drugs currently in use acting on this enzyme belong to the family of the camptothecins, and suffer severe limitations because of their low stability, which is associated with the hydrolysis of the δ-lactone moiety in their E ring. Luotonin A is a natural camptothecin analogue that lacks this functional group and therefore shows a much-improved stability, but at the cost of a lower activity. Therefore, the development of luotonin A analogues with an increased potency is important for progress in this area. In the present paper, a small library of luotonin A analogues modified at their A and B rings was generated by cerium(IV) ammonium nitrate-catalyzed Friedländer reactions. All analogues showed an activity similar or higher than the natural luotonin A in terms of topoisomerase 1 inhibition and some compounds had an activity comparable to that of camptothecin. Furthermore, most compounds showed a better activity than luotonin A in cell cytotoxicity assays. In order to rationalize these results, the first docking studies of luotonin-topoisomerase 1-DNA ternary complexes were undertaken. Most compounds bound in a manner similar to luotonin A and to standard topoisomerase poisons such as topotecan but, interestingly, the two most promising analogues, bearing a 3,5-dimethylphenyl substituent at ring B, docked in a different orientation. This binding mode allows the hydrophobic moiety to be shielded from the aqueous environment by being buried between the deoxyribose belonging to the G(+1) guanine and Arg364 in the scissile strand and the surface of the protein and a hydrogen bond between the D-ring carbonyl and the basic amino acid. The discovery of this new binding mode and its associated higher inhibitory potency is a significant advance in the design of new topoisomerase 1 inhibitors.

A straightforward synthesis of didehydro analogues of N-acetylardeemin

The didehydro analogue of N-acetylardeemin 1b was synthesised in a seven step process that started with tryptamine. A regioselective oxidation of the 2-substituted precursor 3b, followed by a diastereoselective anti-cyclization reaction involving an acyliminium intermediate formed from the unisolated tosylate 2b, is the key-step of this strategy. Application of this procedure to 3a afforded, instead of the cyclization product, the cis-1-hydroxy derivative 2c which, after acid treatment, gave a 6/4 mixture of trans- and cis-isomers of the hexacyclic compound 1a.

Synthesis of 5-N-acetylardeemin seco-analogues

Abstract Piperazinediones derived from ehtyl N -indolylmethyl- glicinate or L-alaninate and different α-amino esters were cyclized with anthranilic acid in two steps with retention of configuration of the stereocenters to afford compounds which are analogues of 5- N -acetylardeemin, a MDR reversal agent.

ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia

During brain ischemia, oxygen and glucose deprivation induces calcium overload, extensive oxidative stress, neuroinflammation, and, finally, massive neuronal loss. In the search of a neuroprotective compound to mitigate this neuronal loss, we have designed and synthesized a new multitarget hybrid (ITH14001) directed at the reduction of calcium overload by acting on two regulators of calcium homeostasis; the mitochondrial Na+/Ca2+ exchanger (mNCX) and L-type voltage dependent calcium channels (VDCCs). This compound is a hybrid of CGP37157 (mNCX inhibitor) and nimodipine (L-type VDCCs blocker), and its pharmacological evaluation revealed a moderate ability to selectively inhibit both targets. These activities conferred concentration-dependent neuroprotection in two models of Ca2+ overload, such as toxicity induced by high K+ in the SH-SY5Y cell line (60% protection at 30 μM) and veratridine in hippocampal slices (26% protection at 10 μM). It also showed neuroprotective effect against oxidative stress, an activity related to its nitrogen radical scavenger effect and moderate induction of the Nrf2-ARE pathway. Its Nrf2 induction capability was confirmed by the increase of the expression of the antioxidant and anti-inflammatory enzyme heme-oxygenase I (3-fold increase). In addition, the multitarget profile of ITH14001 led to anti-inflammatory properties, shown by the reduction of nitrites production induced by lipopolysaccharide in glial cultures. Finally, it showed protective effect in two acute models of cerebral ischemia in hippocampal slices, excitotoxicity induced by glutamate (31% protection at 10 μM) and oxygen and glucose deprivation (76% protection at 10 μM), reducing oxidative stress and iNOS deleterious induction. In conclusion, our hybrid derivative showed improved neuroprotective properties when compared to its parent compounds CGP37157 and nimodipine.

Synthesis of Polysubstituted, Functionalized Quinolines through a Metal-Free Domino Process Involving a C4–C3 Functional Group Rearrangement

4-Alkyl-1,2,3,4-tetrahydroquinolines bearing a 4-vinyl unit ending in an electron-withdrawing group were efficiently transformed into polysubstituted, C(3)-functionalized quinolines upon heating in refluxing o-dichlorobenzene, in a domino reaction involving an unusual C(4)-C(3) functional group rearrangement.