Giovanni Sorba

The tubulin colchicine domain: A molecular modeling perspective

Computational approaches have been increasingly applied to drug design over the past three decades and have already provided some useful results in the discovery of anticancer drugs. Given the increased availability of crystal structures in recent years, a growing number of molecular modeling studies on tubulin have been reported. Herein we present a brief overview of the role played by computational methods in anti‐tubulin research, specifically in the context of colchicine binding agent research. An overview of current structures is reported, along with a brief discussion on the issues associated with the various tubulin isotypes. Finally, a summary of the most recent and relevant results is presented, highlighting the challenges and opportunities faced by researchers in this field.

A Novel Potent Nicotinamide Phosphoribosyltransferase Inhibitor Synthesized via Click Chemistry

The inhibition of NAD synthesis or salvage pathways has been proposed as a novel target for antitumoral drugs. Two molecules with this mechanism of action are at present undergoing clinical trials. In searching for similar novel molecules, we exploited copper-catalyzed [3 + 2] cycloaddition between azides and alkynes (click chemistry) to synthesize 185 novel analogues. The most promising compound displays an IC(50) for cytotoxicity in vitro of 3.8 +/- 0.3 nM and an IC(50) for NAD depletion of 3.0 +/- 0.4 nM. Herein, we strengthen previous data suggesting that this class of compounds induces autophagic cell death. In addition to characterizing this compound and providing a rationale via molecular docking, we reinforce the excellent potential of click chemistry for rapidly generating structure-activity relationships and for drug screening.

Are 1,4- and 1,5-disubstituted 1,2,3-triazoles good pharmacophoric groups?

Over the last decade, 1,2,3‐triazoles have received increasing attention in medicinal chemistry thanks to the discovery of the highly useful and widely applicable 1,3‐dipolar cycloaddition reaction between azides and alkynes (click chemistry) catalyzed by copper salts and ruthenium complexes. After a decade of medicinal chemistry research on 1,2,3‐triazoles, we feel that the time is ripe to demonstrate the real ability of this heterocycle to participate in important and pivotal binding interactions with biological targets while maintaining a good pharmacokinetic profile. In this study, we retrieved and analyzed X‐ray crystal structures of complexes between 1,2,3‐triazoles and either proteins or DNA to understand the pharmacophoric role of the triazole. Furthermore, the metabolic stability, the capacity to inhibit cytochromes, and the contribution of 1,2,3‐triazoles to the overall aqueous solubility of compounds containing them have been analyzed. This information should furnish fresh insight for medicinal chemists in the design of novel bioactive molecules that contain the triazole nucleus.

Computer-aided identification, design and synthesis of a novel series of compounds with selective antiviral activity against chikungunya virus.

Chikungunya virus (CHIKV) is an Arbovirus that is transmitted to humans primarily by the mosquito species Aedes aegypti. Infection with this pathogen is often associated with fever, rash and arthralgia. Neither a vaccine nor an antiviral drug is available for the prevention or treatment of this disease. Albeit considered a tropical pathogen, adaptation of the virus to the mosquito species Aedes albopictus, which is also very common in temperate zones, has resulted in recent outbreaks in Europe and the US. In the present study, we report on the discovery of a novel series of compounds that inhibit CHIKV replication in the low μM range. In particular, we initially performed a virtual screening simulation of ∼5 million compounds on the CHIKV nsP2, the viral protease, after which we investigated and explored the Structure-Activity Relationships of the hit identified in silico. Overall, a series of 26 compounds, including the original hit, was evaluated in a virus-cell-based CPE reduction assay. The study of such selective inhibitors will contribute to a better understanding of the CHIKV replication cycle and may represents a first step towards the development of a clinical candidate drug for the treatment of this disease.

NO donors: Focus on furoxan derivatives

The article focuses attention on furoxan derivatives (1,2,5 oxadiazole 2-oxides) as NO donors. Possible mechanisms for NO release from these products in physiological solution and in segments of rabbit femoral artery are briefly considered. The in vitro anti aggregatory activities and the in vitro and in vivo vasodilating properties of a number of furoxans are examined with particular reference to involvement of NO in these actions. The use of the furoxan system to design new NO donor/drug hybrids is discussed in connection with the problem of the balance between NO- and drug dependent activities of the resulting structures. Whether other biological activities (as yet, little studied) of furoxans, such as their antiparasite, antimicrobial, and antitumoral effects, are NO dependent, is a matter still to be explored.

Replacement of the double bond of antitubulin chalcones with triazoles and tetrazoles: Synthesis and biological evaluation.

In the chalcone scaffold, it is thought that the double bond is an important structural linker but it is likely not essential for the interaction with tubulin. Yet, it may be a potential site of metabolic degradation and interaction with biological nucleophiles. In this letter, we have replaced this olefinic portion of chalcones with two metabolically stable and chemically inert heterocyclic rings, namely triazole or tetrazole. Yet, our biologic data suggest that, unlike in other antitubulinic structures, the olephinic ring might not be merely a structural linker.

Synthesis and biological evaluation of isosteric analogues of FK866, an inhibitor of NAD salvage.

One of the great challenges of medicinal chemistry is to create novel, effective, chemotherapeutic agents that show specificity for cancer cells combined with low systemic toxicity. A novel idea is to target the enzymes of the NAD biosynthesis and recycling pathways given that cancer cells display a higher NAD turnover rate than healthy cells. To this end, the compound FK866 (APO866; (E)‐N‐[4‐(1‐benzoylpiperidin‐4‐yl) butyl]‐3‐(pyridin‐3‐yl) acrylamide), which blocks nicotinamide phosphoribosyltransferase (NMPRTase) has entered clinical trials as a potential chemotherapeutic agent. Here we report the synthesis of analogues of FK866 synthesized by click chemistry.

Solution-Phase Parallel Synthesis and Biological Evaluation of Combretatriazoles

Combretastatin A-4 is an antitumoral and antitubulin agent that is active only in its cis configuration. In the present manuscript, we have synthesized cis-locked combretastatins containing a triazole ring (combretatriazoles). To achieve this, we have developed a column chromatography-free parallel solution-phase synthesis that exploits the reaction between azides and alpha-keto phosphorus ylids, which is known to regioselectively generate the 1,5-disubstituted triazoles. The prepared compounds were screened as antitubulinic agents, allowing us to identify three new compounds with high potency, two of which show a new mechanism of action that induces cells to appear multinucleated and display a high number of mitotic spindles.

Synthesis, Biological Evaluation, and Molecular Docking of Ugi Products Containing a Zinc-Chelating Moiety as Novel Inhibitors of Histone Deacetylases

HDAC inhibitors show great promise for the treatment of cancer. As part of a broader effort to explore the SAR of HDAC inhibitors, synthesis, biological evaluation, and molecular docking of novel Ugi products containing a zinc-chelating moiety are presented. One compound shows improved inhibitory potencies compared to SAHA, demonstrating that hindered lipophilic residues grafted on the peptide scaffold of the alpha-aminoacylamides can be favorable in the interaction with the enzyme.

Estrogenic Analogues Synthesized by Click Chemistry

The estrogen receptors, responsible for the effects of this hormone, are known to be able to recognize nonsteroidogenic molecules, and this has led to the development of molecules with therapeutic potential. The phenomenon of nonsteroidal ligands of the estrogen receptors is also thought to play a major role in food and environmental sciences, with the winepolyphenol resveratrol and the insecticide DDT thought to act as estrogenic substances. It is therefore evident that it is of great interest to develop specific nonsteroidal substances that interfere with the estrogen receptors in a receptor-specific and/or tissue-specific manner and that display agonistic, antagonistic, or partial agonistic properties. Indeed, a number of strategies have been or could be employed to generate new structures, namely the screening of existing chemical libraries, the screening of natural compound libraries, novel modifications of known compounds with estrogenic potential, or the de novo generation of chemical libraries using rapid synthetic methods. Click chemistry is an increasingly common method for rapid synthesis of novel biologically active compounds. This term, coined by Barry K. Sharpless, now refers to reactions yielding the product in high yield without the need for further purification, without generating offensive byproducts, and operating in a benign solvent, usually water. In this way, it is possible to generate a plethora of new compounds reliably and thereby accelerate the process of drug discovery. Briefly, the paradigmatic “click” reaction is the [3+2] cycloaddition between an azide and an alkyne in the presence of copper (I) salts which generate the 1,4 disubstituted 1H-1,2,3-triazole ring in excellent yield. Three distinct observations have drawn our attention to the possibility of applying click chemistry to the synthesis of ER ligands: 1) reports that a pyrazole core can be used to build compounds that are ER ligands, 2) the successful bioisosteric replacement of pyrazole with a triazole in fibronil, an insecticide acting as a GABA receptor antagonist, and 3) our report that several resveratrol analogues synthesized by click chemistry retain estrogen-like activity. We have therefore used the archetypical [3+2] azide-alkyne cycloaddition to link two phenol rings, bearing the hydroxyl moieties in different positions, with a distance comparable to estradiol or diethylstilbestrol. Azides (1–3, Figure 1) were obtained by reacting commercially available amine phenols, via diazonium salt, with sodium azide. The desired ethynyl phenols (4–6, Figure 1) were ob-