Adriana Chilin

Coumarin as attractive casein kinase 2 (CK2) inhibitor scaffold: an integrate approach to elucidate the putative binding motif and explain structure-activity relationships.

Casein kinase 2 (CK2) is an ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Recently, using different virtual screening approaches, we have identified several novel CK2 inhibitors. In particular, we have discovered that coumarin moiety can be considered an attractive CK2 inhibitor scaffold. In the present work, we have synthetized and tested a small library of coumarins (more than 60), rationalizing the observed structure-activity relationship. Moreover, the most promising inhibitor, 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC), has been also crystallized in complex with CK2, and the experimental binding mode has been used to derive a linear interaction energy (LIE) model.

Using the TOPS-MODE approach to fit multi-target QSAR models for tyrosine kinases inhibitors.

Tyrosine kinases constitute an eligible class of target for novel drug discovery. They resulted often overexpressed and/or deregulated in several cancer diseases. Thus, the development of novel tyrosine kinases inhibitors is of value, as well as the finding of novel cheminformatic tools for their design. Among the different ways to rationally design novel compounds, the Quantitative Structure-Activity Relationship (QSAR) plays a key role. The QSAR approach, in fact, allow the prediction of activity against a number of targets (multi-target QSAR), thus leading to models able to predict not only the activity of a compound, but also its selectivity versus a set of targets. Despite it is well known that tyrosine kinase inhibitors have to show multi-kinases inhibitory potency to be useful in anticancer therapy, only few multi-target computational tools have been developed to help medicinal chemists in the design of novel compounds. Herein we present the development of several multi-target classification QSAR (mtc-QSAR) models useful to assess the activity profile of the tyrosine kinases inhibitors.

Exploring Epidermal Growth Factor Receptor (EGFR) Inhibitor Features: The Role of Fused Dioxygenated Rings on the Quinazoline Scaffold

A number of dioxolane, dioxane, and dioxepine quinazoline derivatives have been synthetized and evaluated as EGFR inhibitors. Their cytotoxic activity has been tested against two cell lines overexpressing and not expressing EGFR. Most derivatives were able to counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound PD153035. The size of the fused dioxygenated ring was crucial for the biological activity, the dioxane derivatives being the most promising class of this series.

Synthesis and antitumor activity of novel amsacrine analogs: the critical role of the acridine moiety in determining their biological activity.

A new series of N-[4-(2-oxo-2H-pyrano[2,3-b]quinolin-5-ylamino)-phenyl]-methanesulfonamides was prepared and analyzed as novel amsacrine-like derivatives. Our preliminary biological evaluation has shown that the replacement of the acridine moiety with the analogous 2-oxo-2H-pyrano[2,3-b]quinoline system drastically reduced both their anticancer activity and their propency to intercalate into double stranded DNA.

Quinazoline derivatives as potential anticancer agents: a patent review (2007 - 2010).

Introduction : Due to the increase in knowledge about cancer pathways, there is a growing interest in finding novel potential drugs. Quinazoline is one of the most widespread scaffolds amongst bioactive compounds. A number of patents and papers appear in the literature regarding the discovery and development of novel promising quinazoline compounds for cancer chemotherapy. Although there is a progressive decrease in the number of patents filed, there is an increasing number of biochemical targets for quinazoline compounds. Areas covered : This paper provides a comprehensive review of the quinazolines patented in 2007 – 2010 as potential anticancer agents. Information from articles published in international peer-reviewed journals was also included, to give a more exhaustive overview. Expert opinion : From about 1995 to 2006, the anticancer quinazolines panorama has been dominated by the 4-anilinoquinazolines as tyrosine kinase inhibitors. The extensive researches conducted in this period could have caused the progressive reduction in the ability to file novel patents as shown in the 2007 – 2010 period. However, the growing knowledge of cancer-related pathways has recently highlighted some novel potential targets for therapy, with quinazolines receiving increasing attention. This is well demonstrated by the number of different targets of the patents considered in this review. The structural heterogeneity in the patented compounds makes it difficult to derive general pharmacophores and make comparisons among claimed compounds. On the other hand, the identification of multi-target compounds seems a reliable goal. Thus, it is reasonable that quinazoline compounds will be studied and developed for multi-target therapies.

Microwave-promoted mono-N-alkylation of aromatic amines in water: a new efficient and green method for an old and problematic reaction

A greener improvement to direct mono-N-alkylation of aromatic amines by alkyl halides was achieved using microwave irradiation in water without any catalyst.

Quinazoline-based multi-tyrosine kinase inhibitors: synthesis, modeling, antitumor and antiangiogenic properties

In this work the synthesis and the biological evaluation of some novel anilinoquinazoline derivatives carrying modifications in the quinazoline scaffold and in the aniline moiety were reported. Preliminary cytotoxicity studies identified three derivatives, carrying dioxygenated rings fused on the quinazoline portion and the biphenylamino substituent as aniline portion, as the most effective compounds. Further investigations revealed that these compounds exhibited antiproliferative activity on a wide panel of human tumor cell lines through the inhibition of both receptor and nonreceptor TKs. Furthermore, the compound bearing the dioxolane nucleus was also able to inhibit inxa0vivo tumor growth. Molecular modeling of these compounds into kinase domain suggested that the phenyl group allows favorable interaction energies with the target proteins: this feature is favored by fused dioxygenated ring at the 6,7 positions, whereas free rotating functions do not allow the correct placement of the molecule, thus impairing the inhibitory potency. Finally, the biphenylamino derivatives, at noncytotoxic concentrations, acted as antiangiogenic agents both in inxa0vitro and inxa0vivo assays.

Development of a novel furocoumarin derivative inhibiting NF-κB dependent biological functions: design, synthesis and biological effects.

Nuclear Factor kappaB (NF-κB) plays a very important role in the control of gene expression and is deeply involved in several human pathologies. Accordingly, molecules targeting NF-κB dependent biological functions are considered of great interest. Virtual screening of furocoumarin libraries against NF-κB p50 allowed to rank compounds in respect to their expected ability to bind NF-κB and the identified compound might be considered for the development of analogs to be tested for biological activity on inhibition of NF-κB/DNA complex formation. The data reported in the present paper suggest that, following this approach, the best ranked compounds identified by virtual screening (a) strongly bind in silico to NF-κB and (b) efficiently inhibit the molecular interactions between (32)P-labeled NF-κB double stranded DNA and p50 or p50/p65 complex. These data allowed to develop a novel lead of great interest for inhibiting NF-κB dependent biological functions. This novel molecule (compound 2), bearing a methyl group in the 9 position of the psoralen nucleus, exhibits high efficiency in inhibiting NF-κB/DNA interactions. In addition, we found that compound 2 is a potent inhibitor of IL-8 gene expression in TNF-α treated IB3-1 cystic fibrosis cells. Taken together, our data indicate that compound 2 might find an important place in the set of molecules of interest for the development of pharmaceutical strategies against the inflammatory phenotype of cystic fibrosis.

DNA damage induced by 4,6,8,9-tetramethyl-2H-furo[2,3-h]quinolin-2-one, a new furocoumarin analog: biological consequences.

Abstract 4,6,8,9-Tetramethyl-2H-furo[2,3-h]quinolin-2-one (HFQ) and its isomer FQ (1,4,6,8-tetramethyl-2H-furo[2,3-h]quinolin-2-one) showed very strong antiproliferative activity in mammalian cells, about two times greater than 8-methoxypsoralen (8-MOP). Both compounds induced DNA–protein cross-links (DPC) but not interstrand cross-links. The FQ generated DPC in a biphotonic process, yielding a new kind of diadduct, whereas HFQ induced DPC by a monophotonic one, probably without its physical participation in the covalent bridge. These lesions gave different toxic responses. Sensitization of FQ led to extensive DNA fragmentation and to a number of chromosomal aberrations. Conversely, HFQ seemed to be completely inactive and 8-MOP gave intermediate results. A strict relationship between DPC formation and induction of chromosomal aberrations was observed. The HFQ did not induce light skin erythemas, whereas FQ was more phototoxic than 8-MOP, thus suggesting that FQ lesions, DPC in particular, may be implicated in skin phototoxicity. Ehrlich ascites cells, a transplantable mouse tumor, inactivated by furoquinolinone sensitization and injected into healthy mice, protected them from a successive challenge by viable tumor cells. This response appeared to be based on an immune mechanism. Comparable amounts of base substitution revertants were scored when testing furoquinolinones and 8-MOP in bacteria but no DPC were detected. This suggests that classic mutagenesis tests on bacteria are insufficient to give adequate information on furocoumarin genotoxicity. Given its features, HFQ can be regarded as an interesting new agent for psoralen plus UVA photochemotherapy and photopheresis.

Psoralen derivatives as inhibitors of NF-κB/DNA interaction: synthesis, molecular modeling, 3D-QSAR, and biological evaluation.

Some new psoralen derivatives were synthesized and evaluated as inhibitors of NF-κB/DNA interaction, with the aim to investigate the structural determinants required to inhibit this interaction. Starting from molecular docking studies, several possible protein binding sites were proposed and several three-dimensional quantitative structure-activity relationship (3D-QSAR) models were built using the docked poses of 29 (the most active psoralen in the series) as templates for alignment of the inhibitors. The selected best model was validated through the prediction of the activity of 17 novel compounds. All the experimental data agreed with the computational experiments, supporting the reliability of the computational approach. The hypothesis about the interaction with NF-κB was also supported by surface plasmon resonance based assays using compound 29. All the collected data allowed the identification of compound 29 as a potential candidate for the development of pharmaceutical strategies against the inflammatory phenotype of cystic fibrosis.