Search

N-heterocyclic carbenes (NHCs) represent suitable ligands for rapid and efficient drug design, because they offer the advantage of being easily chemically modified and can bind several substituents, including transition metals as, for instance, gold derivatives. Gold-NHC complexes possess various biological activities and were demonstrated good candidates as anticancer drugs. Besides, carbazole derivatives are characterized by various pharmacological properties, such as anticancer, antibacterial, anti-inflammatory, and anti-psychotropic. Amongst the latter, N-thioalkyl carbazoles were proved to inhibit cancer cells damaging the nuclear DNA, through the inhibition of human topoisomerases. Herein, we report the design, synthesis and biological evaluation of nine new hybrid molecules in which NHC-Au(I) complexes and N-alkylthiolated carbazoles are linked together, in order to obtain novel biological multitarget agents. We demonstrated that the lead hybrid complexes possess anticancer, anti-inflammatory and antioxidant properties, with a high potential as useful tools for treating distinct aspects of several diseases, amongst them cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

3-(Alkyl(dialkyl)amino)benzothieno[2,3-f]quinazolin-1(2H)-ones (4-9) have been designed using Ellipticine structure as a model, replacing the carbazole core and the pyridine ring with a dibenzothiophene and a pyrimidine moiety, respectively. New benzothienoquinazolinones (4-9) have been synthesized by a simple one-pot reaction employing 3-aminodibenzothiophene as starting material. The benzothienoquinazolinones obtained (4-9), were evaluated for their anticancer activity against two breast cancer cell lines, MDA-MB-231 and MCF-7. The results revealed that compounds 4 and 7 presented a good antitumor activity toward the triple negative MDA-MB-231, without cytotoxicity against non-tumoral cells. Furthermore, the compounds 4 and 7 can be considered important molecular multi-target tools for their dual inhibition of different cellular proteins, i.e. Tubulin and human Topoisomerase I, involved in relevant cellular processes, as predicted by in silico studies and demonstrated by in vitro assays (for compound 4)., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A series of unknown 3-(alkyl(dialkyl)amino)benzofuro[2,3-f]quinazolin-1(2H)-ones 4-17 has been synthesized as new ellipticine analogs, in which the carbazole moiety and the pyridine ring were replaced by a dibenzofuran residue and a pyrimidine ring, respectively. The synthesis of these benzofuroquinazolinones 4-17 was performed in a simple one-pot reaction using 3-aminodibenzofuran or its 2-methoxy derivative, as starting materials. From 3-(dipropylamino)-5-methoxybenzofuro[2,3-f] quinazolin-1(2H)-one (13), we prepared 3-(dipropylamino)-5-hydroxybenzofuro[2,3-f]quinazolin-1(2H)-one (18), referred to as DPA-HBFQ-1. The cytotoxic activities of all the synthesized compounds, tested in different human breast cancer cell lines, revealed that DPA-HBFQ-1 was the most active compound. In particular, the latter was able to inhibit anchorage-dependent and -independent cell growth and to induce apoptosis in estrogen receptor alpha (ERα)-positive and -negative breast cancer cells. It did not affect proliferation and apoptotic responses in MCF-10A normal breast epithelial cells. The observed effects have been ascribed to an enhanced p21(Cip1/WAF1) expression in a p53-dependent manner of tumor suppressor and to a selective inhibition of human topoisomerase II. In addition, DPA-HBFQ-1 exerted growth inhibitory effects also in other cancer cell lines, even though with a lower cytotoxic activity. Our results indicate DPA-HBFQ-1 as a good candidate to be useful as cancer therapeutic agent, particularly for breast cancer., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

This paper reports the synthesis and cardiac activity of new β-blockers derived from (Z/E)-indeno[1,2-c]pyrazol-4(1H)-one oximes (5a,b). The latter compounds were allowed to react with epichlorohydrin, followed by reacting the oxiranyl derivatives formed (6a,b) with some aliphatic amines to give the target compounds (Z/E)-1-phenyl-1H-indeno[1,2-c]pyrazol-4-one O-((2-hydroxy-3-(substituted amino)propyl)oxime (7a-c) and (Z/E)-1-methyl-1H-indeno[1,2-c]pyrazol-4-one O-((2-hydroxy-3-(substituted amino)propyl)oxime (8a-c). These final products 7a-c and 8a-c were evaluated for their ability to modulate the cardiac performance of a prototype mammalian heart. The results showed that, out of these molecules tested, 7b elicits a more potent depressant effect on contractility and relaxation, and competitively antagonizes β1-adrenergic receptors., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

A new series of 5-substituted oxazolidinones derived from linezolid, having urea and thiourea moieties at the C-5 side chain of the oxazolidinone ring, were prepared and their in vitro antibacterial activity was evaluated. The compound 10f demonstrated high antimicrobial activity, comparable to that of linezolid against Staphylococcus aureus., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The signalling pathway of Janus tyrosine Kinases-Signal Transducers and Activators of Transcription (JAK-STAT) is activated by a number of cytokines, hormones (GH, erythropoietin and prolactin), and growth factors. JAK-STAT signalling is involved in regulation of cell proliferation, differentiation and apoptosis. These activities are due to different members of JAK-STAT family consisting of: JAK1, JAK2, JAK3, Tyk2 and STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6. Recent studies suggest a key role for STAT family proteins, in particular for STAT3, in selectively inducing and maintaining a pro-carcinogenic inflammatory microenvironment, that promote tumour cells transformation. Moreover, a striking correlation between cancer development/progression and STAT3 persistent activation exists, probably due to STAT3 promoting of the pro-oncogenic inflammatory pathways, like NF-kB, IL-6 and JAK family kinases. Recent study demonstrated that carbazoles can inhibit STAT3 mediated transcription. From these evidences, STAT3 represents a therapeutic target, so we have synthesized a new set of N-alkylcarbazole derivatives substituted in positions 2, 4 and 6, to evaluate their activity on STAT3. Some of these compounds showed an interesting activity as STAT3 selective inhibitors; in particular, compounds 9a 9b and 9c revealed to inhibit the STAT3 activation for the 50%, 90% and 95%, respectively., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Five titanocene derivatives and one zirconium analogous, having cyclopentadienylethenylmethoxy ligand, were synthesized and fully characterized by NMR, FT-IR, and elemental analysis. Two of these complexes showed a good cytotoxic activity on human breast cancer (MCF-7) cell lines. Moreover, the half-titanocene disclosed also a good cytotoxic activity on human embryonic kidney (HEK-293). Additionally, a study on the rate of hydrolysis of these compounds showed that the leaving groups significantly affect the rate of hydrolysis of cyclopentadienyl groups too. The different activity of synthesized compounds was tentatively related to the rate of hydrolysis., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Complexes of scandium, yttrium, samarium and neodymium bearing monoanionic tridentate ancillary ligands have been synthesized and characterized. The cytotoxic activities of novel compounds, as well as that of similar compounds previously reported have been evaluated on rat glioma (C6), murine fibrosarcoma (WHEI-164) and human embryonic kidney (HEK-293) cell lines. Scandium complex with quinolinephenoxyamine (NNHO) ligand showed very interesting activity against C6 cell line., (2010 Elsevier Masson SAS. All rights reserved.)

A series of novel N(3/8)-disubstituted-3,8-diazabicyclo[3.2.1]octanes in order to improve the in vitro activity of the prototype 3,8-bis[2-(3,4,5-trimethoxyphenyl)pyridyl-4-yl)methylpiperazine (1) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines. Compounds 2a,b,f and m demonstrated not only growth-inhibitory activities against leukemia cancer cells, but also fairly good activities against the growth of certain solid tumors. Among them, 2a is the most potent one with IC(50) values in the low micromolar range. Moreover, compound 2a has been selected for in vitro testing on MCF-7 cell to evaluate the mode of action of this lead compound.