Paola Corona

Among a new series of 28 3-carboxy or carbethoxy quinoxalines bearing a substituted benzylamino or N-[4-(aminomethyl)benzoyl]glutamate group on position 2 of the ring and various substituents at C-6, 7 positions, 21 were selected at the National Cancer Institute for evaluation of their in vitro anticancer activity. The results obtained seem to confirm that the carboxy or carbethoxy group on position 3 is not helpful, with a few exceptions, for the anticancer activity.

A series of novel 5,7-diamino-3-phenyl-2-benzylamino, 2-phenoxy, and 2-thiophenyl substituted quinoxalines has been designed, synthesized and evaluated for their in vitro antitumor activity towards cell lines of nine different types of human cancers. Some of these compounds exhibited inhibitory effects on the growth of a wide range of cancer cell lines generally at 10(-6) M, in some cases at 10(-7) M and 10(-8) M concentrations. Within this series the benzylamino quinoxaline derivatives 1b-7b were the most active, whereas compound 2c showed the highest MG_MD value (-5.66).

Fifteen imidazo[1,2-a] and [1,2,4]triazolo[4,3-a]quinoxalines were prepared. These compounds bear at position 4 various substituents related to the moieties present in classical and non-classical antifolic agents. And we evaluated in vitro antimicrobial, antiviral and antiproliferative activities. In particular, title compounds were evaluated in vitro against representative strains of Gram-positive and Gram-negative bacteria (S. aureus, Salmonella spp.), mycobacteria (M. fortuitum, M. smegmatis ATCC 19420 and

Department of Medicinal and Toxicological Chemistry, University of Sassari, Via Muroni 23/a, 07100 Sassari, Italy Abstract: Angular N-tricyclic systems as triazolo[4,5-f]quinolines, triazolo[4,5-h]quinolines, imidazo[4,5-f]quinolines, imidazo[4,5-h]quinolines were in the ...

Twenty eight pyrrolo[1,2-a]quinoxalines bearing at position 4 various substituents related to the moieties present in classical and non classical antifolic agents were prepared and evaluated in vitro for antiproliferative activity. In an in vitro screening performed at NCI, several compounds emerged as potent antiproliferative agents at concentrations ranging between 10 and 100 microM. Interestingly, some of these compounds proved active also against bovine and murine DHFR (Farmaco 53 (1998) 480). More recently, a compound of classical antifolate type has been reported to be a potent inhibitor of hDHFR in vitro (Farmaco 58 (2003) 51). We then synthesized new derivatives that, in our hands, were endowed with in vitro antiproliferative activities as low as 3.4 microM against a panel of cell lines derived from hematological and solid tumours. In addition, a complete screening of cytotoxicity, antiretroviral HIV-1 and antimicrobial activity has been carried out.

Continuing our program of research concerning the antiviral activity of a wide series of new angular and linear azolo bicyclic and tricyclic derivatives, now we have simplified and modified the 4-chloro-2-(4-nitrophenyl)-3H-imidazo[4,5-g]quinoline 1, which previously resulted the most active derivative, through either the elimination of the central ring or the opening of the imidazole ring, obtaining various imidazopyridines and N-benzylidenequinolinamines respectively. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against representatives of two DNA virus families as wells as against representatives of RNA virus families containing single-stranded, either positive-sense (ssRNA(+)) or negative-sense (ssRNA(-)), and double-stranded genomes (dsRNA). Some imidazo[4,5-b]pyridines emerged as new derivatives endowed with antiviral activity against Vaccinia Virus (VV) at concentrations ranging from 2 to 16 μM. In particular, compound 2b demonstrate to be about 10 times more potent than Cidofovir, used as reference drug. Similarly, the imidazo[4,5-c]pyridines and N-benzylidenequinolinamines derivatives resulted active against Bovine Viral Diarrhoea virus (BVDV), at concentrations ranging from 1.2 to 28 μM. Above all compounds 1, 3a and 3f showed an EC50 of the same order of magnitude of the reference drug, the 2'-C-methyl-guanosine. Moreover, several N-benzylidenequinolinamines showed an interesting activity against Respiratory Syncytial Virus (RSV) at concentrations between 12 and 26 μM.

As a follow up of an anti-Flaviviridae project, a new series of variously substituted 2-styryl-benzimidazoles were synthesized and tested in vitro for biological activity. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Pestiviruses and Flaviviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae) as well as for cytotoxicity tests, run in parallel with antiviral assays,against MDBK, BHK and Vero 76 cells. In the series examined, new leads emerged against BVDV, CVB-2 and RSV. Compounds 11, 12, 17, 18, 24, 31 exhibited anti-BVDV activity in the concentration range 1.7-16 microM; among them, compound 17 was the most active, with an EC(50) = 1.7 microM. Compounds 18 and 21 were equally active against CVB-2, with EC(50) values of 7 - 8 microM, while the derivative 30 was active against RSV with EC(50)= 1 microM and represents a new lead compound.

Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase. Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes. Compound 6a displayed a K(i) of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:6a ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds. A second round of design, synthesis, and assay produced a compound (6b) with a significantly improved K(i) ...

Thirty quinoxalines bearing a substituted phenoxy or hydroxybenzoylglutamate group on position 2, a carboethoxy or carboxy group on position 3 and a trifluoromethyl group on position 6 or 7 of the heterocycle were prepared in order to evaluate the in vitro anticancer activity. Screening over 21 compounds selected at the National Cancer Institute (Bethesda, MD) showed that only few derivatives exhibited a moderate growth inhibition activity on various tumor panel cell lines at 10(-4) molar concentration. The acid derivatives showed no growth inhibition activity. The results obtained in this series seem to indicate that in general carboxy or carboethoxy groups close to O-link with phenyl or benzoyl glutamates on position 2 are detrimental for anticancer activity.

Twenty-four out of twenty-nine quinoxalines were selected at the National Cancer Institute, Bethesda, Md, USA, for in vitro anticancer screening. Among these, 10 derivatives exhibited high values of percent tumor growth inhibition at a concentration of 10(-4) M in all cancer cell lines. Four of these compounds maintained these values at 10(-5) M, whereas a certain number exhibited significant values of percent inhibition at the most diluted concentrations (10(-8)-10(-6) M). Inhibitory activity against dihydrofolate reductase (DHFR) (bovine and rat liver) was determined for the most active compounds. This test showed that this type of quinoxaline exhibited an appreciable activity in comparison with the previously described aza analogues. In the other test (Lactobacillus casei, thymidylate synthase (TS), human HTS) no or poor activity was detected in both series of compounds.

Based on our previous results on the ascertained potent growth inhibition effect against a panel of 60 human tumors cell lines at National Cancer Institute of Bethesda (NCI), we have synthesized a novel series of thirty-one 2-[N-methyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines (1-31). The lead compound 1 was previously reported to be endowed with significant inhibition against hDHFR enzyme, with a Ki of 0.2 μM. Docking studies were performed on compound 1 and here reported to predict its binding conformation to human dihydrofolate reductase (hDHFR). All compounds (1-31) were assayed versus hDHFR and human thymidylate synthase (hTS). From the screening emerged that all compounds inhibited hDHFR with Ki values included between 0.2 and 11 μM, while only a few (6, 21, 24, 27, 29) showed great activity and selectivity towards hTS. Evaluation of the anticancer activity was performed by NCI, first against the three cell line panel, and only the most active compounds (17, 21, 24, 26, 27) were evaluated on a panel of 60 human tumor cell lines. Compound 21 was the most active against all cell lines with log GI50 equal to -5.49 and log LC50 equal to -4.19 and maintained significant percent of growth inhibition on seven cancer cell lines at the concentration of 1 μM. Compound 17 was the second most active and moreover showed interesting selectivity against some cell lines (Lung cancer: A549/ATCC, Melanoma: UACC-257, Ovarian Cancer: ovcar-8 and Renal cancer: RXF 393) at all concentration examined (100-0.01 μM).

Among twenty-eight novel compounds (twenty-two 2,3-disubstituted-6-[(substituted-phenoxy)methyl-quinoxalines and six 4-[(2,3-disubstituted-quinoxalin-6-yl methoxylbenzoylglutamates) only thirteen were selected at NO for evaluation of their in vitro anticancer activity. The results have shown that compounds 31,c,b,e and 4b were endowed with significantly high values of percent tumor growth inhibition on several tumor cell lines at 10−4 M, while compound 3t was characterized by a high selectivity, being still strongly inhibiting on three cell lines at 10−5 M. Comparison of the presently observed activity with that of the previously described aza-analogues confirms that the effected isosteric substitution is highly valuable in some cases.