3-(Dipropylamino)-5-hydroxybenzofuro[2,3-f]quinazolin-1(2H)-one (DPA-HBFQ-1) plays an inhibitory role on breast cancer cell growth and progression.

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.

Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium.

A preliminary in vitro screening of compounds belonging to various chemical families from our library revealed the thieno[3,2-d]pyrimidin-4(3H)-one scaffold displayed a promising profile against Plasmodium falciparum. Then, 120 new derivatives were synthesized and evaluated in vitro; compared to drug references, 40 showed good activity toward chloroquine sensitive (IC50 35-344 nM) and resistant (IC50 45-800 nM) P. falciparum strains. They were neither cytotoxic (CC50 15-50 µM) toward HepG2 and CHO cells, nor mutagenic. Structure-activity relationships were defined. The lead-compound also appeared active against the Plasmodium liver stages (Plasmodium yoelii IC50 = 35 nM) and a preliminary in vivo evaluation indicated the in vitro activity was preserved (45% reduction in parasitemia compared to untreated infected mice). A mechanistic study demonstrated these molecules do not involve any of the pathways described for commercial drugs and exert a specific activity on the ring and trophozoite stages.

(6-bromo-1,4-dimethyl-9H-carbazol-3-yl-methylene)-hydrazine (carbhydraz) acts as a GPER agonist in breast cancer cells.

Estrogens control a wide number of aspects of human physiology and play a key role in multiple diseases, including cancer. Estrogens act by binding to and activating the cognate receptor (ER), however numerous studies have revealed that the G protein-coupled receptor named GPR30/GPER mediates also estrogen signals. As ER and GPER share the ability to bind to same compounds, the use of GPER-selective ligands has allowed a better understanding of the biological responses mediated by GPER. In the present study, we designed and synthesized two novel carbazole derivatives and then investigated their ability to interact with and activate the GPER-mediated transduction pathway in breast cancer cells. Both compounds did not activate the classical ER in MCF7 cells, whereas one of the two compounds synthesized triggered through GPER the rapid ERK activation in ER-negative SkBr3 cells, demonstrating a good affinity for GPER in docking studies. The characterization of this novel selective GPER agonist could represent a potential useful tool to provide further insights into the physiopathological role exerted by GPER.

Synthesis and in vitro evaluation of 4-trichloromethylpyrrolo[1,2-a]quinoxalines as new antiplasmodial agents.

Thanks to a preliminary in vitro screening of several CCl3-substituted-nitrogen containing heterocycles belonging to our chemical library, the 2-trichloromethylquinoxaline scaffold appeared to be of potential interest for developing new antiplasmodial agents. Then, combining these experimental results to the antimalarial properties reported for various pyrrolo[1,2-a]quinoxaline derivatives, an original series of fifteen 7-substituted-4-trichoromethylpyrrolo[1,2-a]quinoxalines was synthesized in a 4 to 5 reaction steps pathway. All molecules were evaluated in vitro toward both their antiplasmodial activity on the K1 multi-resistant Plasmodium falciparum strain and their cytotoxicity on the HepG2 human cell line. Thus, 3 hit molecules were identified, displaying IC50 values in the micromolar range and low cytotoxicity values, reaching good selectivity indexes, in comparison with the reference drugs chloroquine and doxycycline. Structure-activity relationship studies showed that the pyrrolo[1,2-a]quinoxaline scaffold can support selective antiplasmodial activity when substituted at position 4 by a CCl3 group. However, substitution at position 7 of the same scaffold is neither beneficial for cytotoxicity nor favourable for the solubility in the biological media.

Synthesis and evaluation of cytotoxic activities of new guanidines derived from carbazoles.

Several new alkylguanidines derived from carbazole have been synthesized in a simple one-pot reaction starting from 3-aminocarbazole derivatives. The aminocarbazoles were reacted with ethoxycarbonylisothiocyanate, to give thiourea intermediates, followed by the addition of an alkylamine and HgCl2 to give ethoxycarbonylguanidine intermediates. The reaction mixture was then heated at 160 °C to give the N-(1,4-dimethyl-9H-carbazol-3-yl)-N'-alkylguanidines. The cytotoxic activity of all the synthesized guanidines was evaluated against different cell lines.

Antiproliferative activity of some 1,4-dimethylcarbazoles on cells that express estrogen receptors: part I.

Several 9H-carbazole derivatives are used for various pharmacological applications. Many of these compounds demonstrated cytotoxic and anticancer activities. In this work, we have investigated the cytotoxic activity of some substituted carbazoles against cancer cell lines (MCF-7, and ISK). The derivative 2a showed the highest inhibitory activity against both cell lines.

tert-Butyl 6-bromo-1,4-dimethyl-9H-carbazole-9-carboxyl-ate.

The title compound, C(19)H(20)BrNO(2), consists of a carbazole skeleton with methyl groups at positions 1 and 4, a protecting group located at the N atom and a Br atom at position 6. The pyrrole ring is oriented at dihedral angles of 1.27 (7) and 4.86 (7)° with respect to the adjacent benzene rings. The dihedral angle between the benzene rings is 5.11 (7). The crystal structure is determined mainly by intra-molecular C-H⋯O and inter-molecular π-π inter-actions. π-stacking between adjacent molecules forms columns with a parallel arrangement of the carbazole ring systems. The presence of the tert-but-oxy-carbonyl group on the carbazole N atom and the intra-molecular hydrogen bond induce a particular conformation of the exocyclic N-C bond within the mol-ecule.

Synthesis, inhibition of NO production and antiproliferative activities of some indole derivatives.

The synthesis and the biological evaluation of pyrano[3,2-e]indoles and their reaction intermediates are described. The compounds prepared were evaluated for their inhibition of NO production, antioxidant activity and also for their ability to inhibit in vitro the growth of four human tumor cell lines: large lung carcinoma (COR-L23), alveolar basal epithelial carcinoma (A549), amelanotic melanoma (C32) and melanoma (A375). The two reaction intermediates, 5a and 5b, showed the highest inhibition of NO production in murine monocytic macrophage (IC(50) = 1.1 microM and IC(50) = 2.3 microM respectively). Compound 5a was the most active against melanotic melanoma (IC(50) = 11.8 microM) while the other compounds exhibited weak cytotoxicity with IC(50) values >50 microM on all cell lines.

9-Ethyl-1,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole and 6-bromo-9-ethyl-1,4-dimethyl-9H-carbazole.

The title carbazolyl boronic ester, C(22)H(28)BNO(2), (I), is a building block for the synthesis of new carbazole derivatives of potential utility as pharmaceutically active compounds. The crystal structure of (I) and of the title bromocarbazole compound, C(16)H(16)BrN, (II), the synthetic precursor of (I), were solved and analysed with the aim of understanding the lack of reactivity of (I) under Suzuki cross-coupling reaction conditions. In both structures, the methyl groups are coplanar with the carbazole ring system, and the ethyl group lies out of the carbazole plane. The dioxaborolane ring of boronic ester (I) adopts a half-chair conformation but lies approximately in a planar orientation with respect of the carbazole ring system, whereas the Br atom of (II) is coplanar with the carbazole plane. In (I), the carbazole-boronic ester C-B bond length is 1.5435 (14) A, which is somewhat shorter than the usual value of 1.57 A.

Efficient and simple synthesis of 6-aryl-1,4-dimethyl-9H-carbazoles.

A synthetic method for the preparation of 6-aryl-1,4-dimethyl-9H-carbazoles involving a palladium catalyzed coupling reaction of 1,4-dimethyl-9H-carbazole-6-boronic acids and (hetero)aryl halides is described.

Synthesis of new L-ascorbic ferulic acid hybrids.

A feasibility and chemical study of the coupling conditions of L-ascorbic acid with ferulic acid derivatives are described on the basis of the known synergistic effects of mixtures of various antioxidants. Novel L-ascorbic ferulic hybrids linked at the C-3 hydroxyl group were prepared with the aim to protect the alcohol function and the enediol system.

Molecular modeling studies focused on 5-HT7 versus 5-HT1A selectivity. Discovery of novel phenylpyrrole derivatives with high affinity for 5-HT7 receptors.

The present study discusses the well-known 5-HT7/5-HT1A selectivity issue through a new series of phenylpyrrole derivatives. The first hits emerged from a virtual screening performed on a chemolibrary. Further study led to an optimization of a preliminary 5-HT7 pharmacophore model. The importance of each pharmacophoric feature is confirmed, but these characteristics have to be coupled to geometric constraints in order to achieve a 5-HT7 selectivity. Indeed, 5-HT1A affinity probably arises from extended conformations, whereas a bent one appears to be best suited for 5-HT7 selectivity.

3D-QSAR and docking studies of selective GSK-3beta inhibitors. Comparison with a thieno[2,3-b]pyrrolizinone derivative, a new potential lead for GSK-3beta ligands.

The three-dimensional structures of 3-anilino-4-arylmaleimides, selective GSK-3beta inhibitors, were correlated to their biological affinities by 3D-QSAR studies (CoMFA method). The cocrystallographic data of GSK-3beta vs 3-anilino-4-arylmaleimide allowed us to compare 3D-QSAR results to experimental intermolecular interactions. The results of the CoMFA analysis did not really correspond to the interactions recorded in the active site, but they characterized fundamental features (areas of the active site) of the interactions ligand-receptor. These studies were the starting point to analyze a new GSK-3beta ligand, a thieno[2,3-b]pyrrolizinone derivative. This comparison based on docking and simulation approaches allowed us to confirm one preferential orientation of this ligand inside the active site, explaining the relationship with the reference 3-anilino-4-arylmaleimide derivatives and its biological affinity.

Solution-phase parallel synthesis of a 1140-member ureidothiophene carboxylic acid library.

A 1140-library of thiophene ureidoacids was synthesized by the reaction of a set of 60 primary or secondary amines with a number of 19 thieno[3,2-d]- or thieno[2,3-d][1,3]oxazine-2,4-diones. All compounds were obtained by a simple solution-phase combinatorial strategy on a 200-400-mg scale with over 70% yields and purities over 80%. Sixty library members chosen at random were successfully characterized by standard 1H NMR, HPLC/MS, and IR studies. Analgesic, antalgic, and antiinflammatory potential were investigated. The 1140-member ureidothiophene carboxylic acid library will be used in high-throughput screening assays.

Molecular design based on 3D pharmacophores. Applications to 5-HT7 receptors.

A definition of a pharmacophore for the 5-HT7 antagonists was carried out by searching the common chemical features of selective antagonists from the literature. A molecular design is described by analyzing the differences between this new pharmacophore and three other 3D serotonin pharmacophores previously described. This comparison led to the synthesis of a new series of potent 5-HT7 antagonists.

An efficient two-step total synthesis of the quaterpyridine nemertelline.

Regioselective and univocal Suzuki cross-coupling reactions performed on halopyridinyl boronic acids provide a flexible and versatile route to a multigram scale synthesis of 2,2'-dichloro-3,4'-bipyridine 14, which allows couplings with excess pyridin-3-yl boronic acid to give a new and efficient two-step rapid synthesis of nemertelline, the quaterpyridine neurotoxin isolated from a Hoplonemertine sea worm.

2-bromo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, a new unexpected bifunctional building block for combinatorial chemistry.

The first reported structure of a pyridin-2-ylboron derivative, viz. the title compound, C(11)H(15)BBrNO(2), (I), is compared with its regioisomer 2-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, (II) [Sopková-de Oliveira Santos, Lancelot, Bouillon & Rault (2003). Acta Cryst. C59, o111-o113]. Structural differences are observed, firstly in the orientation of the dioxaborolane ring with respect to the pyridine ring and secondly in the bond angles of the BO(2) group. These differences do not explain the experimentally observed differences in chemical reactivity between (I) and (II) but do confirm the relatively lower stability of (I). However, ab initio calculations of the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital), based on the known crystal structures of the two compounds, show different distributions, which correspond to the differences observed during chemical reactions.

In vitro anti-acanthamoeba action by thioureidic derivatives.

The anti-amoebic power of a series of bis-thioureidic derivatives against amoeba, responsible for a serious form of keratitis of the cornea, has been analysed. The synthesis of these products is also described.

Synthesis and preliminary biological evaluation of a new pyridocarbazole derivative covalently linked to a thymidine nucleoside as a potential targeted antitumoral agent. I.

The therapy of human cancer is one of the more pursued goals by medicinal chemistry research. Most of the compounds clinically used as a treatment owe their efficacy to their cytotoxic interaction (direct or indirect) with nuclear DNA. This interaction results in the inhibition of DNA synthesis and the degradation of nucleic strands. Ellipticine is a naturally occurring 6H-pyrido[4,3-b]carbazole alkaloid endowed with antitumor activity, and several ellipticine derivatives have been used in clinical trials. We previously reported some 1,4-dimethyl-9H-carbazole derivatives structurally related to ellipticine. The purpose of our research was to transform the pyridocarbazole in a prodrug so that it would have more penetration in the tumor cells and block their replication. Our prodrug is slowly hydrolyzed in human plasma in the corresponding acid. From these preliminary results, we deduce that our compound can block cellular replication. Our hypothesis is that the antitumoral activity is probably related to the induction of damage to DNA, without cellular lysis in the short term.