Conformationally restricted macrocyclic analogues of combretastatins

New analogues of combretastatins have been evaluated as inhibitors of tubulin polymerization. These compounds present a macrocyclic structure, in which the para positions of the aromatic moieties have been linked by a 5- or 6-atoms chain, in order to produce a conformational restriction. This could contribute to determine the active conformation for these ligands. Such a conformational restriction and/or the steric hindrance makes them less potent inhibitors than the model compound CA-4.     

Synthesis and biological activity of new quinoxaline antibiotics of echinomycin analogues

Novel quinoxaline antibiotics having the methylenedithioether bridge as an analogue of echinomycin have been synthesized by insertion of methylene moiety between -S-S- bond. The compound 1a shows remarkable cytotoxicities against human tumor various cell lines, and is active VRE (vancomycin-resistant enterococci) within MIC range 0.5-8 microg/mL. According to the eukaryotic or prokaryotic data, 1a might be a first analogue to replace echinomycin.     

Synthesis and anti-tumor activity of novel combretastatins: combretocyclopentenones and related analogues

A series of 2-(3,4,5-trimethoxyphenyl)-3-arylcyclopent-2-ene-1-ones (8a-8e) and their related analogues, including pentenone 9a, pentenol 10a, pentene 12a, and furane 15, were synthesized and evaluated for cytotoxicity against murine and human tumor cell lines. Compounds 8a-c, 8e and 9a showed strong cytotoxicity with IC(50) values in the range of 8-34ng/mL. Compound 8e exhibited significant anti-tumor activity in BDF1 mice bearing Lewis lung carcinoma cells with an inhibition ratio of 59%.     

Synthesis and evaluation of new antimalarial analogues of quinoline alkaloids derived from Cinchona ledgeriana Moens ex Trimen

In the course of attempts to develop antimalarial drugs, we have designed and synthesized a series of quinoline alkaloide derivatives. Three of them, N-(4-methoxy-3,5-di-tert-butylbenzyl)cinchonidinium bromide (OSL-5), O-benzyl-N-(3,5-di-tert-butyl-4-methoxybenzyl)cinchonidinium bromide (OSL-7), and N-(3,5-di-tert-butyl-4-methoxybenzyl)quininium bromide (OSL-14) show potent activity against Plasmodium falciparum.     

Investigating biological activity spectrum for novel quinoline analogues

The lack of the wide spectrum of biological data is an important obstacle preventing the efficient molecular design. Quinoline derivatives are known to exhibit a variety of biological effects. In the current publication, we tested a series of novel quinoline analogues for their photosynthesis-inhibiting activity (the inhibition of photosynthetic electron transport in spinach chloroplasts (Spinacia oleracea L.) and the reduction of chlorophyll content in Chlorella vulgaris Beij.). Moreover, antiproliferative activity was measured using SK-N-MC neuroepithelioma cell line. We described the structure-activity relationships (SAR) between the chemical structure and biological effects of the synthesized compounds. We also measured the lipophilicity of the novel compounds by means of the RP-HPLC and illustrate the relationships between the RP-HPLC retention parameter logK (the logarithm of capacity factor K) and logP data calculated by available programs.     

Interaction of 4-arylcoumarin analogues of combretastatins with microtubule network of HBL100 cells and binding to tubulin

The synthesis of different 4-arylcoumarin analogues of combretastatin A-4 led to the identification of two new compounds (1 and 2) with potent cytotoxic activity on a CEM leukemia cell line and a third one completely inactive (compound 3). It was suggested that the cytotoxicity of compounds 1 and 2 may be related to their interaction with microtubules and tubulin, since these compounds inhibit microtubule formation from purified tubulin in vitro [Bailly et al. (2003) J. Med. Chem. 46 (25), 5437-5444]. In the present study, tubulin was identified as the main target of these molecules. We studied structure-activity relationships of these compounds using biological experiments specific for tubulin binding. The modification of cell cycle progression induced by compounds 1 and 2 was characterized by an apoptotic induction on human breast cells (HBL100). In addition, these two molecules disturbed cell survival by depolymerizing the microtubule network, leading to a mitotic block. We then determined the thermodynamic parameters of their interaction with purified tubulin by fluorescence spectroscopy and isothermal microcalorimetry. These results, together with a superimposition of the molecule on colchicine in the X-ray-determined three-dimensional structure model of tubulin-colchicine complex, allowed us to identify the pharmacophore of the combretastatin A-4 analogues responsible for their biological activity.     

Microwave-assisted synthesis of quinoline, isoquinoline, quinoxaline and quinazoline derivatives as CB2 receptor agonists

Quinoline, isoquinoline, quinoxaline, and quinazoline derivatives were synthesized using microwave-assisted synthesis and their CB1/CB2 receptor activities were determined using the [3?S]GTPγS binding assay. Most of the prepared quinoline, isoquinoline, and quinoxalinyl phenyl amines showed low-potency partial CB2 receptor agonists activity. The most potent CB2 ligand was the 4-morpholinylmethanone derivative (compound 40e) (-log EC?? = 7.8; E(max) = 75%). The isoquinolin-1-yl(3-trifluoromethyl-phenyl)amine (compound 26c) was a high efficacy CB2 agonist (-log EC?? = 5.8; E(max) = 128%). No significant CB1 receptor activation or inactivation was shown in these studies, except 40e, which showed weak CB1 agonist activity (CB1 -log EC?? = 5.0). These ligands serve as novel templates for the development of selective CB2 receptor agonist.     

A series of quinoline analogues as potent inhibitors of C. albicans prolyl tRNA synthetase

A series of quinoline inhibitors of C. albicans prolyl tRNA synthetase was identified. The most potent analogue, 2-(4-bromo-phenyl)-6-chloro-8-methyl-4-quinolinecarboxylic acid, showed IC50 = 5 nM (Ca. ProRS) with high selectivity over the human enzyme.     

Enantioselective synthesis of new analogues of neplanocin A

An efficient synthesis of analogues of (-)-aristeromycin (1) and (-)-neplanocin A (2) has been developed in an enantioselective and stereocontrolled manner by chemicoenzymatic strategy. The symmetric unsaturated dimethyl ester (3) was quantitatively hydrolyzed with pig liver esterase to yield a half ester (4). Decarboxylative ozonolysis followed by chemical transformation afforded versatile chiral intermediates, cyclopentylamine (7) and cyclopentenylamine (9), which were converted to carbocyclic analogues of 5-aminoimidazole-4-carboxamide riboside (16), (18), uridine (21), cytidine (23), and guanosine (25). The cytidine analogue (23) was found most active against KB cells in culture.     

Synthesis and biological activity of mustard derivatives of combretastatins

A series of chimeric compounds bearing the combretastatin and the nitrogen mustard cores were synthesized. All the compounds were cytotoxic and inhibited tubulin polymerization. When combretastatin was joined to chlorambucil via an ester linkage, the resultant compound proved to be significantly more potent than the two compounds put together. When combretastatin was joined to nitrogen mustard via an ether linkage or when a true hybrid was synthesized, loss of potency was observed. Nonetheless, these latter compounds appeared to be more efficacious and surprisingly were able to inhibit tubulin depolymerization at high concentrations.     

A new family of bacterial condensins

Condensins play a central role in global chromatin organization. In bacteria, two families of condensins have been identified, the MukBEF and SMC-ScpAB complexes. Only one of the two complexes is usually found in a given species, giving rise to a paradigm that a single condensin organizes bacterial chromosomes. Using sequence analysis, we identified a third family of condensins, MksBEF (MukBEF-like SMC proteins), which is broadly present in diverse bacteria. The proteins appear distantly related to MukBEF, have a similar operon organization and similar predicted secondary structures albeit with notably shorter coiled-coils. All three subunits of MksBEF exhibit significant sequence variation and can be divided into a series of overlapping subfamilies. MksBEF often coexists with the SMC-ScpAB, MukBEF and, sometimes, other MksBEFs. In Pseudomonas aeruginosa, both SMC and MksB contribute to faithful chromosome partitioning, with their inactivation leading to increased frequencies of anucleate cells. Moreover, MksBEF can complement anucleate cell formation in SMC-deficient cells. Purified PaMksB showed activities typical for condensins including ATP-modulated DNA binding and condensation. Notably, DNA binding by MksB is negatively regulated by ATP, which sets it apart from other known SMC proteins. Thus, several specialized condensins might be involved in organization of bacterial chromosomes.     

Antifungal properties of new series of quinoline derivatives

The series of quinoline derivatives were prepared. The synthetic approach, analytical, and spectroscopic data of all synthesized compounds are presented. All the prepared derivatives were analyzed using the reversed-phase high performance liquid chromatography (RP-HPLC) method for the lipophilicity measurement. In the present study, the correlation between RP-HPLC retention parameter log K (the logarithm of capacity factor K) and various calculated log P data is shown. The relationships between the lipophilicity and the chemical structure of the studied compounds are discussed as well. The prepared compounds were tested for their in vitro antifungal activity. 2-[(3-Hydroxyphenylimino)methyl]quinolin-8-ol (8), 2-[(4-hydroxyphenylimino)methyl]quinolin-8-ol (9) and 2-[(2,5-dichloro-4-nitrophenylamino)methoxymethyl]quinolin-8-ol (10) showed in vitro antifungal activity comparable to or higher than that of the standard fluconazole. Structure-activity relationships among the chemical structure, the physical properties, and the biological activities of the evaluated compounds are discussed in the article.     

Selective activity against Mycobacterium tuberculosis of new quinoxaline 1,4-di-N-oxides

New series of 3-phenylquinoxaline 1,4-di-N-oxide with selective activity against Mycobacterium tuberculosis have been prepared and evaluated. Thirty-four of the seventy tested compounds showed an MIC value less than 0.2 μg/mL, a value on the order of the MIC of rifampicin. Furthermore, 45% of the evaluated derivatives showed a good in vitro activity/toxicity ratio. The most active and selective compounds carry a fluorine atom in the quinoxaline 7-position or in the phenyl substituent para-position. In conclusion, the potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for synthesizing new analogues, particularly compound 7-methyl-3-(4’-fluoro)phenylquinoxaline-2-carbonitrile 1,4-di-N-oxide (MIC <0.2 μg/mL and SI >500).     

Synthesis and cytotoxicity of epoxide and pyrazole analogs of the combretastatins

Twenty-six epoxide and corresponding pyrazole derivatives, of the structurally related chalcones and combretastatin A-4 (CA-4), were synthesized and tested for in vitro cytotoxicity. These molecules were synthesized by epoxidation of the relevant chalcones, followed by reaction with hydrazine. The structures of epoxides 3 and 7, and pyrazole 17, were confirmed by X-ray diffraction studies. The relatively coplanar conformation of a 3',3',4',4',5',5'-hexamethoxypyrazole 17 was in good agreement with the shape for 3',3',4',4',5'-pentamethoxypyrazole 16, which was determined from molecular mechanics optimization. In vitro cytotoxicity of each class of compounds was obtained using a 72 h continuous exposure MTT assay against two murine cancer cell lines; B16 melanoma and L1210 leukemia. The effect of substitution in the A-ring is addressed: three methoxy groups versus two, generally increased cytotoxicity across both cell lines. In the majority of cases, the pyrazoles are generally more active than the epoxides, with the most active, 5-(3'-amino-4'-methoxyphenyl)-3-(3',4',5'-trimethoxyphenyl)pyrazole 21, possessing an IC(50) value of 5 and 2.4 microM (B16 and L1210, respectively). Due to their planar conformations, the pyrazoles are typically less active than the corresponding chalcones, which adopt angular conformations similar to CA-4. B-ring modifications confirmed that in general the amino compounds are more active than the corresponding nitro compounds. Varying the number and orientation of methoxy groups on the A-ring did not produce any significant differences in toxicity in the cell lines studied.     

Synthesis and molecular modeling study of new trimeric quinoline derivatives

Di- and trimeric quinoline derivatives have been recently described as potential modulators of Bcl-2 family protein interactions. However, only a few trimeric compounds have been described so far and an enlargement of the number of analogs of this class is needed to expand the structure–activity relationship study. Therefore, the synthesis of six new trimeric quinoline derivatives is reported. Moreover molecular modeling experiments were performed to study the conformational arrangement of compound 36 in Bak binding site of Bcl-x_L, showing that these compounds could be potential ligands for Bcl-x_L.