New N-ribosides and N-mannosides of rhodanine derivatives with anticancer activity on leukemia cell line: Design, synthesis, DFT and molecular modelling studies.

N-ribosylation and N-mannosylation compounds have a great role in compounds activity as anticancer. The reaction of 2-thioxo-4-thiazolidinone (rhodanine) derivatives, as aglycon part, was done with ribofuranose and mannopyranose sugars (glycone part) followed by deacetylation without cleavage of the rhodanine under acidic medium. Conformational analysis has been studied using NMR methods (2D, DQF-COSY, HMQC and HMBC). All final the new deprotected nucleosides were screened against leukemia 1210, and were found to be considerably less potent (Ic50% 1.4-10.6 µM) than doxorubicin (Ic50% 0.02 µM). Compounds 10d and 10e which contain ribose moiety have better activity than those with mannose sugar. DFT calculations with B3LYP/6-31 + G (d) level were used to analyze the electronic and geometric characteristics deduced from the stable structure of the compounds. The principal quantum chemical descriptors showed a good correlation with the experimental observations. Rapid Overlay Comparison Similarity (ROCS) study was operated to explain the compounds similarity and to figure out the most important pharmacophoric features.

A new approach for the N- and S-galactosylation of 5-arylidene-2-thioxo-4-thiazolidinones.

N- and S-galactosylation was carried out via the reaction of 5-((Z)-arylidene)-2-thioxo-4-thiazolidinones with 2,3,4,6-tetra-O-acetyl-α-d-galactopyranosyl bromide under alkaline conditions or under silylation conditions. Deacetylation of the N-galactosylation products was performed with concentrated hydrochloric acid in methanol (3.5%) or sodium methoxide in methanol without cleavage of the 2-thioxo-4-thaizolidinone ring by means of acid hydrolysis. The anomers were separated by flash column chromatography, and their configurations were assigned by NMR spectroscopy. The deprotected nucleosides were screened against leukemia L-1210 and were found inactive.

Synthesis and modeling of new benzofuranone histone deacetylase inhibitors that stimulate tumor suppressor gene expression.

New benzofuranones were synthesized and evaluated toward NCI-H661 non-small cell lung cancer cells. Benzamide derivatives possessed micromolar antiproliferative and histone deacetylase inhibitory activities and modulate histone H4 acetylation. Hydroxamic acids were found to be potent nanomolar antiproliferative agents and HDAC inhibitors. Computational analysis presented a rationale for the activities of the hydroxamate derivatives. Impact of the HDAC inhibition on the expression of E-cadherin and the SEMA3F tumor suppressor genes revealed new promising compounds for lung cancer treatments.

Synthesis and biological evaluation of glucuronide prodrugs of the histone deacetylase inhibitor CI-994 for application in selective cancer chemotherapy.

Two glucuronide prodrugs of the histone deacetylase inhibitor CI-994 were synthesized. These compounds were found to be soluble in aqueous media and stable under physiological conditions. The carbamoyl derivatisation of CI-994 significantly decreased its toxicity towards NCI-H661 lung cancer cells. Prodrug incubation with beta-glucuronidase in the culture media led efficiently to the release of the parent drug and thereby restoring its ability to decrease cell proliferation, to inhibit HDAC and to induce E-Cadherin expression.

Gem-difluorination of aminoalkynes via highly reactive dicationic species in superacid HF-SbF5: application to the efficient synthesis of difluorinated cinchona alkaloid derivatives.

A variety of alkynylated amines, amides, and imides are reacted in the superacid system HF-SbF5 to give regioselectively new beta-gem-difluoroamines. The reaction, which is not observed in pure HF, is consistent with the formation of a dicationic intermediate (i.e., both vinylic and adjacent protonated N-ammonium cations). Application to the regioselective and efficient synthesis of difluorinated cinchona alkaloid derivatives is described.

Antiproliferative activities of a library of hybrids between indanones and HDAC inhibitor SAHA and MS-275 analogues.

New compounds derived from inhibitors of histone deacetylases (HDACs) have been synthesized and their antiproliferative activities towards non small lung cancer cell line H661 evaluated. Their design is based on hybrids between indanones to limit conformational mobility and other known HDAC inhibitors (SAHA, MS-275). The synthesis of these new derivatives was achieved by alkylation of appropriate indanones to introduce the side chain bearing a terminal ester group, the latter being a precursor of hydroxamic acid and aminobenzamide derivatives. These new analogues were found to be moderately active to inhibit H661 cell proliferation.

Design, synthesis and biological evaluation of 1,4-benzodiazepine-2,5-dione-based HDAC inhibitors.

New histone deacetylase inhibitors have been synthesized and evaluated for their activity against non-small lung cancer cell line H661. These compounds have been designed with diversely substituted 1,4-benzodiazepine-2,5-dione moieties as cyclic peptide mimic cap structures, and a hydroxamate side chain. Biological evaluations demonstrated that benzodiazepine-based HDACi bearing an aromatic substituent at the N1 position exhibited promising antiproliferative and HDAC-inhibitory activities.

First O-glycosylation of hydroxamic acids.

The first O-glycosylation of hydroxamic acids is reported. This process involves the use of glycosyl N-phenyl trifluoroacetimidates as glycosyl donors in the presence TMSOTf and 4 A molecular sieves in dichloromethane. Under such conditions, a wide range of new glycosyl donors including glucosyl, galactosyl, mannosyl, glucuronyl, and ribosyl hydroxamates were prepared in good to high yields. This procedure appears to be an advantageous alternative for the synthesis of glycosyl hydroxamates of biological interest.

Click chemistry with O-dimethylpropargylcarbamate for preparation of pH-sensitive functional groups. A case study.

Click chemistry has became an important tool for molecular constructs such as biopolymers. During the development of biodegradable multifunctional poly(ethylene oxide) (PEO) polymers suitable for click chemistry in water, an unexpected reaction leading to a mixture of triazole cycloadducts was observed. This result was attributed to an intramolecular ligand effect, and alternative conditions were evaluated. An efficient method was then implemented allowing the access in high yields to the expected triazolylcarbamate. pH sensitivity of the obtained isopropyltriazolylcarbamate was demonstrated at acidic pH.

Synthesis and biological evaluation of the suberoylanilide hydroxamic acid (SAHA) beta-glucuronide and beta-galactoside for application in selective prodrug chemotherapy.

The beta-O-glucuronide and beta-O-galactoside of SAHA have been prepared and evaluated as prodrugs for selective cancer chemotherapy (ADEPT, PMT). These new compounds are stable under physiological conditions and do not exhibit any antiproliferative activity compared to the parent drug after a 48-h treatment of H661 cells. The glucuronide derivative did not lead to the release of the drug in the presence of either Escherichia coli or bovine liver beta-glucuronidase. On the other hand, under enzymatic cleavage of galactoside prodrug by the corresponding enzyme, a rapid release of SAHA was observed demonstrating that the beta-O-galactoside of SAHA is a promising candidate for in vivo investigations.

Synthesis of rigid trichostatin A analogs as HDAC inhibitors.

New inhibitors of histone deacetylase (HDAC) have been synthesized and evaluated for their activity toward non small lung cancer cell line H661. Their design is based on indanone (or tetralone) systems leading to trichostatin A (TSA) analogs with limited conformational mobility. Molecular modelization at the AM1 level revealed that the conformations of indane-based analogs and TSA bound to HDAC like protein are similar. The synthesis of these new analogs was achieved by alkylation of an appropriate indanone (or tetralone) to introduce the side chain bearing a terminal ester group, the latter being a precursor of hydroxamic acid and aminobenzamide derivatives. Hydroxamic acids with the TSA side chain were found to be the most active compounds and the presence of the dimethylamino group on the phenyl ring turned out to be essential to achieve low micromolar activities against H661 cancer cells.

A new linker for glucuronylated anticancer prodrugs.

The synthesis, enzymatic hydrolysis and self decomposition of model glucuronylated prodrugs, incorporating a new linker with different aryl substituents, have been studied. Determination of kinetic parameters (V(max), K(m) and t(1/2)) showed the important role of aromatic substitution in enzymatic recognition and linker decomposition.

A new approach to the synthesis of benzothiazole, benzoxazole, and pyridine nucleosides as potential antitumor agents.

A modified nitrogen and sulfur glycosylation reaction involving benzothiazole benzoxazole and pyridine nucleoside bases with furanose and pyranose sugars are described. Conformational analysis has been studied by homo- and heteronuclear two-dimensional NMR methods (2D DFQ-COSY, HMQC and HMBC). The N and S sites of glycosylation were determined from the 1H, 13C heteronuclear multiple-quantum coherence (HMQC) experiments. All the deprotected nucleosides were tested for their potential antitumor activity.

Total synthesis and conformational analysis of the antifungal agent (-)-PF1163B.

[reaction: see text]. (-)-PF1163B, a new macrocyclic antifungal antibiotic isolated from Streptomyces sp., has been prepared in eight steps from (S)-citronellene. The key step is a ring-closing metathesis reaction of an ester and amide derivative obtained from a substituted N-methyl-l-tyrosine.

Synthesis and cytotoxic activity of tetracenomycin D and of saintopin analogues.

Regiospecific synthesis of title compounds is based either on cycloaddition of ketene acetals derived from Hagemann's ester or of homophthalic anhydrides. Thus, tetracenomycin D and 3,8-di-O-methyl saintopin have been prepared in few steps. New derivatives of 10-deoxysaintopin have been also obtained. Evaluation of their cytotoxicity against L1210 leukemia cells are reported.