Synthesis of isoxazole and isothiazole derivatives of curcumin

Curcumin is a chemical compound with antioxidant properties as well as strong anti-inflammatory, antiviral, analgesic, antimicrobial and antitumor effect, contained in the tuberous rhizomes of the turmeric plant (Curcuma longa). Curcumin derivatives are being intensively studied as potential drugs – antitumor drugs for the treatment of certain forms of cancer. The presence of reactive functional groups makes curcumin a convenient starting compound for the further chemical modification. The esters of curcumin and 5-phenylisoxazole-3-carboxylic acid, 5-(p-tolyl)isoxazole-3-carboxylic acid, 4,5- dichloroisothiazole-3-carboxylic acid and adduct of 5-(p-tolyl)isoxazol-3-carbaldehyde with curcumin were synthesized. Esters were obtained by acylation of curcumin with heterocycle-containing carboxylic acid chloride in diethyl ether in the presence of triethylamine. The IR and NMR spectra of the obtained compounds are described.

Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments

Background and Objective: The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors. Methods: New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling. Results: 13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21–94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86–4.08 µM. Molecular modelling against the TDP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7- dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549. Conclusion: The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.

Crystal structures of 1′-aminocobaltocenium-1-carboxylic acid chloride monohydrate and of its azo dye 1′-[2-(1-amino-2,6-dimethylphenyl)diazen-1-yl]cobaltocenium-1-carboxylic acid hexafluoridophosphate monohydrate

1′-Aminocobaltocenium-1-carboxylic acid chloride, [Co(C5H6N)(C6H5O2)]Cl·H2O, (3), and its azo derivative 1′-[2-(1-amino-2,6-dimethylphenyl)diazen-1-yl]cobaltocenium-1-carboxylic acid hexafluoridophosphate, [Co(C13H14N3)(C6H5O2)]PF6·H2O (5) were obtained from cobaltocenium-1,1′-dicarboxylic acid hexafluoridophosphate by converting one carboxyl group to its chlorocarboxyl derivative followed by chloride/azide exchange, Curtius rearrangement, diazotiation and azo coupling with 2,6-dimethylaniline. Both title compounds crystallize as their monohydrates. In the crystal structure of 3, both functional groups lie in the same direction, with the Cp rings being nearly eclipsed, and participate in an extended hydrogen-bonded supramolecular network including the counter-ion and the water molecule of crystallization. Although the functional groups in 5 are somewhat further apart, bearing a greater torsion angle with the Cp rings now staggered, a similar supramolecular network is observed with not only the carboxylic acid and azo groups, but also with the more remote amino group participating in a hydrogen-bonded network, again including the counter-ion and the water molecule. The hexafluoridophosphate ion shows positional disorder. Compound 3 was refined as an inversion twin. In 5, each of the six F atoms is disordered over two sets of sites in a 1:1 ratio.

Synthesis and Characterization of the Germathioacid Chloride Coordinated by an N-Heterocyclic Carbene §

Carboxylic acid chlorides are useful substrates in organic chemistry. Many germanium analogues of carboxylic acid chloride have been synthesized so far. Nevertheless, all of the reported germathioacid chlorides use bidentate nitrogen ligands and contain germanium-nitrogen bonds. Our group synthesized germathioacid chloride, Ge(S)Cl{C6H3-2,6-Tip2}(Im-i-Pr2Me2), using N-heterocyclic carbene (Im-i-Pr2Me2). As a result of density functional theory (DFT) calculation, it was found that electrons are localized on sulfur, and the germanium-sulfur bond is a single bond with a slight double bond property.

Synthesis of 3,3′-carbonyl-bis(chromones) and their activity as mammalian alkaline phosphatase inhibitors

Hitherto unknown 3,3′-carbonyl-bis(chromones) 8, dimeric chromones bridged by a carbonyl group, were prepared by reaction of chromone-3-carboxylic acid chloride with 3-(dimethylamino)-1-(2-hydroxyphenyl)-2-propen-1-ones 9.

Cytotoxic Properties of Titanocenyl Amides on Breast Cancer Cell Line MCF-7

A new titanocenyl amide containing flavone as pendant group has been synthesized by reaction of titanocenyl carboxylic acid chloride and 7-Aminoflavone and structurally characterized by spectroscopic methods. This species and eight previously synthesized titanocenyl amide complexes have been tested in breast adenocarcinoma cancer cell line, MCF-7. The functionalization of titanocene dichloride with amides enhances the cytotoxic activity in MCF-7. Two sets of titanocenyl amides can be identified, with IC50<100 μM and IC50>100 μM. The most cytotoxic species is Cp(CpCO-NH-C6H4-(CH2)2CH3)TiCl2 with an IC50 of 24(2) μM, followed by Cp(CpCO-NH-C6H4-Br)TiCl2, IC50 of 46(4) μM and Cp(CpCO-NH-C6H4-OCF3)TiCl2, IC50 of 49(6) μM. There is no correlation between the nature of the para substituent on the phenyl ring and the cytotoxic properties on MCF-7 cell line.

Synthesis of conjugates of L-fucose and ortho-carborane as potential agents for boron neutron capture therapy

The synthesis of three potential boron neutron capture therapy agents (6–8) is reported. The compounds synthesized are comprised of ortho-carborane covalently attached to L-fucose via C-6. Incorporation of the carborane moiety was achieved either through the reaction of an L-fucose-derived alkyne with decaborane or by the coupling of a 6-amino-L-galactopyranose derivative with carborane carboxylic acid chloride (18).Key words: L-fucose, fucosyltransferase, boron neutron capture therapy, ortho-carborane.