Synthesis of carbohydrate-based vinyl selenides via Wittig-type reactions

Carbohydrate-based vinyl selenides of the arabino, ribo and 2-deoxy-ribo configuration have been prepared by Wittig-type reactions of various protected furanoses. Moderate yields were always obtained due to the nature and reactivity of both carbohydrate lactols and selenium-based olefinating reagents under the conditions tested. A detailed study of the olefination reaction and the behaviour of vinyl selenides towards the electrophilic-induced cyclization will be discussed.     

Synthesis,molecular properties prediction and biological evaluation of indole-vinyl sulfone derivatives as novel tubulin polymerization inhibitors targeting the colchicine binding site

Twenty-two novel indole-vinyl sulfone derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors. The physicochemical and drug-likeness properties of all target compounds were predicted by Osiris calculations. All compounds were evaluated for their antiproliferative activities, among them, compound 7f exhibited the most potent activity against a panel of cancer cell lines, which was 2–7 folds more potent than our previously reported compound 4. Especially, 7f displayed about 8-fold improvement of selective index as compared with compound 4, indicating that 7f might have lower toxicity. Besides, 7f inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further investigations showed that compound 7f effectively disrupted microtubule network, caused cell cycle arrest at G2/M phase and induced cell apoptosis in K562 cells. Moreover, 7f reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, the in vivo anti-tumor activity of 7f was validated in H22 liver cancer xenograft mouse model without apparent toxicity, suggesting that 7f is a promising anti-tubulin agent for cancer therapy.     

Selective inhibition of carbonic anhydrase IX by sulphonylated 1,2,3-triazole incorporated benzenesulphonamides capable of inducing apoptosis

In search of selective carbonic anhydrase (CA) IX inhibitors endowed with apoptotic inducing properties, we designed and synthesised two subsets of 4- and 3-(5-aryl-(4-phenylsulphonyl)-1H-1,2,3-triazol-1-yl)benzenesulphonamides. All compounds were assayed for human carbonic anhydrase (hCA) isoforms I, II, IV, and IX inhibition. Isoforms hCA I and hCA IV were weakly inhibited by most of the synthesised compounds. Many four-substituted benzenesulphonamides displayed low nanomolar inhibition against isoform hCA II, unlike the three-substituted analogues. All target compounds exhibited good inhibition profile with K_I values ranging from 16.4 to 66.0 nM against tumour-associated isoform hCA IX. Some selective and potent inhibitors of hCA IX were assayed for in vitro apoptotic induction in goat testicular cells. Compounds 10d and 10h showed interesting apoptotic induction potential. The present study may provide insights into a strategy for the design of novel anticancer agents based on hCA inhibitors endowed with apoptotic interference.     

A click chemistry approach for the synthesis of cyclic ureido tethered coumarinyl and 1-aza coumarinyl 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis H37Rv and their in silico studies

Nucleoside bases like uracil, pharmacophoric triazoles and benzimidazolones have been used during the present study to design molecular matrices for antitubercular activity, employing Click Chemistry. Click triazoles 4/7/10 have been obtained by the reaction of 4-(Azidomethyl)-2H-chromen-2-ones/quinolin-2(1H)-ones 3 and propargyl ethers 2/6/9 derived from theophylline/6-methyl uracil/2-benzimidazolone respectively. In addition to spectral data structures have been confirmed by single crystal X-ray diffraction studies in case of uracil bis alkyne (6) and theophylline mono triazole (4c). Theophylline linked mono triazoles, 4(a-d) and 6-methyl uracil linked bis triazoles, 7(a-e) have been found to inhibit Mycobacterium tuberculosis H37Rv with MIC values in the range 55.62–115.62 μM. Benzimidazolone bis triazoles, 10(a-n) showed better activity with MIC in the range 2.33–18.34 μM. Molecular modeling studies using Surflex-Dock algorithm supported our results.     

Craniofacial and axial skeletal defects induced by the fungicide triadimefon in the mouse

BACKGROUND: Triadimefon is an antifungal derived from triazole. In in vitro whole-rodent embryo cultures, triazole-derivatives showed specific teratogenic effects at the branchial apparatus. The aim of the present work was to test in vivo triadimefon (FON), in order to verify a relationship between triazole exposure, embryonic abnormalities, and/or fetal malformations. METHODS: Pregnant CD-1 mice were treated with 0-300 mg/kg FON by gavage on day 8 post coitum (p.c.) at 10:00 AM, and sacrificed on day 8 p.c. at 1:00 PM, on day 9 p.c. at 10:00 AM, on day 10 p.c. at 10:00 AM, and at term of gestation (day 18 p.c.). At midgestation, the embryos were processed for specific immunostainings to visualize the hindbrain segmentation (day 8 p.c.) and the neural crest cell migration (days 8 and 9 p.c.). Fetuses explanted at term were all processed for skeletal examination after double-staining of osseous and cartilaginous tissues. RESULTS: At midgestation, the immunostaining of rhombomeres 3 and 5 showed a light scattering of the immunostained areas; the neural crest cell migration was unaffected, but their localization at the branchial arch level was abnormal. At term, several severe malformations were observed at the craniofacial and at the axial skeletal level. Ectopic cartilage was observed at the upper jaw. CONCLUSIONS: Triadimefon is teratogenic. The observed craniofacial malformations could be explained by an alteration of the rhombomeric organization and neural crest migration to the branchial arches; the axial abnormalities could be explained by the abnormal segmental identity specification.     

Selection and Characterization of Nickel-Tolerant Tobacco Cells

Tobacco (Nicotiana tabacum L. cv. BY-2) cell lines tolerant to 700 M Ni in which unselected cells can not grow, were selected. The Ni-tolerant cells were also more tolerant to Co, but not to Cd than unselected cells. Ni concentrations in Ni-tolerant cells were always higher than those in medium. Since buthionine sulfoximine did not affect their Ni-tolerance, it is suggested that phytochelatins are not involved in Ni-tolerance of Ni-tolerant cells. On the other hand, histidine contents in Ni-tolerant and unselected cells, which were treated with Ni, were higher that those treated without Ni, and the degree of the elevation of histidine contents by Ni-treatment was higher in Ni-tolerant cells than in unselected cells. Additionally, exogenous histidine reduced the inhibitory effect of Ni on the growth of unselected cells. In addition, the cells that were tolerant to histidine-analogue, had higher contents of histidine and Ni-tolerance. These results suggest that histidine is involved in Ni-tolerance and the detoxification of Ni in symplast in Ni-tolerant cells.     

Expedient synthesis of coumarin-coupled triazoles via ‘click chemistry’ leading to the formation of coumarin-triazole-sugar hybrids

Coumarin-based triazoles were synthesized from 3-azidomethylcoumarin and a terminal acetylenic compound. Uncatalysed thermal conditions result in a mixture of both 1,4- and 1,5-regioisomers or the thermodynamically more stable 1,4-regioisomer, whereas the Cu(I)-catalysed reaction affords only the favourable 1,4-regioisomer. B3LYP/6-31G(d) level of theory has been used to calculate geometry and frequency features of the reactants, transition states (TSs) and products. Computational studies further reveal that 1,4-regioisomeric products are more favourable and also thermodynamically more stable compared to the 1,5-regioisomers.     

Unusual addition of amines to C-2 of vinyl sulfone-modified-beta-D-pent-2-enofuranosyl carbohydrates: synthesis of a new class of beta-anomeric 2-amino-2,3-dideoxy-D-threo-pentofuranosides

When 3-C-sulfonyl-pent-2-enofuranosides and 3-C-sulfonyl-hex-2-enofuranosides were reacted with primary and secondary amines, only the beta-anomeric methoxy group of the pent-2-enofuranoside did not cause any hindrance to incoming nitrogen nucleophiles. This resulted in the 'unusual' addition of amines, in which the diastereoselectivity of the reaction was overwhelmingly in favor of amino sugars of the D-arabino configuration. Selected products were desulfonylated to obtain a new class of beta-anomeric 2-amino-2,3-dideoxy-D-threo-pentofuranosides.     

C(15) Acetogenins from the red alga Laurencia obtusa.

Four C(15) acetogenins, 13-epilaurencienyne (3Z) (1), 13-epipinnatifidenyne (3E) (2), (3E, 6S(*), 7R(*), 9S(*), 10S(*), 12R(*))-9-chloro-13-bromo-6:12-epoxy-7, 10-diacetoxypentadec-3-en-1-yne (3), (3Z, 6S(*), 7R(*), 9S(*), 10S(*), 12R(*))-9-chloro-13-bromo-6:12-epoxy-7, 10-diacetoxypentadec-3-en-1-yne (4), along with the known 13-epilaurencienyne (3E) (5), have been isolated from the organic extract of the red alga Laurencia obtusa, collected in the Aegean Sea, Greece. The structures of the new natural products, as well as their relative stereochemistry, were established by means of spectral data analysis, including 2D NMR spectroscopic experiments. Some of the new metabolites exhibited significant insecticidal activity.     

Pharmacokinetic stability of macrocyclic peptide triazole HIV‐1 inactivators alone and in liposomes

Previously, we reported the discovery of macrocyclic peptide triazoles (cPTs) that bind to HIV‐1 Env gp120, inhibit virus cell infection with nanomolar potencies, and cause irreversible virion inactivation. Given the appealing virus‐killing activity of cPTs and resistance to protease cleavage observed in vitro, we here investigated in vivo pharmacokinetics of the cPT AAR029b. AAR029b was investigated both alone and encapsulated in a PEGylated liposome formulation that was designed to slowly release inhibitor. Pharmacokinetic analysis in rats showed that the half‐life of FITC‐AAR029b was substantial both alone and liposome‐encapsulated, 2.92 and 8.87 hours, respectively. Importantly, liposome‐encapsulated FITC‐AAR029b exhibited a 15‐fold reduced clearance rate from serum compared with the free FITC‐cPT. This work thus demonstrated both the in vivo stability of cPT alone and the extent of pharmacokinetic enhancement via liposome encapsulation. The results obtained open the way to further develop cPTs as long‐acting HIV‐1 inactivators against HIV‐1 infection.