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Quinoline amide, azaindole amide and pyridine amides were synthesized and tested for in vitro antifungal activity against fungi. These synthesized amides have potent antifungal activity against Candida albicans and Aspergillus fumigatus. Our results suggest that hetero ring amides may be potent antifungal agents that operate by inhibiting the function of Gwt1 protein in the GPI biosynthetic pathway.

In the process of angiogenesis, endothelial adhesion molecules play a significant role in vascular morphogenesis, in coordination with angiogenic factor signaling. Here we report that a novel angiogenesis inhibitor, E7820 (an aromatic sulfonamide derivative), inhibited in vitro proliferation and tube formation of human umbilical vascular endothelial cell (HUVEC). E7820 decreased integrin alpha2, 3, 5, and beta1 in confluent culture of HUVEC, and integrin alpha2 was initially suppressed in mRNA level, followed by decrement of integrins alpha3, 5, and beta1. The inhibition of integrin alpha2 expression in HUVEC showed dose dependence but did not alter the level of CD31. Up-regulation of integrin alpha2 by phorbol 12-myristate 13-acetate abrogated the inhibitory effect of E7820 on tube formation within type I collagen gel, whereas addition of antibody against integrin alpha2 canceled the phorbol 12-myristate 13-acetate effect. These results suggest that E7820 inhibited tube formation through the suppression of integrin alpha2. Oral administration of E7820 remarkably resulted in inhibition of tumor-induced angiogenesis in mouse dorsal air sac model, and tumor growth of human colorectal tumor cell lines (WiDr and LoVo) was inhibited in xenotransplanted model in mice. This is the first time that a small molecule has been shown to modulate integrins, and this finding may provide the basis for a new approach to antiangiogenic therapy through the suppression of integrin alpha2 on endothelium.

Background Lenvatinib is an oral inhibitor of multiple receptor tyrosine kinases (RTKs) targeting vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor (FGFR1-4), platelet growth factor receptor α (PDGFR α), RET and KIT. Antiangiogenesis activity of lenvatinib in VEGF- and FGF-driven angiogenesis models in both in vitro and in vivo was determined. Roles of tumor vasculature (microvessel density (MVD) and pericyte coverage) as biomarkers for lenvatinib were also examined in this study. Method We evaluated antiangiogenesis activity of lenvatinib against VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. Effects of lenvatinib on in vivo angiogenesis, which was enhanced by overexpressed VEGF or FGF in human pancreatic cancer KP-1 cells, were examined in the mouse dorsal air sac assay. We determined antitumor activity of lenvatinib in a broad panel of human tumor xenograft models to test if vascular score, which consisted of high MVD and low pericyte coverage, was associated with sensitivity to lenvatinib treatment. Vascular score was also analyzed using human tumor specimens with 18 different types of human primary tumors. Result Lenvatinib inhibited VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. In vivo angiogenesis induced by overexpressed VEGF (KP-1/VEGF transfectants) or FGF (KP-1/FGF transfectants) was significantly suppressed with oral treatments of lenvatinib. Lenvatinib showed significant antitumor activity in KP-1/VEGF and five 5 of 7 different types of human tumor xenograft models at between 1 to 100 mg/kg. We divided 19 human tumor xenograft models into lenvatinib-sensitive (tumor-shrinkage) and relatively resistant (slow-growth) subgroups based on sensitivity to lenvatinib treatments at 100 mg/kg. IHC analysis showed that vascular score was significantly higher in sensitive subgroup than relatively resistant subgroup (p

Enantioselective synthesis of (1R,4R)-2-azabicyclo[2.2.0]-hexane-3,5-dione and (1R, 4R,5S)-5-hydroxy-2-azabicyclo[2.2.0] hexan-3-one (new building blocks for carbapenems) from 4-(l-menthoxy)-pyridin-2(1H)-one via photopyridone formation is reported.

Asymmetric synthesis of [1S, 2S, 3R, 4R]-2, 3-dihydroxy-4-hydroxymethylcyclopent-1-ylmalonate (its racemic form is already known as a versatile building block for carbocyclic C-nucleosides) was achieved by Diels-Alder reaction of cyclopentadiene with di-l-menthyl acetoxymethylenemalonate, followed by retrograde aldol C-C bond fission under reductive conditions. Asymmetric induction in Diels-Alder reactions using the chiral dienophile and its nor-acetoxy derivative is discussed from a mechanistic viewpoint and a new concept for asymmetric induction is proposed.

Dimethyl lyxopyranosylmalonates were synthesized in stereospecific manner from the adducts obtained from Diels–Alder reaction of 3,4-dialkoxyfurans and dimethyl acetoxymethylenemalonate, through retrograde aldol C–C bond fission under reductive condition as a key step.

Reaction of 2, 3, 5-tri-O-benzyl-D-ribofuranose (4) with carboalkoxychloromethylenetriphenyl-phosphoranes (5a, b) gave an E, Z mixture of the corresponding alkyl 4, 5, 7-tri-O-benzyl-2-chloro-2, 3-dideoxy-D-ribo-hept-2-enonates (6a, b). Cyclization of 6a, b with triethylamine afforded exclusively the β-C-glycosides 7a, b which were diastereomeric at the carbon bearing chlorine. Hydrolysis of 7a, b with 5% aq. sodium hydroxide in dioxane gave the carboxylic acid 8. Treatment of 8 with thionyl chloride (or trifluoroacetic anhydride) in the presence of triethylamine, followed by reaction with the 2-arylideneaminopyridine 2a or ethyl N-(2-pyridyl) formimidates (2b, c) gave the corresponding fully protected pyrido [1, 2-a] pyrimidine C-nucleosides (15a-c), which were deprotected with boron trichloride to give the C-nucleosides (17b, c).

A new carbocyclic C-nucleoside precursor, the carbocyclic analogue of β-ribofuranosylmalonate, has been synthesized through Diels-Alder addition of cyclopentadiene to dimethyl acetoxymethylene-malonate, followed by retrograde C-C bond fissino under reductive conditions.

Treatment of the β-D-ribofuranosyl cyanide 5 with sodium methoxide, followed by reaction with diketene, gave the spiro 1, 3-oxazine 6, which underwent the ring transformation with ammonia and phenylhydrazine to give the protected pyrimidine (8) and 1, 2, 4-triazole (13) C-nucleosides, respectively. Deprotection of 8 with 90% trifluoroacetic acid gave the pyrimidine C-nucleoside 9. Passage of hydrogen chloride gas over a solution of the cyanide 1 and benzyl hydrosulfide gave the fully protected ribofuranosylthioformimidate 15. Treatment of 15 with triethylamine, followed by reaction with diketene gave the dihydrofuran derivative 16. Compound 16, on treatment with ammonia, hydroxylamine, and phenylhydrazine, was transformed into the corresponding furan derivatives 17-19.

Dimethyl lyxopyranosylmalonates were synthesized in stereospecific manner from the adducts obtained from Diels–Alder reaction of 3,4-dialkoxyfurans and dimethyl acetoxymethylenemalonate, through retrograde aldol C–C bond fission under reductive condition as a key step.

Reaction of 2, 3, 5-tri-O-benzyl-D-ribofuranose (4) with carboalkoxychloromethylenetriphenyl-phosphoranes (5a, b) gave an E, Z mixture of the corresponding alkyl 4, 5, 7-tri-O-benzyl-2-chloro-2, 3-dideoxy-D-ribo-hept-2-enonates (6a, b). Cyclization of 6a, b with triethylamine afforded exclusively the β-C-glycosides 7a, b which were diastereomeric at the carbon bearing chlorine. Hydrolysis of 7a, b with 5% aq. sodium hydroxide in dioxane gave the carboxylic acid 8. Treatment of 8 with thionyl chloride (or trifluoroacetic anhydride) in the presence of triethylamine, followed by reaction with the 2-arylideneaminopyridine 2a or ethyl N-(2-pyridyl) formimidates (2b, c) gave the corresponding fully protected pyrido [1, 2-a] pyrimidine C-nucleosides (15a-c), which were deprotected with boron trichloride to give the C-nucleosides (17b, c).

The methoxymethylenemalonate (I) is converted to the acetoxy derivative (II) which reacts with cyclopentadiene (III), yielding the adduct (IV).

Treatment of the β-D-ribofuranosyl cyanide 5 with sodium methoxide, followed by reaction with diketene, gave the spiro 1, 3-oxazine 6, which underwent the ring transformation with ammonia and phenylhydrazine to give the protected pyrimidine (8) and 1, 2, 4-triazole (13) C-nucleosides, respectively. Deprotection of 8 with 90% trifluoroacetic acid gave the pyrimidine C-nucleoside 9. Passage of hydrogen chloride gas over a solution of the cyanide 1 and benzyl hydrosulfide gave the fully protected ribofuranosylthioformimidate 15. Treatment of 15 with triethylamine, followed by reaction with diketene gave the dihydrofuran derivative 16. Compound 16, on treatment with ammonia, hydroxylamine, and phenylhydrazine, was transformed into the corresponding furan derivatives 17-19.

Synthese a partir du chloro-2 [O-isopropylidene-2',3' O-trityl-5' β-D-ribofuranosyl]-2 acetate de methyle

Esterification of malonic acid with (-)-menthol and subsequent condensation reaction with paraformaldehyde yield the dimenthyl methylenemalonate (II) which undergoes Diels-Alder reaction with cyclopentadiene (I) to give the bicyclo(2.2.1)heptenedicarboxylate (III) as the major isomer.

Le compose du titre est prepare a partir du L-menthol et de la dimethyl-2,2 hydroxymethylene-5 dioxanne-1,3 dione-4,6. Il reagit avec le cyclopentadiene pour donner un acetoxy-3 norbornene-5 dicarboxylate de menthyle qui reagit lui-meme avec NaBH 4 pour donner un derive de cyclopenta dioxole, analogue de C-nucleoside

The Diels–Alder adduct prepared from cyclopentadiene and methyl (E)-3-acetoxy-2-cyanoacrylate (a newly synthesized dienophile) can be converted stereospecifically into the title compound using a retrograde aldol reaction under reductive conditions as a key step.