Nine bisabolangelone reduction derivatives were synthesized and separated as potential anti-ulcer agent. Their structures were characterized by 2D NMR, IR, ESI-MS, elemental analysis and single-crystal X-ray diffraction analysis. Preliminarily H + /K + -ATPase activity evaluation indicated that all the target compounds had a certain inhibitory effect, and compounds II and IV exhibited the better inhibitory activity against H + /K + -ATPase than bisabolangelone and the commercial omeprazole with the IC 50 of 23.21 and 65.32 µmol/L, respectively. The initial structure-activity analysis suggested that the presence of carbonyl group in six-membered ring and double bond in side-chain seemed to be necessary to the activity.
Eleven triazolyl substituted tetrahydrobenzofuran derivatives were synthesized in high yields as novel H+/K+‐ATPase inhibitor via one‐pot CuI‐catalyzed three‐component click reaction of azide, secondary amine and 3‐bromopropyne under mild conditions in water. Their structures were characterized by NMR, IR, ESI‐MS, elemental analysis and single‐crystal X‐ray diffraction analysis. Most of the target compounds exhibited better H+/K+‐ATPase inhibitory activity than commercial omeprazole with IC50 values less than 15 µmol·L−1. The initial structure‐activity analysis suggested that the triazole substituted by cycloalkyl, aromatic ring or O‐containing side‐chain seemed to be beneficial for enhancing the activity.
Source of materialBisabolangelone(0.25 g, 1.0mmol) and Pd/C(0.02 g, 10 % w/w) weredissolved in MeOH (20 ml) at 10°C under dry nitrogen atmosphere, then hydrogen gas (99 %) was bubbled into the vigorously stirred solution (100 ml/minute) for 0.5 hu ntil the bisabolangelone wasconsumed. Thecatalystwas filtered off and thesolventsevaporatedatreduced pressure to give awhite solid, whichw as purified by column chromatography on silica with ethylacetate/petroleum ether (1:6) as eluent to give thepuretargetcompoundascolorless needles (0.18 g). X-ray quality crystals were obtained by vapor diffusion of diethyl ether into asolution of the target compound in CHCl 3 at room temperature, and the colorless orthorhombic crystal was selected for measurement.
ExperimentalAllofthe non-hydrogen atoms were located from the difference Fourier maps,and then refined anisotropically [1].The hydrogen atomswere added according to the theoretical model. The positionsofall Hatoms were determined geometrically andrefined using ar iding model with d(C-H) =0 .93-0.97 Åa nd U iso (methyl H) =1.5 U eq (C) and 1.2 U eq for other Hatoms.The structure was checked with PLATON [2]. The absolute configuration of the title crystal structure could not be determined using data collectedwithMoK a radiation(Flackparameter x =2(3)).The huge R values are presumably caused by the poor quality of thecrystal.Wehave been fortunate to obtain the single crystals from the very limited amount of material synthesized through reducing of bisabolangelone, which was isolated from the roots of Angelica polymorpha Maxim.
DiscussionThe H + /K + -ATPasei st he proton pump responsible for gastric acid secretion [ 3].B isabolangelone,asesquiterpene isolated from the roots of Angelica polymorpha Maxim with the traditional Tujia medicine name of Zijinsha [4], displayed attractive bioactivity such as anti-feeding and insecticidal effect [5][6][7]. Recently,wefound bisabolangelonealso exhibited remarkable preventive and therapeutic action on gastric ulcer, and its anti-ulcer mechanism might be related to inhibition of the H + /K + -ATPase and reduction of the secretion of H + [8].However, it was found to be moderately acutetoxic towards mice, e.g. administrated with the LD 50 of 76.60 mg/kg in our previous reports [9].With the aim of studying the relationship between its structure and H + /K + -ATPase inhibitiona ctivity, especiallyf or decreasingi ts acute toxicity, the catalytic hydrogenationofbisabolangelone was undertaken. Therefore, the structure determination of the title compound was conducted by X-ray single-crystal analysis for the first time. Compared with the crystal structure of bisabolangelone [10], most bond lengths in the crystal were in the normalrange of single or double bonds. The bond angles containing unsaturated bonds in ÐO1-C1-C2, ÐC2-C3-C7 and ÐC11-C9-C8 ranged from 121°to 128°. The torsion angles of C4-C5-C5-C8a nd O2-C5-C6-C1 were equal to 86.7(3)°and 157.9(3)°, respectively. Theside chain of 3-methylbutylidene in tetrahydrofuran ring disordere...
A CuI‐catalyzed three‐component alkyne‐azide cycloaddition in the presence of an excess of secondary amine is used for the synthesis of triazolyl‐substituted tetrahydrobenzofuran derivatives.
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