{
"document_id": 14408,
"page": 3,
"width_pt": 612,
"height_pt": 792,
"rotation": 0,
"pipeline_version": "paddleocr-vl-1.6+paul-48",
"engine": "paddleocr_vl",
"source_run_id": 14519,
"item_count": 42,
"counts_by_type": {
"caption": 3,
"formula": 5,
"header": 3,
"heading": 2,
"text": 29
},
"build_ms": 10,
"items": [
{
"id": "p3.1",
"order": 1,
"type": "header",
"bbox": {
"l": 53.76,
"t": 765.6,
"r": 70.08,
"b": 756.96
},
"text": "506",
"attrs": {
"block_label": "number"
},
"level": 2
},
{
"id": "p3.2",
"order": 2,
"type": "header",
"bbox": {
"l": 76.08,
"t": 766.08,
"r": 264.48,
"b": 756
},
"text": "Journal of Natural Products, 1999, Vol. 62, No. 3",
"attrs": {
"block_label": "header"
},
"level": 2
},
{
"id": "p3.3",
"order": 3,
"type": "header",
"bbox": {
"l": 501.36,
"t": 766.08,
"r": 559.92,
"b": 756
},
"text": "Invited Review",
"attrs": {
"block_label": "header"
},
"level": 2
},
{
"id": "p3.4",
"order": 4,
"type": "formula",
"bbox": {
"l": 52.32,
"t": 745.92,
"r": 295.2,
"b": 545.04
},
"text": "",
"attrs": {
"block_label": "image",
"alt": "Skeletal structure of cyclogoniodenin T, a bis-THF acetogenin with a butenolide, hydroxyl groups at C4 and C22, and a C12H25…",
"source": "vision"
},
"children": [
{
"id": "p3.4.1",
"order": 5,
"type": "caption",
"bbox": {
"l": 147.12,
"t": 647.28,
"r": 202.32,
"b": 637.92
},
"text": "Cyclogoniodenin T",
"attrs": {
"block_label": "figure_title"
}
},
{
"id": "p3.4.2",
"order": 6,
"type": "caption",
"bbox": {
"l": 208.32,
"t": 555.6,
"r": 262.8,
"b": 545.76
},
"text": "Cyclogoniodenin T",
"attrs": {
"block_label": "figure_title"
}
}
]
},
{
"id": "p3.5",
"order": 7,
"type": "caption",
"bbox": {
"l": 51.84,
"t": 543.6,
"r": 288.48,
"b": 532.56
},
"text": "Figure 2 Biogenetic schemes for goniocin and cyclogoniodenin T.",
"attrs": {
"block_label": "figure_title"
}
},
{
"id": "p3.6",
"order": 8,
"type": "text",
"bbox": {
"l": 51.84,
"t": 522.24,
"r": 296.16,
"b": 342.24
},
"text": "using NMR-derived information, goniocin was assigned an S absolute stereocenter at C-10. This means that goniocin and cyclogoniodenin T have to be epimeric at each of the seven chiral centers across the tri-THF ring system. The absolute stereochemistry of all of these compounds had been determined using Mosher ester methodology.[p3.6.1] To help verify this remarkable coexistence of these naturally multicentered enantiomers, Sinha et al. at Scripps[p3.6.2] totally synthesized both compounds and confirmed that their absolute configurations were, indeed, correct as proposed. They relied upon the subtle differences of the chemical shifts of the methoxy group of the Mosher ester derivatives of both compounds and comparison with the original spectra of goniocin.[p3.6.3] They interpreted this unique coexistence to be a result of two alternative modes of tandem ring-closure routes, both starting with epimeric 1O-hydroxy intermediates (Figure 2). [p3.6.4]",
"children": [
{
"id": "p3.6.1",
"order": 9,
"type": "text",
"bbox": {
"l": 51.84,
"t": 522.24,
"r": 296.16,
"b": 342.24
},
"text": "^{[49]}",
"attrs": {
"inline": true,
"text_offset": 330,
"text_span": 8,
"bbox_estimated": true
}
},
{
"id": "p3.6.2",
"order": 10,
"type": "text",
"bbox": {
"l": 51.84,
"t": 522.24,
"r": 296.16,
"b": 342.24
},
"text": "^{[50,51]}",
"attrs": {
"inline": true,
"text_offset": 451,
"text_span": 8,
"bbox_estimated": true
}
},
{
"id": "p3.6.3",
"order": 11,
"type": "text",
"bbox": {
"l": 51.84,
"t": 522.24,
"r": 296.16,
"b": 342.24
},
"text": "^{[46,50,51]}",
"attrs": {
"inline": true,
"text_offset": 766,
"text_span": 8,
"bbox_estimated": true
}
},
{
"id": "p3.6.4",
"order": 12,
"type": "text",
"bbox": {
"l": 51.84,
"t": 522.24,
"r": 296.16,
"b": 342.24
},
"text": "^{[51]}",
"attrs": {
"inline": true,
"text_offset": 952,
"text_span": 8,
"bbox_estimated": true
}
}
]
},
{
"id": "p3.7",
"order": 13,
"type": "heading",
"bbox": {
"l": 52.56,
"t": 333.84,
"r": 236.88,
"b": 323.28
},
"text": "Extraction, Isolation, and Purification",
"attrs": {
"block_label": "paragraph_title"
},
"level": 3
},
{
"id": "p3.8",
"order": 14,
"type": "text",
"bbox": {
"l": 51.6,
"t": 317.76,
"r": 296.16,
"b": 118.56
},
"text": "The Annonaceous acetogenins are readily soluble in most organic solvents. Ethanol extraction of the dried plant material followed by solvent partitions, to concentrate the compounds, is still the method of choice in our laboratory.[p3.8.1] Two methods are in use to monitor the fractionation, which is mainly achieved by open column chromatography; these are bioactivity-guided fractionation using the brine shrimp lethality test (BST)[p3.8.2] and/or TLC spot visualization using Kedde’s reagent.[p3.8.3] Kedde’s reagent is not specific for the acetogenins; it detects the unsaturated conjugated lactones and does not detect the translactonized ketolactones; thus, the BST is superior in guiding fractionation and quickly leads to the most bioactive compounds. After open column chromatography, HPLC is then the most efficient method to purify individual compounds from the complex mixtures of the closely related acetogenins. Reversed-phase[p3.8.4] HPLC is superior to silica gel normal-phase HPLC in achieving separation of single-positional epimeric pairs, diastereomeric acetogenins, and/or closely related isomers.",
"children": [
{
"id": "p3.8.1",
"order": 15,
"type": "text",
"bbox": {
"l": 51.6,
"t": 317.76,
"r": 296.16,
"b": 118.56
},
"text": "⁴",
"attrs": {
"inline": true,
"text_offset": 231,
"text_span": 8,
"bbox_estimated": true
}
},
{
"id": "p3.8.2",
"order": 16,
"type": "text",
"bbox": {
"l": 51.6,
"t": 317.76,
"r": 296.16,
"b": 118.56
},
"text": "^{52,53}",
"attrs": {
"inline": true,
"text_offset": 435,
"text_span": 8,
"bbox_estimated": true
}
},
{
"id": "p3.8.3",
"order": 17,
"type": "text",
"bbox": {
"l": 51.6,
"t": 317.76,
"r": 296.16,
"b": 118.56
},
"text": "⁴",
"attrs": {
"inline": true,
"text_offset": 496,
"text_span": 8,
"bbox_estimated": true
}
},
{
"id": "p3.8.4",
"order": 18,
"type": "text",
"bbox": {
"l": 51.6,
"t": 317.76,
"r": 296.16,
"b": 118.56
},
"text": "C₁₈",
"attrs": {
"inline": true,
"text_offset": 941,
"text_span": 8,
"bbox_estimated": true
}
}
]
},
{
"id": "p3.9",
"order": 19,
"type": "text",
"bbox": {
"l": 51.6,
"t": 118.08,
"r": 296.4,
"b": 33.12
},
"text": "Countercurrent chromatography (CCC) has now been used for the first time in isolating Annonaceous acetogenins; this was demonstrated by the independent work of Duret et al.[p3.9.1] and Hopp et al.[p3.9.2]. While Duret et al. were the first to use the technique, Hopp et al. were the first to isolate new compounds using CCC. Duret et al. have used a biphasic mixture of heptane/ethyl acetate/methanol/water to isolate four pairs of acetogenins, which were then purified with HPLC. Hopp et al. developed a biphasic system, hexane/dichloromethane and methanol/water (1O.5:7:3), because it yielded nearly identical bioactivity in the two phases. Using the BST, after a sample of the bioactive fraction FOO5 had been partitioned between the two phases, Hopp et al. were able to isolate quickly four known and three new acetogenins; the last purification step was achieved by HPLC. CCC could be utilized to provide adequate amounts for further testing the major compounds from the crude extracts, in relatively short time.",
"children": [
{
"id": "p3.9.1",
"order": 20,
"type": "text",
"bbox": {
"l": 51.6,
"t": 118.08,
"r": 296.4,
"b": 33.12
},
"text": "^{[41]}",
"attrs": {
"inline": true,
"text_offset": 172,
"text_span": 8,
"bbox_estimated": true
}
},
{
"id": "p3.9.2",
"order": 21,
"type": "text",
"bbox": {
"l": 51.6,
"t": 118.08,
"r": 296.4,
"b": 33.12
},
"text": "^{[42]}",
"attrs": {
"inline": true,
"text_offset": 196,
"text_span": 8,
"bbox_estimated": true
}
}
]
},
{
"id": "p3.10",
"order": 22,
"type": "text",
"bbox": {
"l": 314.64,
"t": 745.92,
"r": 559.44,
"b": 640.56
},
"text": "purified with HPLC. Hopp et al. developed a biphasic system, hexane/dichloromethane and methanol/water (1Q 5:7:3), because it yielded nearly identical bioactivity in the two phases. Using the BST, after a sample of the bioactive fraction FOO5 had been partitioned between the two phases, Hopp et al. were able to isolate quickly four known and three new acetogenins; the last purification step was achieved by HPLC. CCC could be utilized to provide adequate amounts for further testing the major compounds from the crude extracts, in relatively short time."
},
{
"id": "p3.11",
"order": 23,
"type": "text",
"bbox": {
"l": 314.64,
"t": 639.6,
"r": 559.68,
"b": 397.68
},
"text": "By far, the major contribution to the detection, isolation, characterization, and dereplication of Annonaceous acetogenins in the last two years has come through the application of liquid chromatography–electrospray ionization mass spectrometry (LC/EIMS) techniques.[p3.11.1] Using the positive-ion mode and under conditions of atmospheric pressure in-source collision-induced dissociation (APICID), the acetogenins have provided reproducibly characteristic ion patterns and fragment ions.[p3.11.2] Analyzing the selected ion chromatograms (SIC), the presence of these acetogenins and other derivatives in crude plant extracts and chromatographic fractions can be readily detected. Utilizing the LC(+)ESI-APCID-MS technique, acetogenins produce characteristic ion patterns consisting of[p3.11.3] and[p3.11.4] molecular ions, as well as ions showing the consecutive losses of[p3.11.5] from the[p3.11.6] ion. LCMS screening of a 2μg aliquot of a bioactive crude methanol-soluble fraction of Rollinia mucosa detected the presence of some 40 known acetogenins in this plant species, in addition to four new acetogenins of diverse structure.[p3.11.7] As an example of the utility of this method, Gu et al. then applied the LC(+)-ESI-MS method to direct the isolation of two of the new compounds. [p3.11.8]",
"children": [
{
"id": "p3.11.1",
"order": 24,
"type": "text",
"bbox": {
"l": 314.64,
"t": 639.6,
"r": 559.68,
"b": 397.68
},
"text": "^{[54,55]}",
"attrs": {
"inline": true,
"text_offset": 266,
"text_span": 9,
"bbox_estimated": true
}
},
{
"id": "p3.11.2",
"order": 25,
"type": "text",
"bbox": {
"l": 314.64,
"t": 639.6,
"r": 559.68,
"b": 397.68
},
"text": "^{[54]}",
"attrs": {
"inline": true,
"text_offset": 489,
"text_span": 9,
"bbox_estimated": true
}
},
{
"id": "p3.11.3",
"order": 26,
"type": "formula",
"bbox": {
"l": 314.64,
"t": 639.6,
"r": 559.68,
"b": 397.68
},
"text": "[M + Na]⁺",
"attrs": {
"latex": "[M + Na]^{+}",
"inline": true,
"text_offset": 786,
"text_span": 9,
"bbox_estimated": true,
"alt": "M plus Na to the power of plus",
"mathml": ""
}
},
{
"id": "p3.11.4",
"order": 27,
"type": "formula",
"bbox": {
"l": 314.64,
"t": 639.6,
"r": 559.68,
"b": 397.68
},
"text": "[M + H]⁺",
"attrs": {
"latex": "[M + H]^{+}",
"inline": true,
"text_offset": 799,
"text_span": 9,
"bbox_estimated": true,
"alt": "M plus H to the power of plus",
"mathml": ""
}
},
{
"id": "p3.11.5",
"order": 28,
"type": "formula",
"bbox": {
"l": 314.64,
"t": 639.6,
"r": 559.68,
"b": 397.68
},
"text": "H₂O",
"attrs": {
"latex": "H_{2}O",
"inline": true,
"text_offset": 874,
"text_span": 9,
"bbox_estimated": true,
"alt": "H sub 2 O",
"mathml": ""
}
},
{
"id": "p3.11.6",
"order": 29,
"type": "formula",
"bbox": {
"l": 314.64,
"t": 639.6,
"r": 559.68,
"b": 397.68
},
"text": "[M + H]⁺",
"attrs": {
"latex": "[M + H]^{+}",
"inline": true,
"text_offset": 892,
"text_span": 9,
"bbox_estimated": true,
"alt": "M plus H to the power of plus",
"mathml": ""
}
},
{
"id": "p3.11.7",
"order": 30,
"type": "text",
"bbox": {
"l": 314.64,
"t": 639.6,
"r": 559.68,
"b": 397.68
},
"text": "^{[54]}",
"attrs": {
"inline": true,
"text_offset": 1136,
"text_span": 9,
"bbox_estimated": true
}
},
{
"id": "p3.11.8",
"order": 31,
"type": "text",
"bbox": {
"l": 314.64,
"t": 639.6,
"r": 559.68,
"b": 397.68
},
"text": "^{[55]}",
"attrs": {
"inline": true,
"text_offset": 1291,
"text_span": 9,
"bbox_estimated": true
}
}
]
},
{
"id": "p3.12",
"order": 32,
"type": "text",
"bbox": {
"l": 314.64,
"t": 397.68,
"r": 559.44,
"b": 186.96
},
"text": "In another study which evaluated the monthly variations of acetogenin content in crude[p3.12.1] extracts of twigs collected from a single paw paw (A. triloba) tree, Gu et al. used the LCMSMS technique to quantify the contents of the three most biologically potent acetogenins.[p3.12.2] The quantified contents of these acetogenins showed good correlation with potencies as observed in the BST and demonstrated the highest activities in extracts from the May and June samples. These results clearly demonstrated seasonal variations in acetogenin content and suggest that May and June are the best time to collect paw paw twigs for maximizing bioactivities. Most recently, these methods have confirmed that the BST-active extracts of the zebra swallowtail (Eurytides marcellus) butterflies and larvae, which are obligate parasites on the paw paw leaves, contain the potent acetogenins bullatacin, bullatalicin, trilobacin, and/or asimicin.[p3.12.3] This well-defined LCMSMS method will undoubtedly be widely applied in the quantitative analysis of other desirable natural components in crude extracts in the future.",
"children": [
{
"id": "p3.12.1",
"order": 33,
"type": "text",
"bbox": {
"l": 314.64,
"t": 397.68,
"r": 559.44,
"b": 186.96
},
"text": "CH₂Cl₂",
"attrs": {
"inline": true,
"text_offset": 86,
"text_span": 9,
"bbox_estimated": true
}
},
{
"id": "p3.12.2",
"order": 34,
"type": "text",
"bbox": {
"l": 314.64,
"t": 397.68,
"r": 559.44,
"b": 186.96
},
"text": "^{[56]}",
"attrs": {
"inline": true,
"text_offset": 276,
"text_span": 9,
"bbox_estimated": true
}
},
{
"id": "p3.12.3",
"order": 35,
"type": "text",
"bbox": {
"l": 314.64,
"t": 397.68,
"r": 559.44,
"b": 186.96
},
"text": "^{[57]}",
"attrs": {
"inline": true,
"text_offset": 937,
"text_span": 9,
"bbox_estimated": true
}
}
]
},
{
"id": "p3.13",
"order": 36,
"type": "heading",
"bbox": {
"l": 315.36,
"t": 177.6,
"r": 426.72,
"b": 166.8
},
"text": "Structural Elucidation",
"attrs": {
"block_label": "paragraph_title"
},
"level": 3
},
{
"id": "p3.14",
"order": 37,
"type": "text",
"bbox": {
"l": 314.4,
"t": 161.28,
"r": 559.44,
"b": 56.16
},
"text": "Synthetic models of known stereochemistry are used routinely to predict the relative stereochemistry of both the THF and the [p3.14.1]-lactone ring systems bearing the nearby 4-hydroxyl of the acetogenins.[p3.14.2] The locations of the THF ring and/or the free hydroxyls continue to be determined by careful analysis of mass spectral fragments.[p3.14.3] No significant changes have been introduced in the methods for structural elucidation of Annonaceous acetogenins in the last two years. Nevertheless, the following three contributions merit discussion.",
"children": [
{
"id": "p3.14.1",
"order": 38,
"type": "text",
"bbox": {
"l": 314.4,
"t": 161.28,
"r": 559.44,
"b": 56.16
},
"text": "γ",
"attrs": {
"inline": true,
"text_offset": 125,
"text_span": 9,
"bbox_estimated": true
}
},
{
"id": "p3.14.2",
"order": 39,
"type": "text",
"bbox": {
"l": 314.4,
"t": 161.28,
"r": 559.44,
"b": 56.16
},
"text": "^{[58-62]}",
"attrs": {
"inline": true,
"text_offset": 205,
"text_span": 9,
"bbox_estimated": true
}
},
{
"id": "p3.14.3",
"order": 40,
"type": "text",
"bbox": {
"l": 314.4,
"t": 161.28,
"r": 559.44,
"b": 56.16
},
"text": "^{[2-4]}",
"attrs": {
"inline": true,
"text_offset": 344,
"text_span": 9,
"bbox_estimated": true
}
}
]
},
{
"id": "p3.15",
"order": 41,
"type": "text",
"bbox": {
"l": 314.64,
"t": 55.44,
"r": 559.44,
"b": 33.36
},
"text": "Duret et al. have noticed that the non-4-hydroxylated [p3.15.1]-lactone moiety of the Annonaceous acetogenins may be",
"children": [
{
"id": "p3.15.1",
"order": 42,
"type": "text",
"bbox": {
"l": 314.64,
"t": 55.44,
"r": 559.44,
"b": 33.36
},
"text": "γ",
"attrs": {
"inline": true,
"text_offset": 54,
"text_span": 9,
"bbox_estimated": true
}
}
]
}
],
"excluded_furniture": {
"first": [],
"last": []
}
}