{ "document_id": 13701, "page": 6, "width_pt": 612, "height_pt": 792, "rotation": 0, "pipeline_version": "paddleocr-vl-1.6+paul-48", "engine": "paddleocr_vl", "source_run_id": 13812, "item_count": 50, "counts_by_type": { "caption": 3, "figure": 2, "formula": 1, "header": 3, "heading": 1, "text": 40 }, "build_ms": 7, "items": [ { "id": "p6.1", "order": 1, "type": "header", "bbox": { "l": 53.76, "t": 766.08, "r": 112.08, "b": 756 }, "text": "Invited Review", "attrs": { "block_label": "header" }, "level": 2 }, { "id": "p6.2", "order": 2, "type": "header", "bbox": { "l": 350.4, "t": 766.08, "r": 540.24, "b": 756.24 }, "text": "Journal of Natural Products, 1999, Vol. 62, No. 3", "attrs": { "block_label": "header" }, "level": 2 }, { "id": "p6.3", "order": 3, "type": "header", "bbox": { "l": 543.12, "t": 765.84, "r": 558.96, "b": 756.96 }, "text": "509", "attrs": { "block_label": "number" }, "level": 2 }, { "id": "p6.4", "order": 4, "type": "text", "bbox": { "l": 52.08, "t": 746.16, "r": 295.44, "b": 692.16 }, "text": "genin if the distance is too long. It was also observed that when one THF ring is replaced with a tetrahydropyran ring (THP) the activity remains comparable. Stereochemical differences did not show any significant differences in potency." }, { "id": "p6.5", "order": 5, "type": "heading", "bbox": { "l": 52.8, "t": 682.8, "r": 143.76, "b": 671.76 }, "text": "Biological Activity", "attrs": { "block_label": "paragraph_title" }, "level": 3 }, { "id": "p6.6", "order": 6, "type": "text", "bbox": { "l": 51.6, "t": 666.96, "r": 295.92, "b": 582.48 }, "text": "As previously noted, this class of diverse, but still closely related, compounds, has several interesting and potent biological activities, including antibacterial, antimalarial, in vivo antitumor, parasiticidal, and pesticidal effects.[p6.6.1] Potentially of greatest importance, in the last two years the Annonaceous acetogenins have emerged as promising new leads to thwart resistance in multidrug resistant (MDR) tumors and in pesticide-resistant insects. [p6.6.2]", "children": [ { "id": "p6.6.1", "order": 7, "type": "text", "bbox": { "l": 51.6, "t": 666.96, "r": 295.92, "b": 582.48 }, "text": "²⁻⁶", "attrs": { "inline": true, "text_offset": 236, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.6.2", "order": 8, "type": "text", "bbox": { "l": 51.6, "t": 666.96, "r": 295.92, "b": 582.48 }, "text": "¹⁹⁻²²", "attrs": { "inline": true, "text_offset": 460, "text_span": 8, "bbox_estimated": true } } ] }, { "id": "p6.7", "order": 9, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "In vitro and in vivo Cytotoxicity Results. Some Annonaceous acetogenins may be among the most potent cytotoxic agents ever known; e.g., trilobacin[p6.7.1] and asiminocin[p6.7.2] have shown ED[p6.7.3] values of <10[p6.7.4] [p6.7.5]g/mL in several human tumor cell lines. Yet, cytotoxic selectivities, among various cell lines, have been observed concurrently, e.g., squamotacin with an ED[p6.7.6] value of 10[p6.7.7] [p6.7.8]g/mL against the human prostate cell line (PC-3),[p6.7.9] mosin C with an ED[p6.7.10] of 10[p6.7.11] [p6.7.12]g/mL against pancreatic carcinoma cells (PACA-2),[p6.7.13] and pyranicin with an ED[p6.7.14] of 10[p6.7.15] [p6.7.16]g/mL also against PACA-2 [p6.7.17]A series of acetogenins all show greater cytotoxic effects to cancerous vs noncancerous cells.[p6.7.18] Thus, these agents are not “general cytotoxins” as some authorities continue to profess. It is not yet clear how the acetogenins can inhibit the growth of 50% of in vitro grown cancerous cells at concentrations of <10[p6.7.19] [p6.7.20]g/mL. Several factors, such as intracellular transportation, metabolism, and inactivation and receptor geometry may all contribute to this phenomenon of selectivity, and it is even possible that hydrogen peroxide, induced by apoptosis and resulting radical oxygen formation, diffuses into neighboring cells where it is lethal.", "children": [ { "id": "p6.7.1", "order": 10, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "¹⁰²", "attrs": { "inline": true, "text_offset": 146, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.7.2", "order": 11, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "¹⁰³", "attrs": { "inline": true, "text_offset": 169, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.7.3", "order": 12, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "₅₀", "attrs": { "inline": true, "text_offset": 191, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.7.4", "order": 13, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "⁻¹²", "attrs": { "inline": true, "text_offset": 213, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.7.5", "order": 14, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "μ", "attrs": { "inline": true, "text_offset": 222, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.7.6", "order": 15, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "₅₀", "attrs": { "inline": true, "text_offset": 387, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.7.7", "order": 16, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "⁻⁸", "attrs": { "inline": true, "text_offset": 407, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.7.8", "order": 17, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "μ", "attrs": { "inline": true, "text_offset": 416, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.7.9", "order": 18, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "¹⁰⁴", "attrs": { "inline": true, "text_offset": 473, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.7.10", "order": 19, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "₅₀", "attrs": { "inline": true, "text_offset": 500, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.7.11", "order": 20, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "⁻⁴", "attrs": { "inline": true, "text_offset": 515, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.7.12", "order": 21, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "μ", "attrs": { "inline": true, "text_offset": 525, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.7.13", "order": 22, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "¹⁰⁵", "attrs": { "inline": true, "text_offset": 583, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.7.14", "order": 23, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "₅₀", "attrs": { "inline": true, "text_offset": 617, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.7.15", "order": 24, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "⁻²", "attrs": { "inline": true, "text_offset": 632, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.7.16", "order": 25, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "μ", "attrs": { "inline": true, "text_offset": 642, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.7.17", "order": 26, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "¹⁰", "attrs": { "inline": true, "text_offset": 676, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.7.18", "order": 27, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "¹⁹", "attrs": { "inline": true, "text_offset": 779, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.7.19", "order": 28, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "⁻¹²", "attrs": { "inline": true, "text_offset": 1006, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.7.20", "order": 29, "type": "text", "bbox": { "l": 51.6, "t": 581.76, "r": 296.16, "b": 350.64 }, "text": "μ", "attrs": { "inline": true, "text_offset": 1016, "text_span": 9, "bbox_estimated": true } } ] }, { "id": "p6.8", "order": 30, "type": "text", "bbox": { "l": 51.36, "t": 348.96, "r": 296.4, "b": 77.04 }, "text": "While extensive and comprehensive in vivo testing has yet to be conducted, the Annonaceous acetogenins have, indeed, already shown promising in vivo results. Uvaricin originally showed in vivo activity against 3PS (murine lymphocytic leukemia) (157% T/C at 1.4 mg/kg),[p6.8.1] and the rolinones (147% T/C at 1.4 mg/kg) and asimicin (124% T/C at 25 [p6.8.2]g/kg) were active in the same assay.[p6.8.3] It must be remembered that the murine leukemias are used as indicators of in vivo antitumor activity, in general, and are not just predictors for antileukemic agents. At the Upjohn Co., bullatacin and (2,4-cis and trans)-bullatacinones were tested against L121O (murine leukemia) in normal mice and in tumor xenografts of A278O (human ovarian carcinoma) in athymic mice.[p6.8.4] Bullatacin, effective at only 50 [p6.8.5]g/kg, was over 300 times more potent than paclitaxel against L121O and bullatacin, at 50 [p6.8.6]g/kg, and bullatalicin, at 1 mg/kg, were almost equivalent to cis-platinum; in addition, the acetogenins caused much less weight loss than the standards.[p6.8.7] Previously unpublished results, obtained by the late G. Grindey at the Eli Lilly Co., showed similar effectiveness of bullatacin (67% tumor inhibition at 50 [p6.8.8]g/kg) against X-5563 plasma cell myeloma grafts in normal mice. With water-soluble derivatives in hand and with better understanding of their SAR, development of the optimum compounds into clinically useful antitumor agents should be a top priority.", "children": [ { "id": "p6.8.1", "order": 31, "type": "text", "bbox": { "l": 51.36, "t": 348.96, "r": 296.4, "b": 77.04 }, "text": "⁷", "attrs": { "inline": true, "text_offset": 268, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.8.2", "order": 32, "type": "text", "bbox": { "l": 51.36, "t": 348.96, "r": 296.4, "b": 77.04 }, "text": "μ", "attrs": { "inline": true, "text_offset": 348, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.8.3", "order": 33, "type": "text", "bbox": { "l": 51.36, "t": 348.96, "r": 296.4, "b": 77.04 }, "text": "⁶", "attrs": { "inline": true, "text_offset": 392, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.8.4", "order": 34, "type": "text", "bbox": { "l": 51.36, "t": 348.96, "r": 296.4, "b": 77.04 }, "text": "¹⁵", "attrs": { "inline": true, "text_offset": 771, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.8.5", "order": 35, "type": "text", "bbox": { "l": 51.36, "t": 348.96, "r": 296.4, "b": 77.04 }, "text": "μ", "attrs": { "inline": true, "text_offset": 813, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.8.6", "order": 36, "type": "text", "bbox": { "l": 51.36, "t": 348.96, "r": 296.4, "b": 77.04 }, "text": "μ", "attrs": { "inline": true, "text_offset": 910, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.8.7", "order": 37, "type": "text", "bbox": { "l": 51.36, "t": 348.96, "r": 296.4, "b": 77.04 }, "text": "⁴", "attrs": { "inline": true, "text_offset": 1071, "text_span": 8, "bbox_estimated": true } }, { "id": "p6.8.8", "order": 38, "type": "text", "bbox": { "l": 51.36, "t": 348.96, "r": 296.4, "b": 77.04 }, "text": "μ", "attrs": { "inline": true, "text_offset": 1237, "text_span": 8, "bbox_estimated": true } } ] }, { "id": "p6.9", "order": 39, "type": "text", "bbox": { "l": 51.6, "t": 76.56, "r": 296.16, "b": 33.6 }, "text": "Annonaceous Acetogenins vs Multidrug Resistant Cells. MDR tumors, whether intrinsic or acquired, continue to limit the life span of cancer patients in remission. MDR tumors are usually associated with an increased" }, { "id": "p6.10", "order": 40, "type": "figure", "bbox": { "l": 317.52, "t": 743.76, "r": 557.52, "b": 560.4 }, "text": "", "attrs": { "kind": "chart", "block_label": "chart" } }, { "id": "p6.11", "order": 41, "type": "caption", "bbox": { "l": 406.32, "t": 566.16, "r": 497.04, "b": 558 }, "text": "log[concentration ( [p6.11.1]g/mL)]", "attrs": { "block_label": "figure_title" }, "children": [ { "id": "p6.11.1", "order": 42, "type": "text", "bbox": { "l": 406.32, "t": 566.16, "r": 497.04, "b": 558 }, "text": "μ", "attrs": { "inline": true, "text_offset": 20, "text_span": 9, "bbox_estimated": true } } ] }, { "id": "p6.12", "order": 43, "type": "caption", "bbox": { "l": 314.88, "t": 554.4, "r": 558.72, "b": 501.6 }, "text": "Figure 3. Effect of exposure for 6 days to the standard antineoplastic drugs, adriamycin, vincristine, and vinblastine, against MCF-7/Adr cells. Values are expressed as percentages of the vehicle-treated controls with each point representing the normalized average of four values and the error bars representing the standard deviation about each average. The concentration values are log dose units in [p6.12.1]g/mL.", "attrs": { "block_label": "figure_title" }, "children": [ { "id": "p6.12.1", "order": 44, "type": "text", "bbox": { "l": 314.88, "t": 554.4, "r": 558.72, "b": 501.6 }, "text": "μ", "attrs": { "inline": true, "text_offset": 402, "text_span": 9, "bbox_estimated": true } } ] }, { "id": "p6.13", "order": 45, "type": "figure", "bbox": { "l": 316.56, "t": 492.96, "r": 556.8, "b": 306.96 }, "text": "", "attrs": { "kind": "chart", "block_label": "chart" } }, { "id": "p6.14", "order": 46, "type": "caption", "bbox": { "l": 314.88, "t": 303.6, "r": 558.72, "b": 251.04 }, "text": "Figure 4. Effect of exposure for 6 days to the standard antineoplastic drugs, adriamycin, vincristine, and vinblastine against MCF-7/wt cells. Values are expressed as percentages of the vehicle-treated controls with each point representing the normalized average of four values and the error bars representing the standard deviation about that average. The concentration values are log dose units in [p6.14.1]g/mL.", "attrs": { "block_label": "figure_title" }, "children": [ { "id": "p6.14.1", "order": 47, "type": "text", "bbox": { "l": 314.88, "t": 303.6, "r": 558.72, "b": 251.04 }, "text": "μ", "attrs": { "inline": true, "text_offset": 400, "text_span": 9, "bbox_estimated": true } } ] }, { "id": "p6.15", "order": 48, "type": "text", "bbox": { "l": 314.16, "t": 243.6, "r": 559.92, "b": 33.12 }, "text": "expression of P-glycoprotein, a 170 kDa transmembrane energy-dependent drug efflux pump. In our recent work,[p6.15.1] we showed that acetogenins, because of their potent ability to block ATP production, can selectively inhibit the growth of MDR tumors cells in vitro. A thorough examination of the acetogenins against in vivo models of multidrug resistance is now suggested. Using both wild-type and adriamycin-resistant human mammary adenocarcinoma cells in vitro (MCF-7/wt and MCF-7/Adr, respectively), Oberlies et al. observed that the MCF-7/Adr cells were more susceptible to acetogenin treatment and elicited a linear dose response curve. Alternatively, against the MCF-7/wt cells, a plateau near the IC[p6.15.2] value was observed (this is commonly seen with acetogenins). This observation led to the hypothesis that the acetogenins were cytotoxic to the MCF-7/Adr cells but more cytotoxic to the MCF-7/wt cells. For example, in contrast to adriamycin, vincristine, and vinblastine (Figures 3 and 4), bullatacin was effective at inhibiting the growth of the MDR MCF-7/Adr cells and exhibited a linear dose-response curve over a concentra-", "children": [ { "id": "p6.15.1", "order": 49, "type": "text", "bbox": { "l": 314.16, "t": 243.6, "r": 559.92, "b": 33.12 }, "text": "^{[20,21]}", "attrs": { "inline": true, "text_offset": 108, "text_span": 9, "bbox_estimated": true } }, { "id": "p6.15.2", "order": 50, "type": "formula", "bbox": { "l": 314.16, "t": 243.6, "r": 559.92, "b": 33.12 }, "text": "[The region is a paragraph of body text, not a formula. The transcription \"₅₀\" covers only a fragment of the subscript \"IC₅₀\" in the text.]", "attrs": { "latex": "\\text{[The region is a paragraph of body text, not a formula. 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