著者

榊原 和征 内田 亜希

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集 36 (ISSN:24331856)

巻号頁・発行日

pp.439-444, 1994-09-20 (Released:2017-08-18)

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Endogenous digitalis-like substances(EDLS) or factors(EDLF) are putative substances which have been thought to be pathogens to hypertention and to possess cardiotonic activity through inhibiting of Na/K ATPase. Some of them seem to regulate natriuresis in kidney and those or the others of them seem to possess an unknown function in eyes, though recognized so far only as pathogens to cataract A lot of compounds have been reported as a substance of EDLF so far. Recently, a conclusion that EDLF was ouabain itself was reported by Hamlyn et al. However, it is still controversial if their ouabain is really endogenous, because it has been known that the digitalis activity derived from foods, especially vegitables, may accumulate in adrenal wherefrom it may be released into blood. Several years ago, Inagami et al reported their EDLF isolated from bovine adrenals possessed the molecular weight of 336. This fact, as well as several information by Grave et al, Bricker et al, and Goto et al, prompted us to deduce a structure for Inagami-Tamura's EDLF and thus lead us to a possible structure, (1). In order to reveal the structure more, we attempted to isolate a lot of amount of the EDLF from 92 kg of bovine adrenals. However, that work ended unsuccessfully. Thus, we decided to elucidate its structure through the repetetion of designing of a target molecule, synthesis, and biological evaluation. Target molecules, (26) and (29), synthesized through 17 steps from estradiol (2), showed the contractile activity on an isolated rat aorta and an isolated Guinea pig atrium. However, they were less potent than less oxygenated compounds, (30) and (31). (See Fig. 3,4,5,and 6.) These results suggest the structure (1) is substancially probable but a further study for a true character of the EDLF should be continued.

著者

山本 恵子 山田 幸子 大田 雅照

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集 36 (ISSN:24331856)

巻号頁・発行日

pp.290-297, 1994-09-20 (Released:2017-08-18)

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Hydroxyl groups play a major role in binding to a receptor protein. To clarify the side chain conformation of 1,25(OH)_2D_3 (1) to bind to VDR, we analyzed the mobility of the side chain of 1 and its 20-epimer (2) in terms of the spatial region accessible by the 25-hydroxyl group and the results were displayed as a dot map. The dot map indicates that each vitamin D has two major densely populated regions: A and G for 1 and EA and EG for 2. We designed six 22-substituted analogs of active vitamin D, 3-8, whose side chain hydroxyl is restricted to occupy one of the four spatial regions defined above and the analogs were classified into group A, G, EA, and EG accordingly. Syntheses of analogs, 3-8, were performed via diastereoselective conjugate addition of alkyl cuprate to steroidal (E)-and (Z)-22-en-24-ones (12 and 13) and -22-en-24-oates (16, 17, 20 and 21) as the key step. The activity of the analogs, 3-8, to bind to VDR was examined in compared with 1. It is apparent that the members of A ( 4 and 6) and EG (7) group analogs show much higher activity than the others, G(3, 5) and EA (8). The contrasting activities of the two 22-methyl analogs (3 and 4) are especially outstanding: VDR binding (3:4:1=1/50:1/3:1); differentiation of HL-60 cells (3:4:1=1/70:1:1). The results suggest that the conformation of 1,25(OH)_2D_3 (1) involved in binding to VDR and responsible for activity is the C(17,20,22,23)-anti form and the region where the 25-hydroxyl group occupies is the A.