title: Synthesis and biological activities of the two C(23) epimers of 1alpha,23,25-trihydroxy-24-oxo-19-nor-vitamin D(3): novel analogs of 1alpha,23(S),25-trihydroxy-24-oxo-vitamin D(3), a natural metabolite of 1alpha,25-dihydroxyvitamin D(3).
abstract: In a previous report, we indicated that 1alpha,23(S), 25-trihydroxy-24-oxovitamin D(3) [1alpha,23(S), 25(OH)(3)-24-oxo-D(3)], a natural metabolite of 1alpha, 25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] is almost equipotent to 1alpha,25(OH)(2)D(3) in suppressing parathyroid hormone (PTH) secretion (Lee et al., 1997. Biochemistry 36, 9429-9437). Also, 1alpha,23(S),25(OH)(3)-24-oxo-D(3) has been shown to possess only weak in vivo calcemic actions. Thus, vitamin D(3) analogs structurally related to 1alpha,23(S),25(OH)(3)-24-oxo-D(3) may have therapeutic value. Furthermore, biologic activity studies of various synthetic analogs of 1alpha,25(OH)(2)D(3) showed that the removal of carbon-19 (C-19) reduces the calcemic activity of 1alpha, 25(OH)(2)D(3.) Therefore, in an attempt to produce vitamin D(3) analogs with a better therapeutic index, we synthesized C(23) epimers of 1alpha,23,25(OH)(3)-24-oxo-19-nor-vitamin D(3) [1alpha,23, 25(OH)(3)-24-oxo-19-nor-D(3)]. The two epimers were compared to 1alpha,25(OH)(2)-19-nor-D(3) and 1alpha,25(OH)(2)D(3) in their ability to generate biologic activities in several in vitro assay systems. In the assay measuring the suppression of parathyroid hormone (PTH) secretion in bovine parathyroid cells, 1alpha,23(S), 25(OH)(3)-24-oxo-19-nor-D(3) was as potent as 1alpha, 25(OH)(2)-19-nor-D(3) but was less potent than 1alpha,25(OH)(2)D(3). In the same assay 1alpha,23(R),25(OH)(3)-24-oxo-19-nor-D(3) exhibited greater potency than 1alpha,23(S), 25(OH)(3)-24-oxo-19-nor-D(3). In the assays measuring the ability of vitamin D compounds to inhibit clonal growth and to induce differentiation of human promyelocytic leukemia (HL-60) cells, 1alpha,23(S),25(OH)(3)-24-oxo-19-nor-D(3) was less potent than 1alpha,25(OH)(2)-19-nor-D(3) but was equipotent to 1alpha, 25(OH)(2)D(3). More importantly, in the same assays, 1alpha,23(R), 25(OH)(3)-24-oxo-19-nor-D(3) was more potent than 1alpha,23(S), 25(OH)(3)-24-oxo-19-nor-D(3) and was equipotent to 1alpha, 25(OH)(2)-19-nor-D(3). Also, the vitamin D receptor-mediated transcriptional activity of 1alpha,23(R), 25(OH)(3)-24-oxo-19-nor-D(3) was almost equal to that of 1alpha, 25(OH)(2)-19-nor-D(3), but higher than that of 1alpha,23(S), 25(OH)(3)-24-oxo-19-nor-D(3). This finding explains in part the greater in vitro biologic activities of 1alpha,23(R), 25(OH)(3)-24-oxo-19-nor-D(3). In summary, our results indicate that 1alpha,23(R),25(OH)(3)-24-oxo-19-nor-D(3) and to a lesser extent 1alpha,23(S),25(OH)(3)-24-oxo-19-nor-D(3) are potent 19-nor vitamin D(3) analogs, which suppress PTH secretion in bovine parathyroid cells and strongly inhibit clonal growth and induce differentiation of HL-60 cells in vitro.
authors.affiliation: Department of Chemistry, Simmons College, Boston, MA 02115, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Lee
authors.forename: P G
authors.initials: PG
authors.lastname: Williard
authors.forename: A J
authors.initials: AJ
authors.lastname: Brown
authors.forename: M J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
authors.forename: S
authors.initials: S
authors.lastname: Peleg
authors.forename: D S
authors.initials: DS
authors.lastname: Rao
authors.forename: G S
authors.initials: GS
authors.lastname: Reddy
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D002417:Cattle; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells / Q000166:cytology; D018922:HL-60 Cells / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006887:Hydroxycholecalciferols / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology*; D007536:Isomerism; D016177:Macrophage-1 Antigen / Q000096:biosynthesis / Q000187:drug effects; D010280:Parathyroid Glands / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000502:physiology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: C408942:1,23,25-trihydroxy-24-oxo-19-norvitamin D(3); D006887:Hydroxycholecalciferols; D016177:Macrophage-1 Antigen; D010281:Parathyroid Hormone; D017382:Reactive Oxygen Species; D002117:Calcitriol