title: Relationship between differentiation-inducing activity and hypercalcemic activity of hexafluorotrihydroxyvitamin D3 derivatives.
abstract: Among 16 newly synthesized hexafluorotrihydroxyvitamin D3 derivatives, 24-Homo-26,26,26,27,27,27-hexafluoro (24H-F6)-1,24(S), 25(OH)3 vitamin D3 (VD3) (DD-011) [16] induced differentiation (i.e., appearance of NBT-positive cells) of human promyelocytic leukemic HL-60 cells most efficiently (EC50=0.5 nM), followed by 24H-F6-1,25(OH)2-22-oxa-VD3 (DD-006) [11] > F6-1,25(OH)2-VD3 (F6VD3) [2] > F6-1,25(OH)2-22-ene-VD3 (DD-009) [14] > 24H-F6-1,25(OH)2-VD3 (F6C28) [3] > 24H-F6-1,25(OH)2-1,23(S),25(OH)3-VD3 (DD-015) [18] > 24H-F6-1,25(OH)2-22-ene-VD3 (mvd1400) [6] > 22H-F6-1,25(OH)2-24-ene-VD3 (mvd3400) [5] > 24H-F6-1,23(R),25(OH)3-VD3 (DD-014) [17] > 24H-F6-1,22(S),25(OH)3-VD3 (DD-003) [7] > 24H-F6-1,22(S),25(OH)3-24-yne-VD3 (DD-005) [9] > 24H-F6-1,22(R),25(OH)3-24-yne-VD3 (mvd-1235) [10] > F6-1,25(OH)2-22-ene-VD3 (DD-008) [13] = 1,25(OH)2VD3 [1] (CC50=6 nM). On the other hand, 24H-F6-1,22(R),25(OH)3-VD3 (DD-004) [8], which is an isomer of DD-003 [7], showed much reduced activity (CC50=100 nM), suggesting the importance of the configuration of the OH group at the C-22. When their differentiation-inducing activity was plotted vs. the octanol-water partition coefficient (log P) used as a parameter of hydrophobicity, a bell-shaped curve was produced, with the bottom at log P=5.4-5.8. There was no clear-cut relationship between the differentiation-inducing activity and hypercalcemic activity (serum calcium elevating activity). Compounds [3, 7, 11, 17] showed relatively higher differentiation-inducing activity, with lesser hypercalcemic activity, as compared with [1]. Administration of [7] showed potent antiproliferation activity against colon cancer transplanted in nude mice. These results further confirmed the antitumor potential of hexafluorotrihydroxyvitamin D3 derivatives.
authors.affiliation: Department of Dental Pharmacology, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
authors.forename: Senwa
authors.initials: S
authors.lastname: Unten
authors.forename: Mariko
authors.initials: M
authors.lastname: Ishihara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002762:Cholecalciferol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D019073:HT29 Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D006934:Hypercalcemia / Q000139:chemically induced*; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D023041:Xenograft Model Antitumor Assays
chemical_list: D006845:Hydrocarbons, Fluorinated; D002762:Cholecalciferol