Systematic solution-phase parallel synthesis of active vitamin D3 analogs with elongated side chains and their cell differentiation activities.
Side-chain elongation of active vitamin D3 is acknowledged as a structural modification to enhance its cell differentiation activity; however, the comprehensive structure-activity relationship (SAR) as a result of this modification has not been reported. To clarify the SAR, we synthesized six analogs systematically elongated at the 24-position, 26,27-position, or both by methylene (normal A-ring series 1a-f) in a facile parallel solution-phase synthesis. Using parallel synthesis, we expanded the side chain-elongation study into two 19-exomethylene analog series: 19-nor-A-ring (4a-f) and 2-methylene-19-nor-A-ring (5a-f). In the 19-nor-A-ring analog series, the SAR induced by side-chain elongation was similar to the normal A-ring analog series, but in the 2-methylene-19-nor-A-ring series, the SAR was unique.
Ono
Yoshiyuki
Y
Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. onoysy@chugai-pharm.co.jp
Kashiwagi
Hirotaka
H
Esaki
Tohru
T
Tadakatsu
Takahashi
T
Sato
Hideki
H
Fujii
Nobutaka
N
D002454:Cell Differentiation / Q000187:drug effects*; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D015394:Molecular Structure; D012996:Solutions; D013329:Structure-Activity Relationship
D012996:Solutions; D002762:Cholecalciferol