Synthesis and biological properties of 2-methylene-19-nor-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactones--weak agonists.
In a continuing effort to explore the 2-methylene-1alpha-hydroxy-19-norvitamin D(3) class of pharmacologically important vitamin D compounds, two novel 2-methylene-19-nor-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactones, GC-3 and HLV, were synthesized and biologically tested. Based on reports of similarly structured molecules, it was hypothesized that these compounds might act as antagonists, at least in vitro. The pathway designed to synthesize these compounds was based on two key steps: first, the Lythgoe-type Wittig-Horner coupling of Windaus-Grundmann-type ketone 18, with phosphine oxide 15, followed, later in the synthesis, by the Zn-mediated Reformatsky-type allylation of aldehyde 20 with methylbromomethylacrylate 8. Our biological data show that neither compound has antagonistic activity but acts as weak agonists in vitro and in vivo.
Chiellini
Grazia
G
Department of Biochemistry, College of Agriculture and Life Sciences, 433 Babcock Drive, University of Wisconsin-Madison, Madison, WI 53706-1544, USA.
Grzywacz
Pawel
P
Plum
Lori A
LA
Barycki
Rafal
R
Clagett-Dame
Margaret
M
DeLuca
Hector F
HF
D000447:Aldehydes / Q000737:chemistry; D000498:Allyl Compounds / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D008689:Methacrylates / Q000737:chemistry; D010720:Phosphines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
C468519:2-methylene-1,25-dihydroxy-19-norvitamin D3; D000447:Aldehydes; D000498:Allyl Compounds; D007783:Lactones; D008689:Methacrylates; D010720:Phosphines; D002117:Calcitriol; D015032:Zinc