Development of Analogues of 1α,25‐Dihydroxyvitamin D₃ with Biased Side‐Chain Orientation: C20 Methylated Des‐C,D‐homo Analogues

Abstract

The discovery that 1α,25-dihydroxyvitamin D 3 is effective in the inhibition of cellular proliferation and in the induction of cellular differentiation has led to a search for analogues in which these activities and the classical calcemic activity of the hormone are dissociated. In this context, the synthesis and biological evaluation are reported for six CD-ring modified structural analogues that were conceived so as to enforce a particular orientation of the 25-hydroxylated side chain. The analogues are characterized by the absence of the Cring and the presence of an unnatural six-membered D-ring.

Aromatic-Based Design of Highly Active and Noncalcemic Vitamin D Receptor Agonists

“…16 This synthesis has been used to access the natural hormone 1,25D 17 and a variety of vitamin D analogues modified at the side chain, 13 triene system, 18 C-ring, 19 and Aring, 11,20 that were required to establish structure−function relationships for the development of active ligands of the VDR with potential therapeutic value. Biological studies on analogues with modified C/D region that comprise C-ring analogues lacking the D-ring, 21,22 D-ring analogues lacking the C-ring 23,24 and six-membered D-ring analogues, 25,26 have demonstrated that the native bicyclic CD-core is not required for biological activity and its alteration might lower the calcemic activity. 27 In a search for vitamin D analogues that are highly active in the circulation but with low or negligible calcemic effects, we describe a modification of the reported synthetic approach for rapid and economic access to novel vitamin D analogues 2 (Figure 1a) and disclose their structures and their biological activities with respect to cell differentiation-proliferation, transactivation, and secondary calcemic effects.…”

Analogs of Calcitriol

“…The replacement of the five-membered D-ring of analog SL 117 by a six-membered ring (BL 269) resulted in a more potent analog (three-fold increased inhibition of MCF-7 or keratinocytes proliferation compared to 1,25(OH) 2 D 3 ) (Table 76.9) [34,35]. The introduction of other modifications (20-epi; 16-ene-23-yne) did not enhance the potency of BL 269.…”

“…Over the years numerous analogs were developed featuring a more substantially modified CD-region such as the six-membered C-ring analogs (lacking the D-ring, Tables 76.3e76.4) [30,31], five-membered D-ring analogs (lacking the C-ring, Tables 76.5e76.8) [32,33] and six-membered D-ring analogs (lacking the C-ring and possessing an enlarged D-ring, Table 76.9) [34,35]. In comparison with the natural compound 1,25(OH) 2 D 3 , the non-steroidal analogs described in this section possess a greater flexibility.…”

“…In particular, the relative orientation of the methyl substituents at C-13, C-16, or C-20 determines the distinct conformation of the side chain at C-17. The most biologically active compounds of this series of D6-ring analogs were the ones with the side chain associated with the active region (based on calculated occupancies of the side chain) [35,38].…”

Total Synthesis of (+)-Kingianin A by Enantioselective Cycloaddition of Strained Cyclobutenone

“…9 Therefore, Peterson olefination was chosen to inhibit undesired epimerization. Happily, the Peterson olefination (LDA, TMSCH 2 CO 2 Et) 10 of 10 gave desired enoate 11 in 91% yield as a mixture of Z / E isomers (1.25:1). Subsequent copper hydride reduction 11 was sluggish when using PhSiH 3 as reductant.…”