Design, Synthesis, Evaluation and Structure of Allenic 1α,25‐Dihydroxyvitamin D₃ Analogs with Locked Mobility at C‐17

Abstract

Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25-dihydroxyvitamin D 3 analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd 0 -mediated cyclization/Suzuki-Miyaura cross-coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester-Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)-1α, 25-dihydroxy-17,20-dien-24homo-21-nor-vitamin D 3 bound to binding domain of the vitamin D receptor, provide information concerning sidechain conformational requirements for biological activity.

The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands

“…Figure 30 (2020-2022) [384][385][386][387][388][389]. Des-C-ring aromatic D-ring analogs 1712 and 1713 [373] showed a remarkable lack of calcemic activity together with significant antiproliferative and transcriptional properties in breast cancer cell lines, suggesting a therapeutical potential for 1712 and 1713 in breast tumor treatment.…”

Pd(0)‐Catalyzed‐Mediated Synthesis of Vitamin D Compounds

“…The Pd(0)-catalyzed carbocyclization/Suzuki-Miyaura approach I, has proven to be useful to synthesize several vitamin D 3 and 1,25D 3 analogs including the hormone 1,25D 3 , [92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108] and 25-hydroxyvitamin D 3 (Scheme 16). [109] A drawback of the this approach is that the A-ring-enyne synthons 24a and 85 are not commercially purchasable and must be prepared in the laboratory.…”

Homoallenylboration of carbonyl compounds using inert 2-pinacolateboryl 1,3-butadienes via in situ generated borinic–TFA mixed anhydrides: efficient synthesis of homoallenyl alcohols

“…Homoallenyl alcohols are synthetically valuable building blocks in organic synthesis, as they are often employed in the preparation of natural products and bioactive molecules. 1 Yet, the efficient and practical access to homoallenyl alcohols remains a challenging task to date. Among the few known approaches, 2 homoallenylation of carbonyl compounds using reactive 2-(1,3-butadienyl)metallic reagents represents a straightforward protocol and has attracted significant attention.…”