The Synthesis and Biological Evaluation of D-Ring-Modified Vitamin D Analogues

Abstract

The vitamin D3 structure consists of the A-ring, a linker originating from the B-ring, C-ring, D-ring, and side-chain moieties. Each unit has its unique role in expressing the biological activities of vitamin D3. Many efforts have been made to date to assess the possible clinical use of vitamin D. Some organic chemists focused on the D-ring structure of vitamin D and synthesized D-ring-modified vitamin D analogues, and their biological activities were studied. This review summarizes the synthetic methodologies of D-ring-modified vitamin D analogues, except for seco-D, and their preliminary biological profiles.

The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D3 and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities

“…Selective protection of the C8 secondary hydroxy group of 12 with a TBS group, followed by oxidation at the C22 primary alcohol by TPAP/NMO, afforded aldehyde ( 16) [27]. The aldehyde was subjected to the Horner-Emmons reagent (17) under basic conditions to create triethylsilyl enol ether (18), which was converted to α-ketoester (19) by selective desilylation of the silyl enol ether unit using TBAF in the presence of acetic acid [23]. The C23-difluoro unit was constructed using DAST toward α-ketoester (19), and the obtained difluoro methyl ester (20) was converted to a Weinreb amide (13) (Scheme 4).…”

“…To the solution of Horner-Emmons reagent (17) (2.35 g, 7.24 mmol) in THF (3.5 mL), LDA (lithium diisopropylamide) (3.5 mL, 2 M THF/heptane/ethylbenzene solution, 1.75 mmol) was added at −40 • C; the mixture was stirred at the same temperature for 20 min, and a solution of 16 [27] (977.0 mg, 3.01 mmol) in THF (3.5 mL) was added. The reaction mixture was stirred at 0 • C for 20 min.…”

“…In recent years, new aspects of vitamin D 3 function have been discovered [12][13][14][15], and syntheses of various vitamin D 3 analogues have been carried out [16,17]. As a result, the importance of developing comprehensive and straightforward synthetic methods for fluorinated vitamin D 3 analogues has increased.…”

Discovery of Cytotoxic Truncated Vitamin D Derivatives Against Both Bortezomib‐Sensitive and Resistant Multiple Myeloma Phenotypes

“…Moreover, mono and di-acetylation of VDF-2 were performed using acetic anhydride and pyridine at 0 °C and under reflux affording VDF-6 and VDF-7, respectively (Fig. 2) [31,32].…”

Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3 (Calcitriol): Refinement of the Side Chain

“…Despite wide potential clinical applications, 1,25D 3 benefit in the clinics is limited, mainly because the required doses induce hypercalcemia . In order to potentiate the beneficial properties of 1,25D 3 and/or reduce their hypercalcemic side effects, thousands of analogues were synthesized, and a few of them went to the clinics. , Most of the 1,25D 3 analogues developed to date are modified in the side chain and A-ring, but only a few having structural alterations in the C-ring and/or D-ring have been developed due to synthetic difficulties. − The biological studies on 1,25D 3 analogues that lack the D-ring, the C-ring, and the bicyclic CD-ring or are modified on the C- or D-ring − show that the natural CD core of 1,25D 3 is not necessary for biological activity and its modification can reduce the calcemic activity.…”