Synthesis of 22-oxaspiro[4.5]decane CD-ring modified analogs of 1α,25-dihydroxyvitamin D3

Buysser, Frederik De; Verlinden, Lieve; Verstuyf, Annemieke; Clercq, Pierre J. De

doi:10.1016/j.tetlet.2009.05.005

Cited by 12 publications

(9 citation statements)

References 25 publications

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“…SW123 is five times more potent in inhibiting MCF-7 cell proliferation and is more than 200 times less calcemic than 1,25(OH) 2 D 3 . The introduction of a 22-oxa-23-yne-26,27-F 6 side chain (analog FDB198E) further enhanced the antiproliferative action and reduced the calcemic effects of SW123 [8]. Fig.…”

Section: Non-steroidal Cd-ring Analogs Of 125(oh) 2 Dmentioning

confidence: 96%

CD-ring modified vitamin D3 analogs and their superagonistic action

Eelen

Verlinden

Bouillon

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

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Non-steroidal analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] represent a most particular class of analogs because they are either not directly derived from the core 1,25(OH)2D3-structure or they have modifications in the core structure that are so drastic that the steroidal structure is lost. Non-steroidal CD-ring analogs of 1,25(OH)2D3 have been developed to study the role of the central rigid CD-ring system in the biological activity of 1,25(OH)2D3. Here we review the different classes of CD-ring analogs and highlight some representative analogs such as the fluorinated D-ring analogs CD578, WU515 and WY1113 which show markedly increased differentiating activity on human SW480-ADH colon cancer cells, characterized by a stronger induction of the invasion suppressor E-cadherin and a stronger repression of the beta-catenin/TCF target oncogene c-Myc. Correspondingly, CD578, WU515 and WY1113 are more potent inhibitors of beta-catenin/TCF signaling than 1,25(OH)2D3 and induce stronger VDR-coactivator interactions. Underlying the increased biological potency of analog CD578 are additional contacts between the side chain fluorine atoms of the analog with specific residues of helix 12 (H12) of the Vitamin D Receptor (VDR) and subsequent stronger VDR-coactivator interactions.

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Section: Non-steroidal Cd-ring Analogs Of 125(oh) 2 Dmentioning

confidence: 96%

CD-ring modified vitamin D3 analogs and their superagonistic action

Eelen

Verlinden

Bouillon

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

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“…The 16-ene-homoallylic alcohol (35) provided by an ene reaction of olefin (34) was first converted to tosylate via tosylation of the primary hydroxy group and triethylsilylation of the secondary hydroxy group. Tosylate was converted to nitrile upon treatment with KCN, followed by reduction with DIBAL-H to give aldehyde (36). Introduction of the 24,24-difluoro unit was accomplished with the Reformatsky reaction using ethyl bromodifluoroacetate and activated zinc powder.…”

Section: -Ene-vitamin D 3 Analoguesmentioning

confidence: 99%

“…For the synthesis of analogue 42, the known aldehyde (36) was used as a starting material (Scheme 6). Reduction of aldehyde (36) and iodination of the primary alcohol yielded iodide (51).…”

Section: -Ene-vitamin D 3 Analoguesmentioning

confidence: 99%

“…For the synthesis of analogue 42, the known aldehyde (36) was used as a starting material (Scheme 6). Reduction of aldehyde (36) and iodination of the primary alcohol yielded iodide (51). After conversion of the iodide to sulfide (52), oxidation of the sulfide using oxone provided sulfone (53), and subsequent PDC oxidation of the C8-OH group gave ketone (54).…”

Section: -Ene-vitamin D 3 Analoguesmentioning

confidence: 99%

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

2021

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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.

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“…The C/Dring modification was later expanded to CF-spiro [4.5] decanes and [5.5]undecanes (WO 2006060884 and WO 2006060885). The synthesis of the latter has been reported [25,26]. Investigators have also combined structural elements of the 2-methylenes with the des-CD ring scaffold to give a molecule with binding affinity two orders of magnitude greater than 2MD.…”

Section: Identification Structure and Biological Characterizationmentioning

confidence: 99%