Efficient and Convergent Coupling Route for the Short‐Step Synthesis of Enantiopure 2α‐ and 2β‐Alkylated 1α,25‐Dihydroxy‐19‐norvitamin D<sub>3</sub> Analogues.

Yoshida, Akihiko; Ono, Keiichiro; Suhara, Yoshitomo; Saito, Nozomi; Takayama, Hiroaki; Kittaka, Atsushi

doi:10.1002/chin.200341220

Cited by 6 publications

(20 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We decided to connect one of the double bonds of the target diene of MART-10/MART-11 between the C5 (A-ring) and C6 (two carbons elongated CD-ring from the 8-keto group) positions using the Julia coupling approach, and the reactions turned out to be successful ( Figure 2 ). Finally, the target products were separated using a reversed phase HPLC to obtain two diastereomers, MART-10 (2 α -form) and MART-11 (2 β -form) [ 48 ].…”

Section: Development Of the Less Calcemic 19-norvitamin D Analogsmentioning

confidence: 99%

Novel Vitamin D Analogs for Prostate Cancer Therapy

Chen

Kittaka

2011

ISRN Urology

Self Cite

View full text Add to dashboard Cite

Prostate cells contain specific receptors for 1α,25-dihydroxyvitamin D [1α,25(OH)2D] or calcitriol, the active form of vitamin D. 1α,25(OH)2D is known to inhibit the proliferation and invasiveness of prostate cancer cells. These findings support the use of 1α,25(OH)2D for prostate cancer therapy. However, 1α,25(OH)2D can cause hypercalcemia, analogs of 1α,25(OH)2D that are less calcemic but exhibit potent antiproliferative activity would be attractive as therapeutic agents. To accomplish these goals, different strategies, based on metabolism, molecular mechanism of actions, and structural modeling, have been taken to modify the structure of vitamin D molecule with the aims to improve the efficacy and decrease the toxicity of vitamin D to treat different diseases. During the past four decades, over 3,000 analogs have been synthesized. In this paper, we discuss the development and the biological analysis of a unique class of vitamin D analogs with a substitution at the carbon 2 of 19-nor-1α,25(OH)2D3 molecule for potential application to the prevention and treatment of prostate cancer as well as other cancers.

show abstract

Section: Development Of the Less Calcemic 19-norvitamin D Analogsmentioning

confidence: 99%

Novel Vitamin D Analogs for Prostate Cancer Therapy

Chen

Kittaka

2011

ISRN Urology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The diastereoselectivity based on the C2-C5-C6 axis was approximately 1:1 for 13a/13b and 2.4:1 for 13a´/13b´ . The axially epimeric mixture 13 was deprotected by 10-camphorsulfonic acid (CSA) in methanol to give the mixture of MART-10 (2a) and MART-11 (2b) , which was separated by a reversed phase HPLC [33]. The other diastereo mixture 13´ was deprotected and followed by pivaloylation of the primary hydroxy group to afford the epimeric mixture 14´ , which was separated into 14a´ and 14b´ with a reverse-phase HPLC.…”

Section: The Chemistry Of Novel Synthetic Schemes For the C2-substitumentioning

confidence: 99%

Potent 19-Norvitamin D Analogs For Prostate And Liver Cancer Therapy

et al. 2012

Self Cite

View full text Add to dashboard Cite

The active form of vitamin D3, 1α,25(OH)2D3 or calcitriol, is known to inhibit the proliferation and invasiveness of many types of cancer cells, including prostate and liver cancer cells. These findings support the use of 1α,25(OH)2D3 for prostate and liver cancer therapy. However, 1α,25(OH)2D3 can cause hypercalcemia, thus, analogs of 1α,25(OH)2D3 that are less calcemic but exhibit potent antiproliferative activity would be attractive as therapeutic agents. We have developed 2α-functional group substituted 19-norvitamin D3 analogs with and without 14-epimerization. Among them, 2α- and 2β-(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3 (MART-10 and -11, respectively) and 14-epi-2α- and 14-epi-2β-(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3 (14-epi-MART-10 and 14-epi-MART-11, respectively) were found to be the most promising. In this review, we discuss the synthesis of this unique class of vitamin D analogs, the molecular mechanism of anticancer actions of vitamin D, and the biological evaluation of these analogs for potential application to the prevention and treatment of prostate and liver cancer.

show abstract

“…This compound showed a selective activity profile, combining high potency in inducing differentiation of malignant cells with very low, or no bone calcification activity [63]. Further modifications to the 19-nor A-ring were also studied, such as the deletion of one of the hydroxy groups [64,65], and the introduction of a functional group at the C2 position [66][67][68][69][70][71][72][73][74][75][76]. Recent studies revealed that 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D 3 (2MD, 17a) induces bone formation selectively [69].…”

Section: Simultaneous Modification At Both C2 and C10 Positions: C2 Mmentioning

confidence: 99%

“…The A-ring precursor, methyl 4-allylquinicate 21, was obtained from DeLuca's thioimidazolide [62], through radical C-C bond formation using allyltributyltin (IV) and AIBN [73]. Reduction of 21 with NaBH 4 in EtOH, and the subsequent oxidative cleavage of the resulting vicinal diol using NaIO 4 gave ketone 22 in 82% yield in two steps.…”

Section: Simultaneous Modification At Both C2 and C10 Positions: C2 Mmentioning

confidence: 99%

See 1 more Smart Citation

Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity

Saito¹,

Honzawa²,

Kittaka

2006

CTMC

Self Cite

View full text Add to dashboard Cite

The structure-activity relationships of 1alpha,25-dihydroxyvitamin D3 on simultaneous modification at both C2alpha and CD-ring side chain, including 20-epimerization, double side chain (gemini), and vitamin D receptor (VDR) antagonists TEI-9647 and TEI-9648 lactone rings, and also on simultaneous modifications at both C2 and C10 positions, i.e., C2 modified active 19-norvitamin D3, have been studied in our laboratory to find new seeds of B-seco-steroidal medicine for treating bone diseases, psoriasis, secondary hyperparathyroidism, and certain kinds of cancers. We developed an efficient and systematic route to the 2alpha-substituted 1alpha,25-dihydroxyvitamin D3 analogs, i.e., VDR-agonists (20-epi-2-4, double side chain 13a-c, 19-nor 15a-c) and antagonists (36a-c, 37a-c). The A-ring precursors (11a-o) for these analogs were synthesized from D-glucose as a chiral template. In the 19-nor series, we used radical coupling reaction for preparing the A-ring parts from (-)-quinic acid, and the resulting 2-substituted A-ring moiety was coupled with 25-hydroxy Grundmann's ketone utilizing Julia olefination to connect between the C5 and C6 positions. We also synthesized the highly potent VDR-antagonists by introducing the 2alpha-functional group to the TEI-9647 and TEI-9648 skeletons.

show abstract

Efficient and Convergent Coupling Route for the Short‐Step Synthesis of Enantiopure 2α‐ and 2β‐Alkylated 1α,25‐Dihydroxy‐19‐norvitamin D₃ Analogues.

Cited by 6 publications

References 1 publication

Novel Vitamin D Analogs for Prostate Cancer Therapy

Novel Vitamin D Analogs for Prostate Cancer Therapy

Potent 19-Norvitamin D Analogs For Prostate And Liver Cancer Therapy

Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity

Contact Info

Product

Resources

About

Efficient and Convergent Coupling Route for the Short‐Step Synthesis of Enantiopure 2α‐ and 2β‐Alkylated 1α,25‐Dihydroxy‐19‐norvitamin D3 Analogues.

Cited by 6 publications

References 1 publication

Novel Vitamin D Analogs for Prostate Cancer Therapy

Novel Vitamin D Analogs for Prostate Cancer Therapy

Potent 19-Norvitamin D Analogs For Prostate And Liver Cancer Therapy

Recent Results on A-Ring Modification of 1&#945;,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity

Contact Info

Product

Resources

About

Efficient and Convergent Coupling Route for the Short‐Step Synthesis of Enantiopure 2α‐ and 2β‐Alkylated 1α,25‐Dihydroxy‐19‐norvitamin D₃ Analogues.

Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity