Synthesis of C2-Alkoxy-Substituted 19-Nor Vitamin D 3 Derivatives: Stereoselectivity and Biological Activity
The active form of vitamin D (D ), 1a,25-dihydroxyvitamn D (1,25D ), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR) studies of D have been conducted, with the aim of separating the biological activities of 1,25D or reducing its side effects, such as h...
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| Veröffentlicht in: | Biomolecules (Basel, Switzerland) Switzerland), 2022-01, Vol.12 (1) |
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| container_title | Biomolecules (Basel, Switzerland) |
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| creator | Mizumoto, Yuka Sakamoto, Ryota Nagata, Akiko Sakane, Suzuka Kittaka, Atsushi Odagi, Minami Tera, Masayuki Nagasawa, Kazuo |
| description | The active form of vitamin D
(D
), 1a,25-dihydroxyvitamn D
(1,25D
), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR) studies of D
have been conducted, with the aim of separating the biological activities of 1,25D
or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D
derivatives with alkoxy groups at C2, by means of the Julia-Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon. The effect of C2 substituents on the stereoselectivity of the coupling reaction was evaluated. The biological activities of the synthesized derivatives were evaluated in an HL-60 cell-based assay. The a-methoxy-substituted
was found to show potent cell-differentiating activity, with an ED
value of 0.38 nM, being 26-fold more potent than 1,25D
. |
| doi_str_mv | 10.3390/biom12010069 |
| format | Article |
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(D
), 1a,25-dihydroxyvitamn D
(1,25D
), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR) studies of D
have been conducted, with the aim of separating the biological activities of 1,25D
or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D
derivatives with alkoxy groups at C2, by means of the Julia-Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon. The effect of C2 substituents on the stereoselectivity of the coupling reaction was evaluated. The biological activities of the synthesized derivatives were evaluated in an HL-60 cell-based assay. The a-methoxy-substituted
was found to show potent cell-differentiating activity, with an ED
value of 0.38 nM, being 26-fold more potent than 1,25D
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(D
), 1a,25-dihydroxyvitamn D
(1,25D
), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR) studies of D
have been conducted, with the aim of separating the biological activities of 1,25D
or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D
derivatives with alkoxy groups at C2, by means of the Julia-Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon. The effect of C2 substituents on the stereoselectivity of the coupling reaction was evaluated. The biological activities of the synthesized derivatives were evaluated in an HL-60 cell-based assay. The a-methoxy-substituted
was found to show potent cell-differentiating activity, with an ED
value of 0.38 nM, being 26-fold more potent than 1,25D
.</description><subject>Cell Differentiation - drug effects</subject><subject>Cholecalciferol - analogs & derivatives</subject><subject>Cholecalciferol - chemical synthesis</subject><subject>Cholecalciferol - chemistry</subject><subject>Cholecalciferol - pharmacology</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>Structure-Activity Relationship</subject><issn>2218-273X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjk1rwkAURYdCqaF113V5f2DsfGBj3GmsuHKTIu5kYl7aVycZmZlI8-_Nwq69HLhwuIvL2KsUE60z8V6Sa6QSUoiP7IElSskZV6nej9g4hF8xZDag9BMb6amYaiXThNmib-MPBgrgasgVX9iT--t50ZUhUuwiViAzvnUedhRNQy2sQMMKPV1MpAuGORQRPbqAFo-DodiDaStYkrPum47GwuLmX9hjbWzA8a2f2dv68yvf8HNXNlgdzp4a4_vD_z19d3AFVEhLdQ</recordid><startdate>20220104</startdate><enddate>20220104</enddate><creator>Mizumoto, Yuka</creator><creator>Sakamoto, Ryota</creator><creator>Nagata, Akiko</creator><creator>Sakane, Suzuka</creator><creator>Kittaka, Atsushi</creator><creator>Odagi, Minami</creator><creator>Tera, Masayuki</creator><creator>Nagasawa, Kazuo</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><orcidid>https://orcid.org/0000-0002-0437-948X</orcidid><orcidid>https://orcid.org/0000-0003-3091-2476</orcidid><orcidid>https://orcid.org/0000-0002-0334-3565</orcidid></search><sort><creationdate>20220104</creationdate><title>Synthesis of C2-Alkoxy-Substituted 19-Nor Vitamin D 3 Derivatives: Stereoselectivity and Biological Activity</title><author>Mizumoto, Yuka ; Sakamoto, Ryota ; Nagata, Akiko ; Sakane, Suzuka ; Kittaka, Atsushi ; Odagi, Minami ; Tera, Masayuki ; Nagasawa, Kazuo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_350532173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Cell Differentiation - drug effects</topic><topic>Cholecalciferol - analogs & derivatives</topic><topic>Cholecalciferol - chemical synthesis</topic><topic>Cholecalciferol - chemistry</topic><topic>Cholecalciferol - pharmacology</topic><topic>HL-60 Cells</topic><topic>Humans</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mizumoto, Yuka</creatorcontrib><creatorcontrib>Sakamoto, Ryota</creatorcontrib><creatorcontrib>Nagata, Akiko</creatorcontrib><creatorcontrib>Sakane, Suzuka</creatorcontrib><creatorcontrib>Kittaka, Atsushi</creatorcontrib><creatorcontrib>Odagi, Minami</creatorcontrib><creatorcontrib>Tera, Masayuki</creatorcontrib><creatorcontrib>Nagasawa, Kazuo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Biomolecules (Basel, Switzerland)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mizumoto, Yuka</au><au>Sakamoto, Ryota</au><au>Nagata, Akiko</au><au>Sakane, Suzuka</au><au>Kittaka, Atsushi</au><au>Odagi, Minami</au><au>Tera, Masayuki</au><au>Nagasawa, Kazuo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of C2-Alkoxy-Substituted 19-Nor Vitamin D 3 Derivatives: Stereoselectivity and Biological Activity</atitle><jtitle>Biomolecules (Basel, Switzerland)</jtitle><addtitle>Biomolecules</addtitle><date>2022-01-04</date><risdate>2022</risdate><volume>12</volume><issue>1</issue><eissn>2218-273X</eissn><abstract>The active form of vitamin D
(D
), 1a,25-dihydroxyvitamn D
(1,25D
), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR) studies of D
have been conducted, with the aim of separating the biological activities of 1,25D
or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D
derivatives with alkoxy groups at C2, by means of the Julia-Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon. The effect of C2 substituents on the stereoselectivity of the coupling reaction was evaluated. The biological activities of the synthesized derivatives were evaluated in an HL-60 cell-based assay. The a-methoxy-substituted
was found to show potent cell-differentiating activity, with an ED
value of 0.38 nM, being 26-fold more potent than 1,25D
.</abstract><cop>Switzerland</cop><pmid>35053217</pmid><doi>10.3390/biom12010069</doi><orcidid>https://orcid.org/0000-0002-0437-948X</orcidid><orcidid>https://orcid.org/0000-0003-3091-2476</orcidid><orcidid>https://orcid.org/0000-0002-0334-3565</orcidid></addata></record> |
| fulltext | fulltext |
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| ispartof | Biomolecules (Basel, Switzerland), 2022-01, Vol.12 (1) |
| issn | 2218-273X |
| language | eng |
| recordid | cdi_pubmed_primary_35053217 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central |
| subjects | Cell Differentiation - drug effects Cholecalciferol - analogs & derivatives Cholecalciferol - chemical synthesis Cholecalciferol - chemistry Cholecalciferol - pharmacology HL-60 Cells Humans Structure-Activity Relationship |
| title | Synthesis of C2-Alkoxy-Substituted 19-Nor Vitamin D 3 Derivatives: Stereoselectivity and Biological Activity |
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