Synthesis and biological activities of 14-epi-MART-10 and 14-epi-MART-11

Implications for cancer and osteoporosis treatment

Atsushi Kittaka, Hideki Hara, Masashi Takano, Daisuke Sawada, Midori A. Arai, Kenichiro Takagi, Takayuki Chida, Yoshifumi Harada, Hiroshi Saito, Kazuya Takenouchi, Seiichi Ishizuka, Keiko Hayashi, Shinichi Ikushiro, Toshiyuki Sakaki, Takayuki Sugiura, Tai C. Chen

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The 14-epimer of MART-10, namely 14-epi-MART-10 ( 14-epi-2α-(3- hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3) and its 2-epimeric analog (14-epi-MART-11) were efficiently synthesized using the Julia coupling reaction to connect between the C5 and C6 positions (steroid numbering). An A-ring precursor was prepared from (-)-quinic acid as shown in the previous MART-10 synthesis. The novel 14-epi-CD-ring coupling partner with an elongated two carbon unit as a sulfone was synthesized from 14-epi-25-hydroxy Grundmann's ketone in good yield. The subsequent coupling reaction followed by a deprotection step afforded a mixture of 14-epi-MART-10 and 14-epi-MART-11 in 40% yield. To separate 14-epi-MART-10 and 14-epi-MART-11, each primary hydroxyl group was esterified with a pivaloyl group and the resulting pivalates 2α and 2β were separated by high performance liquid chromatography. After the separation, the C2-stereochemistry of each (2α or 2β) was determined by 1H NMR (nuclear magnetic resonance) studies including NOE (nuclear Overhauser effect) experiments. The pivaloyl group was removed under basic conditions to obtain the target molecules of 14-epi-MART-10 and 14-epi-MART-11, respectively. The VDR (vitamin D receptor)-binding affinity, HL-60 (human promyelocytic leukemia) cell differentiation activity, antiproliferative activity in PZ-HPV-7 (immortalized normal prostate) cells and transactivation activity of the osteocalcin promoter in HOS (human osteoblast cell line) cells (serum-free conditions) were investigated. In addition, the effects on bone mineral density (BMD) and the blood and urine calcium concentrations of ovariectomized (OVX) rats were examined. 14-epi-MART-10 has much greater antiproliferative and cell differentiation activities compared to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D 3).

Original languageEnglish
Pages (from-to)3563-3569
Number of pages7
JournalAnticancer Research
Volume29
Issue number9
Publication statusPublished - Sep 2009
Externally publishedYes

Fingerprint

Osteoporosis
Neoplasms
Cell Differentiation
Quinic Acid
Sulfones
Calcitriol Receptors
Calcitriol
Osteocalcin
19-nor-2-(3-hydroxypropyl)-1,25-dihydroxyvitamin D3
Ketones
Osteoblasts
Hydroxyl Radical
Bone Density
Transcriptional Activation
Prostate
Leukemia
Magnetic Resonance Spectroscopy
Carbon
Steroids
High Pressure Liquid Chromatography

Keywords

  • 14-epi-MART-10
  • 19-norvitamin D
  • HL-60 cells
  • Julia coupling
  • PZ-HPV-7 cells
  • Synthesis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kittaka, A., Hara, H., Takano, M., Sawada, D., Arai, M. A., Takagi, K., ... Chen, T. C. (2009). Synthesis and biological activities of 14-epi-MART-10 and 14-epi-MART-11: Implications for cancer and osteoporosis treatment. Anticancer Research, 29(9), 3563-3569.

Synthesis and biological activities of 14-epi-MART-10 and 14-epi-MART-11 : Implications for cancer and osteoporosis treatment. / Kittaka, Atsushi; Hara, Hideki; Takano, Masashi; Sawada, Daisuke; Arai, Midori A.; Takagi, Kenichiro; Chida, Takayuki; Harada, Yoshifumi; Saito, Hiroshi; Takenouchi, Kazuya; Ishizuka, Seiichi; Hayashi, Keiko; Ikushiro, Shinichi; Sakaki, Toshiyuki; Sugiura, Takayuki; Chen, Tai C.

In: Anticancer Research, Vol. 29, No. 9, 09.2009, p. 3563-3569.

Research output: Contribution to journalArticle

Kittaka, A, Hara, H, Takano, M, Sawada, D, Arai, MA, Takagi, K, Chida, T, Harada, Y, Saito, H, Takenouchi, K, Ishizuka, S, Hayashi, K, Ikushiro, S, Sakaki, T, Sugiura, T & Chen, TC 2009, 'Synthesis and biological activities of 14-epi-MART-10 and 14-epi-MART-11: Implications for cancer and osteoporosis treatment', Anticancer Research, vol. 29, no. 9, pp. 3563-3569.
Kittaka, Atsushi ; Hara, Hideki ; Takano, Masashi ; Sawada, Daisuke ; Arai, Midori A. ; Takagi, Kenichiro ; Chida, Takayuki ; Harada, Yoshifumi ; Saito, Hiroshi ; Takenouchi, Kazuya ; Ishizuka, Seiichi ; Hayashi, Keiko ; Ikushiro, Shinichi ; Sakaki, Toshiyuki ; Sugiura, Takayuki ; Chen, Tai C. / Synthesis and biological activities of 14-epi-MART-10 and 14-epi-MART-11 : Implications for cancer and osteoporosis treatment. In: Anticancer Research. 2009 ; Vol. 29, No. 9. pp. 3563-3569.
@article{240c7d9729dd4787a123f9f70169cf65,
title = "Synthesis and biological activities of 14-epi-MART-10 and 14-epi-MART-11: Implications for cancer and osteoporosis treatment",
abstract = "The 14-epimer of MART-10, namely 14-epi-MART-10 ( 14-epi-2α-(3- hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3) and its 2-epimeric analog (14-epi-MART-11) were efficiently synthesized using the Julia coupling reaction to connect between the C5 and C6 positions (steroid numbering). An A-ring precursor was prepared from (-)-quinic acid as shown in the previous MART-10 synthesis. The novel 14-epi-CD-ring coupling partner with an elongated two carbon unit as a sulfone was synthesized from 14-epi-25-hydroxy Grundmann's ketone in good yield. The subsequent coupling reaction followed by a deprotection step afforded a mixture of 14-epi-MART-10 and 14-epi-MART-11 in 40{\%} yield. To separate 14-epi-MART-10 and 14-epi-MART-11, each primary hydroxyl group was esterified with a pivaloyl group and the resulting pivalates 2α and 2β were separated by high performance liquid chromatography. After the separation, the C2-stereochemistry of each (2α or 2β) was determined by 1H NMR (nuclear magnetic resonance) studies including NOE (nuclear Overhauser effect) experiments. The pivaloyl group was removed under basic conditions to obtain the target molecules of 14-epi-MART-10 and 14-epi-MART-11, respectively. The VDR (vitamin D receptor)-binding affinity, HL-60 (human promyelocytic leukemia) cell differentiation activity, antiproliferative activity in PZ-HPV-7 (immortalized normal prostate) cells and transactivation activity of the osteocalcin promoter in HOS (human osteoblast cell line) cells (serum-free conditions) were investigated. In addition, the effects on bone mineral density (BMD) and the blood and urine calcium concentrations of ovariectomized (OVX) rats were examined. 14-epi-MART-10 has much greater antiproliferative and cell differentiation activities compared to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D 3).",
keywords = "14-epi-MART-10, 19-norvitamin D, HL-60 cells, Julia coupling, PZ-HPV-7 cells, Synthesis",
author = "Atsushi Kittaka and Hideki Hara and Masashi Takano and Daisuke Sawada and Arai, {Midori A.} and Kenichiro Takagi and Takayuki Chida and Yoshifumi Harada and Hiroshi Saito and Kazuya Takenouchi and Seiichi Ishizuka and Keiko Hayashi and Shinichi Ikushiro and Toshiyuki Sakaki and Takayuki Sugiura and Chen, {Tai C.}",
year = "2009",
month = "9",
language = "English",
volume = "29",
pages = "3563--3569",
journal = "Anticancer Research",
issn = "0250-7005",
publisher = "International Institute of Anticancer Research",
number = "9",

}

TY - JOUR

T1 - Synthesis and biological activities of 14-epi-MART-10 and 14-epi-MART-11

T2 - Implications for cancer and osteoporosis treatment

AU - Kittaka, Atsushi

AU - Hara, Hideki

AU - Takano, Masashi

AU - Sawada, Daisuke

AU - Arai, Midori A.

AU - Takagi, Kenichiro

AU - Chida, Takayuki

AU - Harada, Yoshifumi

AU - Saito, Hiroshi

AU - Takenouchi, Kazuya

AU - Ishizuka, Seiichi

AU - Hayashi, Keiko

AU - Ikushiro, Shinichi

AU - Sakaki, Toshiyuki

AU - Sugiura, Takayuki

AU - Chen, Tai C.

PY - 2009/9

Y1 - 2009/9

N2 - The 14-epimer of MART-10, namely 14-epi-MART-10 ( 14-epi-2α-(3- hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3) and its 2-epimeric analog (14-epi-MART-11) were efficiently synthesized using the Julia coupling reaction to connect between the C5 and C6 positions (steroid numbering). An A-ring precursor was prepared from (-)-quinic acid as shown in the previous MART-10 synthesis. The novel 14-epi-CD-ring coupling partner with an elongated two carbon unit as a sulfone was synthesized from 14-epi-25-hydroxy Grundmann's ketone in good yield. The subsequent coupling reaction followed by a deprotection step afforded a mixture of 14-epi-MART-10 and 14-epi-MART-11 in 40% yield. To separate 14-epi-MART-10 and 14-epi-MART-11, each primary hydroxyl group was esterified with a pivaloyl group and the resulting pivalates 2α and 2β were separated by high performance liquid chromatography. After the separation, the C2-stereochemistry of each (2α or 2β) was determined by 1H NMR (nuclear magnetic resonance) studies including NOE (nuclear Overhauser effect) experiments. The pivaloyl group was removed under basic conditions to obtain the target molecules of 14-epi-MART-10 and 14-epi-MART-11, respectively. The VDR (vitamin D receptor)-binding affinity, HL-60 (human promyelocytic leukemia) cell differentiation activity, antiproliferative activity in PZ-HPV-7 (immortalized normal prostate) cells and transactivation activity of the osteocalcin promoter in HOS (human osteoblast cell line) cells (serum-free conditions) were investigated. In addition, the effects on bone mineral density (BMD) and the blood and urine calcium concentrations of ovariectomized (OVX) rats were examined. 14-epi-MART-10 has much greater antiproliferative and cell differentiation activities compared to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D 3).

AB - The 14-epimer of MART-10, namely 14-epi-MART-10 ( 14-epi-2α-(3- hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3) and its 2-epimeric analog (14-epi-MART-11) were efficiently synthesized using the Julia coupling reaction to connect between the C5 and C6 positions (steroid numbering). An A-ring precursor was prepared from (-)-quinic acid as shown in the previous MART-10 synthesis. The novel 14-epi-CD-ring coupling partner with an elongated two carbon unit as a sulfone was synthesized from 14-epi-25-hydroxy Grundmann's ketone in good yield. The subsequent coupling reaction followed by a deprotection step afforded a mixture of 14-epi-MART-10 and 14-epi-MART-11 in 40% yield. To separate 14-epi-MART-10 and 14-epi-MART-11, each primary hydroxyl group was esterified with a pivaloyl group and the resulting pivalates 2α and 2β were separated by high performance liquid chromatography. After the separation, the C2-stereochemistry of each (2α or 2β) was determined by 1H NMR (nuclear magnetic resonance) studies including NOE (nuclear Overhauser effect) experiments. The pivaloyl group was removed under basic conditions to obtain the target molecules of 14-epi-MART-10 and 14-epi-MART-11, respectively. The VDR (vitamin D receptor)-binding affinity, HL-60 (human promyelocytic leukemia) cell differentiation activity, antiproliferative activity in PZ-HPV-7 (immortalized normal prostate) cells and transactivation activity of the osteocalcin promoter in HOS (human osteoblast cell line) cells (serum-free conditions) were investigated. In addition, the effects on bone mineral density (BMD) and the blood and urine calcium concentrations of ovariectomized (OVX) rats were examined. 14-epi-MART-10 has much greater antiproliferative and cell differentiation activities compared to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D 3).

KW - 14-epi-MART-10

KW - 19-norvitamin D

KW - HL-60 cells

KW - Julia coupling

KW - PZ-HPV-7 cells

KW - Synthesis

UR - http://www.scopus.com/inward/record.url?scp=68549118800&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68549118800&partnerID=8YFLogxK

M3 - Article

VL - 29

SP - 3563

EP - 3569

JO - Anticancer Research

JF - Anticancer Research

SN - 0250-7005

IS - 9

ER -