Synthesis and photochemical transformation of 3β,21-dihydroxypregna-5, 7-dien-20-one to novel secosteroids that show anti-melanoma activity

Michal A. Zmijewski, Wei Li, Jianjun Chen, Tae Kang Kim, Jordan K. Zjawiony, Trevor W. Sweatman, Duane Miller, Andrzej T. Slominski

Research output: Contribution to journalArticle

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Abstract

We have synthesized 3β,21-dihydroxypregna-5,7-dien-20-one (21(OH) 7DHP) and used UVB radiation to induce its photoconversion to analogues of vitamin D (pD), lumisterol (pL) and tachysterol (pT). The number and character of the products and the dynamics of the process were dependent on the UVB dose. The main products: pD and pT compounds were characterized by UV absorption, MS and NMR spectroscopy after RP-HPLC chromatography. In addition, formation of multiple oxidized derivatives of the primary products was detected and one of these derivatives was characterized as oxidized 21-hydroxyisotachysterol compound (21(OH)oxy-piT). These newly synthesized compounds inhibited growth of human melanoma cells in a dose dependent manner, with greater or equal potency to calcitriol. 3β,21-Dihydroxy-9β,10α-pregna-5,7-dien-20-one (21(OH)pL) and 21(OH)oxy-piT had higher potency against pigmented melanoma cells, while the EC50 for compounds 21(OH)7DHP and (5Z,7E)-3β,21-dihydroxy-9,10-secopregna-5,7,10(19)-trien-20-one (21(OH)pD) were similar in both pigmented and non-pigmented cells. Moreover, 21(OH)7DHP and its derivatives inhibited proliferation of human epidermal HaCaT keratinocytes, albeit at a lower activity compared to melanoma cells. Importantly, 21(OH)7DHP derivatives strongly inhibited the colony formation of human melanoma cells with 21(OH)pD being the most potent. The potential mechanism of action of newly synthesized compounds was similar to that mediated by 1,25(OH)2D 3 and involved ligand-induced translocation of vitamin D receptor into the nucleus. In summary, we have characterized for the first time products of UVB-induced conversion of 21(OH)7DHP and documented that these compounds have selective, inhibitory effects on melanoma cells.

Original languageEnglish (US)
Pages (from-to)193-203
Number of pages11
JournalSteroids
Volume76
Issue number1-2
DOIs
StatePublished - Jan 1 2011

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Secosteroids
Melanoma
Derivatives
Ergosterol
Trientine
Calcitriol Receptors
Calcitriol
Chromatography
Ultraviolet spectroscopy
Absorption spectroscopy
Keratinocytes
Vitamin D
Nuclear magnetic resonance spectroscopy
Action Potentials
3,21-dihydroxypregna-5,7-dien-20-one
Magnetic Resonance Spectroscopy
High Pressure Liquid Chromatography
Radiation
Ligands
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Molecular Biology
  • Organic Chemistry
  • Pharmacology

Cite this

Synthesis and photochemical transformation of 3β,21-dihydroxypregna-5, 7-dien-20-one to novel secosteroids that show anti-melanoma activity. / Zmijewski, Michal A.; Li, Wei; Chen, Jianjun; Kim, Tae Kang; Zjawiony, Jordan K.; Sweatman, Trevor W.; Miller, Duane; Slominski, Andrzej T.

In: Steroids, Vol. 76, No. 1-2, 01.01.2011, p. 193-203.

Research output: Contribution to journalArticle

Zmijewski, Michal A. ; Li, Wei ; Chen, Jianjun ; Kim, Tae Kang ; Zjawiony, Jordan K. ; Sweatman, Trevor W. ; Miller, Duane ; Slominski, Andrzej T. / Synthesis and photochemical transformation of 3β,21-dihydroxypregna-5, 7-dien-20-one to novel secosteroids that show anti-melanoma activity. In: Steroids. 2011 ; Vol. 76, No. 1-2. pp. 193-203.
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abstract = "We have synthesized 3β,21-dihydroxypregna-5,7-dien-20-one (21(OH) 7DHP) and used UVB radiation to induce its photoconversion to analogues of vitamin D (pD), lumisterol (pL) and tachysterol (pT). The number and character of the products and the dynamics of the process were dependent on the UVB dose. The main products: pD and pT compounds were characterized by UV absorption, MS and NMR spectroscopy after RP-HPLC chromatography. In addition, formation of multiple oxidized derivatives of the primary products was detected and one of these derivatives was characterized as oxidized 21-hydroxyisotachysterol compound (21(OH)oxy-piT). These newly synthesized compounds inhibited growth of human melanoma cells in a dose dependent manner, with greater or equal potency to calcitriol. 3β,21-Dihydroxy-9β,10α-pregna-5,7-dien-20-one (21(OH)pL) and 21(OH)oxy-piT had higher potency against pigmented melanoma cells, while the EC50 for compounds 21(OH)7DHP and (5Z,7E)-3β,21-dihydroxy-9,10-secopregna-5,7,10(19)-trien-20-one (21(OH)pD) were similar in both pigmented and non-pigmented cells. Moreover, 21(OH)7DHP and its derivatives inhibited proliferation of human epidermal HaCaT keratinocytes, albeit at a lower activity compared to melanoma cells. Importantly, 21(OH)7DHP derivatives strongly inhibited the colony formation of human melanoma cells with 21(OH)pD being the most potent. The potential mechanism of action of newly synthesized compounds was similar to that mediated by 1,25(OH)2D 3 and involved ligand-induced translocation of vitamin D receptor into the nucleus. In summary, we have characterized for the first time products of UVB-induced conversion of 21(OH)7DHP and documented that these compounds have selective, inhibitory effects on melanoma cells.",
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AU - Li, Wei

AU - Chen, Jianjun

AU - Kim, Tae Kang

AU - Zjawiony, Jordan K.

AU - Sweatman, Trevor W.

AU - Miller, Duane

AU - Slominski, Andrzej T.

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N2 - We have synthesized 3β,21-dihydroxypregna-5,7-dien-20-one (21(OH) 7DHP) and used UVB radiation to induce its photoconversion to analogues of vitamin D (pD), lumisterol (pL) and tachysterol (pT). The number and character of the products and the dynamics of the process were dependent on the UVB dose. The main products: pD and pT compounds were characterized by UV absorption, MS and NMR spectroscopy after RP-HPLC chromatography. In addition, formation of multiple oxidized derivatives of the primary products was detected and one of these derivatives was characterized as oxidized 21-hydroxyisotachysterol compound (21(OH)oxy-piT). These newly synthesized compounds inhibited growth of human melanoma cells in a dose dependent manner, with greater or equal potency to calcitriol. 3β,21-Dihydroxy-9β,10α-pregna-5,7-dien-20-one (21(OH)pL) and 21(OH)oxy-piT had higher potency against pigmented melanoma cells, while the EC50 for compounds 21(OH)7DHP and (5Z,7E)-3β,21-dihydroxy-9,10-secopregna-5,7,10(19)-trien-20-one (21(OH)pD) were similar in both pigmented and non-pigmented cells. Moreover, 21(OH)7DHP and its derivatives inhibited proliferation of human epidermal HaCaT keratinocytes, albeit at a lower activity compared to melanoma cells. Importantly, 21(OH)7DHP derivatives strongly inhibited the colony formation of human melanoma cells with 21(OH)pD being the most potent. The potential mechanism of action of newly synthesized compounds was similar to that mediated by 1,25(OH)2D 3 and involved ligand-induced translocation of vitamin D receptor into the nucleus. In summary, we have characterized for the first time products of UVB-induced conversion of 21(OH)7DHP and documented that these compounds have selective, inhibitory effects on melanoma cells.

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