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Synthesis and photo-conversion of androsta- and pregna-5,7-dienes to vitamin D3-like derivatives

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Abstract

Calcitriol (3ß,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-1α,3ß,25-triol) is a powerful oncostatic form of vitamin D3 that is of limited clinical utility due to hypercalcemic (toxic) effects. Since the removal of the side chain reduces or eliminates the calcemic activity of vitamin D3, secosteroidal compounds lacking or with a shortened side chain are good candidates for anti-cancer drugs. In addition, 5,7-steroidal dienes without a side chain can be generated in vivo under pathological conditions. A series of androsta- and pregna-5,7-dienes was efficiently synthesized from their respective 3-acetylated 5-en precursors by bromination-dehydrobromination and deacetylation reactions. Ultraviolet B (UVB) irradiation was used to generate corresponding 9,10-secosteroids with vitamin D-like structures. Additional products with tachysterol-like (T-like) structures or 5,7-dienes with inverted configuration at C-9 and C-10 (lumisterol, L-like) were also detected. Different doses of UVB resulted in formation of various products. At low doses, previtamin D-, T- or L-like compounds were formed as the main products, while higher doses induced further isomerization, with formation of potentially oxidized derivatives. In summary, we describe dynamic UVB induced conversion of androsta- and pregna-5,7-dienes into vitamin D-like compounds and their rearranged analogues; additionally novel T-like and L-like structures were also produced and characterized. Further biological evaluation of newly synthesized compounds should help to select the best candidate(s) for potential treatment of hyperproliferative diseases including cancer.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Michal A. Zmijewski & Andrzej T. Slominski

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Wei Li, Jianjun Chen & Duane D. Miller

  3. Department of Pharmacognosy and National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, 38677-1848, USA

    Jordan K. Zjawiony

  4. Department of Pharmacology and the Center for Cancer Research, University of Tennessee, Health Science Center, Memphis, TN, 38163, USA

    Trevor W. Sweatman

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  1. Michal A. Zmijewski
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  2. Wei Li
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  7. Andrzej T. Slominski
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Additional information

This paper was published as part of the themed issue in honour of Nicholas Turro.

Electronic supplementary information (ESI) available: HPLC chromatogram, UV spectra and additional experimental data for irradiation products of androsta- and pregna-5,7-dienes. NMR spectra for 5a, 5aD, 5aL and 5aT and Table of shifts for androsta- and pregna-5,7-dienes. See DOI: 10.1039/b809005j

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Zmijewski, M.A., Li, W., Zjawiony, J.K. et al. Synthesis and photo-conversion of androsta- and pregna-5,7-dienes to vitamin D3-like derivatives. Photochem Photobiol Sci 7, 1570–1576 (2008). https://doi.org/10.1039/b809005j

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