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Molecules 2018, 23(6), 1422; https://doi.org/10.3390/molecules23061422

(-)-Shikimic Acid as a Chiral Building Block for the Synthesis of New Cytotoxic 6-Aza-Analogues of Angucyclinones

1
Centro de Investigación Farmacopea Chilena, Escuela de Química y Farmacia, Facultad de Farmacia, Universidad de Valparaíso, Av. Gran Bretaña N° 1093, Valparaíso 2340000, Chile
2
Departamento de Química, Universidad Técnica Federico Santa María, Av. España N° 1680, Valparaíso 2340000, Chile
3
Centro de Investigaciones Biomédicas, Escuela de Medicina, Universidad de Valparaíso, Av. Hontaneda N° 2664, Valparaíso 2340000, Chile
4
Departamento de Química, Facultad de Ciencias Básicas, Universidad de Antofagasta, Av. Angamos 601, Antofagasta 1240000, Chile
5
Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Vicuña Mackenna N° 4860, Santiago 6094411, Chile
*
Authors to whom correspondence should be addressed.
Received: 23 May 2018 / Revised: 9 June 2018 / Accepted: 10 June 2018 / Published: 12 June 2018
(This article belongs to the Section Medicinal Chemistry)
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Abstract

We describe the syntheses of nine new angucyclinone 6-aza-analogues, achieved through a hetero Diels-Alder reaction between the shikimic acid derivative-azadiene 13, with different naphthoquinones. The cytotoxic activity of the new synthesized compounds and five angucyclinones, previously reported, was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and one non-tumoral cell line, human colon epithelial cells (CCD841 CoN). Our results showed that most 6-azadiene derivatives exhibited significant cytotoxic activities, which was demonstrated by their IC50 values (less than 10 μM), especially for the most sensitive cells, PC-3 and HT-29. From a chemical point of view, depending on the protected group of ring A and the pattern of substitution on ring D, cytotoxicity elicited these compounds, in terms of their potency and selectivity. Therefore, according to these chemical features, the most promising agents for every cancer cell line were 7a, 17, and 19c for PC-3 cells; 7a, 17, and 20 for HT-29 cells, and 19a for MCF-7 cells. View Full-Text
Keywords: (-)-Shikimic acid; angucyclinone derivatives; hetero-Diels-Alder; cytotoxicity; cancer cell lines (-)-Shikimic acid; angucyclinone derivatives; hetero-Diels-Alder; cytotoxicity; cancer cell lines
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Quiñones, N.; Hernández, S.; Espinoza Catalán, L.; Villena, J.; Brito, I.; Cabrera, A.R.; Salas, C.O.; Cuellar, M.A. (-)-Shikimic Acid as a Chiral Building Block for the Synthesis of New Cytotoxic 6-Aza-Analogues of Angucyclinones. Molecules 2018, 23, 1422.

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