Publication: ÁCIDO SHIKÍMICO, COMPUESTO DE PARTIDA PARA LA SÍNTESIS DE QUINONAS CON POTENCIAL ACTIVIDAD BIOLÓGICA
Date
2019
Authors
HERNÁNDEZ PINO, SANTIAGO TOMÁS
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Las quinonas tetracíclicas son compuestos de interés farmacológico por sus capacidades
para combatir la proliferación de células tumorales. De hecho, en quimioterapia es común
el uso de fármacos que posean este núcleo estructural, como lo son las antraciclinas. No
obstante, estas antraciclinas presentan diversos efectos negativos, como por ejemplo
cardiotoxicidad. Debido a esto, es que se hace imperativo desarrollar nuevos compuestos
que carezcan de daños colaterales para el organismo del paciente sometido a quimioterapia.
Las anguciclinonas son compuestos naturales con esqueleto benz[a]antraquinona con un
amplio grado sustituciones en su esqueleto tetracíclico, lo que sitúa a este grupo de
antibióticos, después de las tetraciclinas y antraciclinas, como la tercera clase de
antibióticos que presentan un esqueleto carbotetracíclico.
Se sintetizaron diez nuevos 6-aza-análogos de anguciclinona empleando el (-)-ácido
shikímico como compuesto de partida. La actividad citotóxica de estos compuestos fue
medida in vitro en tres líneas tumorales; cáncer de próstata (PC-3), cáncer de colon (HT-
29), y cáncer de mama (MCF-7). El compuesto más potente presentó una actividad de IC50
= 0,01 μM contra la línea MCF-7.
Con los valores de actividad citotóxica se logró desarrollar un modelo 2D-QSAR para la
línea MCF-7, y uno 3D-QSAR/CoMFA para la línea PC-3; ambos modelos cumplen con
exhaustivos criterios de validación.
Adicionalmente se sintetizó una serie de ocho análogos de aminonaftoquinona; dos de los
cuales se sintetizaron a partir del (-)-ácido shikímico, mientras que los seis restantes fueron
sintetizado a partir de aminas comerciales. Se midió la actividad citotóxica de estos
compuestos; el más potente presentó un valor de IC50 = 1,1 μM contra la línea HT-29.
Al comparar la citotoxicidad de la serie de 6-aza-anguciclinonas con la serie de
aminonaftoquinonas, se concluye que la estructura tetracíclica de las 6-aza-anguciclinonas
otorga a estos compuestos una mayor selectividad por las células tumorales, junto con una
mayor potencia.
Tetracyclic quinones are compounds of pharmacological interest due to their ability to combat the proliferation of tumor cells. In fact, in chemotherapy it is common to use drugs with this structural nucleus, such as anthracyclines. However, these anthracyclines have several negative effects, such as cardiotoxicity. Because of this, it is imperative to develop new compounds without collateral damage to the organism of the patient undergoing chemotherapy. Angucyclinones are natural compounds with a benz[a]anthraquinone skeleton with a large degree of substitution in its tetracyclic skeleton, which places this group of antibiotics, after tetracyclines and anthracyclines, as the third class of antibiotics with a carbotetracyclic skeleton. Ten new 6-aza-analogues of anguciclinone were synthesized using shikimic (-)-acid as the starting compound. The cytotoxic activity of these compounds was measured in vitro in three tumor lines; prostate cancer (PC-3), colon cancer (HT-29), and breast cancer (MCF- 7). The most potent compound had an activity of IC50 = 0.01 μm against the mcf-7 line. With cytotoxic activity values, a 2D-QSAR model was developed for the MCF-7 line, and a 3D-QSAR/COMFA model for the PC-3 line; both models meet exhaustive validation criteria. Additionally, a series of eight aminaphthoquinone analogues was synthesized; two of which were synthesized from (-)-shikimic acid, while the remaining six were synthesized from commercial amines. The cytotoxic activity of these compounds was measured; the most potent presented a value of IC50 = 1.1 μm against the HT-29 line. When comparing the cytotoxicity of the 6-aza-angucyclinones series with the aminonaphthoquinones series, it is concluded that the tetracyclic structure of the 6-azaangucyclinones gives these compounds greater selectivity for tumor cells, together with greater potency.
Tetracyclic quinones are compounds of pharmacological interest due to their ability to combat the proliferation of tumor cells. In fact, in chemotherapy it is common to use drugs with this structural nucleus, such as anthracyclines. However, these anthracyclines have several negative effects, such as cardiotoxicity. Because of this, it is imperative to develop new compounds without collateral damage to the organism of the patient undergoing chemotherapy. Angucyclinones are natural compounds with a benz[a]anthraquinone skeleton with a large degree of substitution in its tetracyclic skeleton, which places this group of antibiotics, after tetracyclines and anthracyclines, as the third class of antibiotics with a carbotetracyclic skeleton. Ten new 6-aza-analogues of anguciclinone were synthesized using shikimic (-)-acid as the starting compound. The cytotoxic activity of these compounds was measured in vitro in three tumor lines; prostate cancer (PC-3), colon cancer (HT-29), and breast cancer (MCF- 7). The most potent compound had an activity of IC50 = 0.01 μm against the mcf-7 line. With cytotoxic activity values, a 2D-QSAR model was developed for the MCF-7 line, and a 3D-QSAR/COMFA model for the PC-3 line; both models meet exhaustive validation criteria. Additionally, a series of eight aminaphthoquinone analogues was synthesized; two of which were synthesized from (-)-shikimic acid, while the remaining six were synthesized from commercial amines. The cytotoxic activity of these compounds was measured; the most potent presented a value of IC50 = 1.1 μm against the HT-29 line. When comparing the cytotoxicity of the 6-aza-angucyclinones series with the aminonaphthoquinones series, it is concluded that the tetracyclic structure of the 6-azaangucyclinones gives these compounds greater selectivity for tumor cells, together with greater potency.
Description
Keywords
ACIDO SHIKIMICO , SINTESIS DE QUINONAS , ACTIVIDAD BIOLOGICA