Labdane conjugates protect cardiomyocytes from doxorubicin‐induced cardiotoxicity



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Cuadrado Berrocal, Irene and Oramas Royo, Sandra and Gonzalez Cofrade, Laura and Amesty, Ángel and Hortelano, Sonsoles and Estévez Braun, Ana and De las Heras Polo, Beatriz (2022) Labdane conjugates protect cardiomyocytes from doxorubicin‐induced cardiotoxicity. Drug Development Research . pp. 1-12. ISSN 1098-2299

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The cardiovascular side effects associated with doxorubicin (DOX), a wide spectrum anticancer drug, have limited its clinical application. Therefore, to explore novel strategies with cardioprotective effects, a series of new labdane conjugates were prepared (6a–6c and 8a–8d) from the natural diterpene labdanodiol (1). These hybrid compounds contain anti‐inflammatory privileged structures such as naphthalimide, naphthoquinone, and furanonaphthoquinone. Biological activity of these conjugates against DOX‐induced cardiotoxicity was tested in vitro and the potential molecular mechanisms of protective effects were explored in H9c2 cardiomyocytes. Three compounds 6c, 8a, and 8b significantly improved cardiomyocyte survival, via inhibition of reactive oxygen species‐mediated mitogen‐activated protein kinase signaling pathways (extracellular signal‐regulated kinase and c‐Jun N‐terminal kinase) and autophagy mediated by Akt activation. Some structure–activity relationships were outlined, and the best activity was achieved with the labdane–furonaphthoquinone conjugate 8a having an N‐cyclohexyl substituent. The findings of this study pave the way for further investigations to obtain more compounds with potential cardioprotective activity.

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CRUE-CSIC (Acuerdos Transformativos 2022)

Uncontrolled Keywords:Cardioprotection, Doxorubicin, Labdane diterpenes, Naphthalimide,Naphthoquinone
Subjects:Sciences > Chemistry > Chemistry, Organic
Medical sciences > Pharmacy > Pharmacology
ID Code:75726
Deposited On:23 Nov 2022 09:03
Last Modified:24 Nov 2022 08:51

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