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Article

Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells

1
Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
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Team of Chemistry, Department of Pharmacy, Cosmetic Chemicals and Biotechnology, Łukasiewicz Research Network—Industrial Chemistry Institute, 01-793 Warsaw, Poland
3
Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: Sathish Kumar Natarajan
Biomedicines 2021, 9(11), 1517; https://doi.org/10.3390/biomedicines9111517
Received: 15 July 2021 / Revised: 14 October 2021 / Accepted: 16 October 2021 / Published: 21 October 2021
(This article belongs to the Topic Novel Therapeutic Nutrient Molecules)
Plant phenolic compounds have shown the ability to cooperate with one another at low doses in producing enhanced anticancer effects. This may overcome the limitations (e.g., poor bioavailability and high-dose toxicity) in developing these agents as cancer medicines. We have previously reported that the hydroxycinnamic acid derivative (HCAD) methyl-4-hydroxycinnamate and the phenolic diterpene carnosic acid (CA) can synergistically induce massive calcium-dependent apoptosis in acute myeloid leukemia (AML) at non-cytotoxic concentrations of each agent. Here, we explored the chemical nature of the synergy between HCADs and either CA, in inducing cytotoxicity, or the active metabolite of vitamin D (calcitriol), in enhancing the differentiation of AML cells. This was done by determining the structure–activity relationship of a series of hydroxycinnamic acids and their derivatives (methyl hydroxycinnamates and hydroxybenzylideneacetones) in combination with CA or calcitriol. The HCAD/CA synergy required the following critical structural elements of an HCAD molecule: (a) the para-hydroxyl on the phenolic ring, (b) the carbon C7–C8 double bond, and (c) the methyl-esterified carboxyl. Thus, the only HCADs capable of synergizing with CA were found to be methyl-4-hydroxycinnamate and methyl ferulate, which also most potently enhanced calcitriol-induced cell differentiation. Notably, the C7–C8 double bond was the major requirement for this HCAD/calcitriol cooperation. Our findings may contribute to the rational design of novel synergistically acting AML drugs based on prototype combinations of HCADs with other agents studied here. View Full-Text
Keywords: structure-activity relationship; hydroxycinnamates; carnosic acid; vitamin D; acute myeloid leukemia structure-activity relationship; hydroxycinnamates; carnosic acid; vitamin D; acute myeloid leukemia
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MDPI and ACS Style

Trachtenberg, A.; Sidoryk, K.; Alreate, S.; Muduli, S.; Leś, A.; Cybulski, M.; Danilenko, M. Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells. Biomedicines 2021, 9, 1517. https://doi.org/10.3390/biomedicines9111517

AMA Style

Trachtenberg A, Sidoryk K, Alreate S, Muduli S, Leś A, Cybulski M, Danilenko M. Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells. Biomedicines. 2021; 9(11):1517. https://doi.org/10.3390/biomedicines9111517

Chicago/Turabian Style

Trachtenberg, Aviram, Katarzyna Sidoryk, Somaya Alreate, Suchismita Muduli, Andrzej Leś, Marcin Cybulski, and Michael Danilenko. 2021. "Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells" Biomedicines 9, no. 11: 1517. https://doi.org/10.3390/biomedicines9111517

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