Pre-Clinical Activity of Amino-Alcohol Dimeric Naphthoquinones as Potential Therapeutics for Acute Myeloid Leukemia.

Autor:	Ferraris D; McDaniel College Department of Chemistry, Westminster, Maryland 21157, USA., Lapidus R; University of Maryland School of Medicine, Baltimore, MD 21201, USA | Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA., Truong P; McDaniel College Department of Chemistry, Westminster, Maryland 21157, USA., Bollino D; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA | University of Maryland School of Medicine, Baltimore, MD 21201, USA., Carter-Cooper B; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA., Lee M; University of Maryland School of Medicine, Morgan State University, Baltimore, MD,United States., Chang E; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA., LaRossa-Garcia M; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA., Dash S; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA., Gartenhaus R; Hunter Holmes McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine Department of Internal Medicine, Richmond, VA, USA., Choi EY; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA., Kipe O; McDaniel College Department of Chemistry, Westminster, Maryland 21157, USA., Lam V; McDaniel College Department of Chemistry, Westminster, Maryland 21157, USA., Mason K; McDaniel College Department of Chemistry, Westminster, Maryland 21157, USA., Palmer R; McDaniel College Department of Chemistry, Westminster, Maryland 21157, USA., Williams E; McDaniel College Department of Chemistry, Westminster, Maryland 21157, USA., Ambulos N; University of Maryland School of Medicine, Baltimore, MD 21201, USA | Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA., Kamangar F; Hunter Holmes McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine Department of Internal Medicine, Richmond, VA, USA., Zhang Y; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA., Kapadia B; Hunter Holmes McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine Department of Internal Medicine, Richmond, VA, USA., Jing Y; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA., Emadi A; University of Maryland School of Medicine, Baltimore, MD 21201, USA | Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA.
Jazyk:	angličtina
Zdroj:	Anti-cancer agents in medicinal chemistry [Anticancer Agents Med Chem] 2022; Vol. 22 (2), pp. 239-253.
DOI:	10.2174/1871520621666210602131558
Abstrakt:	Background: The clinical outcomes of patients with Acute Myeloid Leukemia (AML) remain unsatisfactory. Therefore the development of more efficacious and better-tolerated therapy for AML is critical. We have previously reported anti-leukemic activity of synthetic halohydroxyl dimeric naphthoquinones (BiQ) and aziridinyl BiQ. Objective: This study aimed to improve the potency and bioavailability of BiQ compounds and investigate antileukemic activity of the lead compound in vitro and a human AML xenograft mouse model. Methods: We designed, synthesized, and performed structure-activity relationships of several rationally designed BiQ analogues with amino alcohol functional groups on the naphthoquinone core rings. The compounds were screened for anti-leukemic activity and the mechanism as well as in vivo tolerability and efficacy of our lead compound was investigated. Results: We report that a dimeric naphthoquinone (designated BaltBiQ) demonstrated potent nanomolar anti-leukemic activity in AML cell lines. BaltBiQ treatment resulted in the generation of reactive oxygen species, induction of DNA damage, and inhibition of indoleamine dioxygenase 1. Although BaltBiQ was tolerated well in vivo, it did not significantly improve survival as a single agent, but in combination with the specific Bcl-2 inhibitor, Venetoclax, tumor growth was significantly inhibited compared to untreated mice. Conclusion: We synthesized a novel amino alcohol dimeric naphthoquinone, investigated its main mechanisms of action, reported its in vitro anti-AML cytotoxic activity, and showed its in vivo promising activity combined with a clinically available Bcl-2 inhibitor in a patient-derived xenograft model of AML. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu