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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

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

Author(s): Dana Ferraris, Rena Lapidus, Phuc Truong, Dominique Bollino, Brandon Carter-Cooper, Michelle Lee, Elizabeth Chang, Maria LaRossa-Garcia, Smaraki Dash, Ronald Gartenhaus, Eun Yong Choi, Olivia Kipe, Vi Lam, Kristopher Mason, Riley Palmer, Elijah Williams, Nicholas Ambulos, Farin Kamangar, Yuji Zhang, Bandish Kapadia, Yin Jing and Ashkan Emadi*

Volume 22, Issue 2, 2022

Published on: 02 June, 2021

Page: [239 - 253] Pages: 15

DOI: 10.2174/1871520621666210602131558

Price: $65

Abstract

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.

Keywords: Acute myeloid leukemia, anti-cancer agents, naphthoquinone, biquinone, ROS, IDO.

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