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

Amino Alcohols / chemistry Animals Antineoplastic Agents / chemistry Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Humans Leukemia, Myeloid, Acute / drug therapy Mice Microsomes, Liver / chemistry Molecular Structure Naphthoquinones / chemistry Structure-Activity Relationship

Acute myeloid leukemia IDO ROS anti-cancer agents biquinone naphthoquinone

Journal

Anti-cancer agents in medicinal chemistry

ISSN: 1875-5992

Titre abrégé: Anticancer Agents Med Chem

Pays: Netherlands

ID NLM: 101265649

Informations de publication

Date de publication:
2022

Historique:

received: 02 10 2020

revised: 03 04 2021

accepted: 12 04 2021

pubmed: 4 6 2021

medline: 31 3 2022

entrez: 3 6 2021

Statut: ppublish

Résumé

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. 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. 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. 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. 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.

Sections du résumé

BACKGROUND

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.

Identifiants

DOI: 10.2174/1871520621666210602131558 PMID: 34080968

pubmed: 34080968

pii: ACAMC-EPUB-115913

doi: 10.2174/1871520621666210602131558

doi:

Substances chimiques

Amino Alcohols 0

Antineoplastic Agents 0

Naphthoquinones 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

239-253

Subventions

Organisme : University of Maryland Greenebaum Comprehensive Cancer Center Support

ID : P30CA134274